WO2012003147A1 - Isoindolone m1 receptor positive allosteric modulators - Google Patents

Isoindolone m1 receptor positive allosteric modulators Download PDF

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Publication number
WO2012003147A1
WO2012003147A1 PCT/US2011/041933 US2011041933W WO2012003147A1 WO 2012003147 A1 WO2012003147 A1 WO 2012003147A1 US 2011041933 W US2011041933 W US 2011041933W WO 2012003147 A1 WO2012003147 A1 WO 2012003147A1
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methyl
dihydro
compound
pharmaceutically acceptable
benzo
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PCT/US2011/041933
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French (fr)
Inventor
Scott D. Kuduk
Douglas C. Beshore
Zhiqiang Yang
Youheng Shu
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Merck Sharp & Dohme Corp.
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Priority to EP11801342.4A priority Critical patent/EP2588104B1/en
Priority to US13/805,346 priority patent/US8697690B2/en
Publication of WO2012003147A1 publication Critical patent/WO2012003147A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
    • C07D209/64—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/10—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 carbon chain containing aromatic rings
    • 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
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D405/14—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 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 invention is directed to a class of isoindolone compounds, their salts, pharmaceutical compositions comprising them and their use in therapy of the human body.
  • the invention is directed to a class of isoindolone compounds which are muscarinic Ml receptor positive alloste ic modulators, and hence are useful in the treatment of Alzheimer's Disease and other diseases mediated by the muscarinic Ml receptor.
  • Alzheimer's Disease is a common neurodegenerative disease affecting the elderly, resulting in progressive memory impairment, loss of language and visuospatial skills, and behavior deficits. Characteristics of the disease include degeneration of cholinergic neurons in the cerebral cortex, hippocampus, basal forebrain, and other regions of the brain, neurofibrillary tangles, and accumulation of the amyloid ⁇ peptide ( ⁇ ).
  • ⁇ is a 39-43 amino acid produced in the brain by processing of the beta-amyloid precursor protein (APP) by the beta-amyloid protein cleaving enzyme ("beta secretase" or "BACE”) and gamma-secretase. The processing leads to accumulation of ⁇ in the brain.
  • APP beta-amyloid precursor protein
  • BACE beta-amyloid protein cleaving enzyme
  • Cholinergic neurotransmission involves the binding of acetylcholine either to the nicotinic acetylcholine receptor (nAChR) or to the muscarinic acetylcholine receptor (mAChR). It has been hypothesized that cholinergic hypofunction contributes to the cognitive deficits of patients suffering from Alzheimer's Disease. Consequently, acetyl cholinesterase inhibitors, which inhibit acetylcholine hydrolysis, have been approved in the United States for use in the treatment of the cognitive impairments of Alzheimer's Disease patients. While acetyl cholinesterase inhibitors have provided some cognitive enhancement in Alzheimer's Disease patients, the therapy has not been shown to change the underlying disease pathology.
  • nAChR nicotinic acetylcholine receptor
  • mAChR muscarinic acetylcholine receptor
  • a second potential pharmacotherapeutic target to counteract cholinergic hypofunction is the activation of muscarinic receptors.
  • Muscarinic receptors are prevalent throughout the body. Five distinct muscarinic receptors (M1-M5) have been identified in mammals. In the central nervous system, muscarinic receptors are involved in cognitive, behavior, sensory, motor and autonomic functions. The muscarinic Ml receptor, which is prevalent in the cerebral cortex, hippocampus and striatum, has been found to have a major role in cognitive processing and is believed to have a role in the pathophysiology of Alzheimer's Disease. See Eglen et al, TRENDS in Pharmacological Sciences, 2001 , 22 : 8, 409-414.
  • Ml agonists also have the potential to treat the underlying disease mechanism of Alzheimer's Disease.
  • the cholinergic hypothesis of Alzheimer's Disease is linked to both ⁇ -amyloid and hyperphosphorylated tau protein. Formation of ⁇ -amyloid may impair the coupling of the muscarinic receptor with G-proteins. Stimulation of the Ml muscarinic receptor has been shown to increase formation of the neuroprotective aAPPs fragment, thereby preventing the formation of the ⁇ peptide.
  • Ml agonists may alter APP processing and enhance aAPPs secretion. See Fisher, Jpn J Pharmacol, 2000, 84: 101 - 1 12.
  • Ml ligands which have been developed and studied for Alzheimer's Disease have produced side effects common to other muscarinic receptor ligands, such as sweating, nausea and diarrhea. See Spalding et al, Mol Pharmacol, 2002, 61 :6, 1297-1302.
  • the muscarinic receptors are known to contain one or more allosteric sites, which may alter the affinity with which muscarinic ligands bind to the primary binding or
  • the compounds of the invention which are muscarinic Ml receptor positive allosteric modulators, are believed to be useful in the treatment of Alzheimer's Disease and other diseases mediated by the muscarinic Ml receptor.
  • the present invention is directed to novel isoindolone compounds of generic formula (I) as indicated below or a pharmaceutically acceptable salt thereof, which is useful as an Ml receptor positive allosteric modulator.
  • the invention is further directed to methods of treating a patient (preferably a human) for diseases or disorders in which the Ml receptor is involved, such as Alzheimer's disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of general formula (I), or a
  • compositions which include an effective amount of a compound of formula (I), or a
  • the invention is directed to isoindolone compounds of general formula (I)
  • Y and Z independently represent CH or N, provided that they both are not N at the same time, W represents aryl, pyridyl, or oxopiperidinyl, optionally substituted with one or more of R x ;
  • R is selected from the group consisting of hydrogen, (CHR 2 ) n C3-io cycloalkyi, (CHR 2 ) n C6-lO aryl, (CHR2) n C5_i0 heterocycle, said cycloalkyi, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of RY; Rl and R?
  • Rl and R3 together with the carbon atom they are attached form a 3-6 cycloalkyi;
  • R x is selected from the group consisting of hydrogen, 0 ⁇ . alkyl, C2-6 aikenyl, halogen, OR 2 ,
  • R2 is selected from the group consisting of hydrogen, or -Ci_g alkyl, and n is 0, 1 or 2.
  • the invention is directed to a compound wherein W is aryl optionally substituted with 1 to 3 groups of R x . In another embodiment the invention is directed to a compound wherein when W is aryl it is phenyl optionally substituted with 1 to 3 groups of R x .
  • the invention is directed to a compound wherein W is pyridyi optionally substituted with 1 to 3 groups of R x .
  • the invention is directed to a compound wherein W is oxopiperidinyl optionally substituted with 1 to 3 groups of R x .
  • the invention is directed to a compound wherein R is C3. 10 cycloalkyl optionally substituted with 1 to 3 groups of Ry.
  • R is cyclohexyl or cyclohexenyl, both optionally substituted with 1 to 3 groups of Ry.
  • the invention is directed to a compound wherein R is (CHR2) n C5_io heterocycle, optionally substituted with 1 to 3 groups of Ry.
  • R is (CHR2) n C5_io heterocycle, optionally substituted with 1 to 3 groups of Ry.
  • R is pyranyl, tetrahydropyranyl, pyridyi, all optionally substituted with 1 to 3 groups of Ry.
  • the invention is directed to a compound wherein R is (CHR2) n C6-io aryl, optionally substituted with 1 to 3 groups of R .
  • R is (CHR2) n C6-io aryl, optionally substituted with 1 to 3 groups of R .
  • a subembodiment of this invention is realized when R is phenyl optionally substituted with 1 to 3 groups of Ry.
  • the Rx substituent attaches to the W in the para position relative to the CI3 ⁇ 4 linker linking W to the rest of the structure.
  • the invention is directed to a compound wherein R x is selected from the goup consisting of hydrogen, hydroxy!, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl.
  • the invention is directed to a compound wherein R is selected from the goup consisting of (CH2)nOH, COOR2, 3 ⁇ 4, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, and CN.
  • the invention is directed to a compound represented by structural formula 0:
  • Y, Z, W, Rx, and R are as originally described.
  • a subembodiment of the compound of formula II is realized when R is selected from the group consisting of cyclohexyl or cyclohexenyl, pyranyl, tetrahydropyranyl, pyridyi and phenyl all of which are optionally substituted with 1 to 3 groups of Ry.
  • Another subembodiment of the compound of formula II is realized when W is phenyl.
  • Still another subembodiment of the compound of formula II is realized when W is pyridyl.
  • Yet another subembodiment of the compound of formula II is realized when W is oxopiperidinyl.
  • Another subembodiment of the compound of formula II is realized when Y and Z are both CH. Another subembodiment of the compound of formula II is realized when Y is N and Z is CH. Still another subembodiment of the compound of formula II is realized when Y is CH and Z is N.
  • a subembodiment of the compound of formula ⁇ is realized when W is phenyl. Still another subembodiment of the compound of formula III is realized when W is pyridyl. Yet another subembodiment of the compound of formula III is realized when W is oxopiperidinyl. Another subembodiment of the compound of formula III is realized when Y and Z are both CH. Another subembodiment of the compound of formula III is realized when Y is N and Z is CH. Still another subembodiment of the compound of formula III is realized when Y is CH and Z is N. Yet another subembodiment of the compound of formula III is represented by structural formula Ula:
  • Y, Z, W, Ry and R x are as originally described.
  • a subembodiment of the compound of formula Ilia is realized when Ry is OH, W is pyridyl, Rx is selected from the group consisting of hydroxy 1, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and metliylpyrazoiyl and Ry is OH or H.
  • Rx is selected from the group consisting of hydroxyl, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and Ry is OH or H.
  • a subembodiment of the compound of formula IVa is realized when Ry is OH.
  • Another subembodiment of the compound of formula IVa is realized when Ry is OH, W is pyridyl, Rx is selected from the group consisting of hydroxy!, methoxy, halogen, CF3, tnorpholino, S-methyl , methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and Ry is OH or H.
  • Rx is selected from the group consisting of hydroxyl, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and Ry is OH or H.
  • Y, Z, W, Ry, and R x are as originally described and P is pyridyl.
  • a subembodiment of the compound of formula V is realized when W is phenyl. Still another subembodiment of the compound of formula V is realized when W is pyridyl. Yet another subembodiment of the compound of formula V is realized when W is oxopiperidinyl. Another subembodiment of the compound of formula V is realized when Y and Z are both CH. Another subembodiment of the compound of formula V is realized when Y is N and Z is CH. Still another subembodiment of the compound of formula V is realized when Y is CH and Z is N.
  • Yet another subembodiment of the compound of formula V is realized when W is pyridyl, Y and Z are both CH or Y is N and Z is CH, R is selected from the group consisting of hydroxyl, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and Ry is selected from the goup consisiting of (CI3 ⁇ 4)n H, COOR2, ⁇ 3 ⁇ 4, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, and CN.
  • Still another subembodiment of the compound of formula V is realized when W is phenyl, Y and Z are both CH, or Y is N and Z is CH, R x is selected from the group consisiting of hydroxyl, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and Ry is selected from the goup consisiting of (CH2)nO3 ⁇ 4 COOR2, N3 ⁇ 4, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, and CN.
  • the invention is directed to a compound represented by structural formula VI:
  • a subembodiment of the compound of formula VI is realized when W is phenyl. Still another subembodiment of the compound of formula VI is realized when W is pyridyl. Yet another subembodiment of the compound of formula VI is realized when is oxopiperidinyl. Another subembodiment of the compound of formula VI is realized when Y and Z are both CH. Another subembodiment of the compound of formula VI is realized when Y is N and Z is CH. Still another subembodiment of the compound of formula VI is realized when Y is CH and Z is N.
  • CN ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and Ry is selected from the goup consisiting of (CH2)nOH, COOR2, N3 ⁇ 4 ; methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, and CN.
  • Still another subembodiment of the compound of formula VI is realized when W is phenyl, Y and Z are both CH, or Y is N and Z is CH, R x is selected from the group consisiting of hydroxyl, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and
  • Ry is selected from the goup consisiting of (CH2)nOH, COOR2, ⁇ 3 ⁇ 4, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, and CN.
  • the invention is directed to methods of treating a patient
  • Ml receptor preferably a human
  • diseases in which the Ml receptor is involved such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders, by
  • the invention is also directed to the use of a compound of formula (I) for treating diseases or disorders in which the Ml receptor is involved, such as Alzheimer's disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders.
  • a compound of formula (I) for treating diseases or disorders in which the Ml receptor is involved, such as Alzheimer's disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders.
  • the invention is further directed to a method for the manufacture of a medicament or a composition for treating diseases or disorders in which the Ml receptor is involved, such as
  • Alzheimer's disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders comprising combining a compound of formula (I) with one or more pharmaceutically acceptable carriers.
  • the invention is also directed to methods of treating a patient (preferably a human) for diseases or disorders in which the Ml receptor is involved, such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • a patient preferably a human
  • diseases or disorders in which the Ml receptor is involved such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders
  • the invention is also directed to the use of a compound of formula (1), for treating a disease or disorder in which the Ml receptor is involved, such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders, by administering to the patient a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • a disease or disorder in which the Ml receptor is involved such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders
  • the invention is also directed to medicaments or pharmaceutical compositions for the treatment of diseases or disorders in a patient (preferably a human) in which the Ml receptor is involved, such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders, and sleep disorders, which comprise a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention is also directed to a method for the manufacture of a medicament or a pharmaceutical composition for treating diseases in which Ml receptor is involved, such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders, and sleep disorders, comprising combining a compound of formula (I), or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.
  • diseases in which Ml receptor is involved such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders, and sleep disorders, comprising combining a compound of formula (I), or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.
  • variable e.g. aryl, heterocycle, R ⁇ , etc.
  • its definition on each occurrence is independent at every other occurrence.
  • combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
  • R a is -O- and attached to a carbon it is referred to as a carbonyl group and when it is attached to a nitrogen (e.g., nitrogen atom on a pyridyl group) or sulfur atom it is referred to a N-oxide and sulfoxide group, respectively.
  • a nitrogen e.g., nitrogen atom on a pyridyl group
  • sulfur atom it is referred to a N-oxide and sulfoxide group, respectively.
  • alkyl encompasses groups having the prefix “alk” such as, for example, alkoxy, alkanoyl, alkenyl, and alkynyl and 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, and heptyl.
  • alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond.
  • alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
  • alkenyl is C2-C6 alkenyl.
  • Preferred alkynyl are C2-C6 alkynyl.
  • Alkenyl “alkynyl” and other like terms include carbon chains containing at least one unsaturated C-C bond.
  • fluoroalkyl refers to an alkyl substituent as described herin containing at least one fluorine substituent.
  • cycloalkyl refers to a saturated hydrocarbon containing one ring having a specified number of carbon atoms.
  • examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Ci_6 includes alkyls containing 6, 5, 4, 3, 2, or 1 carbon atoms
  • alkoxy as used herein, alone or in combination, includes an alkyl group connected to the oxy connecting atom.
  • alkoxy also includes alkyl ether groups, where the term 'alkyl' is defined above, and 'ether' means two alkyl groups with an oxygen atom between them.
  • alkoxy groups examples include methoxy, ethoxy, n- propoxy, i-propoxy, n-butoxy, s-butoxy, t ⁇ butoxy, methoxymethane (also referred to as 'dimethyl ether'), and methoxyethane (also referred to as 'ethyl methyl ether').
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, napthyl, tetrahydronapthyl, indanyl, or biphenyl.
  • heterocycle, heterocyclyl, or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, 0, and S, and including any bicyclic group in which any of the above-defmed heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocycle or heterocyclic includes heteroaryl moieties.
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,
  • the heterocyclic group is a heteroaryl group.
  • heteroaryl as used herein except where noted, represents a stable 5- to 7-membered
  • any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heteroaryl groups include, but are not limited to, benzimidazole, benzisothiazole, benzisoxazole, benzofuran, benzothiazole, benzothiophene, benzotriazoie, benzoxazole, carboline, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and N-oxides thereof.
  • the heterocyclic group is fused to an aryl or heteroaryl group.
  • fused heterocycles include, without limitation,
  • heterocycloalkyl as used herein except where noted, repressents a non- aromatic cyclic or polycyclic group having from five to twelve ring atoms selected from C, O, N or S, at least one of which is O, N or S.
  • heterocycloalkyls include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyranyl, tetrahydrofuranyl, imidazolinyl, pyroiidin-2-one, piperidin-2-one, and thiomorpholinyl.
  • heteroatom means O, S or N, selected on an independent basis.
  • a moiety that is substituted is one in which one or more hydrogens have been independently replaced with another chemical substituent.
  • substituted phenyls include 2-fiurophenyl, 3,4-dichlorophenyl, 3 ⁇ chloro-4-iTuoro-phenyl, 2,4- difluoro-3-propylphenyl.
  • substituted n-octyls include 2,4 dimethyl-5-ethyl-octyl and 3-cyclopentyloctyl. Included within this definition are methylenes (- CH 2 -) substituted with oxygen to form carbonyl (-CO-).
  • Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular -CH- substituted with oxo is -C(0)-) ⁇ nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, , alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.
  • Preferred substituents, which are themselves not further substituted are:
  • Halogen or “halo” refers to fluorine, chlorine, bromine and iodine.
  • the term “mammal” “mammalian” or “mammals” includes humans, as well as animals, such as dogs, cats, horses, pigs and cattle.
  • the compounds of the invention may have one or more asymmetric centers. Compounds with asymmetric centers give rise to enantiomers (optical isomers), diastereomers
  • Formula (I) are shown above without a definite stereochemistry.
  • the present invention includes all stereoisomers of formula (I), and pharmaceutically acceptable salts thereof.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers or diastereomers 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 using chiral stationary phases, which methods are well known in the art.
  • any enantiomer or diastereoraer 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 atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
  • different isotopic forms of hydrogen (H) include protium (Ifi) and deuterium (3 ⁇ 4[). Protiuro is the predominant hydrogen isotope found in nature.
  • Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically- enriched reagents and/or intermediates.
  • the compounds of the invention may be prepared according to the following reaction Schemes, in which variables are as defined before or are derived, using readily available starting materials, from reagents and conventional synthetic procedures. It is also possible to use variants which are themselves known to those of ordinary skill in organic synthesis art, but are not mentioned in greater detail.
  • the present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of the invention.
  • the protecting groups may be removed at a convenient sequent stage using methods known from the art.
  • substantially pure means that the isolated material is at least 90% pure, and preferably 95% pure, and even more preferably 99% pure as assayed by analytical techniques known in the art.
  • muscarinic Ml receptor refers to one of the five subtypes of the muscarinic acetylcholine receptor, which is from the superfamily of G-protein coupled receptors.
  • the family of muscarinic receptors is described, for example, in Pharmacol Ther, 1993, 58:319-379; Eur J Pharmacol, 1996, 295:93-102, and Mol Pharmacol, 2002, 61 :1297- 1302.
  • the muscarinic receptors are known to contain one or more ailosteric sites, which may alter the affinity with which muscarinic ligands bind to the primary binding or
  • the terms "positive ailosteric modulator” and “ailosteric potentiator”, are used interchangeably, and refer to a ligand which interacts with an ailosteric site of a receptor to activate the primary binding site.
  • the compounds of the invention are positive ailosteric modulators of the muscarinic Ml receptor.
  • a modulator or potentiator may directly or indirectly augment the response produced by the endogenous ligand (such as acetylcholine or xanomeline) at the orthosteric site of the muscarinic Ml receptor in an animal, in particular, a human.
  • ligands at ailosteric receptor sites may also be understood according to the "ailosteric ternary complex model," as known by those skilled in the art.
  • the ailosteric ternary complex model is described with respect to the family of muscarinic receptors in Birdsall et al, Life Sciences, 2001, 68:2517-2524.
  • Christopoulos Nature Reviews: Drug Discovery, 2002, 1 : 198- 210.
  • the compounds of the invention bind to an ailosteric binding site that is distinct from the orthosteric acetylcholine site of the muscarinic Ml receptor, thereby augmenting the response produced by the endogenous ligand acetylcholine at the orthosteric site of the Ml receptor. It is also believed that the compounds of the invention bind to an ailosteric site which is distinct from the xanomeline site of the muscarinic Ml receptor, thereby augmenting the response produced by the endogenous ligand xanomeline at the orthosteric site of the Ml receptor.
  • the compounds of the invention may be mono, di or tris salts, depending on the number of acid functionalities present in the free base form of the compound.
  • Free bases and 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 5 diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolarnine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucarnine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, ⁇ propylamine, tromethamine, and the like.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, trifluoroacetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, j a-toluenesulfonic acid, and the like.
  • Suitable pharmaceutically acceptable salts include ammonium, sodium, potassium, hydrochloride, hydrobromide and fumarate.
  • the present invention is directed to the use of the compounds of formula (I) disclosed herein as Ml allosteric modulators in a patient or subject such as a mammal in need of such activity, comprising the administration of an effective amount of the compound.
  • Ml allosteric modulators in a patient or subject such as a mammal in need of such activity, comprising the administration of an effective amount of the compound.
  • a variety of other mammals can be treated according to the method of the present invention.
  • the compounds of the present invention have utility in treating or ameliorating
  • the compounds may also be useful in treating or ameliorating other diseases mediated by the muscarinic Ml receptor, such as schizophrenia, sleep disorders, pain disorders (including acute pain, inflammatory pain and neuropathic pain) and cognitive disorders (including mild cognitive impairment).
  • Other conditions that may be treated by the compounds of the invention include Parkinson's Disease, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, schizophrenia, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral
  • HCVWA-D Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld- Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes, autism and atherosclerosis.
  • the compounds of the invention are useful in treating
  • Alzheimer's Disease cognitive disorders, schizophrenia, pain disorders and sleep disorders.
  • the compounds may be useful for the prevention of dementia of the Alzheimer's type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the Alzheimer's type.
  • Potential schizophrenia conditions or disorders for which the compounds of the invention may be useful include one or more of the following conditions or diseases:
  • schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (phencyclidine, ketanine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine) psycho sispsychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, "schizophrenia-spectrum” disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), including both the positive and the negative symptoms of schizophrenia and other psychoses; cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson'
  • the present invention provides a method for treating schizophrenia or psychosis comprising administering to a patient in need thereof an effective amount of a compound of the present invention.
  • DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders
  • the text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder.
  • DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders
  • the term "schizophrenia or psychosis” includes treatment of those mental disorders as described in DSM-IV-TR.
  • the skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress.
  • the term “schizophrenia or psychosis” is intended to include like disorders that are described in other diagnostic sources.
  • Potential sleep conditions or disorders for which the compounds of the invention may be useful include enhancing sleep quality; improving sleep quality; augmenting sleep maintenance; increasing the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing difficulties in falling asleep; increasing sleep continuity; decreasing the number of awakenings during sleep; decreasing nocturnal arousals; decreasing the time spent awake following the initial onset of sleep; increasing the total amount of sleep; reducing the fragmentation of sleep; altering the timing, frequency or duration of REM sleep bouts; altering the timing, frequency or duration of slow wave (i.e.
  • Pain disorders for which the compounds of the invention may be useful include neuropathic pain (such as postherpetic neuralgia, nerve injury, the "dynias”, e.g., vulvodynia, phantom limb pain, root avulsions, painful diabetic neuropathy, painful traumatic pain (such as postherpetic neuralgia, nerve injury, the "dynias”, e.g., vulvodynia, phantom limb pain, root avulsions, painful diabetic neuropathy, painful traumatic pain (such as postherpetic neuralgia, nerve injury, the "dynias”, e.g., vulvodynia, phantom limb pain, root avulsions, painful diabetic neuropathy, painful traumatic pain (such as postherpetic neuralgia, nerve injury, the "dynias”, e.g., vulvodynia, phantom limb pain, root
  • central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system); postsurgical pain syndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stump pain); bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia); perioperative pain (general surgery, gynecological), chronic pain, dysmennorhea, as well as pain associated with angina, and inflammatory pain of varied origins (e.g.
  • osteoarthritis rheumatoid arthritis, rheumatic disease, teno- synovitis and gout
  • headache migraine and cluster headache, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization.
  • Compounds of the invention may also be used to treat or prevent dyskinesias.
  • compounds of the invention may be used to decrease tolerance and/or dependence to opioid treatment of pain, and for treatment of withdrawal syndrome of e.g., alcohol, opioids, and cocaine.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present invention have utility, where the combination of the drugs together are safer or more effective than either drug alone. Additionally, the compounds of the present invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the present invention. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with the compounds of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to the compounds of the present invention. The combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen.
  • beta-secretase inhibitors for example beta-secretase inhibitors; alpha 7 nicotinic agonists, such as ABT089, SSR180711 and MEM63908; ADAM 10 ligands or activators; gamma-secretase inhibitors, such as LY450139 and TA 070; gamma secretase modulators; tau phosphorylation inhibitors; glycine transport inhibitors; LXR ⁇ agonists; ApoE4 conformational modulators; NR2B antagonists; androgen receptor modulators; blockers of ⁇ oligomer formation; 5-HT4 agonists, such as PRX-03140; 5-HT6 antagonists, such as GSK 742467, SGS-518, FK-962, SL-65.0155, SRA-333 and xaliproden; 5 -HT 1 a antagonists, such as lecozotan; p25/CDK5 inhibitors; NK1 N 3 receptor antagonists; COX
  • nitroflurbiprofen ND-1251, VP-025, HT-0712 and EHT-202; PPAR gamma agonists, such as pioglitazone and rosiglitazone; CB-1 receptor antagonists or CB-1 receptor inverse agonists, such as AVE 1625; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMD A) receptor antagonists, such as memantine, neramexane and EVT101; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, tacrine, phenserine, ladostigil and ABT-089;
  • growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine 3 ⁇ 4 receptor antagonists such as ABT-834, ABT 829, GSK 189254 and CEP 16795 ;
  • AMPA agonists or AMPA modulators such as CX-717, LY 451395, LY404187 and S- 18986; PDE IV inhibitors, including MEM1414, HT0712 and AVE8112; GABAA inverse agonists;
  • GSK3P inhibitors including AZD1080, SAR502250 and CEP16805; neuronal nicotinic agonists; selective Ml agonists; HDAC inhibitors; and microtubule affinity regulating kinase (MARK) ligands; or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention.
  • combinations of the compounds include combinations with agents for the treatment of schizophrenia, for example in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitripryline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, a
  • the subject compound may be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMD A receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole.
  • levodopa with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide
  • anticholinergics such as biperi
  • the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.
  • a pharmaceutically acceptable salt for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.
  • the subject compound may be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent.
  • phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine,
  • Suitable examples of thioxanthenes include chlorprothixene and thiothixene.
  • An example of a dibenzazepine is clozapine.
  • An example of a butyrophenone is haloperidol.
  • An example of a diphenylbutylpiperidine is pimozide.
  • An example of an indolone is molindolone.
  • Other neuroleptic agents include loxapine, sulpiride and risperidone.
  • the neuroleptic agents when used in combination with the subject compound may be in the form of a pharmaceutically acceptable salt, for example, ⁇ hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, fiurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
  • a pharmaceutically acceptable salt for example, ⁇ hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, fiurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochlor
  • Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
  • the subject compound may be employed in combination with acetophenazine, alentemol, aripiprazole, amisuipride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, Ievodopa, Ievodopa with benserazide, Ievodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine
  • tetrabenazine frihexyphenidyl, thioridazine, thiothixene, trifluoperazine or ziprasidone.
  • combinations of the compounds include combinations with agents for the treatment of pain, for example non-steroidal anti-inflammatory agents, such as aspirin, diclofenac, duflunisal, fenoprofen, flurbiprofen, ibuprofen, mdomethacin, ketoprofen, ketorolac, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2 inhibitors, such as celecoxib, rofecoxib, vaidecoxib, 406381 and 644784; CB-2 agonists, such as 842166 and SAB378; V -1 antagonists, such as AMG517, 705498, 782443, PAC20030, VI 14380 and A425619; bradykinin B 1 receptor antagonists, such as SSR240 12 and NVPSAA1 4; sodium channel blockers and antagonists, such as VX409 and SPI860; nitric oxide synthase
  • AZD4282 potassium channel openers; AMPA/kainate receptor antagonists; calcium channel blockers, such as ziconotide and NMED160; GABA-A receptor IO modulators (e.g., a GABA- A receptor agonist); matrix metalloprotease (MMP) inhibitors; thrombolytic agents; opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene; neutrophil inhibitory factor (NIF); pramipexole, ropinirole; anticholinergics; amantadine; monoamine oxidase B15 ("MAO- B !!
  • mGlu5 antagonists such as AZD9272
  • alpha agonists such as AGNXX/YY
  • neuronal nicotinic agonists such as ABT894
  • NMDA receptor agonists or antagonists such as AZD4282
  • NKI antagonists selective serotonin reuptake inhibitors ("SSRI”) and/or selective serotonin and norepinephrine reuptake inhibitors ("SSNRI”), such as duloxetine; tricyclic antidepressant drugs, norepinephrine modulators;
  • the compounds of the present invention may be administered in combination with compounds useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, orexin antagonists, alpha- 1 antagonists, GAB A agonists, 5HT-2 antagonists including 5HT-2A antagonists and 5HT- 2A/2C antagonists, histamine antagonists including histamine H3 antagonists, histamine H3 inverse agonists, imidazopyridines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, other orexin antagonists, orexin agonists, prokineticin agonists and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, triazolopyridines, and the like, such as: adinazolam
  • the subject or patient to whom the compounds of the present invention is administered is generally a human being, male or female, in whom Ml allosteric modulation is is desired, but may also encompass other mammals, such as dogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys, chimpanzees or other apes or primates, for which treatment of the above noted disorders is desired.
  • composition as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, 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.
  • 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 compound which is a compound of formula (I) is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • oral or parenteral including intravenous
  • compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil- in-water emulsion or as a water-in-oil liquid emulsion.
  • the compounds of the invention, or pharmaceutically acceptable salts thereof may also be administered by controlled release means and/or delivery devices.
  • 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
  • Tablets may 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.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.1 mg to about 500 mg of the active ingredient and each cachet or capsule preferably containing from about 0.1 mg to about 500 mg of the active ingredient.
  • 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.
  • compositions include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous
  • oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension, or in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions, h all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like.
  • compositions can be in a form suitable for use in transdermal devices.
  • These formulations may be prepared via conventional processing methods.
  • a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can also be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories.
  • suitable carriers include cocoa butter and other materials commonly used in the art.
  • 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.
  • administering a should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual's body in a therapeutically useful form and therapeutically useful amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP, and the like;
  • transdermal dosage forms including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.
  • an effective amount or “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.
  • treatment means any administration of a compound of the present invention and includes (1) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (2) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
  • compositions containing compounds of the present invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • unit dosage form is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person
  • unit dosage forms are tablets or capsules for oral administration, single dose vials for injection, or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.
  • compositions containing compounds of the present invention may conveniently be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient.
  • kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient.
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 mg to about 100 mg per kg 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 fonn.
  • the total daily dosage is from about 1.0 mg to about 2000 mg, preferably from about 0.1 mg to about 20 mg per kg of body weight. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration to humans may conveniently contain from about 0.005 mg to about 2.5 g of active agent, compounded with an appropriate and convenient amount of carrier material.
  • Unit dosage forms will generally contain between from about 0.005 mg to about 1000 mg of the active ingredient, typically 0.005, 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 . mg, 600 mg, 800 mg or 1000 mg, administered once, twice or three times a day.
  • HMDS hexamethyldi silazane
  • TPAP tetra-rc-propyl ammonium perruthenate
  • NMO N-methyl morpholine N-oxide
  • DMEM Dulbecco's Modified Eagle Medium (High Glucose)
  • N-bromosuccinimide 0.23 g, 4.62 mmol
  • benzoyl peroxide 0.056 g, 0.23 mmoL
  • dichloromethane (7.2 mg, 0.0098 mmol). The mixture was heated at 50 °C for 3 hr and then cooled to ambient temperature. Additional dimethyl zinc (1.2 M in tetrahydrofuran, 0.16 mL, 0.20 mmol) and [l 5 -bis(diphenylphosphino)ferrocene]dichloro-palladium(II) 5 1 :1 complex with dichloromethane (7.2 mg, 0.0098 mmol) were added and the mixture was heated at 50 °C for an additional 12 hr. The mixture was cooled to ambient temperature and concentrated in vacuo.
  • Example 4 gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 409.1 for [M+H] + : 1H NMR (400 MHz, CDC1 3 ) ⁇ 8.45 (s, IH), 7.97-7.95 (m, IH), 7.92-7.89 (m 5 IH), 7.76 (s, IH), 7.64 ⁇ 7.56 (m, 2H), 7.52-7.48 (m, IH), 7.29-7.26 (m, IH), 4.85-4.74 (m, 2H), 4.51 (s, 2H), 4.39-4.32 (m, IH), 2.33-2.30 (m, IH), 2.10-2.01 (m s IH), 1.92-1.82 (m, 2H),
  • the filtercake was washed 3x with toluene (2 L) and the combined filtrate and washes were concentrated to a total volume of 3 L to provide an organic solution of 4,4-dimethoxydihydro-2H-pyran-3( ⁇ H)-one.
  • the resultant brown oil was purified via silica gel chromatography, eluting with 0-15% ethyl acetate in hexanes to provide (55)-3-(benzylyoxy)-4,4-dimethoxytetrahydro-2H-pyran.
  • the mixture was irradiated in a microwave reactor at 140 °C for 1.5 hr, cooled to ambient temperature, and diluted with ethyl acetate.
  • the organic solution was washed with water, dried with sodium sulfate, filtered, and concentrated in vacuo.
  • 5-Bromo-2-(2-fluorophenyl)-l,2-di ydro-3H-benzo[e]isoindol-3-one was prepared employing the procedures described for the construction of 5-brorno-2-[(/5 ? 2S ⁇ -2-hydroxycyclohexyl]-l,2- dihydro-3H-benzo[ ⁇ 2]isoindol-3-one in Example 1, substituting 2-fluoroaniline for (IS, 2S)-2- aminocyclohexanol.
  • iodomethane (0.026 mL, 0.42 mmol) was added dropwise and after an additional 1 hr, the mixture was warmed to ambient temperature, treated with saturated aqueous ammonium chloride, and extracted 2x with ethyl acetate. The combined organic extracts were washed with water and brine, dried with magnesium sulfate, filtered, and concentrated in vacuo.
  • the title compound was prepared employing the procedures described for the construction of 2- [(IS, 23 ⁇ 4-2-hydroxycyclohexyl]-5-(4-methoxybeiizyl)-l,2-dihydro-3H-benzo[e]isoindol"3-one in Example 1, substituting 5-bromo-2-(2-fluorophenyl)-l-methyl-l,2-dihydro-3H ⁇ benzo[e]isoindol- 3-one for 5-bromo-2-[(7S , J 25)-2-hydroxycyclohexyl]-l,2-dihydro-3H-benzo[e]isoindol-3-one and substituting (2-chloro-5-pyridyl)methylzinc chloride for 4-methoxybenzylzinc chloride.
  • N-bromosuecinimide (1.53 g, 8.58 mmol). After 2 hr, the mixture was diluted with water, and a solid was collected via filtration. The filter cake was washed with additional water to provide methyl 4-bromo-l-oxo ⁇ l,2- dihydroisoquinoline-3-carboxylate.
  • cyanoborohydride (3.7 mg, 0.058 mmol), and 4A molecular sieves.
  • the mixture was irradiated in a microwave reactor at 100 °C for 20 min, cooled to ambient temperature, and filtered.
  • the filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
  • the aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo.
  • the residue was dissolved in 2 mL of dichloromethane and treated with hydrochloric acid (6 M aqueous, 4 drops).
  • dichloromethane and 5 mL of methanol was cooled to -78 °C and saturated with ozone. After 15 min, the solution was sparged with nitrogen and resin-bound triphenylphosphine (3 mmol/g, 2.0 g, 6.0 mmol) was added. The mixture was warmed to ambient temperature and after 1.5 hr, the mixture was filtered through Celite and the filtercake was washed with a 5:1 mixture of dichloromethane:methanol.
  • the utility of the compounds as Ml receptor positive allosteric modulators may be demonstrated by methodology known in the art, including by the assay described below.
  • the assay is designed to select compounds that possess modulator activity at the acetylcholine muscarinic Ml receptor or other muscarinic receptors expressed in CHOnfat cells by measuring the intracellular calcium with a FLIPR.384 Fluorometric Imaging Plate Reader System.
  • the assay studies the effect of one or several concentrations of test compounds on basal or acetyl choline-stimulated Ca ⁇ + levels using FLIPR.
  • Compounds are prepared and subjected to a preincubation period of 4 min. Thereafter, a single EC20 concentration of acetylcholine is added to each well (3 nM final). The intracellular Ca2+ level of each sample is measured and compared to an acetylcholine control to determine any modulatory activity.
  • CHOnfat/hMl, hM2, hM3 or hM4 cells are plated 24 hr before the assay at a density of 18,000 cells/well (100 L) in a 384 well plate.
  • CHOnfat/hMl and CHOnfai/hM3 Growfh Medium 90% DMEM (Hi Glucose); 10% HI FBS; 2 mM L-glutamine; 0.1 mM NEAA; Pen-Strep; and lmg/ml Geneticin, are added.
  • M2Gqi5CHOnfat and M4Gqi5CHOnfat cells an additional 600 ug/ml hygromycin is added.
  • Assay Buffer Hanks Balanced Salt Solution, with 20 mM Hepes, 2.5 mM Probenecid (Sigma P-8761) first dissolved in 1 N NaOH, 1% Bovine Serum Albumin (Sigma A- 9647).
  • Dye Loading Buffer Assay Buffer plus 1% Fetal Bovine Serum and Fluo-4AM/Pluronic Acid Mixture. 2 mM Fluo-4AM ester stock in DMSO (Molecular Probes F- 14202)
  • EC20 Acetylcholine: 10 mM in water, working stock of 9 nM (3x), and final concentration in assay is 3 nM. This is used after the preincubation with test compounds. Addition of the EC20 Acetylcholine to each well with a test compound will ascertain any modulator activity. 24 wells contain 3nM Acetylcholine alone as a control.
  • Screening Plate Compounds are titrated in 96-well plates (columns 2-1 1), 100% DMSO, started at a concentration of 15 mM (150x stock concentration), and 3-fold serial dilutions using Genesis Freedom200 System.
  • Four 96-well plates are combined into a 384- well plate using Mosquito Nanolitre Pipetting System by transferring 1 ⁇ of serial diluted compounds to each well, and 1 mM acetylcholine (lOOx stock concentration) were added as a control.
  • 49 ⁇ assay buffer is added to each well of the 384-well plate right before assay.
  • Acetylcholine (3x) is pipetted into wells corresponding to the screening compounds, and into control wells.
  • the 30 ⁇ acetylcholine control (3x) is added into control wells, and the 3x agonist plate is transferred into a 384 well plate.
  • the cells are washed three times with 100 iL of buffer, leaving 30 ⁇ , of buffer in each well
  • the cell plate, screening plate, and agonist addition plates are placed on the platform in the FLiPR and the door closed.
  • a signal test to check background fluorescence and basal fluorescence signal is performed. Laser intensity is adjusted if necessary.
  • the EC20 value of acetylcholine (3 nM final) is added to determine any modulator activity.
  • IP inflection point
  • the inflection point is calculated from the FLIPR values, and is a measure of activity. Such a result is indicative of the intrinsic activity of the compounds in use as Ml allosteric modulators.
  • IP values from the aforementioned assay for representative exemplary compounds of the invention are provided below in Table 2 below: Table 2

Abstract

The present invention is directed to isoindolone compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

Description

TITLE OF THE INVENTION
ISOINDOLONE Ml RECEPTOR POSITIVE ALLOSTERIC MODULATORS
FIELD OF THE INVENTION
The invention is directed to a class of isoindolone compounds, their salts, pharmaceutical compositions comprising them and their use in therapy of the human body. In particular, the invention is directed to a class of isoindolone compounds which are muscarinic Ml receptor positive alloste ic modulators, and hence are useful in the treatment of Alzheimer's Disease and other diseases mediated by the muscarinic Ml receptor.
BACKGROUND OF THE INVENTION
Alzheimer's Disease is a common neurodegenerative disease affecting the elderly, resulting in progressive memory impairment, loss of language and visuospatial skills, and behavior deficits. Characteristics of the disease include degeneration of cholinergic neurons in the cerebral cortex, hippocampus, basal forebrain, and other regions of the brain, neurofibrillary tangles, and accumulation of the amyloid β peptide (Αβ). Αβ is a 39-43 amino acid produced in the brain by processing of the beta-amyloid precursor protein (APP) by the beta-amyloid protein cleaving enzyme ("beta secretase" or "BACE") and gamma-secretase. The processing leads to accumulation of Αβ in the brain.
Cholinergic neurotransmission involves the binding of acetylcholine either to the nicotinic acetylcholine receptor (nAChR) or to the muscarinic acetylcholine receptor (mAChR). It has been hypothesized that cholinergic hypofunction contributes to the cognitive deficits of patients suffering from Alzheimer's Disease. Consequently, acetyl cholinesterase inhibitors, which inhibit acetylcholine hydrolysis, have been approved in the United States for use in the treatment of the cognitive impairments of Alzheimer's Disease patients. While acetyl cholinesterase inhibitors have provided some cognitive enhancement in Alzheimer's Disease patients, the therapy has not been shown to change the underlying disease pathology.
A second potential pharmacotherapeutic target to counteract cholinergic hypofunction is the activation of muscarinic receptors. Muscarinic receptors are prevalent throughout the body. Five distinct muscarinic receptors (M1-M5) have been identified in mammals. In the central nervous system, muscarinic receptors are involved in cognitive, behavior, sensory, motor and autonomic functions. The muscarinic Ml receptor, which is prevalent in the cerebral cortex, hippocampus and striatum, has been found to have a major role in cognitive processing and is believed to have a role in the pathophysiology of Alzheimer's Disease. See Eglen et al, TRENDS in Pharmacological Sciences, 2001 , 22 : 8, 409-414.
In addition, unlike acetyl cholinesterase inhibitors, which are known to provide only symptomatic treatment, Ml agonists also have the potential to treat the underlying disease mechanism of Alzheimer's Disease. The cholinergic hypothesis of Alzheimer's Disease is linked to both β-amyloid and hyperphosphorylated tau protein. Formation of β-amyloid may impair the coupling of the muscarinic receptor with G-proteins. Stimulation of the Ml muscarinic receptor has been shown to increase formation of the neuroprotective aAPPs fragment, thereby preventing the formation of the Αβ peptide. Thus, Ml agonists may alter APP processing and enhance aAPPs secretion. See Fisher, Jpn J Pharmacol, 2000, 84: 101 - 1 12.
However, Ml ligands which have been developed and studied for Alzheimer's Disease have produced side effects common to other muscarinic receptor ligands, such as sweating, nausea and diarrhea. See Spalding et al, Mol Pharmacol, 2002, 61 :6, 1297-1302.
The muscarinic receptors are known to contain one or more allosteric sites, which may alter the affinity with which muscarinic ligands bind to the primary binding or
orthosteric sites. See, e.g.., S. Lazareno et al, Mol Pharmacol, 2002, 62:6, 1491-1505; S.
Lazareno et al, Mol Pharmacol, 2000, 58, 194-207. See also WO2005056552,
WO2005030188, WO2007067489, US Patent Appln. Nos. US61/329,690; US61/199740;
61/288,567; 61/286,122; 61/253,629; 61/247,705; 61/238,457; 61/208,331 ; and 61/170,744; and Attorney Docket Nos., MRL-NOP-00095-US-PSP; MRL-NOP-114-US-PSP; and MRL- NOP-125-US-PSP.
Thus the compounds of the invention, which are muscarinic Ml receptor positive allosteric modulators, are believed to be useful in the treatment of Alzheimer's Disease and other diseases mediated by the muscarinic Ml receptor.
SUMMARY OF THE INVENTION
The present invention is directed to novel isoindolone compounds of generic formula (I) as indicated below or a pharmaceutically acceptable salt thereof, which is useful as an Ml receptor positive allosteric modulator.
The invention is further directed to methods of treating a patient (preferably a human) for diseases or disorders in which the Ml receptor is involved, such as Alzheimer's disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of general formula (I), or a
pharaiaceutically acceptable salt thereof. The invention is also directed to pharmaceutical compositions which include an effective amount of a compound of formula (I), or a
pharaiaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.
DETAILED DESCRIPTION OF THE INVENTION In one embodiment the invention is directed to isoindolone compounds of general formula (I)
Figure imgf000004_0001
and pharmaceutically acceptable salts thereof, wherein
Y and Z independently represent CH or N, provided that they both are not N at the same time, W represents aryl, pyridyl, or oxopiperidinyl, optionally substituted with one or more of Rx;
R is selected from the group consisting of hydrogen, (CHR2)nC3-io cycloalkyi, (CHR2)nC6-lO aryl, (CHR2)nC5_i0 heterocycle, said cycloalkyi, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of RY; Rl and R? independently represent H, C ] _6 alkyl, C2-6 aikenyl, (CH2)nC6„ i oaryl, (CH2)nO(CH2)nC6- 10-iryl, said alkyl and aikenyl optionally substituted with 1 to 3 groups of OH, CF3, halo, or N(R2)2, or
Rl and R3 together with the carbon atom they are attached form a 3-6 cycloalkyi; Rx is selected from the group consisting of hydrogen, 0\ . alkyl, C2-6 aikenyl, halogen, OR2,
(CHR2)nC5-10 heterocyclyl, (CHR2)nC6-10 aryl, -0(CHR2)nC6- 1 Oaryl, CN, SR2, N(R2)2, (CH2)nCF3, ~0(CH2)nCF3, C3-6 cycloalkyi, said heterocyclyl and aryl optionally substituted with 1 to 3 groups of Ci_6 alkyl, halogen, hydroxy 1, (CH2)nCF3,or CN, Ry is selected from the group consisting of hydrogen, Ci_6 alkyl, C2-6 aikenyl, halogen, COOR2, OR2 CN, SR2, N(R2)2, and (CH2)nCF3,
R2 is selected from the group consisting of hydrogen, or -Ci_g alkyl, and n is 0, 1 or 2.
In another embodiment the invention is directed to a compound wherein W is aryl optionally substituted with 1 to 3 groups of Rx. In another embodiment the invention is directed to a compound wherein when W is aryl it is phenyl optionally substituted with 1 to 3 groups of Rx.
In one embodiment the invention is directed to a compound wherein W is pyridyi optionally substituted with 1 to 3 groups of Rx.
In another embodiment the invention is directed to a compound wherein W is oxopiperidinyl optionally substituted with 1 to 3 groups of Rx.
In another embodiment the invention is directed to a compound wherein R is C3. 10 cycloalkyl optionally substituted with 1 to 3 groups of Ry. A subembodiment of this invention is realized when R is cyclohexyl or cyclohexenyl, both optionally substituted with 1 to 3 groups of Ry.
In yet another embodiment the invention is directed to a compound wherein R is (CHR2)nC5_io heterocycle, optionally substituted with 1 to 3 groups of Ry. A subembodiment of this invention is realized when R is pyranyl, tetrahydropyranyl, pyridyi, all optionally substituted with 1 to 3 groups of Ry.
In still another embodiment the invention is directed to a compound wherein R is (CHR2)nC6-io aryl, optionally substituted with 1 to 3 groups of R . A subembodiment of this invention is realized when R is phenyl optionally substituted with 1 to 3 groups of Ry.
In another embodiment of the invention the Rx substituent attaches to the W in the para position relative to the CI¾ linker linking W to the rest of the structure.
In another embodiment the invention is directed to a compound wherein Rx is selected from the goup consisting of hydrogen, hydroxy!, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl.
In another embodiment the invention is directed to a compound wherein R is selected from the goup consisting of (CH2)nOH, COOR2, ¾, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, and CN.
In still another embodiment the invention is directed to a compound represented by structural formula 0:
Figure imgf000005_0001
wherein Y, Z, W, Rx, and R, are as originally described. A subembodiment of the compound of formula II is realized when R is selected from the group consisting of cyclohexyl or cyclohexenyl, pyranyl, tetrahydropyranyl, pyridyi and phenyl all of which are optionally substituted with 1 to 3 groups of Ry. Another subembodiment of the compound of formula II is realized when W is phenyl. Still another subembodiment of the compound of formula II is realized when W is pyridyl. Yet another subembodiment of the compound of formula II is realized when W is oxopiperidinyl. Another subembodiment of the compound of formula II is realized when Y and Z are both CH. Another subembodiment of the compound of formula II is realized when Y is N and Z is CH. Still another subembodiment of the compound of formula II is realized when Y is CH and Z is N.
In another embodiment the invention is directed to a compound represented by structural formula III:
Figure imgf000006_0001
wherein Y, Z, W, and Ry are as originally described. A subembodiment of the compound of formula ΙΠ is realized when W is phenyl. Still another subembodiment of the compound of formula III is realized when W is pyridyl. Yet another subembodiment of the compound of formula III is realized when W is oxopiperidinyl. Another subembodiment of the compound of formula III is realized when Y and Z are both CH. Another subembodiment of the compound of formula III is realized when Y is N and Z is CH. Still another subembodiment of the compound of formula III is realized when Y is CH and Z is N. Yet another subembodiment of the compound of formula III is represented by structural formula Ula:
Figure imgf000006_0002
wherein Y, Z, W, Ry and Rx are as originally described. A subembodiment of the compound of formula Ilia is realized when Ry is OH, W is pyridyl, Rx is selected from the group consisting of hydroxy 1, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and metliylpyrazoiyl and Ry is OH or H. Yet another subembodiment of the compound of formula Ilia is realized when Ry is OH, W is phenyl, Rx is selected from the group consisting of hydroxyl, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and Ry is OH or H.
In another embodiment the invention is directed to a compound represented by structural formula IV:
Figure imgf000007_0001
wherein Y, Z, W, R* and Ry are as originally described. A subembodiment of the compound of formula IV is realized when W is phenyl. Still another subembodiment of the compound of formula IV is realized when W is pyridyl. Yet another subembodiment of the compound of formula IV is realized when W is oxopiperidinyl. Another subembodiment of the compound of formula IV is realized when Y and Z are both CH. Another subembodiment of the compound of formula IV is realized when Y is N and Z is CH. Still another subembodiment of the compound of formula IV is realized when Y is CH and Z is N. Yet another subembodiment of the compound of formula ΙΠ is represented by structural formula IVa:
Figure imgf000007_0002
wherein Y, Z, , Ry, and Rx are as originally described. A subembodiment of the compound of formula IVa is realized when Ry is OH. Another subembodiment of the compound of formula IVa is realized when Ry is OH, W is pyridyl, Rx is selected from the group consisting of hydroxy!, methoxy, halogen, CF3, tnorpholino, S-methyl , methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and Ry is OH or H. Yet another subembodiment of the compound of formula IVa is realized when Ry is OH, W is phenyl, Rx is selected from the group consisting of hydroxyl, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and Ry is OH or H.
In another embodiment the invention is directed to a compound represented by structural formula V:
Figure imgf000008_0001
V
wherein Y, Z, W, Ry, and Rx are as originally described and P is pyridyl. A subembodiment of the compound of formula V is realized when W is phenyl. Still another subembodiment of the compound of formula V is realized when W is pyridyl. Yet another subembodiment of the compound of formula V is realized when W is oxopiperidinyl. Another subembodiment of the compound of formula V is realized when Y and Z are both CH. Another subembodiment of the compound of formula V is realized when Y is N and Z is CH. Still another subembodiment of the compound of formula V is realized when Y is CH and Z is N. Yet another subembodiment of the compound of formula V is realized when W is pyridyl, Y and Z are both CH or Y is N and Z is CH, R is selected from the group consisting of hydroxyl, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and Ry is selected from the goup consisiting of (CI¾)n H, COOR2, Ν¾, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, and CN. Still another subembodiment of the compound of formula V is realized when W is phenyl, Y and Z are both CH, or Y is N and Z is CH, Rx is selected from the group consisiting of hydroxyl, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and Ry is selected from the goup consisiting of (CH2)nO¾ COOR2, N¾, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, and CN. In still another embodiment the invention is directed to a compound represented by structural formula VI:
Figure imgf000009_0001
wherein Y, Z, W, Ry, and are as originally described. A subembodiment of the compound of formula VI is realized when W is phenyl. Still another subembodiment of the compound of formula VI is realized when W is pyridyl. Yet another subembodiment of the compound of formula VI is realized when is oxopiperidinyl. Another subembodiment of the compound of formula VI is realized when Y and Z are both CH. Another subembodiment of the compound of formula VI is realized when Y is N and Z is CH. Still another subembodiment of the compound of formula VI is realized when Y is CH and Z is N. Yet another subembodiment of the compound of formula VI is realized when W is pyridyl, Y and Z are both CH or Y is N and Z is CH, Rx is selected from the group consisiting of hydroxyl, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl,
CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and Ry is selected from the goup consisiting of (CH2)nOH, COOR2, N¾; methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, and CN. Still another subembodiment of the compound of formula VI is realized when W is phenyl, Y and Z are both CH, or Y is N and Z is CH, Rx is selected from the group consisiting of hydroxyl, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and
Ry is selected from the goup consisiting of (CH2)nOH, COOR2, Ν¾, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, and CN.
Another embodiment, the invention is directed to methods of treating a patient
(preferably a human) for diseases in which the Ml receptor is involved, such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders, by
administering to the patient a therapeutically effective amount of a compound of general formula (I).
The invention is also directed to the use of a compound of formula (I) for treating diseases or disorders in which the Ml receptor is involved, such as Alzheimer's disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders. The invention is also directed to medicaments or pharmaceutical compositions for treating diseases or disorders in which the Ml receptor is involved, such as Alzheimer's disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders, which comprise a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention is further directed to a method for the manufacture of a medicament or a composition for treating diseases or disorders in which the Ml receptor is involved, such as
Alzheimer's disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders, comprising combining a compound of formula (I) with one or more pharmaceutically acceptable carriers.
Examples of compounds of formula (I) are:
2- [( IS, 25)- 2-Hydroxycyclohexyl] - 5 -(4-methoxybenzyl)- ,2-dihydro-3 H-benzo [e] isoind ol-3 -one
2-[(lS, 25)-2-Hydroxycyclohexyl]-5-[(6-methylpyridin-3-yl)methyl]-l,2-dihydro-3H-benzo[e]isoindoI-3- one
2-{(lS, 2(S)-2-Hydroxycyclohexyi]-5-[(6-vinylpyridin-3-yi)tnethyI]- 1 ,2-dihydro-3H-benzo[e]iso doI-3- one
5-[(6-Chloropyridin-3-yl)methyi]-2-[(2S)-2-fluorocyclohexyl]-l,2-dihydro-3H-benzo[e]isoindol-3-one 5 - [(6-Chloropyridin-3 -y l)methy 1] ~2-cyclohex-2-en- 1 -yl- 1 ,2-dihydro-3H-benzo[e] isoindol-3-one
2~[(1S, 2S)-2-Hydroxycyclohexyl]-5-(pyridin-3-ylmethyl)-l,2-dihydro-3H-benzo[e]isoindol-3-one 2-[(lS, 2S)-2-Hydroxycyclohexyl]-5-[(6-morpholin-4-ylpyridin-3-yl)methyl]-l ,2-dihydro-3H- benzo[<?]isoindol-3-one
5~[(6»Chloropyridin-3-yl)methyl]-2-[(3R, 4S)-3 -hydroxy tetrahydro-2H-pyran-4-yl]-l,2-dihydro-3H- benzo [e] i soindol-3 -one
5~({2~[(JS, 2S)-2-Hydroxycyclohexyl]-3-oxo-2,3-dihydro-lH-benzo[e]isoindol-5-yl}methyl)pyridine-2- carbonitrile
2-[(75i 2S 2-Hy<3xoxycyclohexyl]-5-{[6-(melhyithio)pyrid
benzo[e]isoindol-3~one
2-[(3S, ¥5)-4-Hydroxytetrahydro-2H-pyran-3-yl]-5-[(6-methoxypyridin-3-yl)methyl]-l,2-dihydro-3H- benzo[e] isoi ndol~3 -one
2-0-Acetyl-l,5~anhydro-3,4-dideoxy-3-{3-oxo-5-[(6-oxo-l,6-dihydroyridin-3-yl)methyl]-l,3-dihydro- benzo[e]isoindol~2»yl)-L~i/irei)-pentitol
1 ,5-Aiihydro-2,3 -dideoxy-3 - {3 -oxo-5 -[(6-oxo- 1 ,6-dihydropyridin-3-yl)methyl]- 1 ,3-dihydro-2H- benzo[e]isoindol-2-yl}-L~i r<?< pentitol
5-[(6-Methoxypyridin-3-yl)methyl]~2~[3-(trifl^
3-one
(±)"5"[(6"ChIoropyridin-3-yl)methyl]-2-(2-fluorophenyl)-l-methyl-l,2-dihydro-3H-benzo[e]isoinoi-3-one (±)-5-[(6~Chloropyridin-3-yl)methyl]^
c]isoquinoline-3-one
(±)-2-[/rans-2-Hydroxycyclohexyl]-5- { [6-( 1 H-pyrazol- 1 -yl)pyridine~3 ~yl]methyl } - 1 s2-dihydro-3H- pyrro!o[3 ,4-c] isoquinol ine-3-one
8-[(/S, 2S 2~Hydroxycyclohexyl]-5-[(6-methoxypyr^^
pyrrolo[3,4-ft]quinoIin-7-one
5-{[6-Benzyloxy)pyridine"3~yl]raethyl}-8-[( 5, 2S)-2-hydroxycyclohexyl]~8,9-dihydro~7H"pyrrolo[3,4- A]quinolin-7-one
8-[(75, 2S)-2-Hydroxycyclohexyl]-5-[(6"Oxopiperidin-3-yl)methyl]-3,9-dihydro~7H-pyrrolo[3,4- A]quinolin-7-one
5-[(6-Chloropyridin-3-yI)methyl]"9"(2,3-dihydroxypropyl)~8-[(/(S', 2S)-2-hydroxycyclohexyI]-859- dihydro-7H-pyrrolo[3,4-A]quinolm-7-one
S-[(1S, 2<S)-2-Hydroxycyclohexyl]~5-[(6-oxopiperidin-3-yl)methyl]-3,9-dihydro-7H"pyrrolo[3,4- A]quinolin-7-one
5-[(6-Chloropyridin-3-yI)methyl]-9"(2,3-dihydroxypropyl)-8-[(/,S', 25 2~hydroxycyclohexyl]-8,9- dihydro-7H-py rrolo [3 ,4-h] quinolm-7-one
{5-[(6-Chloropyridi-i-3-yl)met yl]-8-[(/5'i, 2S)-2-hydroxycyclohexyl]"7~oxo~8J9-"dihydro-7H-pyrrolo[3,4- A]quinolin-9-yl}acetaldehyde
5-[(6-Chloropyridin-3-yl)methyl]--9-[2~(dimethylaniino)ethyl]--8-[(/S, 25)~2-hydroxycyclohexyl]-8,9- dihydro-7H-pyrrolo[3,4-A]quinoIin-7-one
5-[(6-Chloropyridin-3-yl)methyI]-8-[(/5, 2jS)-2-hydroxycyclohexyl]~9-(2-hydroxyethyl)-8,9-dihydro-7H- pyrrolo[3,4-A]quinolin-7-one
5-[(6-Cyclopropylpyridin-3-yl)methyl]-8-[(iS, 2S)-2-hydroxycyclohexyl-8,9-dihydro-7H-pyrrolo[3,4- A]quinolin-7-one,
and pharmaceutically acceptable salts thereof.
The invention is also directed to methods of treating a patient (preferably a human) for diseases or disorders in which the Ml receptor is involved, such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
The invention is also directed to the use of a compound of formula (1), for treating a disease or disorder in which the Ml receptor is involved, such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders, by administering to the patient a compound of formula (I), or a pharmaceutically acceptable salt thereof. The invention is also directed to medicaments or pharmaceutical compositions for the treatment of diseases or disorders in a patient (preferably a human) in which the Ml receptor is involved, such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders, and sleep disorders, which comprise a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention is also directed to a method for the manufacture of a medicament or a pharmaceutical composition for treating diseases in which Ml receptor is involved, such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders, and sleep disorders, comprising combining a compound of formula (I), or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.
When any variable (e.g. aryl, heterocycle, R^, etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
If and when Ra is -O- and attached to a carbon it is referred to as a carbonyl group and when it is attached to a nitrogen (e.g., nitrogen atom on a pyridyl group) or sulfur atom it is referred to a N-oxide and sulfoxide group, respectively.
As used herein, "alkyl" encompasses groups having the prefix "alk" such as, for example, alkoxy, alkanoyl, alkenyl, and alkynyl and 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, and heptyl. "Alkenyl" refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. Preferably, alkenyl is C2-C6 alkenyl. Preferred alkynyl are C2-C6 alkynyl.
"Alkenyl," "alkynyl" and other like terms include carbon chains containing at least one unsaturated C-C bond.
As used herein, "fluoroalkyl" refers to an alkyl substituent as described herin containing at least one fluorine substituent.
The term "cycloalkyl" refers to a saturated hydrocarbon containing one ring having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term "Ci_6" includes alkyls containing 6, 5, 4, 3, 2, or 1 carbon atoms The term "alkoxy" as used herein, alone or in combination, includes an alkyl group connected to the oxy connecting atom. The term "alkoxy" also includes alkyl ether groups, where the term 'alkyl' is defined above, and 'ether' means two alkyl groups with an oxygen atom between them. Examples of suitable alkoxy groups include methoxy, ethoxy, n- propoxy, i-propoxy, n-butoxy, s-butoxy, t~butoxy, methoxymethane (also referred to as 'dimethyl ether'), and methoxyethane (also referred to as 'ethyl methyl ether').
As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, napthyl, tetrahydronapthyl, indanyl, or biphenyl.
The term heterocycle, heterocyclyl, or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, 0, and S, and including any bicyclic group in which any of the above-defmed heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The term heterocycle or heterocyclic includes heteroaryl moieties. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,
dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxolanyl, furyl,
imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, mienofuryl, thienothienyl, thienyl and triazolyl.
In certain embodiments, the heterocyclic group is a heteroaryl group. The term "heteroaryl", as used herein except where noted, represents a stable 5- to 7-membered
monocyclic- or stable 9- to 10-membered fused bicyclic heterocyclic ring system which contains an aromatic ring, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heteroaryl groups include, but are not limited to, benzimidazole, benzisothiazole, benzisoxazole, benzofuran, benzothiazole, benzothiophene, benzotriazoie, benzoxazole, carboline, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and N-oxides thereof.
In certain other embodiments, the heterocyclic group is fused to an aryl or heteroaryl group. Examples of such fused heterocycles include, without limitation,
tetrahydroquinolinyl and dihydrobenzofuranyl.
The term "heterocycloalkyl", as used herein except where noted, repressents a non- aromatic cyclic or polycyclic group having from five to twelve ring atoms selected from C, O, N or S, at least one of which is O, N or S. Examples of heterocycloalkyls include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyranyl, tetrahydrofuranyl, imidazolinyl, pyroiidin-2-one, piperidin-2-one, and thiomorpholinyl.
The term "heteroatom" means O, S or N, selected on an independent basis. A moiety that is substituted is one in which one or more hydrogens have been independently replaced with another chemical substituent. As a non-limiting example, substituted phenyls include 2-fiurophenyl, 3,4-dichlorophenyl, 3~chloro-4-iTuoro-phenyl, 2,4- difluoro-3-propylphenyl. As another non-limiting example, substituted n-octyls include 2,4 dimethyl-5-ethyl-octyl and 3-cyclopentyloctyl. Included within this definition are methylenes (- CH2-) substituted with oxygen to form carbonyl (-CO-).
Unless otherwise stated, as employed herein, when a moiety (e.g., cycloalkyl, hydrocarbyl, aryl, alkyl, heteroaryl, heterocyclic, urea, etc.) is described as "optionally substituted" it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents. Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular -CH- substituted with oxo is -C(0)-)} nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, , alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups. Preferred substituents, which are themselves not further substituted (unless expressly stated otherwise) are:
(a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, and
(b) Ci-Cg alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, Ci-Cs alkyl, S02CF3, CF3, S02Me, Ci-Cg alkenyl, C1-C8 alkoxy, Ci-Cg alkoxycarbonyl, aryloxycarbonyl, C2-C8 acyl, C2-C8 acylamino, C1-C8 alkylthio, arylalkylthio, arylthio, Ci-Cgalkylsulfmyl, arylalkylsulfnyl, arylsulfnyl, Cj-Cs alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, CQ-C^
N-alkylcarbamoyl, C2-C15 N.Ndialkylcarbamoyl, C3-C7 cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C3-C7 heterocycle, or any of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above.
"Halogen" or "halo"refers to fluorine, chlorine, bromine and iodine. The term "mammal" "mammalian" or "mammals" includes humans, as well as animals, such as dogs, cats, horses, pigs and cattle.
All patents, patent applications and publications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety and are deemed representative of the prevailing state of the art.
As used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the content clearly dictates otherwise. Thus, for example, reference to "a primer" includes two or more such primers, reference to "an amino acid" includes more than one such amino acid, and the like.
The compounds of the invention may have one or more asymmetric centers. Compounds with asymmetric centers give rise to enantiomers (optical isomers), diastereomers
(configurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. The present invention is meant to encompass all such isomeric forms of the compounds of formula (I).
Formula (I), are shown above without a definite stereochemistry. The present invention includes all stereoisomers of formula (I), and pharmaceutically acceptable salts thereof.
The independent syntheses of the enantiomerically or diastereomerically enriched compounds, 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 that 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 or diastereomers 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 using chiral stationary phases, which methods are well known in the art.
Alternatively, any enantiomer or diastereoraer 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.
In the compounds of generic Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium (Ifi) and deuterium (¾[). Protiuro is the predominant hydrogen isotope found in nature.
Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically- enriched reagents and/or intermediates.
The compounds of the invention may be prepared according to the following reaction Schemes, in which variables are as defined before or are derived, using readily available starting materials, from reagents and conventional synthetic procedures. It is also possible to use variants which are themselves known to those of ordinary skill in organic synthesis art, but are not mentioned in greater detail.
The present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of the invention.
During any of the above synthetic sequences it may be necessary or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W.McOmie, Plenum Press, 1973, and T.W. Greene & P/G.M. Wuts,
Protective Groups in Organic Synthesis, John Wiley & Sons, 1999. The protecting groups may be removed at a convenient sequent stage using methods known from the art.
Specific embodiments of the compounds of the invention, and methods of making them, are described in the Examples herein. The term "substantially pure" means that the isolated material is at least 90% pure, and preferably 95% pure, and even more preferably 99% pure as assayed by analytical techniques known in the art.
As used herein, the term "muscarinic Ml receptor " refers to one of the five subtypes of the muscarinic acetylcholine receptor, which is from the superfamily of G-protein coupled receptors. The family of muscarinic receptors is described, for example, in Pharmacol Ther, 1993, 58:319-379; Eur J Pharmacol, 1996, 295:93-102, and Mol Pharmacol, 2002, 61 :1297- 1302. The muscarinic receptors are known to contain one or more ailosteric sites, which may alter the affinity with which muscarinic ligands bind to the primary binding or
orthosteric sites. See, e.g., S. Lazareno et al, Mol Pharmacol, 2002, 62:6, 1491-1505.
As used herein, the terms "positive ailosteric modulator" and "ailosteric potentiator", are used interchangeably, and refer to a ligand which interacts with an ailosteric site of a receptor to activate the primary binding site. The compounds of the invention are positive ailosteric modulators of the muscarinic Ml receptor. For example, a modulator or potentiator may directly or indirectly augment the response produced by the endogenous ligand (such as acetylcholine or xanomeline) at the orthosteric site of the muscarinic Ml receptor in an animal, in particular, a human.
The actions of ligands at ailosteric receptor sites may also be understood according to the "ailosteric ternary complex model," as known by those skilled in the art. The ailosteric ternary complex model is described with respect to the family of muscarinic receptors in Birdsall et al, Life Sciences, 2001, 68:2517-2524. For a general description of the role of ailosteric binding sites, see Christopoulos, Nature Reviews: Drug Discovery, 2002, 1 : 198- 210.
It is believed that the compounds of the invention bind to an ailosteric binding site that is distinct from the orthosteric acetylcholine site of the muscarinic Ml receptor, thereby augmenting the response produced by the endogenous ligand acetylcholine at the orthosteric site of the Ml receptor. It is also believed that the compounds of the invention bind to an ailosteric site which is distinct from the xanomeline site of the muscarinic Ml receptor, thereby augmenting the response produced by the endogenous ligand xanomeline at the orthosteric site of the Ml receptor.
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. The compounds of the invention may be mono, di or tris salts, depending on the number of acid functionalities present in the free base form of the compound. Free bases and 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-diamine5 diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolarnine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucarnine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, ^propylamine, 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, trifluoroacetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, j a-toluenesulfonic acid, and the like.
Suitable pharmaceutically acceptable salts include ammonium, sodium, potassium, hydrochloride, hydrobromide and fumarate.
The present invention is directed to the use of the compounds of formula (I) disclosed herein as Ml allosteric modulators in a patient or subject such as a mammal in need of such activity, comprising the administration of an effective amount of the compound. In addition to humans, a variety of other mammals can be treated according to the method of the present invention.
The compounds of the present invention have utility in treating or ameliorating
Alzheimer's disease. The compounds may also be useful in treating or ameliorating other diseases mediated by the muscarinic Ml receptor, such as schizophrenia, sleep disorders, pain disorders (including acute pain, inflammatory pain and neuropathic pain) and cognitive disorders (including mild cognitive impairment). Other conditions that may be treated by the compounds of the invention include Parkinson's Disease, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, schizophrenia, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral
Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld- Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes, autism and atherosclerosis.
In preferred embodiments, the compounds of the invention are useful in treating
Alzheimer's Disease, cognitive disorders, schizophrenia, pain disorders and sleep disorders. For example, the compounds may be useful for the prevention of dementia of the Alzheimer's type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the Alzheimer's type.
Potential schizophrenia conditions or disorders for which the compounds of the invention may be useful include one or more of the following conditions or diseases:
schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (phencyclidine, ketanine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine) psycho sispsychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), including both the positive and the negative symptoms of schizophrenia and other psychoses; cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt- Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or age related cognitive decline. Thus, in another specific embodiment, the present invention provides a method for treating schizophrenia or psychosis comprising administering to a patient in need thereof an effective amount of a compound of the present invention.. At present, the text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder. As used herein, the term "schizophrenia or psychosis" includes treatment of those mental disorders as described in DSM-IV-TR. The skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus the term "schizophrenia or psychosis" is intended to include like disorders that are described in other diagnostic sources.
Potential sleep conditions or disorders for which the compounds of the invention may be useful include enhancing sleep quality; improving sleep quality; augmenting sleep maintenance; increasing the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing difficulties in falling asleep; increasing sleep continuity; decreasing the number of awakenings during sleep; decreasing nocturnal arousals; decreasing the time spent awake following the initial onset of sleep; increasing the total amount of sleep; reducing the fragmentation of sleep; altering the timing, frequency or duration of REM sleep bouts; altering the timing, frequency or duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasing the amount and percentage of stage 2 sleep; promoting slow wave sleep; enhancing EEG-delta activity during sleep; increasing daytime alertness; reducing daytime drowsiness; treating or reducing excessive daytime sleepiness; insomnia; hypersomnia; narcolepsy; interrupted sleep; sleep apnea; wakefulness; nocturnal myoclonus; REM sleep interruptions; jet-lag; shift workers' sleep disturbances; dyssomnias; night terror; insomnias associated with depression,
emotional/mood disorders, as well as sleep walking and enuresis, and sleep disorders which accompany aging; Alzheimer's sundowning; conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules; conditions due to drugs which cause reductions in REM sleep as a side effect; syndromes which are manifested by non-restorative sleep and muscle pain or sleep apnea which is associated with respiratory disturbances during sleep; and conditions which result from a diminished quality of sleep.
Pain disorders for which the compounds of the invention may be useful include neuropathic pain (such as postherpetic neuralgia, nerve injury, the "dynias", e.g., vulvodynia, phantom limb pain, root avulsions, painful diabetic neuropathy, painful traumatic
mononeuropathy, painful polyneuropathy); central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system); postsurgical pain syndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stump pain); bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia); perioperative pain (general surgery, gynecological), chronic pain, dysmennorhea, as well as pain associated with angina, and inflammatory pain of varied origins (e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease, teno- synovitis and gout), headache, migraine and cluster headache, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization.
Compounds of the invention may also be used to treat or prevent dyskinesias.
Furthermore, compounds of the invention may be used to decrease tolerance and/or dependence to opioid treatment of pain, and for treatment of withdrawal syndrome of e.g., alcohol, opioids, and cocaine.
The compounds of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present invention have utility, where the combination of the drugs together are safer or more effective than either drug alone. Additionally, the compounds of the present invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the present invention. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with the compounds of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to the compounds of the present invention. The combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen.
Examples of combinations of the compounds of the present invention include
combinations with anti- Alzheimer's Disease agents, for example beta-secretase inhibitors; alpha 7 nicotinic agonists, such as ABT089, SSR180711 and MEM63908; ADAM 10 ligands or activators; gamma-secretase inhibitors, such as LY450139 and TA 070; gamma secretase modulators; tau phosphorylation inhibitors; glycine transport inhibitors; LXR β agonists; ApoE4 conformational modulators; NR2B antagonists; androgen receptor modulators; blockers of Αβ oligomer formation; 5-HT4 agonists, such as PRX-03140; 5-HT6 antagonists, such as GSK 742467, SGS-518, FK-962, SL-65.0155, SRA-333 and xaliproden; 5 -HT 1 a antagonists, such as lecozotan; p25/CDK5 inhibitors; NK1 N 3 receptor antagonists; COX-2 inhibitors; HMG-CoA reductase inhibitors; NSAIDs including ibuprofen; vitamin E; anti-amyloid antibodies (including anti-amyloid humanized monoclonal antibodies), such as bapineuzumab, ACCOOl, CAD 106, AZD3102, H12A11V1; anti-inflammatory compounds such as (R)-flurbiprofen,
nitroflurbiprofen, ND-1251, VP-025, HT-0712 and EHT-202; PPAR gamma agonists, such as pioglitazone and rosiglitazone; CB-1 receptor antagonists or CB-1 receptor inverse agonists, such as AVE 1625; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMD A) receptor antagonists, such as memantine, neramexane and EVT101; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, tacrine, phenserine, ladostigil and ABT-089;
growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine ¾ receptor antagonists such as ABT-834, ABT 829, GSK 189254 and CEP 16795 ;
AMPA agonists or AMPA modulators, such as CX-717, LY 451395, LY404187 and S- 18986; PDE IV inhibitors, including MEM1414, HT0712 and AVE8112; GABAA inverse agonists;
GSK3P inhibitors, including AZD1080, SAR502250 and CEP16805; neuronal nicotinic agonists; selective Ml agonists; HDAC inhibitors; and microtubule affinity regulating kinase (MARK) ligands; or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention.
Examples of combinations of the compounds include combinations with agents for the treatment of schizophrenia, for example in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitripryline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproelone, temazepam, thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, Zolpidem, and salts thereof, and combinations thereof, and the like, or the subject compound may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.
In another embodiment, the subject compound may be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMD A receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole. It will be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.
In another embodiment, the subject compound may be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine,
fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone. It will be appreciated that the neuroleptic agents when used in combination with the subject compound may be in the form of a pharmaceutically acceptable salt, for example, οΙιΙοφΓοηιαζϊηε hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, fiurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form. Thus, the subject compound may be employed in combination with acetophenazine, alentemol, aripiprazole, amisuipride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, Ievodopa, Ievodopa with benserazide, Ievodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride,
tetrabenazine, frihexyphenidyl, thioridazine, thiothixene, trifluoperazine or ziprasidone.
Examples of combinations of the compounds include combinations with agents for the treatment of pain, for example non-steroidal anti-inflammatory agents, such as aspirin, diclofenac, duflunisal, fenoprofen, flurbiprofen, ibuprofen, mdomethacin, ketoprofen, ketorolac, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2 inhibitors, such as celecoxib, rofecoxib, vaidecoxib, 406381 and 644784; CB-2 agonists, such as 842166 and SAB378; V -1 antagonists, such as AMG517, 705498, 782443, PAC20030, VI 14380 and A425619; bradykinin B 1 receptor antagonists, such as SSR240 12 and NVPSAA1 4; sodium channel blockers and antagonists, such as VX409 and SPI860; nitric oxide synthase (NOS) inhibitors (including iNOS and nNOS inhibitors), such as SD6010 and 274150; glycine site antagonists, including lacosamide; neuronal nicotinic agonists, such as ABT 894; NMDA antagonists, such as
AZD4282; potassium channel openers; AMPA/kainate receptor antagonists; calcium channel blockers, such as ziconotide and NMED160; GABA-A receptor IO modulators (e.g., a GABA- A receptor agonist); matrix metalloprotease (MMP) inhibitors; thrombolytic agents; opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene; neutrophil inhibitory factor (NIF); pramipexole, ropinirole; anticholinergics; amantadine; monoamine oxidase B15 ("MAO- B!!) inhibitors; 5HT receptor agonists or antagonists; mGlu5 antagonists, such as AZD9272; alpha agonists, such as AGNXX/YY; neuronal nicotinic agonists, such as ABT894; NMDA receptor agonists or antagonists, such as AZD4282; NKI antagonists; selective serotonin reuptake inhibitors ("SSRI") and/or selective serotonin and norepinephrine reuptake inhibitors ("SSNRI"), such as duloxetine; tricyclic antidepressant drugs, norepinephrine modulators;
lithium; valproate; gabapentin; pregabalin; rizatriptan; zolmitriptan; naratriptan and sumatriptan.
The compounds of the present invention may be administered in combination with compounds useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, orexin antagonists, alpha- 1 antagonists, GAB A agonists, 5HT-2 antagonists including 5HT-2A antagonists and 5HT- 2A/2C antagonists, histamine antagonists including histamine H3 antagonists, histamine H3 inverse agonists, imidazopyridines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, other orexin antagonists, orexin agonists, prokineticin agonists and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, triazolopyridines, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capromorelin, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate, clorethate, clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014, eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine, indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline, MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone, NGD-2-73, isobamate, nitrazepam, nortriptyline, oxazepam,
paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide, secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone, Zolpidem, and salts thereof, and combinations thereof, and the like, or the compound of the present invention may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.
The subject or patient to whom the compounds of the present invention is administered is generally a human being, male or female, in whom Ml allosteric modulation is is desired, but may also encompass other mammals, such as dogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys, chimpanzees or other apes or primates, for which treatment of the above noted disorders is desired.
The term "composition" as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, 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.
In general, 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 compound, which is a compound of formula (I) is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. 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.
The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the
pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil- in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compounds of the invention, or pharmaceutically acceptable salts thereof, may also be administered by controlled release means and/or delivery devices.
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 may 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.
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.1 mg to about 500 mg of the active ingredient and each cachet or capsule preferably containing from about 0.1 mg to about 500 mg of the active ingredient.
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.
Other pharmaceutical compositions include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous
suspensions. In addition, oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension, or in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions, h all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like.
Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can also be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art.
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 or "administering a" compound should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual's body in a therapeutically useful form and therapeutically useful amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP, and the like;
transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.
The terms "effective amount" or "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.
As used herein, the term "treatment" or "treating" means any administration of a compound of the present invention and includes (1) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (2) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
The compositions containing compounds of the present invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The term "unit dosage form" is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person
administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages. Typical examples of unit dosage forms are tablets or capsules for oral administration, single dose vials for injection, or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.
The compositions containing compounds of the present invention may conveniently be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient. Such kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient.
When treating or ameliorating a disorder or disease for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 mg to about 100 mg per kg 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 fonn. The total daily dosage is from about 1.0 mg to about 2000 mg, preferably from about 0.1 mg to about 20 mg per kg of body weight. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may conveniently contain from about 0.005 mg to about 2.5 g of active agent, compounded with an appropriate and convenient amount of carrier material. Unit dosage forms will generally contain between from about 0.005 mg to about 1000 mg of the active ingredient, typically 0.005, 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 . mg, 600 mg, 800 mg or 1000 mg, administered once, twice or three times a day.
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 schemes and examples herein. Starting materials are made according to procedures known in the art or as illustrated herein. The following examples are provided so that the invention might be more fully understood.
The following abbreviations are used throughout the text:
Me: methyl
Et: ethyl
f-Bu: teri-butyl
Ax: aryl
Ph: phenyl
Bn: benzyl
DCE: dichloroethylene
HMDS: hexamethyldi silazane
DMF: dimethylformarnide
DMFDMA: N, N-dimethylformamide dimethylacetal
THF: tetrahydrofuran
BOP: benzotriazolyloxytris (dimethylamino) phosph
hexafiuorophosphate
Boc: ieri-butyloxycarbonyl
TJ S» tert-butyldimethylsilyl TEA: triethylamine
TPAP: tetra-rc-propyl ammonium perruthenate
NMO: N-methyl morpholine N-oxide
Chlorozinc
dppf: diphenylpho sphorousferrocenyl
PMB: -methoxybenzyl
Ms: mesyl
Ac: acetyl
DMSO: dimethylsulfoxide
DCM: dichloromethane
m-CPBA: meta-chloroperoxybenzoic acid
DMEM: Dulbecco's Modified Eagle Medium (High Glucose)
fetal bovine serum
rt: room temperature
aq: aqueous
high performance liquid chromatography
MS: mass spectrometry
GDH-103 **
20 KPJED-130 **
)dex Transaminase panel enzyme P1G5 (commercially available from Codex (Redwood City, California, .) panel products.
The following examples are provided to illustrate the invention and are not to be construed as limiting the scope of the invention in any manner.
25
EXAMPLE 1
2-{(lSt 25)-2-Hydroxycyclohexyl]-5-(4-methoxybenzyl)- 1 ,2-dihydro-3H-benzofe]isoindol-3-one
Figure imgf000029_0001
Figure imgf000030_0001
To a solution of l-hydroxy-2-naphthoic acid methyl ester (5.10 g, 25.2 mmol) in 35 mL of pyridine at -5 °C was added trifiuoromethanesulfonic anhydride (12.8 mL, 76.0 mmol). After 1 hr, the mixture was poured into 250 mL of ice water and extracted with hexanes and ethyl acetate. The combined organic extracts were washed with water and brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes, to provide methyl 1 - { [(trifluoromethyl)suifonyl]oxy } -2-naphthoate
that gave a mass ion (ES+) of 335.1 for [M+H]+.
To a solution of the above compound (4.30 g, 12.9 mmol) in 35 mL of N,N-dimethylforniamide under an atmosphere of nitrogen was added lithium chloride (2.73 g, 64.3 mmol),
bis(triphenylphosphine)palladium(II) chloride (0.451 g, 0.643 mmol), and tetramethyltin (3.92 mL, 28.3 mmol). The mixture was heated at 110 °C for 3 hr, cooled to ambient temperature, and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate, water, and brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-10% ethyl acetate in hexanes, to provide methyl l-methyl-2-naphthoate that gave a mass ion (ES+) of 201.1 for
To a solution of the above compound (1.00 g, 4.99 mmol) in 5 mL of acetic acid under an atmosphere of nitrogen was added a solution of bromine (0.257 mL, 4.99 mmol) in 5 mL of acetic acid. The mixture was heated at 90 °C for 4 hr and then stirred at ambient temperature for 15 hr. The mixture was poured into water and extracted with dichloromethane. The organic extract was washed with saturated aqueous sodium bicarbonate, water, and brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-30% ethyl acetate in hexanes, to provide methyl 4-bromo-l- methyl-2-naphthoate that gave a mass ion (ES+) of 281.1 for [M+H]+.
To a solution of the above compound (1.29 g, 4.62 ramol) in 25 mL of carbon tetrachloride under an atmosphere of nitrogen was added N-bromosuccinimide (0.823 g, 4.62 mmol) and benzoyl peroxide (0.056 g, 0.23 mmoL). The mixture was heated at 90 °C for 1 hr, cooled to ambient temperature, and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate, water, and brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0- 10% ethyl acetate in hexanes, to provide methyl 4-bromo-l-(bromomethyI)-2-naphthoate that gave a proton NMR spectra consistent with theory.
To a solution of the above compound (0.100 g, 0.279 mmol) in 1 mL of tetrahydrofuran was added (IS, 25)-2-aminocyclohexanol (0.161 g, 1.40 mmol). After 15 h5 water (10 mL) was added, the mixture was aged for 30 min and then filtered to provide 5-bromo-2-[(/S', 2S}-2- hydroxycyclohexyl]-l,2-dihydro-3H-benzo[e]isoindol-3-one as a white solid that gave a mass ion (ES+) of 362.3 for [M+Hf.
To a solution of the above compound (0.050 g, 0.14 mmol) in 3 mL of tetrahydrofuran under an atmosphere of nitrogen was added 4-methoxybenzylzinc chloride (0.5 M in tetrahydrofuran, 1.39 mL, 0.0694 mmol) and tetrakis (triphenylphosphine)palladium (0) (0.016 g, 0.014 mmol). The mixture was heated at 90 °C for 3 hr, cooled to ambient temperature, treated with saturated aqueous ammonium chloride, and extracted with dichloromethane. The organic extract was washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 402.4 for [M+H]+: 1H NMR (400 MHz, CDC13) δ 8.08-8.05 (m, IH), 7.87-7.84 (m, 1H), 7.66 (s, 1H), 7.62-7.52 (m, 2H), 7.08-7.05 (m, 2H), 6.82-6.77 (m, 2H), 4.86-4.70 (m, 2H), 4.35 (s, 2H), 4.21-4.12 (m, IH), 3.81-3.75 (m,lH), 3.75 (s, 3H), 2.35-2.20 (m, IK), 2.05-1.98 (m, H), 1.86-1.83 (m, 2H), 1.72-1.62 (m, IH), 1.54-1.31 (m, 3H) ppm.
EXAMPLE 2
2-[(lS, 2S)-2-Hydroxycyclohexyl]-5-[(6-mefhylpyridin-3-yl)methyl]- 1 ,2-dihydro-3H- benzo [e] isoindol-3 -one
Figure imgf000032_0001
5-[(6~Chloropyridm-3-yl)memyl]-2-[(;S, 2S)-2-hydroxycyclohexyl]-l ,2-dihydro~3H- benzo[e]isoindol-3~one was prepared employing the procedures described for the construction of 2-[(lS, 25 -2-hydroxycyclohexyl]-5-(4-methoxybenzyl)- 152~dihydro-3H-benzo[e]isoindol-3-one in Example 1, substituting (2-chloro-5-pyridyl)methyrzinc chloride for 4-methoxybenzylzinc chloride.
To a solution of 5-[(6-chloropyridin-3-yl)methyI]-2-[(iS', 25)-2-hydroxycyclohexyl]-l52-dihydro- 3H-benzo[e]isoindol-3-one (0.040 g, 0.098 lrmoi) in 3 mL of tetrahydrof ran under an atmosphere of nitrogen was added dimethylzinc (1.2 M in tetrahydrofuran, 0.16 mL, 0.20 mmol) and [ls -bis(diphenylphosphino)ferrocene]dichloro-palIadium(II), 1 :1 complex with
dichloromethane (7.2 mg, 0.0098 mmol). The mixture was heated at 50 °C for 3 hr and then cooled to ambient temperature. Additional dimethyl zinc (1.2 M in tetrahydrofuran, 0.16 mL, 0.20 mmol) and [l5 -bis(diphenylphosphino)ferrocene]dichloro-palladium(II)5 1 :1 complex with dichloromethane (7.2 mg, 0.0098 mmol) were added and the mixture was heated at 50 °C for an additional 12 hr. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 387.4 for [M+H]+: 1H NMR (400 MHz, CDC13) δ 8.79 (s, 1H), 7.92™7.84 (m, 3H), 7.69 (s, 1H), 7.65-7.61 (m, 2H), 7.41 (d, J= 8.1 Hz, 1H), 4.87-4.73 (m, 2H), 4.53 (s, 2H), 4.23-4.16 (m, 1H), 3.81-3.75 (m, 1H), .77 (s, 3H), 2.23-2.20 (m, 1H), 2.02-1.99 (m, 1H), 1.87-1.84 (m, 2H), 1.84-1.64 (m, 1H), 1.55-1.33 (m, 3H) ppm.
EXAMPLE 3
2-[(75, 25)-2-Hydroxycyclohexyl]-5-[(6-vinylpyridin-3-yl)methyl]- 1 ,2-dihydro-3H- benzo [e] isoindol-3 -one
Figure imgf000033_0001
To a solution of 5-[(6-chloropyridin-3-yl)methyl]-2-[(iS, 2S)-2-hydroxycyclohexyl]-l,2-dihydro- 3H-benzo[e]isoindol-3-one (0.050 g, 0.12 mmol) in 1 mL of dioxane was added potassium vinyltrifluoroborate (0.033 g, 0.25 mmol), aqueous potassium phosphate (1.27 M, 0.16 mL, 0.21 mmol), tricyclohexylphosphine (0.83 mg, 0.0030 mmol), and
tris[dibenzylideneacetone]dipalladium (0) (1.2 mg, 0.0012 mmol). The mixture was irradiated in a microwave reactor at 140 °C for 30 min, cooled to ambient temperature, and diluted with saturated aqueous sodium bicarbonate. The mixture was extracted twice with dichloromethane and the combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 399.2 for [M+H : !H NMR (400 MHz, CDC13) δ 8.51 (s, 1H), 7.99-7.97 (m, 1H), 7.89-7.87 (m, 1H), 7.68 (s, 1H), 7.61-7.54 (m, 2H), 7.33-7.30 (m, 1H), 7.18-7.16 (m, 1H), 6.79-6.72 (m, 1H), 5.44-5.30 (m, 1H), 4.85-4.70 (m, 2H), 4.39 (s, 2H), 4.21-4.14 (m, 1H), 3.80-3.75 (m, 1H), 2.63-2.61 (m, 1H), 2.24™2.20 (m, 1H), 2.02-1.85 (m, 2H), 1.72-1.68 (m, 1H), 1.62-1.41 (m, 3H) ppm. EXAMPLE 4
5 -[(6-Cl loropyridin-3-yl)niethyl] -2- [(2iS)-2-fluorocyclohexyl] - 1 ,2-dihydro-3H-benzo [e] isoindol-
Figure imgf000034_0001
EXAMPLE 5
Figure imgf000034_0002
To a solution of 5-[(6-chloropyridin-3-yl)metliyl]-2-[(i5'! 2¾-2-hydroxycyclohexyl]-l,2-dihydro- 3H-benzo[e]isoindol-3-one (0.100 g, 0.246 mmol) in 1 mL of tetrahydrofuran was added triethylamine (0.21 mL, 1.5 mmol), perfluorobutanesulfonyl fluoride (0.088 mL, 0.49 mmol), and triethylamine trihydrofluoride (0.080 mL, 0.49 mmol). After 15 hr, additional
perfluorobutanesulfonyl fluoride (0.088 mL, 0.49 mmol) and txiethylamine trihydrofluoride (0.080 mL} 0.49 mmol) were added. After 72 hr, the mixture was diluted with saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide Example 4 and 5 as white solids.
Example 4 gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 409.1 for [M+H]+: 1H NMR (400 MHz, CDC13) δ 8.45 (s, IH), 7.97-7.95 (m, IH), 7.92-7.89 (m5 IH), 7.76 (s, IH), 7.64^7.56 (m, 2H), 7.52-7.48 (m, IH), 7.29-7.26 (m, IH), 4.85-4.74 (m, 2H), 4.51 (s, 2H), 4.39-4.32 (m, IH), 2.33-2.30 (m, IH), 2.10-2.01 (ms IH), 1.92-1.82 (m, 2H),
1.78-1.62 (m, 2H), 1.53-1.37 (m, 3H) ppm.
Example 5 gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 389.1 for [M+H]+: 1H NMR (400 MHz, CDC13) δ 8.40 (s, IH), 7.98-7.96 (m, IH), 7.93-7.91 (m, IH), 7.76 (s, IH), 7.63-7.54 (m, 2H), 7.47-7.43 (m, IH), 7.26-7.23 (m, IH), 6.05-6.02 (m, IH), 5.64 (d, J = 10.0 Hz, IH), 5.12 (br s, IH), 4.72 (s, 2H), 4.50 (s, 2H), 2.18-2.01 (m, 3H), 1.91-1.75 (m, 3H) ppm.
EXAMPLE 6
2-[(lS, ^^^-Hydro ycyclohexylJ-S-i yridin-S-ylmethy^-l^-dihydro-SH-be zofelisomdol-S- one
Figure imgf000035_0001
To a solution of 5-[(6-chloropyridin-3-yl)methyI]-2-[(i5', 5)-2-hydroxycyclohexyl]-l,2-dihydro- 3H-benzo[e]isoindol-3-one (0.035 g, 0.086 mmol) in 1 mL of ethyl acetate under an atmosphere of nitrogen was added palladium on carbon (9.2 mg, 0.086 mmol). The mixture was sparged under an atmosphere of hydrogen (1 atm) for 15 hr, filtered through a pad of Celite and concentrated in vacuo to provide the title compound that gave a proton NMR spectra consistent with theory: 1H NMR (400 MHz, CDC13) δ 8.48 (s, 1H), 8.40-8.38 (m, 1H), 7.90-7.86 (m, 2H)5 7.61-7.52 (m, 3H)> 7.30-7.26 (m, 1H), 7.10-7.06 (m, 1H), 4.87-4.66 (m, 2H), 4.24 (s, 2H), 4.20-4.13 (m, 1H), 3.81-3.74 (m, 1H), 3.39 (br s, 1H), 2.24-2.20 (m, 1H), 2.00-1.95 (m, 1H), 1.86-1.81 (m, 2H), 1.67-1.36 (m, 4H) ppm.
EXAMPLE 7
2-[(lS, S)-2-Hydro ycyclohe yl]-5-[(6-moφholi -4-ylpyridin-3-yl)methyl]-l,2-dihydro-3H- benzo [e] isoindol-3 -one
Figure imgf000036_0001
To a solution of 5-[(6-chloropyridin-3-yl)methyl]-2-[(i5', 2S -2-hydroxycyclohexyl]-l,2-dihydro- 3H-benzo[e] isoindol-3 -one (0.101 g, 0.248 mmol) in 3 mL of toluene was added morpholine (0.032 g, 0.37 mmol), sodium tert-butoxide (0.60 g, 0.62 mmol),
tris[dibenzylideneacetone]dipalladium (0) (0.034 g, 0.037 mmol), and (i?)-(+)-2,2'- bis(diphenylphosphino)-l,l'-binaphthyl (0.011 g, 0.017 mmol). The mixture was heated at 110 °C for 3 hr, cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate (25 mL), and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 458.2 for [M+H : 1H NMR (400 MHz, CDC13) 5 8.15 (s, IH), 8.10-8.07 (m, IH), 7.88-7.86 (m, IH), 7.68 (s, IH), 7.59-7.56 (m, 2H), 7.28-7.25 (m, IH), 6.53 (d, J= 8.8 Hz, IH), 4.82-4.69 (m, 2H), 4.33 (s, 2H), 4.20-4.11 (m, 1H)5 3.82-3.70 (m, 5H), 3.46-3.41 (m, 4H), 2.23-2.20 (m, IH), 2.05-1.98 (m, IH), 1.87-1.64 (m, 4H), 1.51-1.28 (m, 3H) ppm.
EXAMPLE 8
5- [(6-Chloropyridin-3-yl)methyI]-2-[(3i?, 4S 3-hydroxytetrahydro-2H-pyran-4-yl] - 1 ,2-dihydro-
3 H-benzo [e] isoindol-3 -one
Figure imgf000037_0001
Construction of (57?, 4$)-4- Amino tetrahydro-2H-pyran-3-ol.
Figure imgf000037_0002
Me H 10 vol% DMSO 0 A jacketed flask equipped with an overhead stirrer and a thermocouple was charged with 23.0 L of MeOH, and cooled to 5 °C. Potassium hydroxide (1.574 kg, 28.05 mol) was added to the flask, and the resulting solution was aged until homogeneous and recooled to 5 °C. Tetrahydro- ^H-pyran-4-one (LOO kg, 10.0 mol) was then added at a steady rate over 20 min, and the resulting solution was aged for 20-30 min. A solution of iodine (2.778 kg, 10.95 mol) in 18.5 L of MeOH was then added via mechanical pump at a steady rate over 90-100 minutes. After an additional 30 min, the solution was warmed to rt and toluene (42.0 L) was added. The resulting slurry was concentrated in vacuo to a volume of -8.4 L. Additional toluene (8.4 L) was added and the resulting solution was concentrated to a volume of 8.4 L 2x. The resulting slurry was then filtered, and the filter cake was rinsed 2x with toluene (4.0 L). The combined toluene streams were concentrated to ~6 L, and the product is extracted 2x with water (3.0 L) to provide 4s4-dimethyoxytetrahydro-2H-pyran-3-ol.
To a solution of the above compound (1.00 kg, 6.17 mol) in 5 L of water was added acetic acid to pH 5.2-5.4. The mixture was diluted with acetonitrile (4.0 L) and ruthenium trichloride hydrate (6.4 g, 0.028 mol) was added and rinsed in with additional acetonitrile (1.0 L). The flask was placed in a rt water bath and a solution of sodium brornate (650 g, 4.31 mol) in water (1.95 L) was added slowly over -30 min, keeping the temperature below 30 °C. After 2 h, potassium bicarbonate (430 g, 4.30 mol), sodium thiosulfate (1.07 kg, 4.31 mol), potassium chloride (500 g, 6.71 mol) and acetonitrile (5 L) were added sequentially. The layers were separated and the aqueous layer was extracted 3x with acetonitrile (10 L). The combined organic extracts were concentrated to -4 L. Toluene (5 L) was then added and the mixture reconcentrated to 4 L 4x. The mixture was diluted with toluene (7 L) and filtered to remove solids. The filtercake was washed 3x with toluene (2 L) and the combined filtrate and washes were concentrated to a total volume of 3 L to provide an organic solution of 4,4-dimethoxydihydro-2H-pyran-3(^H)-one.
To a 3L 3-neck RB flask with overhead stirring, thermocouple and heating mantle was added sodium dihydrogenphosphate (96.0 g, 800 mmol) in 1.6 L of water. Sodium hydroxide (29 mL, 50 wt%) was added to pH 7.13, followed by hydrochloric acid (5 mL, 6 N) to pH 7.02.
The above organic solution of 4,4-dimethoxydihydro-2H-pyran-3(^H)-one was extracted 3x with phosphate buffered water (0.55 L). To the combined aqueous extracts was added D-glucose (180 g, 100 mmol), and the solution was heated to 30 °C. When the solution exceeded 27 °C upon heating B-NADP+ (1.60 g, 499 mmol), GDH-103 (1.60 g, 499 mmol), and KRED-130 (1.60 g, 499 mmol) were added and the mixture was stirred for 17 h at 30 °C. Potassium chloride (200g, 2.68 mol) and acetonitrile (1.3 L) were added. After 30 min, the reaction mixture was transferred to 6 L sep funnel and additional MeCN (0.67 L) and toluene (0.87 L) were added. The aqueous layer was back extracted lx with a mixture of acetonitrile (1.95L) and toluene (0.65 L), and lx with acetonitrile (1.5 L). The combined organic extracts were concentrated in vacuo to provide (3S)- ,4-dimethoxytetrahydro-2H-pyran- 3 -ol . To a 2L RB flask with overhead stirring, thermocouple, heating mantle and N2 inlet was added a solution of the above compound (72.0 g, 0.444 mol) in 750 mL of THF. After 15 h, sodium tert- butoxide (48.3 g, 492 mmol) was added in one portion, and the mixture was heated to 35 °C for 1 h, and aged at 22 °C for lhr. TetrabutylamiBonium iodide (8.19 g, 22.2 mmol) and benzyl bromide (56.5 ml, 466 mmol) were added, and the mixture was heated to 50°C for 2 h. The solution was cooled to 25 °C, and water (750 mL) and MtBE (2.25 L) were added. The organic layer was separated from the aqueous and concentrated in vacuo. The resultant brown oil was purified via silica gel chromatography, eluting with 0-15% ethyl acetate in hexanes to provide (55)-3-(benzylyoxy)-4,4-dimethoxytetrahydro-2H-pyran. To a solution of the above compound ( 1.1 g, 225 mmol ) in 300 mL of THF was added 2 NHC1 (300 mL, 0.600 mol). After 1.5 h, saturated aqueous potassium carbonate (60 mL) was added via addition funnel to pH 7.4. The aqueous layer was extracted 3x with MtBE (300 mL) and the combined organic extracts were concentrated in vacuo to provide crude (3S)-3- (benzyloxy)tetrahydro- H-pyran-4-one.
To a solution of L- Alanine (200 g, 2.24 mol), sodium formate (76.0 g, 1.12 mmol), and sodium phosphate dibasic (28.7 g, 202 mmol) in 2.25 L of water adjusted to pH 7.5 was added NAD (2.2 g, 3.21 mmol), pyridoxal-5-phosphate (2.2 g, 8.90 mmol), LDH (0.45 g, 0.22 mol), FDH (4.5 g, 0.20 mol), and TA P1 G5 (4.5 g, 0.22 mol). After all the components were completely dissolved, (55)-3-(benzyloxy)tetraliydro-^H-pyran-4-one (45 g, 0.22 mol) was added and the pH was adjusted to pH 7.25 with 6 NHCl and aged at 30 °C. After 15 h, potassium carbonate (700 g, 5.06 mol) was added slowly, followed by ethyl acetate (2.2 L). The mixture was filtered through a bed of Solka Floe and the cake was washed with ethyl acetate (250 mL). The combined filtrates were separated and the aqueous layer was extracted a second time with ethyl acetate (2 L). The combined organic extracts were concentrated in vacuo to provide crude (3R, 4S)-3~
(benzyloxy)tetrahydro-2H-pyran-4-amine.
To a solution of the above compound (38.8 g, 0.187 mol) in 730 mL of methanol was added concentrated hydrochloric acid (23.3 mL). The solution was subjected to hydro genation at 40 psi H2, 25 °C over 10% Pd/C (5.8 g). After 15 h, the mixture was filtered through solka floe and the filtercake was washed 5x with methanol (100 mL). The combined filtrate and washes were concentrated in vacuo to provide (3R, S)-4-aminotetrahydro-2H-pyran~3-ol that gave proton NMR spectra consistent with theory.
The title compound was prepared employing the procedures described for the construction of 2- [(IS, 2^-2-hydroxycyclohexyl]-5-(4-methoxybenzyl)-l,2-dihydro-3H-benzo[e]isoindol-3-one in Example 1, substituting (2-chloro-5-pyridyl)methylzinc chloride for 4-methoxybenzylzinc chloride and substituting (3R, 5}-4-aminotetrahydro-2H-pyran-3-ol for (IS, 2S)~2~
aminocyclohexanoL The resultant yellow solid gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 409.1 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 8.43 (s, 1H), 8.22-8.19 (m, 1H), 8.10-8.08 (m, 1H), 7.71-7.62 (m5 3H), 7.39 (d, J= 8.4 Hz, 1H), 5.13 (d, J= 5.6 Hz, 1H), 4.93-4.82 (m, 2H), 4.57 (s, 2H), 4.13-4.03 (m, 1H), 3.95-3.87 (m, 2H), 3.85-3.77 (m, 1H), 3.46-3.39 (m, 1H), 3.15-3.10 (m, IK), 1.97-1.87 (m, 1H), 1.75-1.72 (m, 1H) ppm.
EXAMPLE 9
5 ~( { 2- [(7S, 2<S)-2-Hydroxycyclohexyl]-3 -oxo-2, 3 -dihydro- 1 H-benzo [e] isoindol- 5 - yl } methyl)pyridine-2-carbonitrile
Figure imgf000040_0001
To a solution of 5-[(6-chloropyridin-3-yl)methyl]-2-[(/5'J 25)-2-hydroxycyclohexyl]-l,2-dihydro- 3H-benzo[e]isoindol-3-one (0.022 g, 0.019 mmol) in 0.5 mL of N.N-dimethylformamide was added zinc cyanide (0.034 g, 0.29 mmol) and tetrakis (triphenylphosphine)palladium (0) (0.039 g, 0.097 mmol). The mixture was irradiated in a microwave reactor at 160 °C for 30 min, cooled to ambient temperature, and purified via preparative reverse phase HPLC and preparative thin layer chromatography, eluting with 50% ethyl acetate in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 398.2 for [M+H : 1H NMR (400 MHz, CDC13) δ 8.62 (s,lH), 7.92 (d, J= 8.1 Hz, 1H), 7.84 (d, J= 8.3 Hz, 1H), 7.66 (s, 1H), 7.64-7.58 (m, 2H), 7.51 (d, J- 8.1 Hz, 1H), 7.46-7.44 (m, 1H), 4.87-4.71 (m, 2H), 4.45 (s, 2H), 4.21-4.09 (m, 1H), 3.79-3.64 (m, 1H), 2.70-2.67 (m, 1H), 2.24-2.21 (m, 1H), 2.01-1.98 (m, 1H), 1.87-1.83 (m, 1H), 1.72-1.61 (m, 1H), 1.56-1.38 (m, 3H) ppm.
EXAMPLE 10
2-[(7^ 25)-2-Hydroxycyclohexyl]-5-{[6-(methylthio)pyridine-3-yl]methyl}-li2-dihydro-3H-
Figure imgf000041_0001
To a solution of 6-fluoromcotinic acid (0.995 g, 7.05 inmol) in 14 mL of diraethylsulfoxide was added sodium thiomethoxide (1.24 g, 17.6 mmol). The mixture was heated 80 °C for 1 hr, cooled to ambient temperature, and treated with concentrated hydrochloric acid (4,5 mL, 0.054 mol). After 15 min, the mixture was diluted with ethyl acetate and concentrated in vacuo to provide 6-(methylthio)nicotinic acid that gave a mass ion (ES+) of 170.1 for [M+H]+. To a solution of the above compound (1.19 g, 7.05 nimol) in a mixture of 20 mL of dichloromethane and 10 mL of methanol was added (trimemyisilyl)diazomethane (2.0 M in hexanes, 17.6 mL, 35.3 mmol). After 16 hr, the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to provide methyl 6-(methylthio)nicotinate that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 184.0 for [M+H]+.
To a solution of the above compound (0.484 g, 2.64 mmol) in a mixture of 5 mL of diethyl ether and 5 mL of dichloromethane at 0 °C was added lithium borohydride (0.086 g, 4.0 mmol) and methanol (0.16 mL, 4.0 mmol). After 5 min, the mixture was warmed to ambient temperature, and after 3 hr, additional lithium borohydride (0.086 g, 4.0 mmol) and methanol (0.16 mL, 4.0 mmol) were added- After an additional 2 hr, the mixture was treated with, saturated aqueous sodium bicarbonate and extracted three times with dichloromethane. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-100% ethyl acetate in hexanes to provide [6-(methylthio)pyridine-3-yl]methanol that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 156.0 for [M+H]+.
To a solution of the above compound (0.155 g, 0.999 mmol) in 10 mL of dichloromethane at 0 °C was added thionyl chloride (0.087 mL, 1.2 mmol). After 45 min, the mixture was
concentrated in vacuo to provide 5-(chloromethyl)-2-(methylthio)pyridine that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 174.0 for [M+H]+.
To a solution of 5-bromo-2-[(75, } 2S)-2-hydroxycyclohexyl]-l,2-dihydro-3H-benzo[e]isoindol-3- one (see Example 1 , 1.00 g, 2.78 mmol) in 20 mL of toluene under an atmostphere of nitrogen was added potassium acetate (0.545 g, 5.55 mmol), bis(pinacolato)diboron (0.775 g, 3.05 mmol), and [l,r-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), 1 :1 complex with
dichloromethane (0.227 g, 0.278 mmol). The mixture was heated at 1 10 °C for 3 hr, cooled to ambient temperature, and poured into water. The mixture was extracted twice with ethyl acetate and the combined organic extracts were washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-75% ethyl acetate in hexanes, to provide 2-[(JS, 25)-2-hydroxycyclohexyl)-5- (4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yI)-l,2-dihydro-3H-benzo[£;]isoindol-3-one that gave a mass ion (ES+) of 408.3 for [M+H]+.
To a solution of the above compound (0.150 g, 0.368 mmol) in a mixture of 3 mL of
tetrahydrofuran and 0.3 mL of water under an atmosphere of nitrogen was added 5- (chloromethyl)-2-(methylthio)pyridine (0,077 g, 0.44 mmol), cesium carbonate (0.300 g, 0.921 mmol), and bis(tri-iert-butylphosphine)palladium (0) (0.038 g, 0.074 mmol). After 1 hr at ambient temperature, the mixture was heated at 45 °C for 4 hr, cooled to ambient temperature and then poured into water and extracted 3 with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-100% ethyl acetate solution of methanol (10%) in hexanes, to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 419.1779 for [M+H]+ [calc'd for C25H27N202S, [M+H]+ = 419.1788]: 1H NMR (400 MHz, CDC13) δ 8.34 (s, 1H), 7.98-7.95 (ra, 1H), 7.89-7.86 (m, 1H), 7.63 (s, 1H), 7.61-7.54 (m, 2H), 7.20-7.17 (m, 1H), 7.03-7.00 (m, 1H), 4.85-4.68 (m, 2H), 4.30 (s, 2H), 4.20-4.09 (m, 1H), 3.80-3.62 (ra, 2H), 2.52 (s, 3H), 2.22-2.20 (m, 1H), 2.00-1.97 (m, 1H), 1.88-1.83 (m, 1H), 1.70-1.55 (m, 1H), 1.54-1.28 (m, 3H) ppm.
EXAMPLE 1 1
2-[(3S, ¥5)-4-Hydroxytetrahydro-2H-pyran-3 -yl] - 5 - [(6-methoxypyridin-3 -yl)methyl] -1,2- dihydro-3H-benzo[e] isoindol-3 -one
Figure imgf000043_0001
Synthesis of (3S, ¥5)-3-aminotetrahydro-2H-pyran-
Figure imgf000044_0001
K2HP04) H3P04, glucose, NADP,
KRED 119
Figure imgf000044_0002
A solution of 4f4-dimethoxydihydro-2H-pyran-3(^H)-one (172 g, 1.07 mol, see Example 1) in 310 mL of toluene was stirred in toluene for 30 min, then extracted 3x with water (270 mL). To the aqueous solution was added potassium dihydrogenphosphate (14.1 g, 0.104 mol), sodium formate (55.1 g, 0.810 mol), and L-Alanine (72.2 g, 0,810 mol). The pH was adjusted to 7.8 with 5N NaOH, and NAD (0.810 g), PLP (0.810 g), LDH (0.162 g), FDH (1.62 g), and Codexis TA P1G5 (4.05 g) were added. The mixture was heated to 45 °C for 12 hr, then cooled to rt. Potassium carbonate (324 g, 2.34 mol) was added and after 30 min, the mixture was diluted with acetonitrile (810 mL). After 30 min, the reaction was filtered through a pad of solka-floc. The filtrate was partitioned and the aqueous layer was extracted with additional acetonitrile (810 mL). The combined organic fractions were concentrated in vacuo to provide crude (3S)-4,4~ dimethoxytetrahydro-2H~pyran-3-amine.
The above residue was redissolved in 700 mL of tetrahydrofuran and 254 mL of water, and cooled to 0 °C. Sodium hydroxide (5 N, 96 mL, 0.48 mol) was added, and the reaction was recooled to -5 °C. Benzyl chloroformate (68.0 mL, 0.476 mol) was added via a syringe pump over 30 min, and the mixture was then warmed to rt. HCl (6 N, 250 mL, 1.50 mol) was added to pH = 0.40, and the mixture was stirred with an overhead stirrer. After 2 h, 3M potassium- carbonate was added to pH = 7.4, and the reaction was diluted with tetrahydrofuran (700 mL). A white solid was removed via filtration, and washed with additional tetrahydrofuran (100 mL). The combined organic fractions were concentrated in vacuo to provide crude benzyl [(35)-4- oxotetrahydro-2H-pyran-3-yl]carbamate.
To a solution of potassium dihydrogen phosphate (62.7 g, 0.461 mol) in 3.6 L of water was added phosphoric acid to pH = 7.0. To this solution was added glucose (112 g, 0.622 mol), NADP (3.6 g), GDH-103 (1.8 g), KRED 119 (3.6 g), and crude benzyl [(55 4-oxotetrahydro- 2H-pyran-3-yl]carbamate (103.4 g, 0.4148 mol). After 17 h, the reaction was adjusted to pH = 6.5 with 5 TV NaOH. A white solid was collected via filtration and washed 2x with water (200 mL). The solid was suspended in 600 mL of toluene and stirred with an overhead stirrer at 105 °C for Ihr, then cooled to ambient temperature. A white solid was collected via filtration and washed with toluene (200 mL) to provide benzyl [(3S, ^5)-4-hydroxytetrahydro-2H-pyran-3- yl]carbamate.
To a solution of the above compound (90.5 g, 0.360 mol) in 1.8 L of methanol was added palladium hydroxide on carbon (9 g). The mixture was subjected to 40 psi of hydrogen at 25 °C for 15 hr, then filtered through solka-floc. The filter cake was washed 3x with methanol (200 mL), and the combined filtrates were concentrated in vacuo to provide crude (3S, 4S)-3- aminotetrahydro-2H-pyran-4-ol that gave proton NMR spectra consistent with theory. 5-Bromo-2-[(35's ^S)-4-hydroxytetrahydro-2i7-pyran-3-yl]-l ,2-dihydro-3H-benzo[e]isoindol-3- one was prepared employing the procedures described for the construction of 5-bromo-2-[(Jr5', 2j$)-2-hydroxycyclohexyl]~l,2-dihydro-3H-bfinzo[e]isoindol-3-one in Example 1, substituting (3S, 4S)-3-aminotetrahydro-2H-pyran-4-ol for 2-amino-cyclohexanol. To a solution of methyl 6-methoxynicotinate (1.00 g, 5.98 mmol) in 20 mL of tetrahydrofuran at 0 °C under an atmosphere of nitrogen was added lithium aluminum hydride (1.0 M in
tetrahydrofuran, 9.0 mL, 9.0 mmol) dropwise. After 30 min, the mixture was warmed to ambient temperature, and after 30 min, the mixture was cooled to 0 °C, diluted with diethyl ether, and treated with water (0.34 mL), 15% aqueous sodium hydroxide (0.34 mL), and additional water (1.02 mL). The mixture was dried with magnesium sulfate and warmed to ambient temperature. After 15 min, the mixture was filtered through Celite and concentrated in vacuo to provide (6- methoxypyridin-3-yl)methanol that gave a proton NMR spectra consistent with theory.
To a solution of the above compound (1.00 g, 7.19 mmol) in 25 mL of dichloromethane at 0 °C was added thionyl chloride (1.57 mL, 21.6 mmol). After 15 hr, the mixture was concentrated in vacuo to provide 5-(chloromethyl)-2-methoxypyridine.
To a solution of 5-(chloromethyl)-2-methoxypyridine (0.109 g, 0.690 mmol) in 0.3 mL of tetrahydrofuran under an atmosphere of nitrogen was added Rieke zinc (0.76 M, 0.91 mL, 0.69 mmol). The mixture was heated at 90 °C for 15 hr, then cooled to ambient temperature. 5-
Bromo-2- [(3S, ^S)-4~hydrox tetrahydro-2H-pyran-3 -yl] - 1 ,2 -dihydro-3 H-benzo [e] isoindol-3 -one (0.050 g, 0.14 mmol) and tetrakis (triphenylphosphine)palladium (0) (0.016 g, 0.014 mmol) were added and the mixture was heated at 90 °C for 3 hr. The mixture was cooled to ambient temperature, diluted with saturated aqueous ammonium chloride and extracted 2x with dichloromethane. The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 405.2 for [M+Hf : Ή NMR (400 MHz, CDC13) δ 8.26 (s, 1H), 7.96-7.86 (m, 2H), 7.65-7.56 (m, 2H)S 7.55-7.50 (m, 2H), 6.77 (d, J- 8.8 Hz, 1H), 4.95-4.70 (m, 2H), 4.52-4.15 (m, 4H), 4.10-4.01 (m, 6H)5 3.99 (s, 3H), 3.61-3.50 (m, 2H), 2.18-2.15 (m, 1H), 1.90-1.80 (m, lH) ppm.
EXAMPLE 12
2-O- Acetyl- i,5-anhydro-3f4-dideoxy-3-{3-oxo-5-[(6-oxo-l,6-dihydroyridin-3-yl)m ethyl]- 1, 3-
Figure imgf000046_0001
lJ5-Anhydro-2,3-dideoxy-3-{5-[(6-methoxypyridin-3-yl)methyl]-3-oxo-1 -dihydro-2H- benzo[e]isoindoi-2-yl}-L-i ?reo-pentitol was prepared employing the procedures described for the construction of 2-[(3S, ^5)-4-hydroxytetrahydro-2H-pyran-3-yI]-5-[(6-metlioxypyridin-3- yl)methyl]-l,2-dihydro-3H-benzo[e]isoindoi-3-one in Example 11, substituting^./?, 4S)-A- aminotetrahydro-2H-pyran-3-ol for (3S, ¥S)-3~aminotetrahydro-2H-pyran-4-ol.
A solution of hydrogen bromide in acetic acid (33%, 1.22 mL, 7.42 mmol) was added to 1,5- anhydro-2,3-dideoxy-3- {5-[(6-methoxypyridin-3-yl)methyl]-3-oxo- 1 ,3-dihydro-2H- benzo[e]isoindol-2-yl}-L-i zreo-pentitol (0.150 g, 0.371 mmol). The mixture was heated at 110 °C in a sealed vial for 2 hr, cooled to ambient temperature, diluted with water, treated with saturated aqueous sodi um bicarbonate until the pH of the solution was 8-9, and extracted with dichloromethane. The organic extract was washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-8% methanol in dichloromethane, to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 433.1762 for [M+H]+ [calc'd for C25H2SN205, [M+H]+ - 433.1758]: 1H NMR (400 MHz, CDC13) δ 7.99-7.90 (m, 2H), 7.70 (s, 1H), 7.64-7.58 (m, 2H), 7.40^7.37 (m, 1H), 6.96 (s, 1H), 6.48 (d, J= 9.3 Hz, 1H), 5.30-5.14 (m, 1H), 4.83-4.64 (m, 3H), 4.29^4.06 (m, 3H), 3.62-3.55 (m, 1H), 3.43-3.38 (m, 1H), 2.16-2.06 (m, 1H), 1.98-1.93 (m, 1H), 1-92 (s, 3H), 1.90 (br s, 1H) ppm.
EXAMPLE 13
1 ,5-Anhydro-2,3-dideoxy-3- {3-oxo-5-[(6-oxo- 1 ,6-dihydropyridin-3-yl)methyl]-l ,3-dihydro-2H-
Figure imgf000047_0001
To a solution of 2-O-acetyl-l,5-anhydro-3,4-dideoxy-3-{3-oxo-5-[(6-oxo-l,6-dihydroyridin-3- yl)methyl]-l,3-dihydro-2H-benzo[e]isoindol-2-yl)-L-t ireo-pentitol (Example 12, 0.021 g, 0.049 mmol) in 0.3 mL of methanol was added aqueous lithium hydroxide (1.0 M, 0.049 mL, 0.049 mmol). After 5 min, the mixture was diluted with water and extracted twice with
dichloromethane. The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 391.15 for [M+H : 1H NMR (400 MHz, CDCI3) 5 7.93-7.85 (m, 2H), 7.66-7.59 (m, 2H), 7.56 (s, 1H), 7.52-7.48 (m, 1H), 7.04 (s, 1H), 6,63 (d, J- 9.2 Hz, 1H), 4.90-4.72 (m, 2H), 4.42-4.35 (m, 1H), 4.21-4.16 (m, 1H), 4.14 (s, 2H), 4.08-4.05 (m, 1H), 3.95-3.89 (m, 1H), 3.60-3.54 (m, 1H), 3.35-3.30 (m, 1H), 2.09-1.96 (m, 2H), 0.90-0.83 (m, lH) ppm.
EXAMPLE 14 5-[(6-Methoxypyridin-3-yl)methyI]-2-[3-(trifluoromethyl)pyridin-2-yl]-ls2-dihyd;
benzo [<?] isoindol-3 -one
Figure imgf000048_0001
5-[(6-Methoxypyridin-3-yl)methyl]- 1 ,2-dihydro-3H-benzo[e]isoindol-3-one was prepared employing the procedures described for the construction of 2- [(IS, 25)-2-hydroxycyclohexyl]-5- {[6-(methylihio)pyridine-3-yl]methyl}-l,2-dihydro-3H-benzo[e]isoindol-3-one in Example 10, substituting ammonium hydroxide for (IS, 2S)-2-aminocyclohexanol, and substituting 5- (chloromethyl)-2-methoxypyridme for 5 -(chloromethyl)-2-(methylthio)pyridine.
To a solution of 5-[(6-methoxypyridin-3-yl)methyl]-l,2-dihydro-3H-benzo[e]isoindol-3-one (0.050 g, 0.16 mmol) in 1 mL of dioxane under an atmosphere of nitrogen was added 2-bromo-3- (trifluoromethyl)pyridine (0.037 g, 0.16 mmol), 4,5-bis(diphenyiphosphino)-9,9- dimethylxanthene (0.014 g, 0.025 mmol), cesium carbonate (0.075 g, 0.23 mmol), and tris[dibenzylideneacetone]dipalladium (0) (7.5 mg, 0.0082 mmol). The mixture was irradiated in a microwave reactor at 140 °C for 1.5 hr, cooled to ambient temperature, and diluted with ethyl acetate. The organic solution was washed with water, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 450.1423 for [M+H]+ jcalc'd for C25H19F3N302, [M+H]+ - 450.1424]: Ή NMR (400 MHz, CDC ) δ 8.79-8.77 (m, 1H), 8.20-8.12 (m, 3H), 7.95-7.91 (m, 1H), 7.76 (s, 1H), 7.69-7.62 (m, 2H), 7.52-7.44 (m, 2H), 6.71 (d, J = 8.6 Hz, 1H), 5.34 (s, 2H), 4.46 (s, 2H), 3.94 (s, 3H) ppm. EXAMPLE 15
(±)-5-[(6-Chloropyridin-3-yl)metliyl]-2-(2-fluorophenyI)- 1 -methyl- 1 ,2-dihydro-3H~
Figure imgf000049_0001
5-Bromo-2-(2-fluorophenyl)-l,2-di ydro-3H-benzo[e]isoindol-3-one was prepared employing the procedures described for the construction of 5-brorno-2-[(/5? 2S^-2-hydroxycyclohexyl]-l,2- dihydro-3H-benzo[<2]isoindol-3-one in Example 1, substituting 2-fluoroaniline for (IS, 2S)-2- aminocyclohexanol.
To a solution of diisopropylamine (0.30 mL, 2.1 mmol) in 1 mL of tetrahydrofuran cooled to 0 °C was added n-butyllithium (2.5 M tetrahydrofuran solution, 0.93 mL, 2.3 mmol) dropwise. After 30 min, the mixture was added to a -78 °C solution of 5-bromo-2-(2-fluorophenyl)-l,2- dihydro-3H-benzo[e]isoindol-3-one (0.150 g, 0.421 mmol) in 2 mL of tetrahydrofuran. After stirring for 30 min at -78 °C, iodomethane (0.026 mL, 0.42 mmol) was added dropwise and after an additional 1 hr, the mixture was warmed to ambient temperature, treated with saturated aqueous ammonium chloride, and extracted 2x with ethyl acetate. The combined organic extracts were washed with water and brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the 5-bromo-2-(2-fluorophenyl)-l -methyl- l,2-dihydro-3H-benzo[e]isoindol-3 -one that gave a proton NMR spectra consistent with theory.
The title compound was prepared employing the procedures described for the construction of 2- [(IS, 2¾-2-hydroxycyclohexyl]-5-(4-methoxybeiizyl)-l,2-dihydro-3H-benzo[e]isoindol"3-one in Example 1, substituting 5-bromo-2-(2-fluorophenyl)-l-methyl-l,2-dihydro-3H~benzo[e]isoindol- 3-one for 5-bromo-2-[(7S, J 25)-2-hydroxycyclohexyl]-l,2-dihydro-3H-benzo[e]isoindol-3-one and substituting (2-chloro-5-pyridyl)methylzinc chloride for 4-methoxybenzylzinc chloride. The resultant yellow solid gave a proton NMR spectra consistent with theory and a mass ion (ES÷) of 417.1 168 for [M+H]+ [calc'd for C25Hi9ClFN20, [M+H]+ = 417.1164]: 1H NMR (400 MHz, CDC13) δ 8.37 (s, IH), 8.07-8.03 (m, 2H), 7.84 (s, IH), 7.67-7.59 (m, 3H), 7.43-7.20 (m, 5H), 5.63-5.58 (m, IH), 4.50 (s, 2H), 1.59 (d, J- 6.8 Hz, 3H) ppm.
EXAMPLE 16
(+)-5-[(6-Chloropyridin-3-yl)methyl]-2-[rrflw-2-hydroxycyclohexyl]-l,2-dihydro-3H- pyrro lo [3 ,4-c]isoquinoline-3 -one
Figure imgf000050_0001
A solution of methyl isocyanoacetate (4.20 mL, 46.2 mmol) and methyl 2-formylbenzoate (6.90 g, 42.0 mmol) in 30 mL of N,N-dimethylformamide was added drop wise to a suspension of sodium hydride (1.21 g, 50.4 mmol) in 20 mL of N,N-dimethylformamide. After 5 hr, the mixture was treated with 10% aqueous acetic acid and water and extracted 2x with ethyl acetate. The combined organic extracts were washed 3x with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was crystallized from 1 : 10 ethyl acetate:hexanes to provide methyl l-oxo-l,2-dihydroisoquinoline-3-carboxylate.
To a solution of the above compound (1.66 g, 8.17 mmol) in a mixture of 20 mL of N,N- dimethylformamide and 3 mL of acetonitrile was added N-bromosuecinimide (1.53 g, 8.58 mmol). After 2 hr, the mixture was diluted with water, and a solid was collected via filtration. The filter cake was washed with additional water to provide methyl 4-bromo-l-oxo~l,2- dihydroisoquinoline-3-carboxylate. To a solution of the above compound (1.19 g, 4.22 mmol) in 5 mL of tetrahydrofuran under an atmosphere of nitrogen was added dimethylzinc (0.5 M in tetrahydrofuran, 25.3 mL, 12.7 mmol) and [l, -bis(diphenylphosphino)ferrocene]dichloro-palladium(II)f 1 :1 complex with
dichloromethane (0.154 g, 0.211 mmol). The mixture was heated at 65 °C for 3 hr, cooled to ambient temperature, diluted with ethyl acetate, and filtered through a pad of Celite. The filtrate was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide methyl 4-methyl-l-oxo-l,2-dihydroisoquinoline-3-carboxylate that gave a mass ion (ES+) of 218.0 for [M+H]+.
To a solution of the above compound (2.16 g, 9.94 mmol) in a mixture of 15 mL of toluene and 15 mL of acetonitrile was added phosphorus oxybromide (3.71 g, 12.9 mmol). The mixture was heated at 65 °C for 15 hr, cooled to amient temperature, and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was filtered through a silica gel plug eluting with 30% ethyl acetate in hexanes to provide methyl 1 -bromo-4-methylisoquinoline- 3-carboxylate that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 282.0 for [M+H]+.
To a solution of the above compound (2.70 g, 9.64 mmol) in 50 mL of carbon tetrachloride was added N-bromosuccinimide (1.72 g, 9.64 mmol) and azobisisobutyronitrile (0.317 g, 1.93 mmol). The mixture was heated at 60 °C for 6 hr, cooled to ambient temperature, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-10% ethyl acetate solution of methanol (10%) in hexanes, to provide methyl l-bromo-4- (bromomethyl)isoquinoline-3-carboxylate that gave a mass ion (ES+) of 359.7 for [ +H]+.
The title compound was prepared employing the procedures described for the construction of 2- [(IS, 25)-2-hydroxycyclohexyl]-5-(4-methoxyberizyl)-l>2-dihydro-3H-benzo[e]isoindol-3-one in Example 1, substituting (±)-/r<ms,-2-aimnocyclohexanoI for (IS, 25)-2-aminocyclohexanol, and, substituting methyl 1 ~bromo~4-(bromomethyl)isoquinoline-3 -carboxylate
for methyl 4-bromo-l-(bromomethyl)-2-naphthoate, and substituting (2-chloro~5- pyridyl)methylzinc chloride for 4-methoxybenzylzinc chloride. The resultant yellow solid gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 407.9 for [3V1+H]+: Ή NMR (400 MHz, CDC13) δ 8.44 (d, J= 8.6 Hz, 1H), 8.39 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.94-7.90 (m, 1-H), 7.84-7.81 (m, 1H), 7.78-7.75 (m, 1H), 7.32 (d, J= 8.2 Hz, 1H), 4.89 (s, 2H), 4.13-4.06 (m, 1H), 3.98-3.83 (m, 1H), 3.34 (s, 2H), 2.13-2.01 (m, 1H), 1.94-1.91 (m, 1H), 1.85-1.72 (m, 3H), 1.50-1.34 (m, 4H) ppm.
EXAMPLE 17
(±)-2- [tm¾y-2-Hydroxycyclohexyl] -5- { [6-( 1 H-pyrazol - 1 -yl)pyridine-3 -yl] methyl }- 1 ,2-dihydro-
Figure imgf000052_0001
To a solution of (±)-5~[(6-chloropyridin-3-yl)methyl]-2-[/rara-2-hydroxycyclohexyl]-l,2- dihydro-3H-pyrrolo[3,4~c]isoquinoline-3-one (Example 16, 0.040 g, 0.098 mmol) and pyrazole (0.020 g, 0.29 mmol) in 1 mL of dimethyl sulfoxide under an atmosphere of nitrogen was added cesium carbonate (1.0 M aqeuous, 0.20 mL, 0.20 mmol), (±)- r w-N,N1-dimethylcyclohexane- 1,2-diamine (1.4 mg, 0.0098 mmol), and copper(I) iodide (0.93 mg, 0.0049 mmol). The mixture was heated at 120 °C for 15 hr, cooled to ambient temperature, and purified via preparative reverse phase HPLC to provide the titled compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 440.9 for [M+Hf : 1H NMR (400 MHz, CD3OD) δ
8.51-8.46 (m, 3H), 8.14 (d, J= 8.2 Hz, 1H), 7.94-7.80 (m, 5H), 6.54-6.44 (m, 1H), 4.90 (s, 2H), 4.12-4.08 (m, 1H), 3.93-3.86 (m, 1H), 3.49-3.40 (m, 1H), 3.31 (s, 2H), 2.20-2.02 (m, 1H), 1.95-1.90 (m, 1H), 1.89-1.70 (m, 3H), 1.54-1.43 (m, 3H) ppm. EXAMPLE 18
8-[(7i5, 2i$ -2-Hydroxycyclohexyl]-5-[(6-methoxypyridin-3-yl)methyl]~9,9-dimethyl-8,9-dihydro-
7H-pyrrolo[3,4-/z]quinolin-7-one
Figure imgf000053_0001
Figure imgf000053_0002
5-Bromo-8-[(i£, 2S)-2-hydrocyclohexyl]-3,9-dihydro-7H-pyrrolo[3i4-/:i]quinolin--7--one was prepared according to the procedures described for the construction of 5-bromo-2-[(i5', 26 -2- hydroxycyclohexyl]-lf2-dihydro-3ii-benzo[e]isoindol-3-one in Example 1 , substituting methyl 8-hydroxyquinoline-7-carboxylate for l-hydroxy-2-naphthoic acid methyl ester.
To a 15 mL dichloromethane solution of 5 -bromo- 8 -[(/<!?, 25)-2-hydroxycyclohexyl]-3,9-dihydro- 7H-pyrrolo[3,4-A]quinolin-7-one (2.00 g, 5.54 mmol) at 0 °C was added 2,6 lutidine (1.29 mL, 11.1 mmol) and tert-butyldimethylsilyl trifluoroniethanesulfonate (1.91 mL, 8.30 mmol). The mixture was warmed to ambient temperature, and after 15 hr, diluted with water and extracted 2x with ethyl acetate. The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The resultant white crystals were collected via filtration and washed with hexanes to provide 5-bromo-8-[(iS', 25)-2~{[feri- butyl(dimethyl)silyl)oxy}cyclohexyl]-8,9-dihydro-7H-pyrrolo[3,4-/i]quinolin-7-one that gave a proton NMR spectra consistent with theory.
To a 0 °C solution of diisopropylamine (2.77 mL, 19.4 mmol) in 20 mL of tetrahydrofuran was added n-butyllithium (2.5 M tetrahydrofuran solution, 8.56 mL, 21.4 mmol) dropwise. After 30 min, the resultant solution was added to a solution of 5~bromo-8-[(AS', 2,S)-2-{[teri- butyl(dimethyl)silyl]oxy}cyclohexyl]-8J9-dihydro-7H-pyrrolo[3,4-¾quinolin-7-one (1.85 g, 3.89 mmol) in 20 mL of tetrahydrofuran cooled to -78 °C. After 30 min, iodomethane (0.27 mL, 4.3 mmol) was added dropwise and after 1 hr, the mixture was warmed to ambient temperature, treated with saturated aqueous ammonium chloride, and extracted 2x with ethyl acetate. The combined organic extracts were washed with water and brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes, to provide 5-bromo-8-[(i5'5 2S)-2-{[tert- butyl(dimethyl)silyl] oxy } cyclohexyl] -9,9-dimethyl-8,9-dihydro-7H-pyrrolo [3 ,4-h] quinolm-7- one.
To a solution of 5-(chloromethyl)-2-methoxypyridine (0.117 g, 0.745 mmol) in 0.3 mL of tetrahydrofuran under an atmosphere of nitrogen was added Rieke zinc (0.76 M, 0.98 mL, 0.74 mmol). The mixture was heated at 90 °C for 2 h and then cooled to 0 °C. 5-Bromo-8-[(iS', 25)- 2- { [ieri-butyl(dimethyl)silyl]oxy) cyclohexyl]-9,9-dimethyl-8,9-dihydro-7H-pyrrolo[3i4- /i]quinolin-7-one (0.075 g, 0.15 mmol) and bis(tri-¾rt-butylphosphine)palladium(0) (2.3 mg, 0.0045 mmol) were added and the mixture was stirred at ambient temperature for 30 min. The mixture was diluted with saturated aqueous ammonium chloride and extracted 2x with dichloromethane. The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC followed by purification via silica gel chromatography, eluting with 0-10% methanolic ammonium hydroxide (10%) in dichloromethane, to provide 8-[(iS'5 25)-2-{[feri- butyl(dimethyl)silyl]oxy}cyclohexyl]-5-[(6-methoxypyridin-3-yl)methyl]-9,9-dimethyl-8,9- dihydro-7H-pyrrol o [3 ,4-h] quinolin-7-one.
To a solution of the above compound (0.080 g, 0.15 mmol) in 0.5 mL of NN-dimethylformamide was added trifluoroacetic acid (0.23 mL, 2.9 mmol). After 1 hr, the mixture was filtered and purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 432.2282 for [M+H]+ [calc'd for C26H3oN303, [M+H]+ - 432.2282]: 1H NMR (400 MHz, CDC13) δ 9.02-9.00 (m, IH),
8.39-8.37 (m, IH), 8.19- (s, IH), 7.70 (s, IH), 7.52-7.46 (m, 2H), 6.74 (d, J= 8.6 Hz, IH), 4.83-4.77 (m, IH), 4.3-8 (s, 2H), 3.96 (s, 3H), 3.25-3.19 (m, IH), 2.45-2.35 (m, IH), 2.20-2.17 (m, IH), 1.88 (s, 3H), 1.84 (s, 3H), 1.83-1.80'(m, 2H), 1.57-1.25 (m, 3H) ppm. EXAMPLE 19
5-{[6~Benzyloxy)pyridine-3-yl]methyl}-8-[(i5', 25 -2-hydroxycyclohexyl]-8,9-dihydro-7H-
Figure imgf000055_0001
Construction of methyl 6-(bert2yloxy)pyridine-3-carboxylate.
Figure imgf000056_0001
To a solution of methyl 6-oxo-l,6-dihydropyridine-3-carboxylate (2.00 g, 13.1 mmol) in 45 n L of benzene was added benzyl bromide (1.86 mL, 15.7 mmol) and silver carbonate (3.96 g, 14.4 mmol). The flask was covered with aluminum foil, and after 85 hr, the mixture was diluted with ethyl acetate, filtered through celite, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes to provide methyl 6- (benzyloxy)pyridine-3 -carboxylate.
5-Bromo-8-[(7tS', 25)-2-hydroxycyclohexyl]-8,9-dihydro-7H-pyrrolo[334- z]quinolin-7-one was prepared employing the procedures described for the construction of 5-bromo-2-[( 5', 2iS -2- hydroxycyclohexyl]-l52-dihydro-3H-benzo[e]isoindol-3-one in Example 1, substituting methyl 8-hydroxyquinoline-7-carboxylate for l-hydroxy-2-naphthoic acid methyl ester.
The title compound was prepared employing the procedures described for the construction of 2- [(IS, 25 -2-hydroxycyclohexyl3-5-{ [6-(methylthio)pyridine-3-yl]methyl} -1 ,2-dihydro-3//~ benzo[e]isoindol-3-one in Example 10, substituting S-bromo-S-IX/S1, 2<S)-2-hydroxycyclohexyl]- 8,9-dihydro-7H-pyrrolo[3,4-¾]quinolin-7-one for 5-bromo-2-[(i5'f 2S)-2-hydroxycyclohexyl]-l,2- dihydro-3H-benzo[e]isoindol-3-one, and substituting methyl 6-(benzyloxy)pyridine-3- carboxylate for methyl 6-(methylthio)nicotinate. The resultant white solid gave a proton NMR spectra consistent with theory: 1H NMR (400 MHz, CDC13) δ 9.00-8.98 (m, IH), 8.43-8.41 (m5 IH), 8.06 (s, IH), 7.80 (s, IH), 7.54-7.51 (m, IH), 7.45-7.42 (m, 2H), 7.38-7.28 (m, 4H), 6.70 . (d, J- 8.5 Hz, IH), 5.33 (s, 2H), 5.30-4.87 (m, 2H), 4.38 (s, 2H), 4.23-4.17 (m, IH), 3.79-3.73 (m, IH), 2.22-2.19 (m, IH), 2.01-1.98 (m, IH), 1.86-1.83 (m, 2H), 1.73-1.63 (m, IH),
1.54-1.31 (ra, 3H) ppm.
EXAMPLE 20
&-[(lS, 2«S)-2-Hydroxycyclohexyl]-5-[(6-oxopiperidin-3-yl)methyl]-3,9-dihydro-7H-pyrrolo[3,4-
/z]quinolin-7-one
Figure imgf000057_0001
To a solution of 5-{[6-benzyloxy)pyridine-3-yl]methyl}-8-[( S, 2S)-2-hydroxycyclohexyl]-8,9- dihydro-7H-pyrrolo[3J4- z]quinolin-7-one (Example 19, 0.070 g, 0.15 mmol) in a mixture of 1 mL of ethyl acetate and 1 n L of ethanol under an atmosphere of nitrogen was added palladium on carbon (1.6 mg, 0.015 mmol). The mixture was placed under an atmosphere of hydrogen (1 atm) for 15 hr, filtered through a pad of Celite and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 394.2134 for [M+H]+ [Calc'd for C23H28N303, [M+H]+ = 394.2134]: 1H NMR (400 MHz, CD3OD) δ 7.54-7.51 (m, 1H), 7.21 (d, J= 1.8 Hz, 1H), 6.90 (s, 1H), 6.59 (d, J- 9.4 Hz, 1H), 4.33-4.22 (m, 2H), 4.00-3.82 (m, 1H), 3.82 (s, 2H), 3.75-3.69 (m, 1H), 3.37-3.32 (m, 1H)5 2.84-2.69 (m, 3H), 2.11-2.09 (m, 1H), 1.97-1.92 (m, 2H), 1.92-1.67 (m, 3H), 1.64-1,57 (m, 1H), 1.44-1.29 (m, 4H) ppm. EXAMPLE 21
5-[(6-Chloropyridin-3-yl)methyl3-9-(2,3-dihydroxypropyI)-8-[(i5', 25 -2-hydroxycyclohexyl]-
8,9-dihydro-7H-pyrrolo [3 ,4- ?] quinolin-7-one
Figure imgf000058_0001
8-[(iS, 2S)-2-{[fe^bulyl(dime ^^
(prop-2-en-l -yl)-8j9-dihydro-7H-pyrrolo[3;4- z]quinolin-7-one was prepared employing the procedures described for the construction of δ-ΐ /.!), 25)-2-{[/ert- butyl(dimethyl)silyl]oxy}cyclohexyl]-5-[(6-methoxypyridin-3-yl)methyl]-9,9-dimethyl-8,9- dihydro-7H-pyrrolo[3,4-h]quinolin-7-one in Example 18, substituting allyl bromide for methyl iodide, and substituting (2-chloro-5-pyridyl)methylzinc chloride for chloro[(6-methoxypyridin-3- yl)methyl]zinc.
To a solution of S- iS". 25)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-5-[(6-chloropyridin- 3-yl)methyl]-9-(prop-2-en-l-yl)-8,9-dihydro-7H-pyrrolo[3,4-/i]quinolin-7-one (0.035 g, 0.062 mmol) in a mixture of 0.5 mL of tetrahydrofuran and 0.15 mL of water was added- osmium tetroxide (4% wt in water, 0.098 mL, 0.012 mmol) and 4-methylmorpholine 4-oxide (7.3 mg, 0.062 mmol). After 2 hr, the mixture was diluted with ethyl acetate, washed 2x with saturated aqueous sodium bicarbonate, dried with sodium sulfate, filtered, and concentrated in vacuo to provide S-J iS1, 2iS)-2-{[t<2rt-buyl(dimethyl)silyl]oxy}cyclohexyl]-5-[(6-chloropyridin-3- yl)methyl]-9-(2!3-dihydroxypropyl)-8,9-dihydro-7H-pyrrolo[3,4-/i]quinolin-7-one. To a solution of the above compound (0.037 g, 0.062 mmol) in 3 mL of tetrahydrofuran was added hydrochloric acid (6 N aqueous, 3 drops). After 12 hr, the mixture was treated with triethylamine until pH 7 and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the titled compound that gave a proton NMR spectra consistent with theoiy and a mass ion (ES+) of 482.1834 for [M+Hf [catc'd for C26H29C1N304, [M+H]+ = 482.1841]: H NMR (400 MHz, CD3OD) δ 8.99-8.97 (m, 1H), 8.64-8.61 (m, 1H), 8.32 (s, 1H), 7.71 (s, 1H), 7.66-7.62 (m, 2H), 7.37 (d, J= 8.4 Hz, 1H), 5.34-5.31 (m, 1H), 4.80 (s, 2H), 3.48-3.44 (m, 1H), 3.24-3.06 (m, 3H), 2.91-2.85 (m, 1H), 2.48-2.41 (m, 1H), 2.27-2.11 (m, 2H)} 1.87-1.77 (m, 2H), 1.46-1.28 (m, 3H), 0.90-0.76 (m, 2H) ppm.
EXAMPLE 22
{5-[(6-Chloropyridin-3-yl)methyl]-8-[(iiS, 25)-2-hydroxycyclohexyl]-7-oxo-8,9-dihydro
Figure imgf000059_0001
To a solution of 8-[(lS, 2¾-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-5-[(6-chloropyridin-3- yl)methyl]-9-(2,3-dihydroxypropyl)-8,9-dihydro-7H-pyrrolo[3,4- z]quinolin-7-one (Example 21 , 0.050 g, 0.084 mmol) in a mixture of 0.8 mL of acetonitrile and 0.6 mL of water at 0 °C was added sodium periodate (0.018 g, 0.084 mmol). After 1.5 hr, the mixture was diluted with dichloromethane, filtered through Celite, and poured into saturated aqueous sodium bicarbonate. The mixture was extracted 3x with dichloromethane and the combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo to provide {8-[(lS, 2S)-2-{[tert- butyl(dimemyl)silyl]oxy}cyclohexyl]-5-[(6-chloropyridin-3-yl)methyl]-7-oxo-8,9-dihydro-7H- pyrrolo[3i4-/z7quinolin-9-yl}acetaldehyde that gave a mass ion (ES+) of 564.5 for [M+H]+.
To a solution of the above compound (0.030 g, 0.053 mmol) in 0.6 mL of THF was added hydrochloric acid (3 N aqueous, 4 drops). After 14 hr, the mixture was diluted with saturated aqueous sodium bicarbonate and extracted 3x with ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the titled compound that gave a mass ion (ES+) of 450.1581 for [M+Hf [calc'd for C25H25CIN3O3, [M+H]+ - 450.1579]: lH NMR (400 MHz, CD3OD) δ 9.57 (s, 1H), 8.95 (s, 1H), 8.34-8.30 (m, 2H), 7.75 (s, 1H), 7.52-7.48 (m, 1H),
7.38-7.35 (m, 1H), 7.22 (d, J= 8.1 Hz, 1H), 5.51-5.48 (m, 1H), 4.55-4.48 (m, 1H), 4.46 (s, 2H), 3.74-3.63 (m, 1H), 3.49-3.40 (m, 1H), 2.20-1.79 (m, 7H), 1.43-1.32 (m, 3H) ppm.
EXAMPLE 23
5- [(6-Chloropyridin-3 -y l)methyl] -9-[2-(dimethylami no)ethy 1] - 8 - [{IS, 2S)~2-hydroxycy clohexyl ] -
8,9-dihydro-7H-pyrrolo[3,4-/z]quinolin-7-one
Figure imgf000060_0001
To a solution of {8-[(JS, 25)-2-{[to -butyl(dimethyl)silyl]oxy}cyclohexylJ-5-[(6-chloropyridin- 3-yl)methyl]-7~oxo-8,9-dihydro-7H-pyrrolo[3,4-¾]quinolin-9-yl}acetaldehyde (see Example 22, 0.033 g, 0.058 mmol) in 1.2 roL of 1 ,2-dichloroethane was added dimethylamine (2 M in tetrahydrofuran, 0.059 mL, 0.12 mmol), acetic acid (0.0034 mL, 0.058 mmol), sodium
cyanoborohydride (3.7 mg, 0.058 mmol), and 4A molecular sieves. The mixture was irradiated in a microwave reactor at 100 °C for 20 min, cooled to ambient temperature, and filtered. The filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in 2 mL of dichloromethane and treated with hydrochloric acid (6 M aqueous, 4 drops). After 14 hr, the mixture was diluted with dichloromethane, washed 2x with saturated aqueous sodium bicarbonate, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 479.2200 for [M+H]+ [calc'd for C27H32CIN402, [M+H]+ - 479.2208]: !H NMR (400 MHz, CDC13) δ 8.97-8.96 (m, 1H),
8.34-8.28 (m, 2H), 7.78 (s, 1H), 7.54-7.50 (m, 1H), 7.44-7.40 (m, 1H), 7.24 (d, J= 8.3 Hz, 1H), 5.21-5.19 (m, 1H), 4.69-4.51 (m, 1H), 4.47 (s, 2H), 3.42-3.33 (m, 1H), 3.29-3.15 (m, 2H), 2.76-2.63 (m, 1H), 2.49 (s, 6H), 2.29-2.17 (m, 2H), 1.81-1.68 (m, 2H), 1.48-1.00 (m, 5H) ppm. EXAMPLE 24
5-[(6-Chloropyridin-3-yl)methyl]-8-[(25, 25)-2-hydroxycyciohexyl]-9-(2-hydroxyethyl)-8,9-
Figure imgf000061_0001
To a solution of { S-[(JS, 2S)-2- { [fer/-butyl(dimethyl)siiyl] ox } cyclohexyl]-5- [(6-chloropyridin- 3-yl)methyl]-7-oxo-8,9-dihydro-7H-pynOlo[3,4-/2]quinolin-9-yl}acetaldehyde (see Example 22, 0.030 g, 0.053 mmol) in a mixture of 0.4 mL of dichloromethane and 0.1 mL of methanol at 0 °C was added sodium borohydride (2.0 mg, 0.053 mmol). The mixture was allowed to warm to ambient temperature and after 15 hr, hydrochloric acid (3 N aqueous, 5 drops) was added. After 24 hr, the mixture was diluted with saturated aqueous sodium bicarbonate and extracted 3x with ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the titled compound that gave a mass ion (ES+) of 452.1735 for [M+H]+ [calc'd for
C25H27C1N303, [M+H]+ = 452.1735]: lH NMR (400 MHz, CD3OD) δ 9.00-8.98 (m, 1H), 8.62-8.59 (m, 1H), 8.31-8.30 (m, 1H), 7.69 (s, 1H), 7.65-7.62 (m, 2H), 7.37 (d, J= 8.3 Hz, 1 H), 5.44-5.41 (m, 2H), 4.60 (s, 2H), 4.42-4.36 (m, 1H), 3.76-3.66 (m, 1H), 3.15-3.01 (m, 2H), 2.58-2.51 (m, 1H), 2.16-2.13 (m, 1H), 1.97-1.93 (m, 2H), 1.82-1.79 (m, 2H), 1.46-1.40 (m, 3H) ppm.
EXAMPLE 25
5-[(6-Cyclopropylpyridin-3-yl)methyl]-8-[(/S', 25)-2-hydroxycyclohexyl-8,9-dihydro-7H-
Figure imgf000062_0001
To a solution of 5-bromo-8-[(iS', 2iS)-2-{[¾ri-butyl(dimethyl)silyl]oxy}cyclohexyl]-8,9-dihydro-7H- pyrrolof3,4- i]quinolin-7-one (see Example 18, 2.00 g, 4.21 mmol) in a mixture of 20 mL of THF and 2 mL of water under an atmosphere of nitrogen was added potassium vinyltrifluoroborate (0.789 g, 5.89 mmol), potassium carbonate (1.45 g, 10.5 mmol), and bis(tri-feri- butylphosphine)palladium(O) (0.215 g, 0.421 mmol). The mixture was heated at 50 °C for 2 hr, cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate and extracted 2x with ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-60% ethyl acetate in hexanes to provide S-[(JS, 25)-2{[tert- butyl(dimethyl)silyl]oxy}cyclohexyl]-5-ethenyl-859-dihydro-7H-pyrrolo[3?4-/2]quinolin-7-one that gave a proton NMR spectra consistent with theoiy and a mass ion (ES+) of 424.4. A solution of the above compound (1.26 g, 2.99 mmol) in a mixture of 20 mL of
dichloromethane and 5 mL of methanol was cooled to -78 °C and saturated with ozone. After 15 min, the solution was sparged with nitrogen and resin-bound triphenylphosphine (3 mmol/g, 2.0 g, 6.0 mmol) was added. The mixture was warmed to ambient temperature and after 1.5 hr, the mixture was filtered through Celite and the filtercake was washed with a 5:1 mixture of dichloromethane:methanol. The filtrate was concentrated in vacuo, and the residue was was purified via silica gel chromatography, eluting with 0-70% ethyl acetate in hexanes to provide 8- [(JS, 2S)-2 { [ ert-butyl(dimethyl)silyl]oxy} cyclohexyl)-7-oxo-8,9-dihydro~7H-pyrrolo[3 ,4- /z]quino!ine-5-carbaldehyde that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 425.4.
To a solution of the above compound (0.496 g, 1.17 mmol) in a mixture of 15 mL of
dichloromethane and 3 mL of methanol at 0 °C was added sodium borohydride (0.055 g, 1.5 mmol). After 5 min, the mixture was warmed to ambient temperature. After an additional 45 min, the mixture was treated with saturated aqueous sodium bicarbonate and stirred vigorously for 1.5 hr. The mixture was poured into water and extracted 2x with dichloromethane. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo to provide 8-jXiS1, 2S)-2-{[½ri-butyl(dimethyl)silyl]oxy}cyclohexyl]~5-(hydroxymethyl)-8}9- dihydro-7H-pyrrolo[3,4-&]quinolin-7-one that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 428.4.
To a suspension of resin-bound triphenylphosphine (3 mmol/g, 0.170 g, 0.510 mmol) in 3 mL of THF was added N-chlorosuccinimide (0.059 g, 0.44 mmol). After 15 min, the above compound (0.075 g, 0.176 mmol) was added. After 2 h, the mixture was filtered and concentrated in vacuo to provide &-[(lS, 21S)-2-{[iert-butyl(dimethyl)silyl]oxy}cyclohexyl]-5-(chloromethyl)-8,9- dihydro-7H-pyrrolo[3,4- 2]quinolin-7-one that gave a mass ion (ES+) of 445.4.
To a solution of the above compound (0.078 g, 0.18 mmol) in a mixture of 5 mL of THF and 0.9 mL of water under an atmosphere of nitrogen was added 6-cyclopropyl-3-pyridinyl boronic acid pinacol ester (0.086 g, 0.35 mmol), cesium carbonate (0.29 g, 0.88 mmol), and [Ι , -bis- (diphenylphosphino)ferrocene]dichloro-palladium(II), 1 :1 complex with dichloromethane (0.026 g, 0.035 mmol). The mixture was heated at 65 °C for 2 h, cooled to ambient temperature, and diluted with water. The mixture was extracted 2x with ethyl acetate and the combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo to provide -{{lS, 25)-2- { [ie7-t-butyl(dimethyl)silyl]oxy}cyclohexyl]-5-[(6-cyclopropylpyridin-3-yl)methyl]-8,9- dihydro-7H-pyrrolo[3,4-/i]quinolin-7-one that gave a mass ion (ES+) of 528.5. To a solution of the above compound (0.093 g, 0.18 mmol) in 5 mL of THF was added hydrochloric acid (1 N aqueous, 1.0 mL, 1.0 mmol; followed by 12 N aqueous hydrochloric acid, 20 drops). After 2 hr, the mixture was treated with saturated aqueous sodium bicarbonate. After stirring for 1 hr, the mixture was poured into water and extracted 2x with ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-8% methanol in dichloromethane, to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 414.2179 for [M+H]+ [calc'd for C26H28N3O2, [M+H]+ =
414.2176]: !H NMR (400 MHz, CDC13) S 8.95-8.94 (m, 1H), 8.38-8.34 (m, 1H), 7.78 (s, 1H), 7.56-7.44 (m, 2H), 7.24-7.18 (m, 1H), 6.99 (d, J= 8.2 Hz, 1H), 4.98-4.86 (m, 2H), 4.40 (s, 2H), 4.22-4.16 (m, 1H), 3.79-3.72 (m, 1H), 2.23-2.19 (m, 1H), 2.13-1.99 (m, 3H), 1.87-1.65 (m, 4H), 1.54-1.40 (m, 3H), 1.07-1.01 (m, 2H) ppm.
The following compounds in Table 1 were prepared according to the general procedure described in the Examples 1 through 25, where appropropriate, substituting the appropriate reagents. The starting materials are either commercially available, known in the literature or may be prepared from commercially available reagents using conventional reactions well known in the art.
Table 1
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000068_0002
1
388.0 Example 2, 16
404.2 Example 11, 16
Figure imgf000069_0001
454.0 Example 3, 16
Figure imgf000069_0002
Figure imgf000069_0003
Figure imgf000070_0001
1
72 *0 H, H 405.3 Example 1 1
OH ^-^OMe
!
73 Η,Η 389.1857 Example 11
OH
1
74 Η, Η 409.1 Example 1 1
OH
1
75 H, H 393.2 Example 11
OH
1
76 *0 OH ¾rCF3 H, H 443.2 Example 11
1
77 ri, Jt 389.2 Example 11
OH Me
1
78 11, Jtl 393.2 Example 1 1
OH F
1
79 H, H 389.2 Example 11
OH
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Biological Utility The utility of the compounds as Ml receptor positive allosteric modulators may be demonstrated by methodology known in the art, including by the assay described below. The assay is designed to select compounds that possess modulator activity at the acetylcholine muscarinic Ml receptor or other muscarinic receptors expressed in CHOnfat cells by measuring the intracellular calcium with a FLIPR.384 Fluorometric Imaging Plate Reader System. The assay studies the effect of one or several concentrations of test compounds on basal or acetyl choline-stimulated Ca^+ levels using FLIPR.
Compounds are prepared and subjected to a preincubation period of 4 min. Thereafter, a single EC20 concentration of acetylcholine is added to each well (3 nM final). The intracellular Ca2+ level of each sample is measured and compared to an acetylcholine control to determine any modulatory activity.
Cells: CHOnfat/hMl, hM2, hM3 or hM4 cells are plated 24 hr before the assay at a density of 18,000 cells/well (100 L) in a 384 well plate. CHOnfat/hMl and CHOnfai/hM3 Growfh Medium: 90% DMEM (Hi Glucose); 10% HI FBS; 2 mM L-glutamine; 0.1 mM NEAA; Pen-Strep; and lmg/ml Geneticin, are added. For M2Gqi5CHOnfat and M4Gqi5CHOnfat cells, an additional 600 ug/ml hygromycin is added.
Equipment: 384 well plate, 120 L addition plate; 96-well Whatman 2 ml Uniplate Incubator, 37 *C, 5% CO2; Skatron BMBLA-384 Plate Washer; Multimek Pipetting System;
Genesis Freedom 200 System; Mosquito System; Temo Nanolitre Pipetting System; and
FLIPR384 Fluorometric Imaging Plate Reader System are used.
Buffers. Assay Buffer: Hanks Balanced Salt Solution, with 20 mM Hepes, 2.5 mM Probenecid (Sigma P-8761) first dissolved in 1 N NaOH, 1% Bovine Serum Albumin (Sigma A- 9647). Dye Loading Buffer: Assay Buffer plus 1% Fetal Bovine Serum and Fluo-4AM/Pluronic Acid Mixture. 2 mM Fluo-4AM ester stock in DMSO (Molecular Probes F- 14202)
Concentration of 2 μΜ in buffer for a final concentration of 1 μΜ in Assay. 20% Pluronic Acid Solution stock, with concentration of 0.04% in Buffer, 0.02% in Assay.
65
Figure imgf000076_0001
of 20% Pluronic Acid. The resulting solution and 650 μΕ FBS is added to the assay buffer for a total volume of 65 mL. Positive Controls: 4-Br-A23187: 10 mM in DMSO; final concentration 10 μΜ. Acetylcholine: 10 mM in water, working stock at both 20 μΜ and 30 μΜ in assay buffer, final concentration of 10 μΜ. This is used to check the maximum stimulation of the CHO l hMl cells. 20 μΜ (2x) acetylcholine is added in the preincubation part of the assay, and the 30 μΜ (3 ) stock is added in the second part. (EC20) Acetylcholine: 10 mM in water, working stock of 9 nM (3x), and final concentration in assay is 3 nM. This is used after the preincubation with test compounds. Addition of the EC20 Acetylcholine to each well with a test compound will ascertain any modulator activity. 24 wells contain 3nM Acetylcholine alone as a control.
Determining Activity of Putative Compounds: Screening Plate: Compounds are titrated in 96-well plates (columns 2-1 1), 100% DMSO, started at a concentration of 15 mM (150x stock concentration), and 3-fold serial dilutions using Genesis Freedom200 System. Four 96-well plates are combined into a 384- well plate using Mosquito Nanolitre Pipetting System by transferring 1 μΐ of serial diluted compounds to each well, and 1 mM acetylcholine (lOOx stock concentration) were added as a control. Using Terno, 49 μΐ assay buffer is added to each well of the 384-well plate right before assay.
In a 96-well Whatman 2ml Uniplate, 9 nM Acetylcholine (3x) is pipetted into wells corresponding to the screening compounds, and into control wells. The 30 μΜ acetylcholine control (3x) is added into control wells, and the 3x agonist plate is transferred into a 384 well plate.
Cells are washed three times with 100 μΐ, of buffer, leaving 30μΙ. of buffer in each well. Using Multimek, 30 μL· of Dye Loading Buffer is added into each well and incubated at 37 °C, 5% CO2 for up to one hr.
After 60 min, the cells are washed three times with 100 iL of buffer, leaving 30 μΐ, of buffer in each well The cell plate, screening plate, and agonist addition plates are placed on the platform in the FLiPR and the door closed. A signal test to check background fluorescence and basal fluorescence signal is performed. Laser intensity is adjusted if necessary.
4 min of preincubation with the test compounds is provided to determine any agonist activity on the Ml receptor by comparison to the 1 mM acetylcholine control. After
preincubation, the EC20 value of acetylcholine (3 nM final) is added to determine any modulator activity.
A further description of the muscarinic FLIPR assay can be found in International patent application WO2004/073639.
In particular, the compounds of the following examples had activity in the
aforementioned assay, generally with an IP (inflection point) of 10 μΜ (10,000 nM) or less. The inflection point is calculated from the FLIPR values, and is a measure of activity. Such a result is indicative of the intrinsic activity of the compounds in use as Ml allosteric modulators.
IP values from the aforementioned assay for representative exemplary compounds of the invention (as described herein) are provided below in Table 2 below: Table 2
Figure imgf000078_0001
While the invention has been described and illustrated with reference to certain pailicular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. It is intended, therefore, that the invention be defined by the scope of the claims that follow and that such claims be interpreted as broadly as is reasonable.

Claims

What is claimed is:
1. A compound of formula (I):
Figure imgf000079_0001
(I)
and pharmaceutically acceptable salts thereof, wherein
Y and Z independently represent CH, or N, provided that they both are not N at the same time,
W represents aryl, pyridyl, or oxopiperidinyl, optionally substituted with one or more of RX;
R is selected from the group consisting of hydrogen, (CHR2)nC3-io cycloalkyl, (CHR2)nC6_io aryl, (CHR2)nC5_io heterocycle, said cycloalkyl, aryl, and heterocycfyl optionally substituted with 1 to 3 groups of RY;
Ri and R3 independently represent H, C\.(, alkyl, C2-6 alkenyl, (CH2)nC6_ioaiyl5 (CH2)nO(CH2)nC$- lOaryl, said alkyl, alkenyl optionally substituted with 1 to 3 groups of OH, CF3, halo, orN(R2)2, or and R3 together with the carbon atom they are attached form a 3-6 cycloalkyl; x is selected from the group consisting of hydrogen, Ci -6 alkyl, C2-6 alkenyl, halogen, OR2, (CHR2)nC5~10 heterocycfyl, (CHR2)nC6 0 aryl, -O(CHR2)nC6-10aryl, CN, SR2, N(R2)2, (CH2)nCF3, -0(CH2)nCF3, C3.6 cycloalkyl, said heterocycfyl and aryl optionally substituted with 1 to 3 groups of Ci-6 alkyl, halogen, hydroxyl, (CH2)nCF3,or CN,
Ry is selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, halogen, COOR2, OR2, CN, SR2, N(R2)2, and (CH2)nCF3, R2 is selected from the group consisting of hydrogen, or -Ci .g alkyl, and n is 0, 1 or 2.
2. The compound of claim 1 wherein W is pyridyl, and pharmaceutically acceptable salts thereof.
3. The compound of claim 1 wherein W is phenyl, and pharmaceutically acceptable salts thereof.
4. The compound of claim 1 wherein R is C3.10 cycloalkyl optionally substituted with 1 to 3 groups of RY> and pharmaceutically acceptable salts thereof.
5. The compound according to claim 4 wherein R is cyclohexyl or cyclohexenyl, both optionally substituted with 1 to 3 groups of Ry> and pharmaceutically acceptable salts thereof.
6. The compound of claim 1 wherein R is (CHR2)nC5-io heterocycle, optionally substituted with 1 to 3 groups of Y> and pharmaceutically acceptable salts thereof.
7. The compound according to claim 6 wherein R is pyranyl, tetrahydropyranyl, or pyridyl, all optionally substituted with 1 to 3 groups of R¾ and pharmaceutically acceptable salts thereof.
8. The compound according to claim 1 wherein R is (CHR2)nC6_i 0 aryl, optionally substituted with 1 to 3 groups of R > and pharmaceutically acceptable salts thereof.
9. The compound according to claim 8 wherein R is phenyl optionally substituted with 1 to 3 groups of RY> and pharmaceutically acceptable salts thereof.
10. The compound according to claim 1 represented by structural formula Π:
Figure imgf000080_0001
II
and pharmaceutically acceptable salts thereof,
wherein R is selected from the group consisting of cyclohexyl or cyclohexenyl, pyranyl, tetrahydropyranyl, pyridyl and phenyl all of which are optionally substituted with 1 to 3 groups of RY, W is phenyl or pyridyl and Y and Z are both CH, Y is N and Z is CH, or Y is CH and Z is N.
11. The compound of claim 10 represented by structural formula Ilia:
Figure imgf000081_0001
IIIci
and pharmaceutically acceptable salts thereof,
wherein W is phenyl or pyridyl, Y and Z are both CH, Y is N and Z is CH, or Y is CH and Z is N, Ry is OH or H, and Rx is selected from the group consisting of hydroxyl, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl,
12. The compound of claim 10 represented by structural formula F a:
Figure imgf000081_0002
and pharmaceutically acceptable salts thereof,
wherein W is phenyl or pyridyl, Y and Z are both CH, Y is N and Z is CH, or Y is CH and Z is N, R is OH or H, and Rx is selected from the group consisting of hydroxyl, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl.
13. The compound of claim 10 represented by structural formula V:
Figure imgf000082_0001
V
and pharmaceutically acceptable salts thereof,
wherein P is pyridyl, W is pyridyl or phenyl, Y and Z are both CH or Y is N and Z is CH, Rx is selected from the group consisitmg of hydroxy!, methoxy, halogen, CF3, morphoHno, S-methyl, methyl, ethyl,
CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and Ry is selected from the goup consisting of (CH2)nOH, COOR2, NH2, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, and CN.
compound of claim 10 represented by structural formula VI:
Figure imgf000082_0002
VI
and pharmaceutically acceptable salts thereof,
wherein P is pyridyl, W is pyridyl or phenyl, Y and Z are both CH or Y is N and Z is CH, Rx is selected from the group consisting of hydroxyl, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl,
CN, ethylene, OCH2CF3, pyrazolyl, and methylpyrazolyl and Ry is selected from the goup consisting of (CH2)nOH, COOR2, N¾, methoxy, halogen, CF3, morpholino, S-methyl, methyl, ethyl, and CN.
15. A compound of formula (I) of claim 1 which is found in Table 1 as well as those listed immediately below:
2-[(lS, 25)-2-Hydroxycyclohexyl]-5-(4-methoxybenzyl)- 1 ,2~dihydro-3H-benzo[e]isoindol-3-one; 2-[(lS, 2S)-2-HydroxycyclohexyI]-5-[(6-methylpyridin-3-yl)methyl]-l,2-dihydro-3H-benzo[e]isoindol-3- one, 2-[(JS, 2S)-2-Hydroxycyclohexyl]~5~[(6~vmylpyridin~3^
one
5-[(6-Chloropyridin-3-yl)methyi]-2-[(2S)-2-fluorocycIohexyl]-l,2-dihydro-3H-benzo[e]isoindol-3-one 5-[(6-Chloropyridm-3-yl)methyl]»2-cyclohex-2-en-l--yl-l 52~dihydi ~3H-benzo[e]isomdol-3-one
2-[(JS, 2S)-2-Hydroxycyclohexyl]-5-(pyridin-3-ylmethyl)~l,2"dihydro~3H~benzo[e]isoindol-3-one
2-[(JS, S)-2-Ηydroxycyclohexyl]-5-[(6-moφholm-4-ylpyridΐ^l"3"yl)methyl]-l,2-dihydro-3H- benzo[e]isoindol-3-one
5-[(6-Chloropyridin-3-yl)methyl]-2-[(-?J?, ^S)-3-hydroxytetrahydro-2H-pyran-4-yl]-l,2-dihydro-3H- benzo[e]isoindol-3-one
5-({2-[(iS, 2S)-2-Hydroxycyclohexyl]-3-oxo-2,3-dihydro-lH-benzo[e]isoindol-5-yl}methyl)pyridine-2- carbonitrile
2-[{lS, 2S)-2-Hydroxycyclohexyl]-5-{[6-(methylthio)pyridiiie-3-yi]methyl}-lJ2-dihydro-3H- benzo[e]isoindol-3-one
2-[(3S, ^-4-Hydroxytetrahydro-2H-pyran-3-yl^
benzo[e]isoindol-3-one
2- 0-Acetyl-l,5-aiihydro-3,4-dideoxy-3-{3-oxo-5-[(6-oxo-l,6-dihydroyridin-3-yI)methyl]-l:3-dihydro benzo[e]isoindol-2-yl)-L-/&reo-pentitol
1. ,5-Anhydro-2f3-dideoxy-3-{3-oxo-5-[(6-oxo- 1 :6-dihydropyridin-3-yl)methyl]-l ,3-dihydro-2H- benzo [e] isoindol-2-y 1 } -L-/¾reo-pentitol
5-[(6-Meihoxypyridin-3-yl)methyI]-2-[3-(trifluoromethyl)pyridin-2-yl]-l,2-dihydro-3H-benzo[e]i
3 - one
(±)-5-[(6-Chloropyridin-3-yl)methyI]-2-(2-fluorophenyi)~ 1 -methyl- 1 ,2~dihydn>3H-benzo[<?]isoinol-3-one
(±)-5-[(6-Chloropyridin-3-yl)me1iiyI]-2-[/ra/i^
c]isoquinoline-3-one
(±)~2-[ira«j'-2-Hydroxycyclohexyl]- 5 - { [6-( 1 H-pyrazol- 1 -yl)pyr iduie-3 -yljmethyl } - 1 ,2-dihydro~3H- pyrrolo[3,4-c]isoquinolme-3-one
8-[(7S, 2S)-2-Hydroxycyclohexyl]-5-[(6-methoxypyridin-3-yl)methyl]-9,9-dimethyl-8!9-dihydro-7H- pyrrolo[3,4-A]quinolm-7-one
5-{[6-Benzyloxy)pyridine-3-yl]methyl}-8-[(7S, 2S)-2-hydroxycyclohexyl]-8,9-dihydro-7H-pyrrolo[3}4- /!]quinolin-7-one
S-fi S1, 25)-2-Hydfoxycyclohexyl]-5-[(6-oxopiperidin-3-yl)methyl]-3,9-dihydro-7H-pynOlo[3,4- /z]quinolin-7-one
5-[(6-Chloropyridin-3-yl)meiliyl]-9-(2i3-dihydiOxypropyl)-8-[(;S, 25 -2-hydroxycyclohexyl]-8,9- dlhydro-7H-pyrrolo[3,4- ?]quinoIin-7-one
8-[(lS, 2S)-2-Hydroxycyclohexyl]-5-[(6-oxopiperWin-3-yl)methyl]-3,9-dihydro-7H-pyrrolo[354- i]quinolin-7-one 5-[(6-Chloropyridin-3-yl)methyl]-9-(253-dihydroxypropyl)-8-[{7Si 2S)-2-hydroxycyclohexyl]-8!9" dihydro-7H-pyrrolo[3,4-A]quinolin-7-one
{5-[(6-Chlorop;yridin-3-yl)m^
?]quinolin-9-yl} acetaldehyde
5-[(6-Chloropyridin-3-yl)methy^9-[2 dime ^
dihydro-7H-pyiTolo[3,4-A]quinolin-7-one
Figure imgf000084_0001
pyrrolo[3,4-/z]quinoliii-7-one
5-[(6-Cyclopropylpyridin-3-yl)methyl]-8~[( S, 25)-2-hydroxycyclohexyI-8,9~dihydro-7H-pyrrolo[3!4- AJquinolin-7-one,
and pharmaceutically acceptable salts thereof,
16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
17. Use of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for the manufacture of a medicament for the treatment of a disease or disorder mediated by the muscarinic Ml receptor, wherein said disease or disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, pain or sleep disorders.
18. A method of treating a disease or disorder mediated by the muscarinic Ml receptor, wherein said disease or disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, pain or sleep disorders in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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