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WO2010114726A1 - Aminobenzotriazole derivatives - Google Patents

Aminobenzotriazole derivatives Download PDF

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Publication number
WO2010114726A1
WO2010114726A1 PCT/US2010/028115 US2010028115W WO2010114726A1 WO 2010114726 A1 WO2010114726 A1 WO 2010114726A1 US 2010028115 W US2010028115 W US 2010028115W WO 2010114726 A1 WO2010114726 A1 WO 2010114726A1
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Prior art keywords
4alkyl
halo
optionally substituted
compound according
methyl
Prior art date
Application number
PCT/US2010/028115
Other languages
French (fr)
Inventor
Vadim Dudkin
Mark Fraley
Cheng Wang
Justin Steen
Original Assignee
Merck Sharp & Dohme Corp.
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Publication date
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Publication of WO2010114726A1 publication Critical patent/WO2010114726A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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

Definitions

  • the excitatory amino acid L-glutamate (sometimes referred to herein simply as glutamate) through its many receptors mediates most of the excitatory neurotransmission within the mammalian central nervous system (CNS).
  • the excitatory amino acids, including glutamate are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
  • Glutamate acts via at least two distinct classes of receptors.
  • One class is composed of the ionotropic glutamate (iGIu) receptors that act as ligand-gated ionic channels. Via activation of the iGIu receptors, glutamate is thought to regulate fast neuronal transmission within the synapse of two connecting neurons in the CNS.
  • the second general type of receptor is the G-protein or second messenger-linked "metabotropic" glutamate (mGluR) receptor. Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol.
  • the present invention relates to potentiators of mGlu receptors, in particular mGluR2 receptors.
  • the mGluR receptors belong to the Type III G- protein coupled receptor (GPCR) superfamily. This superfamily of GPCR's including the calcium- sensing receptors, GABAB receptors and pheromone receptors, which are unique in that they are activated by binding of effectors to the amino-termmus portion of the receptor protein.
  • GPCR G- protein coupled receptor
  • the mGlu receptors are thought to mediate glutamate's demonstrated ability to modulate intracellular signal transduction pathways. Ozawa, Kamiya and Tsuzuski, Prog. Neurobio., 54, 581 (1998).
  • the Group I mGluR receptors which include the mGlulR and mGluSR, are known to activate phospholipase C (PLC) via G ⁇ q-proteins thereby resulting in the increased hydrolysis of phosphoinositides and intracellular calcium mobilization.
  • PLC phospholipase C
  • the Group II mGlu receptors consist of the two distinct receptors, mGluR2 and mGluR3 receptors. Both have been found to be negatively coupled to adenylate cyclase via activation of God-protein. These receptors can be activated by a selective compound such as lS,2S,SR,6S-2 aminobicyclo[3.1.0]hexane-2,6-dicarboxylate. Monn, et al, J. Med. Chem., 4O 5 528 (1997); Schoepp, et al., Neuropharmacol., 36, 1 (1997). This activon leads to inhibition of glutamate release in the synapse (Cartmell et al, J Neurochem 75, 889 (2000)).
  • the Group III mGlu receptors including mGluR4, mGluR6, mGluR7 and mGluR8, are negatively coupled to adenylate cyclase via G ⁇ i and are potently activated by L-AP4 (L- (+) -2-amino-4-phosphonobutyric acid). Schoepp, Neurochem. Int., 24, 439 (1994). Nonselective mGluR2/mGluR3 receptor agonists (Monn, et al., J. Med. Chem.,
  • Such allosteric potentiators do not bind at the glutamate binding site also known as the "orthosteric site", and may benefit by binding to a site other than the highly conserved orthosteric site.
  • a potential advantage to this approach includes the opportunity to have a distinct pharmacological profile by enhancing the activity of the endogenous ligand upon its binding to the orthosteric site.
  • the pharmacological distinctions include the potential for pharmacological specificity between related receptor types that share the same endogenous ligand.
  • positive allosteric modulators of mGluR2 have been shown to potentiate the response of mGluR2 agonists such as LY379268 (Johnson et. At Biochemical Soc. Trans. 32, 881 (2004) and this represents an alternative strategy for treatment using mGluR2 selective PAMs.
  • the present invention is directed to aminobenzotriazole derivatives which are potentiators of metabotropic glutamate receptors, particularly the mGluR2 receptor, and which are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved.
  • the invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which metabotropic glutamate receptors are involved.
  • the invention encompasses a genus of compounds of Formula I
  • each R2 is independently selected from the group consisting of: halo, OH, Ci-4alkyl, C ⁇ _ 4alkoxy, CF3 and -CN;
  • R3 is selected from the group consisting of: H 5 Ci-.4a.kyl, -C(O)-C i_4alkyl and -C(O)-phenyl, wherein said phenyl is optionally substituted with 1 to 5 substituents independently selected from halo and CF3;
  • Y is selected from a bond, ⁇ S(O)2 ⁇ and -[C(R4)23n- > wherein n is I 5 2 or 3 ;
  • each R4 is independently selected from the group consisting of: H, halo, OH, Ci_4alkyl, Ci- 4alkoxy, CF3, -CN and phenyl, and
  • R4 groups on adjacent atom may be joined together with the atoms to which they are attached to form cyclopropyl
  • A is selected from aryl, heteroaryl and heterocycle, wherein said aryl, heteroaryl and heterocycle are optionally substituted with one or more R5 groups up to the maximum number of substitutable positions;
  • aryl at each occurrence is independently selected from the group consisting of: phenyl, naphthyl, anthryl and phenanthryl;
  • heteroaryl at each occurrence independently means a 5- or 6-membered monocyclic aromatic or 9- or I O-membered bicyclic aromatic, wherein at least one atom in the aromatic is selected from N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide, and the remaining atoms are selected from C, N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide;
  • heterocycle at each occurrence independently means a 5- or 6-membered monocyclic non- aromatic ring or 9- or 1 O-membered bicyclic non- or partially-aromatic ring, each optionally substituted with oxo, wherein at least one atom is selected from N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide, and the remaining atoms are selected from C, N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide;
  • each R5 is independently selected from the group consisting of:
  • groups (2) to (7), (15), (16) and (20) to (23) above are optionally substituted from one up to the maximum number of substitutable positions with one or more substituents independently selected from the group consisting of: OH, CN, halo, carboxy, -C(O)-O-C i-4alkyl, Cl-4alkyl, Ci_4alkoxy, Ci-4alkylamino, phenyl and heterocycle, and each R is independently selected from the group consisting of: H and Ci_4alkyl;
  • the invention encompasses a sub-genus of compounds of Formula I wherein X is Br.
  • the invention encompasses a first class of compounds of Formula I wherein Rl is 2,2-dimethylpropyl.
  • the invention encompasses a second class of compounds of Formula I wherein Rl is cyclopropylmethyl.
  • the invention encompasses a third class of compounds of Formula I wherein Y is -CH2-. Also within the sub-genus, the invention encompasses a fourth class of compounds having Formula Ia
  • Rl is selected from cyclopropylmethyl, 2,2-dimethylpropyl and 4,4,4-trifluorobutyl; and pharmaceutically acceptable salts thereof.
  • the invention encompasses a first group of compounds of
  • Formula Ia wherein A is phenyl, optionally substituted with one or more R.5 groups up to the maximum number of substitutable positions.
  • the invention encompasses a first sub-group of compounds of Formula Ia wherein each R.5 is independently selected from the group consisting of: halo, Ci_4alkyl, Ci_4alkoxy, -CF3, -OCF3, -NH2, -CN 5 -OH, -CH2- OH 5 -CH2-O-CH3 , -C(O)OC 1 _4alkyl, -0CH2-C(0)-0H, -NH-C(O)-C 1 ⁇ alkyl and phenyl, optionally substituted with 1 to 5 substituents independenly selected from halo and methyl.
  • the invention encompasses a second group of compounds of Formula Ia wherein A is selected from pyridine, pyradazine, pyrimidine, pyridazine and triazine, optionally substituted with one or more R.5 groups up to the maximum number of substitutable positions.
  • the invention encompasses a second sub-group of compounds of Formula Ia wherein each R.5 is independently selected from the group consisting of: halo, Ci-4alkyl, Ci_4alkoxy, -CF3, -OCF3, -NH2, -CN, -OH, -CH2- OH, -CH2-O-CH3, -C(O)OCi -4alkyl, -0CH2-C(0)-0H, -NH-C(O)-Ci -4alkyl, phenyl optionally substituted with 1 to 5 substituents independenly selected from halo and methyl, and pyridyl optionally substituted with 1 to 4 substituents independenly selected from halo and methyl.
  • the invention encompasses a third group of compounds of Formula Ia wherein A is selected from pyrazole, oxadiazole, th ⁇ adiazole, furan, thiophene, pyrrole, triazole, oxazole, thiazole, imidazole, isoxazole and isothiazole, optionally substituted with one or more R5 groups up to the maximum number of substitutable positions.
  • the invention encompasses a third sub-group of compounds of Formula Ia wherein each R ⁇ is independently selected from the group consisting of: halo, Ci-4alkyl, Ci- 4alkoxy, -CF3, -OCF3, -NH2, -CN, -OH, -CH2-OH, -CH2-O-CH3, -C(O)OC 1 _4alkyl, -0CH2- C(O)-OH, -NH-C(O)-C i_4alkyl, phenyl optionally substituted with 1 to 5 substituents independenly selected from halo and methyl, and pyridyl optionally substituted with 1 to 4 substituents independenly selected from halo and methyl.
  • the invention encompasses a fifth class of compounds having Formula Ib
  • Rl is selected from cyclopropylmethyl, 2,2-dimethylpropyl and 4,4,4-trifiuorobutyl; and pharmaceutically acceptable salts thereof.
  • the invention encompasses a fourth group of compounds of Formula Ib wherein A is phenyl, optionally substituted with one or more R5 groups up to the maximum number of substitutable positions.
  • the invention encompasses a fourth sub-group of compounds of Formula Ib wherein each R5 is independently selected from the group consisting of: halo, Ci_4alkyl, C ⁇ 4alkoxy, -CF3, -0CF3, -NH2, -CN, -OH, -CH2-OH, -CH2-O-CH3, -C(O)OC i_4a ⁇ kyl, -0CH2-C(0)-0H, -NH-C(O)-C i-4alkyl and phenyl, optionally substituted with 1 to 5 substituents independenly selected from halo and methyl.
  • the invention encompasses a fifth group of compounds of Formula Ib wherein A is selected from pyridine, pyradazine, pyrimidine, pyridazine and triazine, optionally substituted with one or more R5 groups up to the maximum number of substitutable positions.
  • the invention encompasses a fifth sub-group of compounds of Formula Ib wherein each R ⁇ is independently selected from the group consisting of: halo, Ci -4alkyl, Ci -4alkoxy, -CF3, -OCF3, -NH2, -CN, -OH, -CH2-OH, -CH2-O-CH3, - C(O)OC 1 -4alkyl, -0CH2-C(0)-0H, -NH-C(O)-C 1 _4alkyl, phenyl optionally substituted with 1 to 5 substituents independenly selected from halo and methyl, and pyridyl optionally substituted with 1 to 4 substituents independenly selected from halo and methyl.
  • the invention encompasses a sixth group of compounds of Formula Ib
  • A is selected from pyrazole, oxadiazole, thiadiazole, furan, thiophene, pyrrole, triazole, oxazole, thiazole, imidazole , isoxazole and isothiazole, optionally substituted with one or more R5 groups up to the maximum number of substitutable positions.
  • the invention encompasses a sixth sub-group of compounds of Formula Ib wherein each R5 is independently selected from the group consisting of: halo, Ci -4alkyl, Ci-4alkoxy, -CF3, -OCF3, -NFfe, -CN 5 -OH, -CH2-OH, - CH2-OCH3, -C(O)OC i_4alkyl, -OCH2-C(O)-OH, -NH-C(O)-C i ⁇ alkyl, phenyl optionally substituted with 1 to 5 substituents independenly selected from halo and methyl, and pyridyl optionally substituted with 1 to 4 substituents independenly selected from halo and methyl.
  • the invention also encompasses a pharmaceutical composition comprising a compound of Formula Ia in combination with a pharmaceutically acceptable carrier.
  • the invention also encompasses a method for treating a neurological or psychiatric disorder associated with glutamate dysfunction in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula I.
  • the invention also encompasses this method wherein the neurological or psychiatric disorder associated with glutamate dysfunction is schizophrenia.
  • Alk as well as other groups having the prefix "alk”, such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl j octyl, nonyl, and the like.
  • Haloalkyl means alkyl as defined above wherein one more hydrogen atoms are replaced by halo.
  • alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl ⁇ 2- butenyl, and the like.
  • alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-I-pentynyl, 2-heptynyl and the like.
  • Cycloalkyl means mono-, bi- or tri-cyclic structures, optionally combined with linear or branched structures, having the indicated number of carbon atoms.
  • Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-l- bicyclo [4.4.0] decyl, and the like.
  • Alkoxy means alkoxy groups of a straight or branched having the indicated number of carbon atoms. Ci_6alkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
  • Cycloalkoxy means cycloalkyl as defined above bonded to an oxygen atom, such as cyclopropyloxy.
  • heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
  • Halogen and “halo” includes fluorine, chlorine, bromine and io
  • the compounds of the present invention are potentiators of metabotropic glutamate (mGluR) receptor function, in particular they are potentiators of mGluR2 receptors. That is, the compounds of the present invention do not appear to bind at the glutamate recognition site on the mGluR receptor, but in the presence of glutamate or a glutamate agonist, the compounds of the present invention increase mGluR receptor response.
  • the present potentiators are expected to have their effect at mGluR receptors by virtue of their ability to increase the response of such receptors to glutamate or glutamate agonists, enhancing the function of the receptors.
  • the compounds of the present invention would be expected to increase the effectiveness of glutamate and glutamate agonists of the mGluR2 receptor.
  • the potentiators of the present invention are expected to be useful in the treatment of various neurological and psychiatric disorders associated with glutamate dysfunction described to be treated herein and others that can be treated by such potentiators as are appreciated by those skilled in the art.
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. Any formulas, structures or names of compounds described in this specification that do not specify a particular stereochemistry are meant to encompass any and all existing isomers as described above and mixtures thereof in any proportion.
  • stereochemistry is specified, the invention is meant to encompass that particular isomer in pure form or as part of a mixture with other isomers in any proportion.
  • the independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein.
  • Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • the present invention also includes all pharmaceutically acceptable isotopic variations of a compound of the Formula I in which one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as 2H and 3 H, carbon such as 1 ⁇ C, 13c and 14c, nitrogen such as 13N and 15N S oxygen such as 15 ⁇ s 1?O and 18 ⁇ s phosphorus such as 32p ; sulfur such as 35s, fluorine such as 18 ⁇ , iodine such as 23l and 125i ⁇ and chlorine such as 36Q.
  • Certain isotopically-labelled compounds of Formula I 5 for example those incorporating a radioactive isotope are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. ⁇ H, and carbon-14, i.e.
  • substitutions with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as 1 *C, ⁇ F, 15 ⁇ and 13N S can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labelled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labelled reagents in place of the non- labelled reagent previously employed.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
  • references to the compounds of Formula I are meant to also include a pharmaceutically acceptable salts.
  • Exemplifying the invention are Examples 1-1 to 1-122, 2-1 to 2-42, 3-1 to 3-9 and 4-1 to 4-27, described herein.
  • the subject compounds are useful in a method of potentiating metabotorpic glutamate receptor activity in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound.
  • the present invention is directed to the use of the subject compounds disclosed herein as potentiators of metabotropic glutamate receptor activity.
  • primates, especially humans a variety of other mammals can be treated according to the method of the present invention.
  • the present invention is further directed to a method for the manufacture of a medicament for potentiating metabotropic glutamate receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
  • the subject treated in the present methods is generally a mammal, preferably a human being, male or female, in whom potentiation of metabotropic glutamate receptor activity is desired.
  • the term "therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. It is recognized that one skilled in the art may affect the neurological and psychiatric disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with the disorders with an effective amount of the compound of the present invention.
  • treatment and “treating” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • administration of and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
  • the utility of the compounds in accordance with the present invention as inhibitors of metabotropic glutamate receptor activity, in particular niGluR2 activity, may be demonstrated by methodology known in the art. Inhibition constants are determined as follows.
  • the compounds of the present invention may be tested in a fluorescence laser imaging plate reader (FLIPR) based assay. This assay is a common functional assay to monitor Ca ⁇ + mobilization in whole cells expressing recombinant receptor coupled with a promiscuous G- protein.
  • FLIPR fluorescence laser imaging plate reader
  • CHO dhfr- cells stably expressing recombinant human mGluR2 and Ga 16 loaded with Fluo-4 AM are treated with dose responses of compounds and the Ca2+ response is monitored on a FLIPR384 (Molecular Devices, Surmydale CA) for agonist activity.
  • the potentiation response is monitored after a subsequent addition of an EC20 concentration of glutamate (900 nM).
  • the maximum calcium response at each concentration of compound for agonist or potentiation are plotted as dose responses and the curves are fitted with a four parameters logistic equation giving EC 50 and Hill coefficient using the iterative non linear curve fitting software program.
  • the compounds of the present invention may also be tested in a [35s] ⁇ GTP ⁇ S assay.
  • the stimulation of [35 S]-GTPyS binding is a common functional assay to monitor G ⁇ i- coupled receptor in native and recombinant receptor membrane preparation.
  • Membrane from cells stably expressing hmGlu2 CHO-Kl (50 ⁇ g) are incubated in a 96 well plate for 1 hour in the presence of GTP ⁇ S35 (0.0SnM) 5 GDP (5 ⁇ M) and compounds.
  • the reaction is stopped by rapid filtration over Unifilter GF/B plate (Packard, Bioscience, Meriden CT) using a 96-well cell harvester (Brandel Gaithersburg, MD).
  • the filter plates are counted using Topcoiint counter (Packard, Bioscience, Meriden CT, USA). When compounds are evaluated as potentiators they are tested in the presence of glutamate (l ⁇ M). The activation (agonist) or the potentiation of glutamate (potentiator) curves are fitted with a four parameters logistic equation giving EC 50 and Hill coefficient using the iterative non linear curve fitting software GraphPad (San Diego CA, USA).
  • Examples 1-1 to 1-122, 2-1 to 2-42, 3-1 to 3-9 and 4-1 to 4-27 were tested and demonstrated activity in potentiating the mGluR2 receptor in the FLIPR assay, generally with an EC50 of less than about 10 ⁇ M.
  • Compounds within the present invention had activity in potentiating the mGluR2 receptor in the FLIPR and GTPyS assays with an EC50 of less than about 1 ⁇ M.
  • Examples 1-1 to 1-122, 2-1 to 2-42, 3-1 to 3-9 and 4-1 to 4-27 resulted in a minimum 1.8-fold potentiation of glutamate response in the presence of an EC20 concentration of glutamate (90OnM). Such results are indicative of the intrinsic activity of the compounds in use as potentiators of mGluR2 receptor activity,
  • Metabotropic glutamate receptors including the mGluR2 receptor have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species.
  • the compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with glutamate dysfunction, including one or more of the following conditions or diseases: 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 AID S -induced dementia), Alzheimer's disease, Hunt ⁇ ngton'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, hyp
  • the present invention provides a method for treating migraine, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.
  • the present invention provides a method for preventing or treating anxiety, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.
  • Particular anxiety disorders of the invention are generalized anxiety disorder, panic disorder, and obsessive compulsive disorder.
  • the present invention provides a method for treating schizophrenia, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.
  • the present invention provides a method for treating epilepsy, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.
  • the present invention provides a method for the treatment of schizophrenia comprising: administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutical composition thereof.
  • schizophrenia is characterized by psychosis (loss of contact with reality), hallucinations (false perceptions), delusions (false beliefs), disorganized speech and behavior, flattened affect (restricted range of emotions), cognitive deficits (impaired reasoning and problem solving), and occupational and social dysfunction.
  • the present invention provides a method for treating migraine, comprising: administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutical composition thereof.
  • migraine is defined as a symptom complex of periodic headaches, usually temporal and unilateral, often with irritability, nausea, vomiting, constipation or diarrhea, and photophobia.
  • migraine migraine
  • the present invention provides a method for treating anxiety, comprising: administering to a patient in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition thereof.
  • anxiety includes treatment of those anxiety disorders and related disorder as described in the DSM-IV.
  • the skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, and particular anxiety, and that these systems evolve with medical scientific progress.
  • the term “anxiety” is intended to include like disorders that are described in other diagnostic sources.
  • the present invention provides a method for treating depression, comprising: administering to a patient in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition thereof.
  • DSM-IV Diagnostic and Statistical Manual of Mental Disorders
  • Psychiatric Association Washington, D.C.
  • Depressive disorders include, for example, single episodic or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias; seasonal affective disorder; or bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder.
  • depression includes treatment of those depression disorders and related disorder as described in the DSM-IV.
  • the present invention provides a method for treating epilepsy, comprising: administering to a patient in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition thereof.
  • epilepsy there are several types and subtypes of seizures associated with epilepsy, including idiopathic, symptomatic, and cryptogenic. These epileptic seizures can be focal (partial) or generalized. They can also be simple or complex.
  • Epilepsy is described in the art, such as Epilepsy: A comprehensive textbook. Ed. by Jerome Engel, Jr. and Timothy A. Pedley. (Lippincott-Raven, Philadelphia, 1997).
  • the International Classification of Diseases, Ninth Revision, ( ⁇ CD-9) provides a diagnostic tool including epilepsy and related disorders.
  • epilepsy includes these all types and subtypes.
  • the skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, including epilepsy, and that these systems evolve with medical scientific progress.
  • the subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
  • the subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents, including an mGluR agonist.
  • potentiated amount refers to an amount of an mGluR agonist, that is, the dosage of agonist which is effective in treating the neurological and psychiatric disorders described herein when administered in combination with an effective amount of a compound of the present invention.
  • a potentiated amount is expected to be less than the amount that is required to provided the same effect when the mGluR agonist is administered without an effective amount of a compound of the present invention.
  • a potentiated amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances.
  • the dose of an mGluR agonist to be administered in combination with a compound of formula I a number of factors are considered by the attending diagnostician, including, but not limited to: the mGluR agonist selected to be administered, including its potency and selectivity; the compound of formula I to be coadministered; the species of mammal; its size, age, and general health; the specific disorder involved; the degree of involvement or the severity of the disorder; the response of the individual patient; the modes of administration; the bioavailability characteristics of the preparations administered; the dose regimens selected; the use of other concomitant medication; and other relevant circumstances.
  • a potentiated amount of an mGluR agonist to be administered in combination with an effective amount of a compound of formula I is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day and is expected to be less than the amount that is required to provided the same effect when administered without an effective amount of a compound of formula I.
  • Preferred amounts of a co-administered mGlu agonist are able to be determined by one skilled in the art.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical composition in unit dosage form may be utilized containing such other drugs and the compound of Formula I.
  • the combination therapy may also includes therapies in which the compound of Formula I and one or. more., other drugs are administered on different overlapping schedules.
  • compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula L
  • the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the present invention may be utilized.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1 :1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the compound of the present invention and other active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV 5 intracisternal injection or infusion, subcutaneous injection, or. implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV 5 intracisternal injection or infusion, subcutaneous injection, or. implant
  • inhalation spray nasal, vaginal, rectal, sublingual, or topical routes of administration
  • nasal, vaginal, rectal, sublingual, or topical routes of administration may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the compounds of the invention are
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • Oily suspensions may be formulated by suspending the active ingredient in a suitable oil
  • Oil-in-water emulsions may also be employed.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • compositions of the present compounds may be in the form of a 5 sterile injectable aqueous or oleagenous suspension.
  • the compounds of the present invention may also be administered in the form of suppositories for rectal administration.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention may be employed.
  • the compounds of the present invention may also be formulated for administered by inhalation.
  • the compounds of the present invention may also be 0 administered by a transdermal patch by methods known in the art.
  • compositions and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0 f 50.O 5 75.0, 100.O 5 150.O 5 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0 ⁇ 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the 5 dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams.
  • the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of this invention may be prepared by employing reactions as shown in the following Reaction Schemes, in addition to other standard manipulations that are known in the literature or exemplified in the experimental procedures.
  • the illustrative Reaction Schemes below are not limited by the compounds listed or by any particular substituents employed for illustrative purposes.
  • Substituent numbering as shown in the Reaction Schemes do not necessarily correlate to that used in the claims and often, for clarity, a single substituent is shown attached to the compound where multiple substituents are optionally allowed under the definitions of Formula A hereinabove.
  • Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in Reaction Schemes I- VI.
  • the 2-Fluoro-5-nitroaniline (i) can undergo an aromatic nucleophilic substitution with amine (ii) to provide a nitrodiaminobenzene intermediate which is then cyclized to form 5-nitrobenzotriazoIe (iii) upon treatment withNaNO2.
  • Hydrogenation of 3 with Pd/C as a catalyst provides 5-aminobenzotriazole (iv) which upon treatment with pyridimum tribromide yields 5-amino-4-bromobenzotrlazole (v).
  • compound v can be synthesized by reductive animation of compound vi with an aldehyde.
  • 2-Fluoro-5-nitroaniline (1) (10.22 g, 65.5 mmol 5 1.0 equiv.) was dissolved in anhydrous DMSO (100 ml), then treated with Neopentylamine (2) (7.71 ml, 65.5 mmol, l.Oequiv,). It was heated at 120 0 C for 2 days when LCMS showed mostly product with trace of starting material. It was cooled to room temperature and treated with Acetic Acid (25 ml), followed by addition of 0.65 M aqueous solution of Sodium nitrite (121 ml ⁇ 79 mmol, 1.2equiv.). Heat and gas were released. LCMS showed product after the reaction mixture was stirred at ambient temperature for 20 minutes.
  • Step 2 l-(2,2-dimethylpropyl)-l/J-l,2,3-benzotriazol-5-amine (4) l-(2,2-dimethylpropyl)-5-nitro ⁇ li ⁇ r -l,2 5 3-benzotriazole (3) (4.46 g 5 19.04 mmol, 1.Oequiv.) was dissolved in Ethanol (50 ml) and flashed with N 2 , then charged with 10% Pd/C (2.026 g, 1.904 mmol, 0.1 equiv.). After purging with first N 2 then H 2 , a hydrogen balloon was attached to set up for hydrogenation. After stirring at room temperature for 5 hrs, the reaction was complete based on LCMS.
  • Step 3 4-bromo-l-(2,2-dimethyl ⁇ ropyl)-lH-l,2,3-benzotriazol-5-amine (5) l-(2 ! 2-dimethylpro ⁇ yl)-l/f-l ? 2 5 3-benzotriazol-5-amine (4) (3.52 g, 17.23 mmol, 1.0 equiv.) was dissolved in CHCl 3 (172 ml), then treated with Pyridinium tribromide (5.51 g, 17.23 mmol, l.Oequiv.). The reaction mixture was stirred at room temperature till LCMS showed almost only product. The solid was collected on top of filter, and washed with hexane.
  • Step 4 N-benzyl-4-bromo-l ⁇ (2,2-dimethylpropyl)4H- -pyrazol-4-yl)-lH- 1,2,3- benzotriazol-5-amine (Example 1-1)
  • Example 1-1 The crude product was purified with reverse phase ⁇ PLC (MeC ⁇ / ⁇ 2 O gradient with 0.1% TFA present) to yield Example 1-1.
  • LRMS m/z (M+H) 373.2 and 375.2 (intensity ratio 1:1) found, 373.1 and 375.1 required.
  • Example 2-1 The crude product was purified with RP-HPLC (MeCNZH 2 O gradient with 0.1% TFA present) to yield Example 2-1.
  • Example 1-1 7V-benzyl-4-bronio-l-(2,2-dimethylpropyl)-l/f- - ⁇ yrazol-4-yl)- l ⁇ r-l,2,3-benzotriazol-5-amine (Example 1-1) (40 mg, 0.107 mmol, l .Oequiv.) in DMF (536 ⁇ l), was added the 60% NaH (17.14 mg, 0.429 mmol, 4.0equiv.) in mineral oil. The resulting mixture was stirred at room temperature till LCMS showed mostly product without starting material. The crude mixture was purified with reverse phase HPLC (MeCNZH 2 O gradient with 0.1% TFA present) to yield Example 3-1.
  • Example 3 The compounds shown in Table 3 were synthesized according to procedures analogous to Example 3-1. The compounds were isolated as a TFA salt or free base.

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Abstract

The present invention is directed to aminobenzotriazole derivatives which are potentiators of metabotropic glutamate receptors, particularly the mGluR2 receptor, and which are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which metabotropic glutamate receptors are involved.

Description

TITLE OF THE INVENTION AMINOBENZOTRIAZOLE DERIVATIVES.
BACKGROUND OF THE INVENTION The excitatory amino acid L-glutamate (sometimes referred to herein simply as glutamate) through its many receptors mediates most of the excitatory neurotransmission within the mammalian central nervous system (CNS). The excitatory amino acids, including glutamate, are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Glutamate acts via at least two distinct classes of receptors. One class is composed of the ionotropic glutamate (iGIu) receptors that act as ligand-gated ionic channels. Via activation of the iGIu receptors, glutamate is thought to regulate fast neuronal transmission within the synapse of two connecting neurons in the CNS. The second general type of receptor is the G-protein or second messenger-linked "metabotropic" glutamate (mGluR) receptor. Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. ScL, 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990). The present invention relates to potentiators of mGlu receptors, in particular mGluR2 receptors. The mGluR receptors belong to the Type III G- protein coupled receptor (GPCR) superfamily. This superfamily of GPCR's including the calcium- sensing receptors, GABAB receptors and pheromone receptors, which are unique in that they are activated by binding of effectors to the amino-termmus portion of the receptor protein. The mGlu receptors are thought to mediate glutamate's demonstrated ability to modulate intracellular signal transduction pathways. Ozawa, Kamiya and Tsuzuski, Prog. Neurobio., 54, 581 (1998). They have been demonstrated to be localized both pre- and post-synaptically where they can regulate neurotransmitter release, either glutamate or other neurotransmitters, or modify the post-synaptic response of neurotransmitters, respectively. At present, there are eight distinct mGlu receptors that have been positively identified, cloned, and their sequences reported. These are further subdivided based on their amino acid sequence homology, their ability to effect certain signal transduction mechanisms, and their known pharmacological properties. Ozawa, Kamiya and Tsuzuski, Prog. Neurobio., 54, 581 (1998). For instance, the Group I mGluR receptors, which include the mGlulR and mGluSR, are known to activate phospholipase C (PLC) via Gαq-proteins thereby resulting in the increased hydrolysis of phosphoinositides and intracellular calcium mobilization. There are several compounds that are reported to activate the Group I mGlu receptors including DHPG, (R/S)-3,5- dihydroxyphenylglycine. Schoepp, Goldworthy, Johnson, Salhoff and Baker, J. Neurochem., 63, 769 (1994); Ito, et al., keurorep., 35 1013 (1992). The Group II mGlu receptors consist of the two distinct receptors, mGluR2 and mGluR3 receptors. Both have been found to be negatively coupled to adenylate cyclase via activation of God-protein. These receptors can be activated by a selective compound such as lS,2S,SR,6S-2 aminobicyclo[3.1.0]hexane-2,6-dicarboxylate. Monn, et al, J. Med. Chem., 4O5 528 (1997); Schoepp, et al., Neuropharmacol., 36, 1 (1997). This activitation leads to inhibition of glutamate release in the synapse (Cartmell et al, J Neurochem 75, 889 (2000)). Similarly, the Group III mGlu receptors, including mGluR4, mGluR6, mGluR7 and mGluR8, are negatively coupled to adenylate cyclase via Gαi and are potently activated by L-AP4 (L- (+) -2-amino-4-phosphonobutyric acid). Schoepp, Neurochem. Int., 24, 439 (1994). Nonselective mGluR2/mGluR3 receptor agonists (Monn, et al., J. Med. Chem.,
43, 4893, (2000)) have shown efficacy in numerous animal models of anxiety and psychosis as well as human clinical trials in schizophrenia patients; Patil et al, Nature Medicine, 13, 1102 (2007). Recent reports indicate that mGluR2 but not the mGluR3 receptor mediates the actions of the dual mGluR2/mGluR3 agonist L Y379268 in mouse models predictive of antipsychotic activity. Woolley et al, Psycopharmacology, 196, 431 (2008). Additionally, recent animal studies demonstrate that selective potentiation of the mGluR2 receptor has similar effects to such nonselective agonists (Galici et al, Journal of Pharmacology and Experimental Therapeutics, 315, 1181 (2005)) suggesting an alternative strategy concerning the discovery of selective, positive allosteric modulators (PAMs or allosteric potentiators) of mGluR2 (Johnson et al, J. Med. Chem. 46, 3189, (2003); Pinkerton et al., J. Med. Chem., 47, 4595 (2004). These potentiators act by enabling the receptor to produce an enhanced response to endogenous glutamate. Such allosteric potentiators do not bind at the glutamate binding site also known as the "orthosteric site", and may benefit by binding to a site other than the highly conserved orthosteric site. A potential advantage to this approach includes the opportunity to have a distinct pharmacological profile by enhancing the activity of the endogenous ligand upon its binding to the orthosteric site. The pharmacological distinctions include the potential for pharmacological specificity between related receptor types that share the same endogenous ligand. In addition, positive allosteric modulators of mGluR2 have been shown to potentiate the response of mGluR2 agonists such as LY379268 (Johnson et. At Biochemical Soc. Trans. 32, 881 (2004) and this represents an alternative strategy for treatment using mGluR2 selective PAMs.
It has become increasingly clear that there is a link between modulation of excitatory amino acid receptors, including the glutamatergic system, through changes in glutamate release or alteration in postsynaptic receptor activation, and a variety of neurological and psychiatric disorders, e.g. Monaghan, Bridges and Cotman, Ann. Rev, Pharmacol. Toxicol., 29, 365-402 (1989); Schoepp and Sacann, Neurobio. Aging, 15, 261-263 (1994); Meldrum and Garthwaite, Tr. Pharmacol. Sci., 11, 379-387 (1990). The medical consequences of such glutamate dysfunction make the abatement of these neurological processes an important therapeutic goal.
SUMMARY OF THE INVENTION
The present invention is directed to aminobenzotriazole derivatives which are potentiators of metabotropic glutamate receptors, particularly the mGluR2 receptor, and which are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which metabotropic glutamate receptors are involved.
DETAILED DESCRIPTION OF THE INVENTION
The invention encompasses a genus of compounds of Formula I
Figure imgf000004_0001
wherein:
X is selected from halo, methyl and -CN; Rl is selected from the group consisting of:
(l) Ci-8alkyl, (2) C2~8alkenyl,
(3) C2-8alkynyl,
(4) Ci-8haloalkyl,
(5) C3_6cycloalkyl-(CH2)p-, wherein p is 0, 1, 2, 3 or 4, and
(6) 4-(2-methylbenzamido)benzyl;
each R2 is independently selected from the group consisting of: halo, OH, Ci-4alkyl, C\ _ 4alkoxy, CF3 and -CN;
R3 is selected from the group consisting of: H5 Ci-.4a.kyl, -C(O)-C i_4alkyl and -C(O)-phenyl, wherein said phenyl is optionally substituted with 1 to 5 substituents independently selected from halo and CF3;
Y is selected from a bond, ~S(O)2~ and -[C(R4)23n-> wherein n is I5 2 or 3 ;
each R4 is independently selected from the group consisting of: H, halo, OH, Ci_4alkyl, Ci- 4alkoxy, CF3, -CN and phenyl, and
two R4 groups on adjacent atom may be joined together with the atoms to which they are attached to form cyclopropyl, and
two R4 groups on the same atom may be joined together to form carbonyl;
A is selected from aryl, heteroaryl and heterocycle, wherein said aryl, heteroaryl and heterocycle are optionally substituted with one or more R5 groups up to the maximum number of substitutable positions; aryl at each occurrence is independently selected from the group consisting of: phenyl, naphthyl, anthryl and phenanthryl;
heteroaryl at each occurrence independently means a 5- or 6-membered monocyclic aromatic or 9- or I O-membered bicyclic aromatic, wherein at least one atom in the aromatic is selected from N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide, and the remaining atoms are selected from C, N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide;
heterocycle at each occurrence independently means a 5- or 6-membered monocyclic non- aromatic ring or 9- or 1 O-membered bicyclic non- or partially-aromatic ring, each optionally substituted with oxo, wherein at least one atom is selected from N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide, and the remaining atoms are selected from C, N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide;
each R5 is independently selected from the group consisting of:
(1) halo,
(2) Ci-galkyl,
(3) C2-6alkenyl,
(4) C2-6alkynyls
(5) C3-6cycloalkyl,
(6) Ci-galkoxy,
(7) C3 -gcycloalkoxy,
(8) -CN,
(9) -OH,
(10) -C(O)-O-C Malkyl,
(H) -C(O)-C i-4alkyl,
(12) -N(R)2,
(13) -C(O)-N(R)2,
(14) -S(0)k-Ci-4alkyl, wherein k is 0, 1 or 2,
(15) -aryl,
(16) -heteroaryl,
(17) -heterocycle, (18) -C(O)-aryl,
(19) -N(R)-aryl,
(20) benzyl,
(21) benzyloxy, (22) phenoxy,
(23) -CO2H,
(24) -SH,
(25) -SO2N(R)R,
(26) -N(R)C(O)N(R)R, (27) -N(R)C(O)C i_4alkyl,
(28) -N(R)SO2N(R)R,
(29) -B(OH)2 and
(30) heterocycle-CH2-
wherein groups (2) to (7), (15), (16) and (20) to (23) above are optionally substituted from one up to the maximum number of substitutable positions with one or more substituents independently selected from the group consisting of: OH, CN, halo, carboxy, -C(O)-O-C i-4alkyl, Cl-4alkyl, Ci_4alkoxy, Ci-4alkylamino, phenyl and heterocycle, and each R is independently selected from the group consisting of: H and Ci_4alkyl;
and pharmaceutically acceptable salts thereof.
Within the genus, the invention encompasses a sub-genus of compounds of Formula I wherein X is Br.
Within the sub-genus, the invention encompasses a first class of compounds of Formula I wherein Rl is 2,2-dimethylpropyl.
Also within the sub-genus, the invention encompasses a second class of compounds of Formula I wherein Rl is cyclopropylmethyl.
Also within the sub-genus, the invention encompasses a third class of compounds of Formula I wherein Y is -CH2-. Also within the sub-genus, the invention encompasses a fourth class of compounds having Formula Ia
Figure imgf000008_0001
Ia
wherein Rl is selected from cyclopropylmethyl, 2,2-dimethylpropyl and 4,4,4-trifluorobutyl; and pharmaceutically acceptable salts thereof. Within the fourth class, the invention encompasses a first group of compounds of
Formula Ia wherein A is phenyl, optionally substituted with one or more R.5 groups up to the maximum number of substitutable positions. Within this first group, the invention encompasses a first sub-group of compounds of Formula Ia wherein each R.5 is independently selected from the group consisting of: halo, Ci_4alkyl, Ci_4alkoxy, -CF3, -OCF3, -NH2, -CN5 -OH, -CH2- OH5 -CH2-O-CH3 , -C(O)OC 1 _4alkyl, -0CH2-C(0)-0H, -NH-C(O)-C 1 ^alkyl and phenyl, optionally substituted with 1 to 5 substituents independenly selected from halo and methyl.
Also within the fourth class, the invention encompasses a second group of compounds of Formula Ia wherein A is selected from pyridine, pyradazine, pyrimidine, pyridazine and triazine, optionally substituted with one or more R.5 groups up to the maximum number of substitutable positions. Within this second group, the invention encompasses a second sub-group of compounds of Formula Ia wherein each R.5 is independently selected from the group consisting of: halo, Ci-4alkyl, Ci_4alkoxy, -CF3, -OCF3, -NH2, -CN, -OH, -CH2- OH, -CH2-O-CH3, -C(O)OCi -4alkyl, -0CH2-C(0)-0H, -NH-C(O)-Ci -4alkyl, phenyl optionally substituted with 1 to 5 substituents independenly selected from halo and methyl, and pyridyl optionally substituted with 1 to 4 substituents independenly selected from halo and methyl.
Also within the fourth class, the invention encompasses a third group of compounds of Formula Ia wherein A is selected from pyrazole, oxadiazole, thϊadiazole, furan, thiophene, pyrrole, triazole, oxazole, thiazole, imidazole, isoxazole and isothiazole, optionally substituted with one or more R5 groups up to the maximum number of substitutable positions. Within this third group, the invention encompasses a third sub-group of compounds of Formula Ia wherein each Rβ is independently selected from the group consisting of: halo, Ci-4alkyl, Ci- 4alkoxy, -CF3, -OCF3, -NH2, -CN, -OH, -CH2-OH, -CH2-O-CH3, -C(O)OC 1 _4alkyl, -0CH2- C(O)-OH, -NH-C(O)-C i_4alkyl, phenyl optionally substituted with 1 to 5 substituents independenly selected from halo and methyl, and pyridyl optionally substituted with 1 to 4 substituents independenly selected from halo and methyl.
Also within the sub-genus, the invention encompasses a fifth class of compounds having Formula Ib
Figure imgf000009_0001
Ib
wherein Rl is selected from cyclopropylmethyl, 2,2-dimethylpropyl and 4,4,4-trifiuorobutyl; and pharmaceutically acceptable salts thereof.
Within the fifth class, the invention encompasses a fourth group of compounds of Formula Ib wherein A is phenyl, optionally substituted with one or more R5 groups up to the maximum number of substitutable positions. Within this fourth group, the invention encompasses a fourth sub-group of compounds of Formula Ib wherein each R5 is independently selected from the group consisting of: halo, Ci_4alkyl, Cμ4alkoxy, -CF3, -0CF3, -NH2, -CN, -OH, -CH2-OH, -CH2-O-CH3, -C(O)OC i_4aϊkyl, -0CH2-C(0)-0H, -NH-C(O)-C i-4alkyl and phenyl, optionally substituted with 1 to 5 substituents independenly selected from halo and methyl.
Also within the fifth class, the invention encompasses a fifth group of compounds of Formula Ib wherein A is selected from pyridine, pyradazine, pyrimidine, pyridazine and triazine, optionally substituted with one or more R5 groups up to the maximum number of substitutable positions. Within this fifth group, the invention encompasses a fifth sub-group of compounds of Formula Ib wherein each R^ is independently selected from the group consisting of: halo, Ci -4alkyl, Ci -4alkoxy, -CF3, -OCF3, -NH2, -CN, -OH, -CH2-OH, -CH2-O-CH3, - C(O)OC 1 -4alkyl, -0CH2-C(0)-0H, -NH-C(O)-C 1 _4alkyl, phenyl optionally substituted with 1 to 5 substituents independenly selected from halo and methyl, and pyridyl optionally substituted with 1 to 4 substituents independenly selected from halo and methyl.
Also within the fifth class, the invention encompasses a sixth group of compounds of Formula Ib The compound according to Claim 13 wherein A is selected from pyrazole, oxadiazole, thiadiazole, furan, thiophene, pyrrole, triazole, oxazole, thiazole, imidazole , isoxazole and isothiazole, optionally substituted with one or more R5 groups up to the maximum number of substitutable positions. Within this sixth group, the invention encompasses a sixth sub-group of compounds of Formula Ib wherein each R5 is independently selected from the group consisting of: halo, Ci -4alkyl, Ci-4alkoxy, -CF3, -OCF3, -NFfe, -CN5 -OH, -CH2-OH, - CH2-OCH3, -C(O)OC i_4alkyl, -OCH2-C(O)-OH, -NH-C(O)-C i^alkyl, phenyl optionally substituted with 1 to 5 substituents independenly selected from halo and methyl, and pyridyl optionally substituted with 1 to 4 substituents independenly selected from halo and methyl. The invention also encompasses a pharmaceutical composition comprising a compound of Formula Ia in combination with a pharmaceutically acceptable carrier. The invention also encompasses a method for treating a neurological or psychiatric disorder associated with glutamate dysfunction in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula I. The invention also encompasses this method wherein the neurological or psychiatric disorder associated with glutamate dysfunction is schizophrenia. "Alkyl", as well as other groups having the prefix "alk", such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptylj octyl, nonyl, and the like.
"Haloalkyl" means alkyl as defined above wherein one more hydrogen atoms are replaced by halo.
"Alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl~2- butenyl, and the like. "Alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-I-pentynyl, 2-heptynyl and the like. "Cycloalkyl" means mono-, bi- or tri-cyclic structures, optionally combined with linear or branched structures, having the indicated number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-l- bicyclo [4.4.0] decyl, and the like. "Alkoxy" means alkoxy groups of a straight or branched having the indicated number of carbon atoms. Ci_6alkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
"Cycloalkoxy" means cycloalkyl as defined above bonded to an oxygen atom, such as cyclopropyloxy. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like. "Halogen" and "halo" includes fluorine, chlorine, bromine and iodine.
The compounds of the present invention are potentiators of metabotropic glutamate (mGluR) receptor function, in particular they are potentiators of mGluR2 receptors. That is, the compounds of the present invention do not appear to bind at the glutamate recognition site on the mGluR receptor, but in the presence of glutamate or a glutamate agonist, the compounds of the present invention increase mGluR receptor response. The present potentiators are expected to have their effect at mGluR receptors by virtue of their ability to increase the response of such receptors to glutamate or glutamate agonists, enhancing the function of the receptors. It is recognized that the compounds of the present invention would be expected to increase the effectiveness of glutamate and glutamate agonists of the mGluR2 receptor. Thus, the potentiators of the present invention are expected to be useful in the treatment of various neurological and psychiatric disorders associated with glutamate dysfunction described to be treated herein and others that can be treated by such potentiators as are appreciated by those skilled in the art.
The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. Any formulas, structures or names of compounds described in this specification that do not specify a particular stereochemistry are meant to encompass any and all existing isomers as described above and mixtures thereof in any proportion. When stereochemistry is specified, the invention is meant to encompass that particular isomer in pure form or as part of a mixture with other isomers in any proportion. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. The present invention also includes all pharmaceutically acceptable isotopic variations of a compound of the Formula I in which one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as 2H and 3 H, carbon such as 1 ϊ C, 13c and 14c, nitrogen such as 13N and 15NS oxygen such as 15θs 1?O and 18θs phosphorus such as 32p; sulfur such as 35s, fluorine such as 18ρ, iodine such as 23l and 125i} and chlorine such as 36Q. Certain isotopically-labelled compounds of Formula I5 for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ^H, and carbon-14, i.e. 14c, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 1 *C, ^F, 15θ and 13NS can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labelled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labelled reagents in place of the non- labelled reagent previously employed.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like. It will be understood that, as used herein, references to the compounds of Formula I are meant to also include a pharmaceutically acceptable salts. Exemplifying the invention are Examples 1-1 to 1-122, 2-1 to 2-42, 3-1 to 3-9 and 4-1 to 4-27, described herein. The subject compounds are useful in a method of potentiating metabotorpic glutamate receptor activity in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound. The present invention is directed to the use of the subject compounds disclosed herein as potentiators of metabotropic glutamate receptor activity. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention.
The present invention is further directed to a method for the manufacture of a medicament for potentiating metabotropic glutamate receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
The subject treated in the present methods is generally a mammal, preferably a human being, male or female, in whom potentiation of metabotropic glutamate receptor activity is desired. The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. It is recognized that one skilled in the art may affect the neurological and psychiatric disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with the disorders with an effective amount of the compound of the present invention. As used herein, the terms "treatment" and "treating" refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder. The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The terms "administration of and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
The utility of the compounds in accordance with the present invention as inhibitors of metabotropic glutamate receptor activity, in particular niGluR2 activity, may be demonstrated by methodology known in the art. Inhibition constants are determined as follows. The compounds of the present invention may be tested in a fluorescence laser imaging plate reader (FLIPR) based assay. This assay is a common functional assay to monitor Ca^+ mobilization in whole cells expressing recombinant receptor coupled with a promiscuous G- protein. CHO dhfr- cells stably expressing recombinant human mGluR2 and Ga 16 loaded with Fluo-4 AM (Invitrogen, Carlsbad CA) are treated with dose responses of compounds and the Ca2+ response is monitored on a FLIPR384 (Molecular Devices, Surmydale CA) for agonist activity. The potentiation response is monitored after a subsequent addition of an EC20 concentration of glutamate (900 nM). The maximum calcium response at each concentration of compound for agonist or potentiation are plotted as dose responses and the curves are fitted with a four parameters logistic equation giving EC 50 and Hill coefficient using the iterative non linear curve fitting software program.
The compounds of the present invention may also be tested in a [35s]~GTPγS assay. The stimulation of [35 S]-GTPyS binding is a common functional assay to monitor Gαi- coupled receptor in native and recombinant receptor membrane preparation. Membrane from cells stably expressing hmGlu2 CHO-Kl (50μg) are incubated in a 96 well plate for 1 hour in the presence of GTPγS35 (0.0SnM)5 GDP (5μM) and compounds. The reaction is stopped by rapid filtration over Unifilter GF/B plate (Packard, Bioscience, Meriden CT) using a 96-well cell harvester (Brandel Gaithersburg, MD). The filter plates are counted using Topcoiint counter (Packard, Bioscience, Meriden CT, USA). When compounds are evaluated as potentiators they are tested in the presence of glutamate (lμM). The activation (agonist) or the potentiation of glutamate (potentiator) curves are fitted with a four parameters logistic equation giving EC50 and Hill coefficient using the iterative non linear curve fitting software GraphPad (San Diego CA, USA).
In particular, Examples 1-1 to 1-122, 2-1 to 2-42, 3-1 to 3-9 and 4-1 to 4-27 were tested and demonstrated activity in potentiating the mGluR2 receptor in the FLIPR assay, generally with an EC50 of less than about 10 μM. Compounds within the present invention had activity in potentiating the mGluR2 receptor in the FLIPR and GTPyS assays with an EC50 of less than about 1 μM. Examples 1-1 to 1-122, 2-1 to 2-42, 3-1 to 3-9 and 4-1 to 4-27 resulted in a minimum 1.8-fold potentiation of glutamate response in the presence of an EC20 concentration of glutamate (90OnM). Such results are indicative of the intrinsic activity of the compounds in use as potentiators of mGluR2 receptor activity,
Representative FLIPR EC50 Values
Figure imgf000016_0001
Metabotropic glutamate receptors including the mGluR2 receptor have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species.
The compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with glutamate dysfunction, including one or more of the following conditions or diseases: 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 AID S -induced dementia), Alzheimer's disease, Huntϊngton'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), autism, autism spectrum disorders, attention deficit/hyperactivity disorder, and conduct disorder.
In an embodiment the present invention provides a method for treating migraine, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. In another embodiment the present invention provides a method for preventing or treating anxiety, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. Particular anxiety disorders of the invention are generalized anxiety disorder, panic disorder, and obsessive compulsive disorder. In another embodiment the present invention provides a method for treating schizophrenia, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. In yet another embodiment the present invention provides a method for treating epilepsy, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.
In an embodiment, the present invention provides a method for the treatment of schizophrenia comprising: administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutical composition thereof. In one of the available sources of diagnostic tools, The Merck Manual (2006-2007), schizophrenia is characterized by psychosis (loss of contact with reality), hallucinations (false perceptions), delusions (false beliefs), disorganized speech and behavior, flattened affect (restricted range of emotions), cognitive deficits (impaired reasoning and problem solving), and occupational and social dysfunction. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, including migraine, and that these systems evolve with medical scientific progress Thus, in an embodiment the present invention provides a method for treating migraine, comprising: administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutical composition thereof. In one of the available sources of diagnostic tools, Dorland's Medical Dictionary (23'd Ed., 1982, W. B. Saunders Company, Philidelphia, PA), migraine is defined as a symptom complex of periodic headaches, usually temporal and unilateral, often with irritability, nausea, vomiting, constipation or diarrhea, and photophobia. As used herein the term "migraine" includes these periodic headaches, both temporal and unilateral, the associated irritability, nausea, vomiting, constipation or diarrhea, photophobia, and other associated symptoms. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, including migraine, and that these systems evolve with medical scientific progress.
In another embodiment the present invention provides a method for treating anxiety, comprising: administering to a patient in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition thereof. At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool including anxiety and related disorders. These include: panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive- compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified. As used herein the term "anxiety" includes treatment of those anxiety disorders and related disorder as described in the DSM-IV. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, and particular anxiety, and that these systems evolve with medical scientific progress. Thus, the term "anxiety" is intended to include like disorders that are described in other diagnostic sources.
In another embodiment the present invention provides a method for treating depression, comprising: administering to a patient in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition thereof. At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American
Psychiatric Association, Washington, D.C.), provides a diagnostic tool including depression and related disorders. Depressive disorders include, for example, single episodic or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias; seasonal affective disorder; or bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder. As used herein the term "depression" includes treatment of those depression disorders and related disorder as described in the DSM-IV.
In another embodiment the present invention provides a method for treating epilepsy, comprising: administering to a patient in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition thereof. At present, there are several types and subtypes of seizures associated with epilepsy, including idiopathic, symptomatic, and cryptogenic. These epileptic seizures can be focal (partial) or generalized. They can also be simple or complex. Epilepsy is described in the art, such as Epilepsy: A comprehensive textbook. Ed. by Jerome Engel, Jr. and Timothy A. Pedley. (Lippincott-Raven, Philadelphia, 1997). At present, the International Classification of Diseases, Ninth Revision, (ΪCD-9) provides a diagnostic tool including epilepsy and related disorders. These include: generalized nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status epilepticus, grand mal status epilepticus, partial epilepsy with impairment of consciousness, partial epilepsy without impairment of consciousness, infantile spasms, epilepsy partialis continua, other forms of epilepsy, epilepsy, unspecified, NOS. As used herein the term "epilepsy" includes these all types and subtypes. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, including epilepsy, and that these systems evolve with medical scientific progress.
The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents, including an mGluR agonist.
The term "potentiated amount" refers to an amount of an mGluR agonist, that is, the dosage of agonist which is effective in treating the neurological and psychiatric disorders described herein when administered in combination with an effective amount of a compound of the present invention. A potentiated amount is expected to be less than the amount that is required to provided the same effect when the mGluR agonist is administered without an effective amount of a compound of the present invention.
A potentiated amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining a potentiated amount, the dose of an mGluR agonist to be administered in combination with a compound of formula I, a number of factors are considered by the attending diagnostician, including, but not limited to: the mGluR agonist selected to be administered, including its potency and selectivity; the compound of formula I to be coadministered; the species of mammal; its size, age, and general health; the specific disorder involved; the degree of involvement or the severity of the disorder; the response of the individual patient; the modes of administration; the bioavailability characteristics of the preparations administered; the dose regimens selected; the use of other concomitant medication; and other relevant circumstances.
A potentiated amount of an mGluR agonist to be administered in combination with an effective amount of a compound of formula I is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day and is expected to be less than the amount that is required to provided the same effect when administered without an effective amount of a compound of formula I. Preferred amounts of a co-administered mGlu agonist are able to be determined by one skilled in the art. The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form may be utilized containing such other drugs and the compound of Formula I. However, the combination therapy may also includes therapies in which the compound of Formula I and one or. more., other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula L
The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention may be utilized. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
The weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1 :1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV5 intracisternal injection or infusion, subcutaneous injection, or. implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm- blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Oily suspensions may be formulated by suspending the active ingredient in a suitable oil Oil-in-water emulsions may also be employed. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
Pharmaceutical compositions of the present compounds may be in the form of a 5 sterile injectable aqueous or oleagenous suspension. The compounds of the present invention may also be administered in the form of suppositories for rectal administration. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention may be employed. The compounds of the present invention may also be formulated for administered by inhalation. The compounds of the present invention may also be 0 administered by a transdermal patch by methods known in the art.
The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
In the treatment, prevention, control, amelioration, or reduction of risk of
15 conditions which require potentiation of metabotorpic glutamate receptor activity an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0f 50.O5 75.0, 100.O5 150.O5 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0} 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the 5 dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
When treating, preventing, controlling, ameliorating, or reducing the risk of neurological and psychiatric disorders associated with glutamate dysfunction or other diseases for
_ which compounds of the present invention are indicated, generally satisfactory results are 0 obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein. The compounds of the present invention can be prepared in a variety of fashions.
All patents, publications and pending patent applications identified are hereby incorporated by reference.
Abbreviations used in the description of the chemistry and in the Examples that follow are: Ac2θ (acetic anhydride); AcOH (acetic acid); AEBSF (p-aminoethylbenzenesulfonyl fluoride); Boc (di-tert-butyl carbamate); (BoC)2O (di-tert-butyl dicarbonate ); BSA (bovine serum albumin); BuLi (n-Butyl lithium); CDCI3 (chloroform-d); CuI (copper iodide); Q1SO4 (copper sulfate); DBU (1,8-DIAZABICYCLO[SAO]UNDEC-T-ENE); DCE (dichloroethane); DCM (dichloromethane); DEAD (diethyl azodicarboxylate); DIPEA (diisopropylethylamine); DMBA (1,3-dimethylbarbituric acid ); DMF (N3N-dimethylformamide); DMP (Dess-Martin periodinane); DMSO (dimethyl sulfoxide); DPPA (diphenylphosphoryl azide); DTT (dithiothreitol); EDTA (ethylene-diamine-tetra-acetic acid); EGTA (ethylene-glycol -tetra-acetic acid); Et2θ (diethylether); EtOAc (ethyl acetate); EtOH (ethanol); HOAc (acetic acid); HPLC (high-performance liquid chromatography); HRMS (high resolution mass spectrum); LAH (lithium aluminum hydride); LCMS (liquid chromato graph-mass spectrometer); LHMDS (lithium bis(trimethylsilyl)amide); LRMS (low resolution mass spectrum); mCPBA (3- chloroperoxybeήzoic acid); MeOH (methanol); MP-B(CN)H3 (Macroporous cyanoborohydride); NaHCO3 (sodium bicarbonate); Na2SO4 (sodium sulfate); Na(0Ac)3BH (sodium triacetoxyborohydride); NH4OAC (ammonium acetate); NBS (N-bromosuccinamide); NFSi (JV- fluorobenzenesulfonimide ); NMP (l-methyl-2-pyrrolidinone); NMR (nuclear magnetic resonance); PBS (phosphate buffered saline); PCR (polymerase chain reaction); Pd(dppf) ([1,T- bis(diphenylphosphino)ferrocene] palladium); Pd(Pli3)4 (palladium(O) tetrakis- triphenylphosphine); POCI3 (phosphorous oxychloride); PS-DIEA (polystyrene diisopropylethylamine); PS-PPh3 (polystyrene-triphenyl phosphine); PTSA (para-toluene sulfonic acid); Pyr (pyridine); Selectfluor (l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); TBAF (tetrabutylammonium fluoride); T- BuOH (tert-butanol); THF (tetrahydrofuran); Tf (trifluoromethanesulfonyl); TFA (trifluoroacteic acid); and TMSCH2N2 (trimethylsilyldiazoniethane).
The compounds of this invention may be prepared by employing reactions as shown in the following Reaction Schemes, in addition to other standard manipulations that are known in the literature or exemplified in the experimental procedures. The illustrative Reaction Schemes below, therefore, are not limited by the compounds listed or by any particular substituents employed for illustrative purposes. Substituent numbering as shown in the Reaction Schemes do not necessarily correlate to that used in the claims and often, for clarity, a single substituent is shown attached to the compound where multiple substituents are optionally allowed under the definitions of Formula A hereinabove.
Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in Reaction Schemes I- VI.
SYNOPSIS OF REACTION SCHEMES
As shown in Reaction Scheme I, the 2-Fluoro-5-nitroaniline (i) can undergo an aromatic nucleophilic substitution with amine (ii) to provide a nitrodiaminobenzene intermediate which is then cyclized to form 5-nitrobenzotriazoIe (iii) upon treatment withNaNO2. Hydrogenation of 3 with Pd/C as a catalyst provides 5-aminobenzotriazole (iv) which upon treatment with pyridimum tribromide yields 5-amino-4-bromobenzotrlazole (v). Finally, compound v can be synthesized by reductive animation of compound vi with an aldehyde. Reaction Scheme I
PyHBr3
Figure imgf000026_0001
Figure imgf000026_0002
EXAMPLES
Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof. The reagents utilized in synthesizing the compounds depicted in the following Tables are either commercially available or are readily prepared by one of ordinary skill in the art.
EXAMPLE 1-1 ΪV-benzyl-4-bromo- 1 -(2,2-dimethylpropyl)- 1 H- -pyrazoI-4-yl)- 1 H- 1 ,2,3-benzotriazol-5-amine
Figure imgf000026_0003
DMF
Figure imgf000026_0005
Figure imgf000026_0004
Step 1: l-(2?2-dimethylpropyl)-5-nitro-l/7-lf2;3-benzotriazole (3)
2-Fluoro-5-nitroaniline (1) (10.22 g, 65.5 mmol5 1.0 equiv.) was dissolved in anhydrous DMSO (100 ml), then treated with Neopentylamine (2) (7.71 ml, 65.5 mmol, l.Oequiv,). It was heated at 120 0C for 2 days when LCMS showed mostly product with trace of starting material. It was cooled to room temperature and treated with Acetic Acid (25 ml), followed by addition of 0.65 M aqueous solution of Sodium nitrite (121 ml} 79 mmol, 1.2equiv.). Heat and gas were released. LCMS showed product after the reaction mixture was stirred at ambient temperature for 20 minutes. The mixture was then neutralized to pH7 with NaOH (IN) and diluted with water which caused a precipitation. The solid was collected on top of filter and washed with water (2x). The crude solid was purified with normal phase silica gel chromatography (EtOAc/Hexane gradient from 0 to 100%) to yield 1 -(2,2-dimethylρropyl)-5- nitro-lH-l,2s3-benzotriazole (3). 1H NMR (500 MHz, CDCl3) δ 9.02 (d, IH5 J= 2.0 Hz), 8.40 (dd, IH5 J= 9.I5 2.0 Hz), 7.62 (d, IH, J= 9.1 Hz), 4.47 (s, 2H)5 1.07 (s, 9H). LRMS m/z (M+H) 235.1 found, 235.3 required.
Step 2: l-(2,2-dimethylpropyl)-l/J-l,2,3-benzotriazol-5-amine (4) l-(2,2-dimethylpropyl)-5-nitro~liϊr-l,253-benzotriazole (3) (4.46 g5 19.04 mmol, 1.Oequiv.) was dissolved in Ethanol (50 ml) and flashed with N2, then charged with 10% Pd/C (2.026 g, 1.904 mmol, 0.1 equiv.). After purging with first N2 then H2, a hydrogen balloon was attached to set up for hydrogenation. After stirring at room temperature for 5 hrs, the reaction was complete based on LCMS. The reaction mixture was filtered through Celited funnel. The residue was washed with MeOH several times. The filtrate was concentrated to give the crude 1- (2,2-dimethylρropyl)4H-l,2,3-benzotriazol-5-amine (4). LRMS m/z (M+H) 205.0 found, 205.3 required.
Step 3: 4-bromo-l-(2,2-dimethylρropyl)-lH-l,2,3-benzotriazol-5-amine (5) l-(2!2-dimethylproρyl)-l/f-l?253-benzotriazol-5-amine (4) (3.52 g, 17.23 mmol, 1.0 equiv.) was dissolved in CHCl3 (172 ml), then treated with Pyridinium tribromide (5.51 g, 17.23 mmol, l.Oequiv.). The reaction mixture was stirred at room temperature till LCMS showed almost only product. The solid was collected on top of filter, and washed with hexane. The solid was taken up in Et2O/EtOAc, and neutralized with saturated NaHCO3. The organic layers were separated and dried over anhydrous MgSO4, filtered and concentrated to give the free base of 4-bromo-l-(2,2-dimethylpropyl)-lH-l,2,3-benzotriazol-5-amine (5) as pale white solid. 1H NMR (500 MHz, CDCl3) δ 7.30 (d, IH, J= 8.8 Hz), 7.07 (sb, 3H), 7.02 (d, IH, J= 8.8 Hz), 4.34 (s, 2H), 1.03 (s, 9H). LRMS m/z (M+H) 283.0 and 285.0 (intensity ratio -1:1) found, 283.1 and 285.1 required.
Step 4: N-benzyl-4-bromo-l~(2,2-dimethylpropyl)4H- -pyrazol-4-yl)-lH- 1,2,3- benzotriazol-5-amine (Example 1-1)
To a solution of 4-bromo-l -(2,2-dimethylpropyl)- IH-1 ,2,3-benzotriazol-5 -amine (5) (50 mg, 0.177 mmol, l.Oequiv.) in DMF (706 μl), was added the Benzylaldehyde (17.93 μl, 0,177 mmol, l.Oequiv.) and Acetic acid (200 μl). The resulting mixture was stirred at room temperature for 20 minutes before adding Sodium cyanoborohydride (55.5 mg, 0.883 mmol,5 equiv.). The reaction mixture was stirred at room temperature overnight. LCMS showed the desired product. The crude product was purified with reverse phase ΗPLC (MeCΝ/Η2O gradient with 0.1% TFA present) to yield Example 1-1. 1H NMR (SOO MHz, CDCl3) δ 7.31 (m, 5H), 7.28(d> IH, J= 9.1 Hz), 6.96 (d, IH, J= 9.0 Hz), 4.53 (s, 2H), 4.32 (s, 2H), 1.02 (s, 9H). LRMS m/z (M+H) 373.2 and 375.2 (intensity ratio =1:1) found, 373.1 and 375.1 required.
The compounds shown in Table 1 were synthesized following Reaction Scheme I and procedures analogous to Example 1-1. The compounds were isolated as a TFA salt or free base.
Table 1.
Ex. Structure Name LRMS m/z (M+Η)
1-2 4-bromo-l -(2,2- LRMS m/z (M+Η) dimethylpropyl)-N- [2- 441.1 and 443.1
(trifluoromethyl)benzyl] - (intensity ratio ~1 : 1 )
1 H-benzotriazol-5-amine found, 441.1 and
443.1 required.
1-3 4-bromo-l -(2,2- LRMS m/z (M+Η) dimethylpropyl)-N-[2- 457.1 and 459.1
(trifluoromethoxy)benzyl (intensity ratio ~1 :1)
] - 1 H-benzotriazol~5 - found, 457.1 and
Figure imgf000028_0001
amine 459.1 required. )
Figure imgf000029_0001
Ex. Structure Name LRMS m/z (M+H)-9 4-bromo-l -(4,4,4- LRMS m/z (M+Η) trifluorobutyl)-N-[2- 497.1 and 499.1 (trifluoromethoxy)benzyl (intensity ratio ~1 : 1) ] - 1 H-benzotriazol-5 - found, 497.0 and amine 499.0 required. -10 4-({[4-bromo-l-(2,2- LRMS m/z (M+Η) dimethylpropyl)- 1 H- 416.1 and 418.1 benzotriazol-5- (intensity ratio -1:1) yl] amino } methyl)-3 - found, 416.1 and
Figure imgf000030_0001
fluorobenzonitrile 418.1 required.-11 4-bromo-N-(2-chloro-6- LRMS m/z (M+Η) fluorobenzyi)-l-(2,2- 425.1 and 427.1 dimethylpropyl)- 1 H- (intensity ratio ~1 : 1 ) benzotriazol-5 --amine found, 425.0 and 427.0 required.
Figure imgf000030_0002
-12 4-bromo-N-(2-chloro-4- LRMS m/z (M+Η) fluorobenzyl)- 1 -(2,2- 425.1 and 427.1 dimethylpropyl)- 1 H- (intensity ratio -1:1) benzotriazol-5 -amine found, 425.0 and 427.0 required.
Figure imgf000030_0003
-13 4-({[4-bromo-l-(2J2- LRMS m/z (M+Η) dimethylpropyl)- 1 H- 434.1 and 436.1 benzotriazol-5- (intensity ratio -1: 1) yl]amino } methyl)-3 ,5- found, 434.1 and difluorobenzonitrile 436.1 required.
Figure imgf000030_0004
Ex. Structure Name LRMS m/z (M+H)-14 2-({[4-brømo-l-(2,2- LRMS m/z (M+Η) dimethylpropyl)- 1 H- 398.1 and 400.1 benzotriazol-5- (intensity ratio ~1 :1) yl]amino } methyl)benzoni found, 398.1 and trile 400.1 required.
Figure imgf000031_0001
-15 4-bromo-l-(2,2- LRMS m/z (M+Η) dimethyIpropyl)-N- [(6- 392.1 and 394.1 fluoropyridin-2- (intensity ratio -1:1) yl)methyl]-lH- found, 392.1 and benzotriazol-5-amine 394.1 required. -16 4-bromo- 1 -(4,4,4- LRMS m/z (M+Η) trifluorobutyl)-lH- 323.0 and 325.0 benzotriazol-5-amine (intensity ratio -1:1) found, 323.0 and 325.0 required.
Figure imgf000031_0002
-17 4-({[4-bromo-l-(2,2- LRMS m/z (M+Η) dimethylpropyl)- 1 H- 398.1 and 400.1 benzotriazol-5- (intensity ratio -1:1) yl] ami no } methyl)benzoni found, 398.1 and trile 400.1 required.
Figure imgf000031_0003
-18 N-benzyl-4-bromo- 1 - LRMS m/z (M+Η) (2,2-dimethylpropyl)-N- 416.1 and 418.1 ethyl- 1 H-benzotriazol-5 - (intensity ratio -1:1) amine found, 416.1 and 418.1 required.
Figure imgf000031_0004
Figure imgf000032_0001
)
)
Figure imgf000033_0001
Ex. Structure Name LRMS m/z (M+H)-29 3-({[4-bromo4-(2,2- LRMS m/z (M+Η) dimethylpropyl)- 1 H- 398.1 and 400.1 benzotriazoi-5- (intensity ratio -1 :1) yl] amino } methyl)benzoni found, 398.1 and trile 400.1 required.
Figure imgf000034_0001
-30 4-bromo-JV-(3,4- LRMS m/z (M+Η) dimethylbenzyl)- 1 -(2,2- 401.1 and 403.1 dimethylpropyl)- IH- (intensity ratio ~1 : 1 ) benzotriazol-5-amine found, 401.1 and 403.1 required.
Figure imgf000034_0002
-31 [2-({[4-bromo-l-(2,2- LRMS m/z (M+Η) dimethylpropyl)-lH~ 417.1 and 419.1 benzotriazol-5- (intensity ratio ~1 : 1 ) yl] amino } methyl)phenyl] found, 417.1 and boronic acid 419.1 required.
Figure imgf000034_0003
-32 [3-({[4-bromo-l-(2J2- LRMS m/z (M+Η) dimethylpropyl)- 1 H- 417.1 and 419.1 benzotriazol-5- (intensity ratio —1:1) yl]amino}methyl)phenyl] found, 417.1 and boronic acid 419.1 required.
Figure imgf000034_0004
-33 4-bromo-l-(2,2- LRMS m/z (M+Η) dimethylpropyl)-N- 363.1 and 365.1 (furan-2-ylmethyl)- 1 H- (intensity ratio -1 :1) benzotriazol-5-amine found, 363.1 and
Figure imgf000034_0005
365.1 required.
Figure imgf000035_0001
Ex. Structure Name LRMS m/z (M+H)-39 4-bromo-N-[(4- LRMS m/z (M+H) bromothiophen-2- 459.0 found, 459.0 yl)methyl]-l-(2,2- required. dimethylpropyl)- 1 H-
Figure imgf000036_0001
benzotriazol-5-amine -40 4-bromo-l-(2,2- LRMS m/z (M+Η) dimethylpropyl)-N-[(5- 393.1 and 395.1 methylthiophen-2- (intensity ratio -1 :1) yl)methyl]4H- found, 393.1 and
Figure imgf000036_0002
benzotriazol-5-amIne 395.1 required. -41 4-bromo-l-(2,2~ LRMS m/z (M+Η) dimethylpropyl)-JV-[4- 419.2 and 421.2 (methylsulfany l)benzyl] - (intensity ratio -1 :1) 1 H-benzotriazol-5 -amine found, 419.1 and 421.1 required.
Figure imgf000036_0003
-42 4~bromo-N-(3?5- LRMS m/z (M+Η) difluoroben2yl)-l-(2,2- 409.1 and 411.1 dimethylpropyl)- 1 H- (intensity ratio ~1 : 1 ) benzotriazol-5-amine found, 409.1 and
Figure imgf000036_0004
411.1 required.-43 4-bromo-l-(2,2- LRMS m/z (M+Η) dimethylpropyl)-N- 363.1 and 365.1
(furan-3-ylmethyl)-lH- (intensity ratio ~1 : 1) benzotriazol- 5 -am ine found, 363.1 and
Figure imgf000036_0005
365.1 required. )
)
Figure imgf000037_0001
Figure imgf000038_0001
)
Figure imgf000039_0001
Figure imgf000040_0001
Ex. Structure Name LRMS m/z (M+H)-63 4-bromo-N-[(2- LRMS m/z (M+H) bromopyridin-3- 454.1 found, 454.0 yl)methyl]-l-(2,2- required. dimethylpropyl)- 1 H- benzotriazol-5-amine
Figure imgf000041_0001
-64 4-bromo-l-(2,2- LRMS m/z (M+Η) dimethylpropyl)-iV-( 1 H- 412.1 and 414.1 indol-4-ylmethyl)-lH- (intensity ratio ~1 : 1 ) benzotriazol-5-amine found, 412.1 and 414.1 required.
Figure imgf000041_0002
-65 4-bromo-l-(2,2- LRMS m/z (M+Η) dimethylproρyl)-N-( 1 H- 412.1 and 414.1 indol-5-ylmethyl)~lH- (intensity ratio -1 :1) benzotriazol- 5 -amine found, 412.1 and 414.1 required.
Figure imgf000041_0003
-66 4-bromo-l-(2,2- LRMS m/z (M+Η) dimethylpropyty-N- 364.1 and 366.1 (isoxazol-5 -ylmethyl)- (intensity ratio ~1 : 1 ) 1 H-benzotriazol-5-amine found, 364.1 and
Figure imgf000041_0004
366.1 required.-67 4-bromo-l-(2,2- LRMS m/z (M+Η) dimethylpropyl)-JV- { [6- 442.1 and 444.1 (trifluoromethyl)pyridin- (intensity ratio -1:1) 3-yl]methyl}-lH- found, 442.1 and benzotriazol- 5 -amine 444.1 required.
Figure imgf000041_0005
Ex. Structure Name LRMS m/z (M+Η)-68 4-bromo-l -(4,4,4- LRMS m/z (M+Η) trifluorobutyl)-N- { [6- 482.0 and 484.0 (trifluoromethyl)pyridin- (intensity ratio ~1 : 1) 3-yl]methyl}-lH- found, 482.0 and benzotriazol-5-aimne 484.0 required.
Figure imgf000042_0001
-69 4-bromo-l -(2,2- LRMS m/z (M+Η) dimethylpropyl)-N-( 1 H- 363.1 and 368.1 pyrazol -4-ylmethyl)- 1 H- (intensity ratio ~1 :1) benzotriazol - 5-amine found, 363.1 and
Figure imgf000042_0002
368.1 required. -70 4-bromo-l -(2,2- LRMS m/z (M+Η) dimethylpropyl)-N- 379.1 and 381.1 (thiophen-2-ylmethyl)- (intensity ratio -1:1) 1 H-benzotriazol-5 -amine found, 379.1 and
Figure imgf000042_0003
381.1 required. -71 4-bromo-Η2,2- LRMS m/z (M+Η) dimethylpropyl)-N- { [5- 407.1 and 409.1 (methoxymelhyl)furan-2- (intensity ratio -1:1) yl]methyl}-lH- found, 407.1 and
Figure imgf000042_0004
benzotriazol-5-amine 409.1 required.-72 4-bromo-l-(2,2- LRMS m/z (M+Η) dimethylpropyl)-N- 424.1 and 426.1 (isoquinolin-1-ylmethyl)- (intensity ratio -1 :1) 1 H-benzotriazo 1-5 -amine found, 424.1 and 426.1 required.
Figure imgf000042_0005
Ex. Structure Name LRMS m/z (M+H)-73 4-bromo-l~(2,2- LRMS m/z (M+Η) dimethylpropyl)-N- 379.1 and 381.1 (thiophen-3-ylmethyl)- (intensity ratio -1 :1) 1 H-benzotriazol- 5 -amine found, 379.1 and
Figure imgf000043_0001
381.1 required. -74 4-bromo-N-JX3- LRMS m/z (M+Η) bromopyridϊn-4- 454.0 found, 454.0 yl)methyl]-l-(2,2- required. dimethylpropyl)- 1 H- benzotriazol-5 -amine
Figure imgf000043_0002
-75 4-bromo-l-(2,2- LRMS m/z (M+Η) dimethylpropyl)-iV-( 1 H- 363.1 and 365.1 imidazol-4-ylmethyl)- (intensity ratio ~1 : 1 ) 1 H-benzotriazol-5-amine found, 363.1 and
Figure imgf000043_0003
365.1 required. -76 N-[6-({[4-bromo-l-(2,2- LRMS m/z (M+Η) dimethy lpropyl)- 1 H- 473.2 and 475.2 benzotriazol-5- (intensity ratio ~1 :1) yl] amino }methyl)pyridin- found, 473.2 and
2-yl]-2,2-dimethyl 475.2 required.
Figure imgf000043_0004
propanamide -77 4-bromo-l-(2,2- LRMS m/z (M+Η) dimethy lpropyl)-N- { 4- 509.2 and 511.2 [(4-methoxybenzyl) (intensity ratio -1:1) oxy]benzyl}-lH- found, 509.2 and benzotriazol-5-amine 511.2 required.
Figure imgf000043_0005
Figure imgf000044_0001
)
)
Figure imgf000045_0001
Figure imgf000046_0001
)
Figure imgf000047_0001
Ex. Structure Name LRMS m/z (M+H) benzotriazol-5 -amine
-96 4-bromo-l-(2,2- LRMS m/z (M+H) d JmethyIpropyl)-N-( (2- 557.2 and 559.2 phenyl-2-[4- (intensity ratio ~1 : 1)
(trifluoromethyl)phenyljc found, 557.1 and
Figure imgf000048_0001
yclopropyl } methyl)- 1 H- 559.1 required. benzotriazol-5-amine -97 4-[l-({4-bromo-l-[(li?> LRMS m/z (M+Η) 1 ,2,2-trimethylpropyl]- 426.1 and 428.1 1 H-benzotriazol- 5 - (intensity ratio ~1 : 1) yl } amino)ethyl]benzomtr found, 426.1 and ile 428.1 required.-98 4-bromθ"N-{[6- LRMS m/z (M+Η) (trifluoromethyl)pyridin- 456.1 and 458.1 3-yl]methyl}-l-t(li?)- (intensity ratio -1: 1) 1 ,2,2-trimethylpropyl]- found, 456.1 and
Figure imgf000048_0002
1 H-benzotriazol- 5 -amine 458.1 required. -99 4-[({4-bromo-l-[(lΛ)- LRMS m/z (M+Η)
1,2,2-trimethylρroρyl]- 412.1 and 414.1 1 H-benzotriazol- 5 - (intensity ratio ~1 : 1) yl } amino)methyl]benzoni found, 412.1 and
Figure imgf000048_0003
trile 414.1 required.
Figure imgf000049_0001
Ex- Structure Name LRMS mfz (M+H)-105 4-bromo-l-(2,2- LRMS m/z (M+Η) dimethylpropyI)-iV- [(4- 394.0 and 396.0 methyl-l,3-thiazol-5- (intensity ratio -1 :1) yl)methyl]-lH- found, 394.1 and
Figure imgf000050_0001
benzotriazol-5-amine 396.1 required. -106 4-bromo-N- [(2-bromo- LRMS mfz (M+H) 1 ,3 -thiazol-4-yl)methyl]- 460.0 found, 460.0 1 -(2s2-dimethylpropyl)- required. 1 H-benzotriazol-5 -amine
Figure imgf000050_0002
-107 4-bromo-l-(2,2- LRMS m/z (M+H) dimethylpropyl)-jV- { [3 - 453.1 and 455.1 (4-methylphenyl)- 1 H- (intensity ratio -1 :1) pyrazol -4-yl] methyl) - 1 H- found, 453.1 and
Figure imgf000050_0003
benzotriazol-5-amine 455.1 required. -108 4-bromo-N- [(2-bromo- LRMS m/z (M+Η) 1 ,3-thiazol-5-yl)methyl]- 460.0 found, 460.0 1 -(2,2-diniethylpropyl)- required. lH-benzotriazol-5-amine
Figure imgf000050_0004
-109 4-bromo-N- [(2,4- LRMS m/z (M+Η) dichloro-1 ,3-thiazol-5- 450.0 found, 450.0 yl)methyl]-l-(2,2- required. dimethylpropyl)- 1 H- benzotriazol-5-amine
Figure imgf000050_0005
Figure imgf000051_0001
Ex. Structure Name LRMS mfz (M+H)-115 4-bromo-l-(2,2- LRMS mfz (M+H) dimethyIpropyI)-N-[4- 441.1 and 443.1 (trifluoromelhyl)benzyl] - (intensity ratio ~1 :1) 1 H-benzotriazol-5 -amine found, 441,1 and 443.1 required.
Figure imgf000052_0001
-116 4-bromo-l-(2,2- LRMS mfz (M+Η) dimethylpropyl)-N- [3 - 441.1 and 443.1 (trifluoromethyl)benzyl] - (intensity ratio -1 :1) 1 H-benzotriazol-5 -amine found, 441.1 and 443.1 required.
Figure imgf000052_0002
-117 4-bromo-N-{[2-(3- LRMS mfz (M+Η) chlorophenyl)- 1.3- 490.0 and 492.0 ttøazol-4-yl]methyl} - 1 - (intensity ratio -1 :1) (2, 2-dimethylpropyl)- IH- found, 490.0 and benzotriazol-5-amine 492.0 required.
Figure imgf000052_0003
-118 4-bromo-l-(2,2- LRMS mfz (M+Η) dimetliylpropyl)-N- [(2- 465.1 and 467.1 morphoϊin-4-yl- 1,3- (intensity ratio -1 :1) thiazol-4-yl)methyl] - 1 H- found, 465.1 and benzotriazol-5-amine 467.1 required.-119 4-bromo-l-(2,2- LRMS mfz (M+Η) dimelhylpropyl)-N- { [3- 469.1 and 471.1 (4-methoxyphenyl)- 1 H- (intensity ratio ~1 :1) pyrazol-4-yl] methyl }- 1 H- found, 469.1 and benzotriazol-5-amine 471.1 required.
Figure imgf000052_0004
Figure imgf000053_0002
EXAMPLE 2-1
4-bromo- 1 -(2,2-dimethy lpropyl)-nzyl-4-bromo- 1 -(2,2-dimethylpropyl)- 1 N -phenyl- 1 H- 1 ,2 ,3 - benzotriazol-5-araine
Figure imgf000053_0001
4-bromo-l-(2J2-dimethylpropyl)-li/-l,2,3-benzotriazol-5-amine (5) (50 mg, 0.177 mmol, l.Oequiv.), Copper(II) acetate (32.1 mg, 0.177 mmol, l.Oequiv.), and grounded 4A molecular sieves were dried in vacuum, then suspended with anhydrous CH2Cl2 (1766 μl), followed by addition of TEA (123 μl, 0.883 mmol, Sequiv.). The greenish suspension was stirred at 25 0C overnight. LCMS showed product and SM. The crude product was purified with RP-HPLC (MeCNZH2O gradient with 0.1% TFA present) to yield Example 2-1. 1H NMR (500 MHz, CDCl3) δ 7.47 (d5 IH, J= 9.0Hz), 7.33 (m, 3H)3 7.09 (ra, 3H)5 4.53 (s, 2H), 4.36 (s, 2H), 1.05 (s, 9H). LRMS m/z (M+H) 359.0 and 361.0 (intensity ratio -1 :1) found, 359.1 and 361.1 required.
EXAMPLE 2-2
4-bromo- 1 ~(2 ,2-dimethylpropyl)-iV-ρyridin~2-yl- 1 H- 1 ,2 , 3 -benzotriazol-5 -amine
Figure imgf000054_0001
A solution of (R)-(-)-l-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t- butylphosphine (0.460 mg, 0.830 μmol, 0.25%equiv.) and palladium(ii) acetate (0.186 mg, 0.830 μmol, 0.25% equiv.) in anhydrous DME (0.3 ml) was syringed in a microwave vial which was charged with 4-bromo-l-(2,2-dimethylpropyl)-lH-l,2,3-benzotriazol-5-amine (5) (94 mg, 0.332 mmol, 1 equiv.) and sodium tert-butoxide (96 mg, 0.996 mmol, 3 equiv.) in DME (0.5 ml) followed by addition of bromopyridine (62.9 mg, 0.398 mmol, 1.2equiv.). The reaction mixture was irradiated at 100 °C and 150 °C in microwave oven till LCMS showed product with little starting material. The crude mixture was purified with reverse phase HPLC (MeCNZH2O gradient with 0.1% TFA present) to yield Example 2-2. 1H NMR (500 MHz, CDCl3) δ , 12.16 (s, IH), 8.00 (d, IH3 J= 6.2 Hz), 7.80 (t, IH, J- 8.1 Hz)5 7.51 (m, 2H)5 6.93 (t, IH5 J- 6.7 Hz)5 6.59 (d, IH, J= 9.0Hz), 4.44 (s, 2H)5 4.36 (s, 2H)5 1.06 (s, 9H). LRMS m/z (M+H) 360.1 and 362.1 (intensity ratio =1 :1) found, 360.1 and 362.1 required. EXAMPLE 2-3
N - [4-bromo- 1 -(2,2-dimethylpropyI)- 1 -bromo- 1 H- 1 ,2,3 -benzotriazol-5 -yl jpyrazine-2- carboxamicle
Figure imgf000055_0001
4-bromo-l-(2,2-dimethylpropyI)4i/-l,2,3-benzotriazol-5-amine (5) (20 mg, 0.071 mmol, l.Oequiv.), Pyrazinyl-2-carboxylic acid (8.76 mg, 0.071 mmol, l .Oequiv.) and l-(chloro-l- pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (23.50 mg, 0.071 mmol, l.Oequiv.) (PyCLu) were suspended in DMF (706 μl). The suspension was stirred at room temperature overnight. LCMS showed the desired product. The crude mixture was purified with reverse phase HPLC (MeCN/H2O gradient with 0.1% TFA present) to yield Example 2-3. 1H NMR (500 MHz, CDCl3) δ , 10.48 (s, IH), 9.55 (s, IH), 8.87 (d, IH, J- 2.4 Hz), 9.77 (d, IH, J= 9.0 Hz), 8.70 (d, IH, J= 2.1 Hz), 7.53 (d, IH, J= 9.0 Hz), 4.44 (s, 2H), 4.43 (s, 2H), 1.07 (s, 9H). LRMS m/z (M+H) 389.1 and 391.1 (intensity ratio =1 :1) found, 389.1 and 391.1 required.
The compounds shown in Table 2 were synthesized according to procedures analogous to Example 2-3. The compounds were isolated as a TFA salt or free base.
Table 2
Ex. Structure Name LRMS m/z (M+H)
2-4 Λq4-bromo-l-(2,2- HRMS m/z (M+H) dimethylpropyl)- 1 H- 471.0644 found, benzotrϊazol-5 -yl] -4- 471.0638 required.
(trifluoromethoxy)benz amide
Figure imgf000055_0002
Figure imgf000056_0001
Ex. Structure Name LRMS m/z (M+H) -10 iV-[4-bromo-l~(4,4,4- LRMS m/z (M+H) trifluorobutyl)- 1 H- 669.1 found and benzotriazol-5-yl] -3 - 669.0 required. (trifluoromethyl)-/V-
(trifluoromethyl)phenyl ]carbonyl } benzamide
Figure imgf000057_0001
-11 _V-[4-bromo-l-(4,4,4- LRMS m/z (M+H) trifiuorobutyl)-lJY- 479.0 found and benzotriazol-5- 479.0 required. yl]quinoxaline-2- carboxamide
Figure imgf000057_0002
-12 JV-[4-bromo-l -(4,4,4- LRMS m/z (M+H) trifluorobutyl)-lH- 430.0 found and benzotriazol-5 -yl] 430.0 required. pyridine-2- carboxamide
Figure imgf000057_0003
-13 ΛT-[4-bromo-l-(2,2- LRMS m/z (M+H) dimethylpropyl)- 1 H- 387.0 found and benzotriazol-5- 387.0 required. yl] benzamide
Figure imgf000057_0004
Figure imgf000058_0001
Ex. Structure Name LRMS m/z (M+H) -19 JV-[4-bromo-l-(2,2- HRMS m/z (M+H) climethylpropyl)- 1 H- 480.1041 found, benzotriazol- 5 -yl] -6- 480.1030 required. ρhenoxypyridine-3 - carboxamide
Figure imgf000059_0001
-20 vV-[4-bromo-l-(2,2- HRMS m/z (M+H) dimethylpropyl)- 1 H- 430.1242 found, 1 ,2,3-benzotriazol-5- 430.1237 required. yl] -3-(dimethylamino) benzamide
Figure imgf000059_0002
-21 _V-[4-bromo-l-(2,2- HRMS m/z (M+H) dimethylpropyl)- 1 H- 486.0940 found, benzolriazol-5-yl]"3-(4- 486.0935 required. fluorophenyl)-5- methylisoxazole-4-
Figure imgf000059_0003
carboxamide -22 Λq4-bromo-l-(252- HRMS m/z (M+H) dimethylpropyl)- 1 H- 552.0044 found, benzotriazol-5-yl]-2- 552.0022 required.
(2,6-dichlorobenzyl)» l,3-thiazole-4- carboxamide
Figure imgf000059_0004
Figure imgf000060_0001
Ex. Structure Name LRMS m/z (M+H) -28 JV~[4~bromo-l-(2,2- HRMS m/z (M+H) dimethylpropyl)- 1 H- 454.0878 found, benzotriazol-5 -yl] -5 - 454.0873 required. phenyl- 1 ,3-oxazole-4-
Figure imgf000061_0001
carboxamide -29 iV-[4-bromo-l-(2,2- HRMS m/z (M+H) dimethylpropyl)- 1 H- 467.1197 found, benzotriazol-5-yl]-5- 467.1189 required. methyl- 1 -phenyl- 1 H- pyrazole-4-
Figure imgf000061_0002
carboxamide -30 4-(acetylamino)-iV- [4- HRMS m/z (M+H) bromo-l-(2,2- 444.1036 found, dimethylpropyl)- 1 H- 444.1030 required. benzotriazol-5- yl]beazamide
Figure imgf000061_0003
-31 JV-[4-bromo-l-(2,2- HRMS m/z (M+H) dimethy lpropyl)- 1 H- 412.0769 found, beαzotriazol- 5 -yl] -A- 412.0767 required. cyanobenzamide
Figure imgf000061_0004
-32 iV-[4-bromo-l-(2,2- HRMS m/z (M+H) dimethy lpropyl)- 1 H- 388.0733 found, 1,2,3 -benzotriazol- 5 - 388.0767 required. yl] isonicotinamide
Figure imgf000061_0005
Figure imgf000062_0001
Figure imgf000063_0001
EXAMPLE 3-1 jV-benzyl-4-bromo- 1 -(2 ,2-dimethylρropyl)-iV-methyl- 1 /f-benzotriazol-5 -amine
Figure imgf000064_0001
To a solution of 7V-benzyl-4-bronio-l-(2,2-dimethylpropyl)-l/f- -ρyrazol-4-yl)- lϋr-l,2,3-benzotriazol-5-amine (Example 1-1) (40 mg, 0.107 mmol, l .Oequiv.) in DMF (536 μl), was added the 60% NaH (17.14 mg, 0.429 mmol, 4.0equiv.) in mineral oil. The resulting mixture was stirred at room temperature till LCMS showed mostly product without starting material. The crude mixture was purified with reverse phase HPLC (MeCNZH2O gradient with 0.1% TFA present) to yield Example 3-1. 1H NMR (500 MHz, CDCl3) δ , 7.32 (m, 7H), 4.39 (s, 2H), 4.32 (s, 2H), 2.83 (s, 3H)5 1.05 (s, 9H). LRMS m/z (M+H) 387.1 and 389.1 (intensity ratio =1 :1) found, 387.1 and 389.1 required.
The compounds shown in Table 3 were synthesized according to procedures analogous to Example 3-1. The compounds were isolated as a TFA salt or free base.
Table 3
Ex. Structure Name LRMS m/z (M+H)
3-2 4-({[4-bromo-l-(2,2- LRMS m/z (M+H) dimethylpropyl)- 1 H- 412.1 and 414.1 benzotriazol-5- (intensity ratio -1:1) yl ](methyl)amino } meth found, 412.1 and yl)benzonitrile 414.1 required.
Figure imgf000064_0002
Ex. Structure Name LRMS m/z (M+H) -3 4-bromo-l-(2.2- LRMS m/z (M+H) dimethylpropyl)-5-(2- 401.1 and 403.1 methoxypyridin-3 -yl)- (intensity ratio — 1 : 1 ) 1 H-benzotriazole found, 401.1 and 403.1 required.
Figure imgf000065_0001
-4 4-bromo-l-(2,2- LRMS m/z (M+H) dimethylpropyl)-iV- 373.1 and 375.1 methyl-N-phenyl- 1 H- (intensity ratio -1:1) benzotriazol-5-amine found, 373.1 and
Figure imgf000065_0002
375.1 required.-5 4-bromo-l-(2?2- LRMS m/z (M+H) dimethylpropyl)-iV- 471.2 and 473.2 methyl-/V-[2- (intensity ratio -1:1)
(trifluoromethoxy)benz found, 471.1 and yl]- 1 H-benzotriazoI-5- 473.1 required.
Figure imgf000065_0003
amine -6 iV-benzyl-JV- [4-bromo- LRMS m/z (M+Η) 1 -(2 ,2-dimethylpropyl)- 415.1 and 417.1 1 H-benzotriazol-5- (intensity ratio -1 :1) yljacetamide found, 415.1 and 417.1 required.
Figure imgf000065_0004
-7 4"bromo-l~(2,2- LRMS m/z (M+Η) dimethylρropyl)-5 -[ 1 - 401.1 and 403.1 methyl-3- (intensity ratio —1 :1)
(trifluoromethyl)- 1 H- found, 401.1 and pyrazol-5-yl]-l//- 403.1 required.
Figure imgf000065_0005
benzotriazole
Figure imgf000066_0003
EXAMPLE 4-1 & EXAMPLE 4-2
Figure imgf000066_0001
N N^CI
Cs2CO3
Figure imgf000066_0002
1 ~(cyclopropylmethyl)-5-nitro- 1 H-benzotriazole (6)
A solution of 2-fluoro-5-nitroamline (I5 5.00 g, 32.0 mmol, 1 equiv) and 1- cyclopropylmethanamine (3.33 mL, 38.4 mmol, 1.20 equiv) in DMSO (40 mL) was heated at 80 0C for 48 h, then allowed to cool to 23 0C. Acetic acid (20 mL) was added followed by a solution of sodium nitrite (2.65 g, 38.4 mmol, 1.20 equiv) in water (50 mL), and the resulting mixture was stirred for 45 min, diluted with water, and neutralized with solid sodium bicarbonate. The aqueous mixture was extracted with ethyl acetate (3 x 150 mL), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (hexanes, grading to 100% ethyl acetate) to give l-(cyclopropylmethyl)-5-nitro-l H-benzotriazole (6) as an orange oil. 1H NMR (300 MHz, CDCl3) δ 9.03 (dd, IH5 J- 1.2, 0.6 Hz)5 8.41 (dd, IH, J - 9.2, 2.1 Hz)3 7.69 (dd, IH, J- 9.2, 0.6 Hz), 4.59 (d, 2H5 J = 7.3 Hz), 1.26 (m, IH), 0.72 (m, 2H), 0.53 (m, 2H). LRMS m/z (M+H) 219.0 found, 219.1 required.
1 -(cycloρropylmethyl)-l H-benzotriazol-5 -amine (7)
A mixture of l-(cyclopropylmethyl)-5-nitro-l H-benzotriazole (6, 5.5 g, 25.2 mmol, 1 equiv) and 10% palladium on carbon (2.0 g) in ethanol (150 mL) was stirred at 23 0C under a hydrogen balloon for 20 h. The catalyst was filtered onto a pad of diatomaceous earth and washed with ethanol (200 mL). The filtrate was concentrated to give l-(cyclopropylmethyl)- lH-benzotriazol-5-amine (7) as a red-brown oil. 5H NMR (300 MHz, CDCl3) δ 7.37 (d, IH, J- 8.9 Hz)5 7.21 (d, IH5 J- 1.5 Hz)5 6.94 (dd, IH5 J= 8.5, 2.1 Hz)5 4.44 (d, 2H5 J= 7.0 Hz), 3.81 (br s, 2H), 1.38 (m, IH), 0.64 (m, 2H), 0.46 (m, 2H). LRMS m/z (M+H) 189.0 found, 189.1 required.
4-bromo- 1 -(cyclopropylmethyl)- 1 H-benzotriazol-5-amine (8)
A solution of l-(cyclopropylmethyl)-lH-benzotriazol-5-amine (7, 4.20 g, 22.3 mmol, 1 equiv) and pyridinium tribromide (7.14 g5 22.3 mmol, 1.00 equiv) in chloroform (150 mL) was stirred at 23 0C for 1 h before additional pyridinium tribromide (1.00 g5 3.13 mmol, 0.14 equiv) was added to complete the transformation. After an additional 30 minutes of stirring, the solid precipitate that formed was filtered, washed with minimal amount of chloroform, air dried, and then partitioned between saturated aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 4~bromo-l-(cyclopropylmethyl)~lH~benzotriazol-5-amine (8) as a dark oil. 1H NMR (300 MHz, CDCl3) δ 7.33 (d, IH, J= 8.5 Hz), 6.99 (d, IH, J= 8.5 Hz)5 4.45 (d, 2H, J = 7.0 Hz), 4.22 (br s, 2H)5 1.37 (m, IH), 0.64 (m, 2H), 0.47 (m, 2H). LRMS m/z (M+H) 269.0 found, 269.1 required.
4-bromo-l~(cyclopropylmethyl)-N-[2-(trifluoromethyl)benzyl]-lH-benzotriazol-5-amine (Example 4-1)
A mixture of 4-bromo-l-(cyclopropylmethyl)-lH-ben2θtriazol-5 -amine (8, 300 mg, 1.12 mmol, 1 equiv), 2-(trifluoromethyl)benzaldehyde (293 mg, 1.69 mmol, 1.50 equiv), sodium cyanoborohydride (212 mg, 3.37 mmol, 3.00 equiv) and acetic acid (321 uL, 5.62 mmol, 5.00 equiv) in anhydrous methanol (30 mL) at 23 0C was stirred for 3 h and then concentrated. The residue was partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated, and the residue purified by flash column chromatography on silica gel (hexanes, grading to 100% ethyl acetate) to give 4-bromo-l-(cyclopropylmethyl)-N-[2- (trifluoromethyl)benzyl]~lH-benzotriazol-5-amine (Example 4-1) as a light brown, viscous oil. 1H NMR (300 MHz, CDCl3) 6 7.71 (d, IH, J= 7.6 Hz)5 7.58 (d, IH, J- 7.6 Hz), 7.49 (t, IH, J = 7.3 Hz), 7.38 (t, IH, J= 7.3 Hz), 7.31 (d} IH, J= 8.8 Hz), 6.80 (d, IH, J- 8.8 Hz), 5.04 (m, IH)5 4.77 (d, 2H, J - 6.1 Hz), 4.43 (d, 2H5 J = 7.0 Hz), 4.22 (br s, 2H), 1.34 (m, IH), 0.63 (m, 2H), 0.45 (m, 2H). LRMS m/z (M+H) 425.1 found, 425.1 required.
4-bromo-l-(cyclopropylmethyl)-N-(pyrimidin-2-yl)-lH-benzotriazol-5-amine (Example 4-2)
A mixture of 4-bromo-l-(cyclopropylmethyl)-lH-benzotriazol-5-amine (8, 300 mg, 1.12 mmol, 1 equiv), 2-chloroρyrimidine (141 mg5 1.23 mmol, 1.00 equiv), and cesium carbonate (366 mg, 1.12 mmol, 1.00 equiv) in DMF (15 mL) was heated at 110 0C for 20 h. The reaction mixture was partitioned between water and ethyl acetate (2 x 75 mL). The combined organic layers were dried over sodium sulfate and concentrated, and the residue purified by flash column chromatography on silica gel (hexanes, grading to 100% ethyl acetate) to give 4-bromo- l-(cyclopropylmethyl)-N-(pyrimidin-2-yl)-lH-benzotriazol-5 -amine (Example 4-2) as an off- white solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (d, IH, J - 9.2 Hz), 8.47 (d, 2H, J = 4.9 Hz), 7.57 (br s, IH), 7.53 (d, IH, J= 8.9 Hz), 6.82 (t, IH, J= 4.9 Hz), 4.52 (d, 2H, J= 7.0 Hz), 1.41 (m, IH), 0.67 (m, 2H), 0.50 (m, 2H). LRMS m/z (M+H) 345-0 found, 345.0 required. The following compounds were prepared using the corresponding amines and benzaldehyde derivatives as described above.
Table 4
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001

Claims

WHAT IS CLAIMED IS:
1. A compound according to Formula I
Figure imgf000075_0001
wherein:
X is selected from halo, methyl and -CN;
R Ms selected from the group consisting of:
(l) Ci-8alkyl,
(2) C2-8aIkenyl,
(3) C2-8aIkynyl, (4) Ci-8haloalkyl,
(5) C3_6cycloalkyl-(CH2)p-, wherein p is 0, 1, 2, 3 or 4, and
(6) 4-(2-methylbenzamido)benzyl;
each R2 is independently selected from the group consisting of: halo, OH, Ci-4alkyl, Ci- 4alkoxy, CF3 and -CN;
R3 is selected from the group consisting of: H, Ci-4alkyl, -C(O)-C i_4allcyl and -C(O)-phenyl, wherein said phenyl is optionally substituted with 1 to 5 substituents independently selected from halo and C F3;
Y is selected from a bond, --S(O)2- and -[C(R4)2]ir~, wherein n is 1 , 2 or 3 ; each R4 is independently selected from the group consisting of: H5 halo, OH, Ci_4alkyl, Ci_ 4alkoxy, CF3, -CN and phenyl, and
two R.4 groups on adjacent atom may be joined together with the atoms to which they are attached to form cyclopropyl, and
two R.4 groups on the same atom may be joined together to form carbonyl;
A is selected from aryl, heteroaryl and heterocycle, wherein said aryl, heteroaryl and heterocycle are optionally substituted with one or more R5 groups up to the maximum number of substitutable positions;
aryl at each occurrence is independently selected from the group consisting of: phenyl, naphthyl, anthryl and phenanthryl;
heteroaryl at each occurrence independently means a 5- or 6-membered monocyclic aromatic or 9- or 10-membered bi cyclic aromatic, wherein at least one atom in the aromatic is selected from N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide, and the remaining atoms are selected from C5 N(R)5 O and S, the sulfur optionally oxidized to sulfone or sulfoxide;
heterocycle at each occurrence independently means a 5- or 6-membered monocyclic non- aromatic ring or 9- or 10-membered bicyclic non- or partially-aromatic ring, each optionally substituted with oxo, wherein at least one atom is selected from N(R), O and S5 the sulfur optionally oxidized to sulfone or sulfoxide, and the remaining atoms are selected from C, N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide;
each R5 is independently selected from the group consisting of:
(1) halo, (2) Ci-galkyl,
(3) C2-6alkenyi,
(4) C2-όalkynyl, (5) C3-6cycloalkyls
(6) Ci_6alkoxy,
(7) C3-6cycloafkoxy,
(8) -CN,
(9)
(10) -C(O)-O-C i_4alkyl,
(1 1) -C(O)-Ci -4alkyl,
(12) -N(R)2,
(13) -C(O)-N(R)2,
(14) -S(O)k-Ci_4alkyl, wherein k is 0, 1 or 2,
(15) -aryl,
(16) -heteroaryl,
(17) -heterocycle,
(18) -C(O)-aryl,
(19) -N(R)-aryl,
(20) benzyl,
(21) benzyloxy,
(22) phenoxy,
(23) -CO2H,
(24) -SH5
(25) -SO2N(R)R5
(26) -N(R)C(O)N(R)R,
(27) -N(R)C(O)C i-4alkyl,
(28) -N(R)SO2N(R)R,
(29) -B(OH)2 and
(30) heterocycle-CH2-
wherein groups (2) to (7), (15), (16) and (20) to (23) above are optionally substituted from one up to the maximum number of substitutable positions with one or more substituents independently selected from the group consisting of: OH, CN, halo, carboxy, -C(O)-O-C i-4alkyl, Ci_4alkyl, Ci_4alkoxy, Ci_4alkylamino, phenyl and heterocycle, and each R is independently selected from the group consisting of: H and Ci~4alkyl;
and pharmaceutically acceptable salts thereof.
2. The compound according to Claim 1 wherein X is Br.
3. The compound according to Claim 2 wherein Rl is 2,2-dimethylpropyl.
4. The compound according to Claim 2 wherein Rl is cyclopropylmethyl.
5. The compound according to Claim 2 wherein Y is -CH2-.
6. The compound according to Claim 2 of Formula Ia
Figure imgf000078_0001
Ia
wherein Rl is selected from cyclopropylmethyl, 2,2-dimethylpropyl and 4,4,4-trifluorobutyl;
and pharmaceutically acceptable salts thereof.
7. The compound according to Claim 6 wherein A is phenyl, optionally substituted with one or more R5 groups up to the maximum number of substitutable positions.
8. The compound according to Claim 7 wherein each R^ is independently selected from the group consisting of: halo, Ci^alkyl, CMalkoxy, -CF3, -OCF3, -NH2, -CN5 -OH5 -CH2-OH, -CH2-O-CH3, -C(O)OC Malkyl, -OCH2~C(O)~OH, -NH-C(O)-C i_4alkyl and phenyl, optionally substituted with 1 to 5 substituents independenly selected from halo and methyl.
9. The compound according to Claim 6 wherein A is selected from pyridine, pyradazine, pyrimidine, pyridazine and triazine, optionally substituted with one or more R5 groups up to the maximum number of substitutable positions.
10. The compound according to Claim 9 wherein each R.5 is independently selected from the group consisting of: halo, Ci_4alkyl, Ci-4alkoxy, -CF3, -OCF3, -NH2, -CN,
-OH, -CH2-OH, -CH2-O-CH3, -C(O)OC i-4alkyl, -0CH2-C(0)-0H, -NH-C(O)-C Malkyl, phenyl optionally substituted with ϊ to 5 substituents independenly selected from halo and methyl, and pyridyl optionally substituted with 1 to 4 substituents independenly selected from halo and methyl.
11. The compound according to Claim 6 wherein A is selected from pyrazole, oxadiazole, thiadiazole, furan, thiophene, pyrrole, triazole, oxazole, thiazole, imidazole, isoxazole and isothiazole, optionally substituted with one or more R.5 groups up to the maximum number of substitutable positions.
12. The compound according to Claim 11 wherein each R5 is independently selected from the group consisting of: halo, Ci-4alkyl, Ci_4alkoxy, -CF3, -0CF3, -NH2, -CN, -OH, -CH2-OH, -CH2-O-CH3, -C(O)OC i-4alkyl, -OCH2~C(O)-OH, -NH-C(O)-C i-4alkyl, phenyl optionally substituted with 1 to 5 substituents independenly selected from halo and methyl, and pyridyl optionally substituted with 1 to 4 substituents independenly selected from halo and methyl.
13. The compound according to Claim 2 of Formula Ib
Figure imgf000080_0001
Ib
wherein R^ is selected from cyclopropylmethyl, 2,2-dimethylpropyl and 4,4,4-trifluorobutyl;
and pharmaceutically acceptable salts thereof.
14. The compound according to Claim 13 wherein A is phenyl, optionally substituted with one or more R.5 groups up to the maximum number of substitutable positions.
15. The compound according to Claim 14 wherein each R.5 is independently selected from the group consisting of: halo, Ci-4alkyl, Ci-4alkoxy, -CF3, -OCF3, -NH2, -CN, -OH, -CH2-OH, -CH2-O-CH3, -C(O)OC i_4alkyl, -OCH2-C(O)-OH, -NH-C(O)-C i_4alkyl and phenyl, optionally substituted with 1 to 5 substituents independenly selected from halo and methyl.
16. The compound according to Claim 13 wherein A is selected from pyridine, pyradazine, pyrimidine, pyridazine and triazine, optionally substituted with one or more R5 groups up to the maximum number of substitutable positions.
17. The compound according to Claim 16 wherein each R^ is independently selected from the group consisting of: halo, Ci-4aikyl, Ci_4alkoxy, -CF3, -OCF3, -NH2, -CN, -OH, -CH2-OH, -CH2-O-CH3, -C(O)OC i-4alkyl, -OCH2-C(O)-OH, -NH-C (O)-C l-4alkyl, phenyl optionally substituted with 1 to 5 substituents independenly selected from halo and methyl, and pyridyl optionally substituted with 1 to 4 substituents independenly selected from halo and methyl.
18. The compound according to Claim 13 wherein A is selected from, pyrazole, oxadiazole, thiadiazole, furan, thiophene, pyrrole, triazole, oxazole, thiazole, imidazole, isoxazole and isothiazole, optionally substituted with one or more R5 groups up to the maximum number of substitutable positions.
19. The compound according to Claim 18 wherein each R5 is independently selected from the group consisting of: halo, Cj^alkyl, Ci_4alkoxy, -CF3, -OCF3, -NH2, -CN, -OH, -CH2-OH, -CH2-O-CH3, -C(O)OC i_4alkyl, -OCH2-C(O)-OH; -NH-C(O)-C Malkyl, phenyl optionally substituted with 1 to 5 substituents independenly selected from halo and methyl, and pyridyl optionally substituted with 1 to 4 substituents independenly selected from halo and methyl.
20. A pharmaceutical composition comprising a compound according to Claim 1 in combination with a pharmaceutically acceptable carrier.
21. A method for treating a neurological or psychiatric disorder associated with glutamate dysfunction in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound according to Claim 1.
22. The method according to Claim 21 wherein the neurological or psychiatric disorder associated with glutamate dysfunction is schizophrenia.
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