ALLOSTERIC MODULATORS OF NICOTINIC ACETYLCHOLINE RECEPTORS

The present disclosure relates to compounds of formula I that are useful as modulators of α 7 nAChR, compositions comprising such compounds, and the use of such compounds for preventing, treating, or ameliorating disease, particularly disorders of the central nervous system such as cognitive impairments in Alzheimer's disease, Parkinson's disease, and schizophrenia, as well as for L-DOPA induced-dyskinesia and inflammation.

FIELD OF THE INVENTION

The present disclosure relates to compounds that are useful as modulators of α7 nAChR, compositions comprising such compounds, and the use of such compounds for preventing, treating, or ameliorating disease, particularly disorders of the central nervous system such as cognitive impairments in Alzheimer's disease, Parkinson's disease, and schizophrenia.

BACKGROUND OF THE INVENTION

The α7 nAChR is a fast desensitizing ligand-gated ion channel that has high permeability to Ca2+. In human brain, α7 nAChRs are highly expressed in the cortex and hippocampus, regions associated with cognition, see for example, Breese et al.J. Comp. Neurol.(1997) 387:385-398. In neurons, α7 nAChRs are localized in both pre-synaptic and post-synaptic structures, where activation of the receptor can modulate neurotransmitter release, neuronal excitability, and intracellular signalling, see for example, Frazier et al.J. Neurosci. (1998) 18:1187-1195.

Cognitive impairments are prevalent in many neurological and psychiatric diseases, including Alzheimer's disease (AD), schizophrenia, and Parkinson's disease, and dysfunction in cholinergic signalling contributes to the cognitive impairments of these diseases, see for example, Francis et al.J. Neurol. Neurosurg. Psychiatry(1999) 66:137-147. For example, a principal feature of the pathogenesis in AD is the loss of cholinergic neurons in the basal forebrain nuclei, whereas increasing cholinergic transmission via inhibition of acetylcholine esterase is the standard of care for the cognitive symptoms of AD. More specific to the α7 nAChR, it was recently demonstrated that encenicline, a partial agonist of the α7 nAChR, improves cognition in Alzheimer's disease, see for example, Moebius H et al., 67thAnnual Meeting. Am. Acad. Neurol. (AAN) 2015, Abst P7.100. Evidence implicating α7 nAChRs in the etiology of schizophrenia comes from studies demonstrating reduced expression of neuronal α7 nAChRs in the brain of schizophrenic patients and the observation that schizophrenics frequently smoke, which is believed to be a form of self-medication. In addition, variants in the promotor region of the gene coding for the α7 nAChR, CHRNA7, which impacts expression of the α7 nAChR protein, are associated with symptoms of schizophrenia, see for example, Sinkus et al.Neuropharmacology(2015) 96:274-288. Moreover, accumulating evidence from clinical trials has indicated that activating α7 nAChR with agonists may have beneficial effects on cognition, see for example, Keefe et al.Neuropsychopharmacology(2015) 40:3053-3060 and Bertrand et al.Pharmacology Reviews(2015) 67:1025-1073. Therefore, targeting the α7 nAChR represents a therapeutic strategy for the treatment of cognitive impairments associated with various cognitive disorders.

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive deficits in motor function, such as tremor, bradykinesia, rigidity and impaired postural reflex. The main pathological finding associated with the disease is degeneration of dopaminergic neurons in the substantia nigra, resulting in loss of dopaminergic tone in the striatum. L-DOPA is the current standard treatment for the motor symptoms in PD. However, chronic treatment with L-DOPA in PD patients also induces dyskinesia, a side effect of L-DOPA therapy. New lines of evidence indicate that activating α7 nAChRs acutely alleviates dyskinesia in several animal models, see for example, Zhang et al.J. Pharmacol. Exp. Ther. (2014) 351:25-32. In addition, accumulating evidence shows that pretreatment with α7 nAChR agonists may protect against neurodegeneration in nigrostriatal neurons, suggesting α7 activation may have disease modifying properties too, see for example, Suzuki et al.J. Neurosci. Res. (2013) 91:462-471. Overall, α7 nAChR is an attractive target for both ameliorating disease progression and managing dyskinesia.

In addition to its expression in the central nervous system, the α7 nAChR is widely expressed in peripheral immune cells including macrophage, monocytes, dendritic cells, and B and T cells, see for example, Rosas-Ballina et al.Science(2011) 334:98-101. Activation of peripheral α7 nAChRs is critical for inhibiting the release of proinflammatory cytokines via the cholinergic anti-inflammatory pathway, see for example, Wang et al.Nature(2003) 421:384-388. Therefore, α7 nAChR is a potential target for several inflammatory diseases such as rheumatoid arthritis, and atherosclerosis, see for example, WJ de Jonge et al.British J. Pharmacol. (2007) 151:915-929.

Cough is one of the most common symptoms for which patients seek medical attention. Chronic cough, defined as a cough of greater than 8 weeks of duration, is a clinical syndrome with distinct intrinsic pathophysiology characterized by neuronal hypersensitivity. Current treatment for chronic cough consists of antitussive therapy to decrease cough frequency or severity. However, the available antitussives have limited efficacy and their utility is further restricted by safety and abuse liabilities. Recent studies performed in healthy human volunteers indicate that activation of nAChR may represent a novel, safe, and effective antitussive strategy, see for example, Davenport et al.Pulm. Pharmacol. Ther. (2009) 22:82-89; Dicpinigaitis.Pulm. Pharmacol. Ther. (2017) 47:45-48. Furthermore, pre-clinical studies suggest that α7 nAChR is likely the target for antitussive nAChR ligands, see for example, Canning et al.Am. J. Respir. Crit. Care. Med. (2017) 195:A4498. Therefore, targeting α7 nAChR represents an attractive antitussive strategy in patients with cough.

In recent years, α7-selective positive allosteric modulators (PAMs) have been proposed as a therapeutic approach to treating cognitive impairments in AD, PD, and schizophrenia, as well as L-DOPA induced-dyskinesia, inflammation, and cough. In contrast to α7 agonists that activate the channel irrespective of endogenous agonist, PAMs increase the potency of the endogenous agonist without perturbing the temporal and spatial integrity of neurotransmission. There are two classes of α7 PAMs, type I and type II, which differ based on the functional properties of modulation. The type I PAMs (e.g. NS1738, see for example, Timmermann et al.J. Pharmacol. Exp. Ther. (2007) 323:294-307) predominantly affect the peak current with little or no effect on receptor desensitization, while the type II PAMs (e.g. PNU120596, see for example, Hurst et al.J. Neurosci. (2005) 25:4396-4405) markedly delay desensitization of the receptor. Additionally, α7 nAChR PAMs may have improved selectivity over related channel targets, presumably through binding to non-conserved regions of the receptor.

The present invention is directed to a new class of compounds that exhibit positive allosteric modulation of the α7 nAChR.

SUMMARY OF THE INVENTION

The present disclosure relates to novel compounds of formula I and Ia and pharmaceutically acceptable salts thereof. These compounds may be useful, either as compounds or their pharmaceutically acceptable salts (when appropriate), in the modulation of the α7 nAChR, the prevention, treatment, or amelioration of disease, particularly disorders of the central nervous system such as cognitive impairments in Alzheimer's disease, Parkinson's disease, and schizophrenia and/or as pharmaceutical composition ingredients. As pharmaceutical composition ingredients, these compounds and their salts may be the primary active therapeutic agent, and, when appropriate, may be combined with other therapeutic agents including but not limited to acetylcholinesterase inhibitors, NMDA receptor antagonists, beta-secretase inhibitors, M4 mAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs, 5-HT6 antagonists, histamine H3 receptor antagonists, PDE4 inhibitors, PDE9 inhibitors, HDAC6 inhibitors, antipsychotics, MAO-B inhibitors, and levodopa.

In one aspect, the present invention relates to a compound of formula I:

The present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions. The present invention further includes methods of preventing, treating, or ameliorating the cognitive impairments associated with Alzheimer's disease, Parkinson's disease, and schizophrenia.

Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes compounds of formula I above, and pharmaceutically acceptable salts thereof. The compounds of formula I are positive allosteric modulators of α7 nAChR.

In a first embodiment of the invention, p is 1 and the other groups are as provided in the general formula above.

In a second embodiment of the invention, p is 2 and the other groups are as provided in the general formula above.

In a third embodiment of the invention, each X is independently CRaRbor NRc, provided that when p is 2 at least one X is CRaRband the other groups are as provide in the general formula above, or as in the first and second embodiments.

In a fourth embodiment of the invention, each X is independently O, S, or CRaRb, provided that when p is 2 at least one X is CRaRband the other groups are provided in the general formula above, or as in the first and second embodiments.

In a fifth embodiment of the invention, w is 0, 1, or 2, and the other groups are provided in the general formula above, or as in the first through fourth embodiments. In a variant of this embodiment, w is 0 or 1 and the other groups are provided in the general formula above, or as in the first through fourth embodiments.

In a sixth embodiment of the invention, Z is CRdand the other groups are provided in the general formula above, or as in the first through fifth embodiments.

In a seventh embodiment of the invention, Z is N and the other groups are provided in the general formula above, or as in the first through fifth embodiments.

In an eighth embodiment of the invention, each Raand Rbis independently hydrogen, halogen, or (C1-C4)alkyl and the other groups are provided in the general formula above, or as in the first through seventh embodiments.

In a ninth embodiment of the invention, each Raand Rbis hydrogen and the other groups are provided in the general formula above, or as in the first through seventh embodiments.

In a tenth embodiment of the invention, Rcis hydrogen, (C1-C4)alkyl or C═O(C1-C4)alkyl and the other groups are provided in the general formula above, or as in the first through ninth embodiments.

In an eleventh embodiment of the invention, Rcis hydrogen, or —C(O)methyl and the other groups are provided in the general formula above, or as in the first through ninth embodiments.

In a twelfth embodiment of the invention, each R5is independently halogen, (C1-C4)alkyl, or cyano and the other groups are provided in the general formula above, or as in the first through eleventh embodiments.

In a thirteenth embodiment of the invention, y is 0 and the other groups are provided in the general formula above, or as in the first through eleventh embodiments.

In a fourteenth embodiment of the invention, each R3is independently selected from halogen, (C1-C6)alkyl, cyano, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, and heteroaryl, wherein said alkyl or alkoxy is optionally substituted with 1-5 fluoro, and wherein said heteroaryl is substituted with 0, 1, 2, or 3 R6substituents and the other groups are provided in the general formula above, or as in the first through thirteenth embodiments.

In a fifteenth embodiment of the invention, each R3is independently selected from methoxy, cyano, fluoro, chloro, bromo, tetrazolyl, triazolyl, isoxazolyl, and pyrimidyl, wherein said heteroaryl is substituted with 0, 1, 2, or 3 R6substituents and the other groups are provided in the general formula above, or as in the first through thirteenth embodiments.

In a sixteenth embodiment of the invention, each R6is independently (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, or aryl(C1-C6)alkyl, wherein said alkyl or alkoxy is substituted with 0, 1, 2, 3, 4, or 5 fluoro and the other groups are provided in the general formula above, or as in the first through fifteenth embodiments.

In a seventeenth embodiment of the invention, each R6is independently methyl or phenylmethyl and the other groups are provided in the general formula above, or as in the first through fifteenth embodiments.

In an eighteenth embodiment of the invention, R4is hydrogen, methyl, ethyl, or propyl and the other groups are provided in the general formula above, or as in the first through seventeenth embodiments. In a variant of this embodiment, R4is hydrogen and the other groups are provided in the general formula above, or as in the first through seventeenth embodiments.

In a nineteenth embodiment of the invention, each R2is independently hydrogen, methyl, ethyl, isopropyl, or propyl and the other groups are provided in the general formula above, or as in the first through eighteenth embodiments. In a variant of this embodiment, R2is hydrogen or methyl and the other groups are provided in the general formula above, or as in the first through eighteenth embodiments.

In a twentieth embodiment of the invention, each R1is independently hydrogen, C1-6alkoxy, C1-6 haloalkyl, halogen, C1-6heteroalkyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, aryl, —(C═O)OC1-4alkyl, or hydroxyC1-4alkyl and the other groups are provided in the general formula above, or as in the first through nineteenth embodiments.

In a twenty-first embodiment of the invention, each R1is independently hydrogen, methoxymethyl, hydroxymethyl, trifluoromethyl, methoxy, difluoromethyl, fluoromethyl, methyl, ethyl, methylcarboxy, hydroxyethyl, or phenyl and the other groups are provided in the general formula above, or as in the first through nineteenth embodiments.

In a twenty-second embodiment of the invention, each R1and R2together with the carbon atom to which they are attached join together to form a ring, wherein said ring is substituted with 0, 1, or 2 hydroxy, halogen, methoxy, or C1-6alkyl and the other groups are provided in the general formula above, or as in the first through nineteenth embodiments. In a variant of this embodiment, each R1and R2together with the carbon atom to which they are attached join together to form a ring selected from cyclobutyl, cyclopropyl, and oxetanyl and the other groups are provided in the general formula above, or as in the first through twenty-first embodiments.

In a twenty-fourth embodiment of the invention, A is selected from phenyl, cyclohexyl, pyridyl, oxadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, chromanyl, isochromanyl, 2,3-dihydrobenzofuranyl, indanyl, thienyl, benzofuranyl, isoxazolyl, and 1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazolyl, wherein A is substituted with 0, 1, 2, or 3 R7substitutents and the other groups are provided in the general formula above, or as in the first through twenty-second embodiments.

In a twenty-fifth embodiment of the invention, each R7is independently selected from hydrogen, halogen, hydroxy, (C1-C6)alkoxy, (C1-C6)haloalkyl, aryl, heteroaryl, (C1-C6)alkyl, aryl(C1-C6)alkyl, (C3-C6)cycloalkyl(C1-C6)alkoxy, and heteroaryloxy, wherein each R7independently is substituted with 0, 1, 2, or 3 R8and the other groups are provided in the general formula above, or as in the first through twenty-fourth embodiments.

In a twenty-sixth embodiment of the invention, each R7is independently selected from ethoxy, hydrogen, methoxy, fluoro, phenyl, hydroxy, methyl, chloro, pyrrolidinyl, difluoromethyl, iodo, pyrrolyl, quinolinyl, benzothiazolyl, pyridyloxy, oxazolyl, bromo, cyclopropylmethyloxy, phenylmethyl, and pyridyl, wherein each R7independently is substituted with 0, 1, 2, or 3 R8and the other groups are provided in the general formula above, or as in the first through twenty-fourth embodiments.

In a twenty-seventh embodiment of the invention, each R8is independently selected from fluoro, chloro, methoxy ethoxy, methyl ethyl and propyl and the other groups are provided in the general formula above, or as in the first through twenty-sixth embodiments. In a variant of this embodiment, R5is chloro or methoxy; and the other groups are provided in the general formula above, or as in the first through twenty-sixth embodiments.

In a twenty-eighth embodiment of the invention, q is 0 and the other groups are provided in the general formula above, or as in the first through twenty-seventh embodiments.

In a twenty-ninth embodiment, q is 0 or 1 and the other groups are provided in the general formula above, or as in the first through twenty-seventh embodiments. In a variant of this embodiment, q is 1 and the other groups are provided in the general formula above, or as in the first through twenty-seventh embodiments.

In a thirtieth embodiment of the invention, Rdis independently hydrogen, halogen, or (C1-C4)alkyl and the other groups are provided in the general formula above, or as in the first through twenty-ninth embodiments.

In a thirty-first embodiment of the invention, Rdis hydrogen and the other groups are provided in the general formula above, or as in the first through twenty-ninth embodiments.

Representative compounds of the present invention are as follows, where each named compound is intended to encompass its individual isomers, mixtures thereof (including racemates and diastereomeric mixtures), as well as pharmaceutically acceptable salts thereof:

The invention is also directed to a compound, or a pharmaceutically acceptable salt thereof, selected from the following exemplified compounds:exo-N-[(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxamide;exo-N-[(1R)-1-cyclohexyl-2-hydroxyethyl]-6-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-6-fluoro-N-[(1R)-2,2,2-trifluoro-1-(2-methoxypyridin-4-yl)ethyl]-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]-5-(2H-tetrazol-5-yl)-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-[(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-N-[3-(4-fluorophenyl)oxetan-3-yl]-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-6-fluoro-N-[3-(4-fluorophenyl)oxetan-3-yl]-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[(1R)-1-(6-ethoxypyridin-3-yl)-2-hydroxyethyl]-6-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-(2-cyclohexyl-2-methoxyethyl)-6-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[1-(4-fluorophenyl)-3-hydroxycyclobutyl]-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[(1R)-1-cyclohexyl-2-hydroxyethyl]-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[(1R)-1-cyclohexyl-2,2-difluoroethyl]-6-fluoro-1,1a2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-6-fluoro-N-(1-phenylcyclobutyl)-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-6-fluoro-N-[1-(4-fluorophenyl)cyclopropyl]-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[1-(2-methoxypyridin-4-yl)cyclopropyl]-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[1-(6-ethoxypyridin-3-yl)cyclobutyl]-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[1-(2-methoxypyridin-4-yl)cyclobutyl]-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[(1R)-1-(6-ethoxypyridin-3-yl)-2,2,2-trifluoroethyl]-6-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[(1R)-1-(6-ethoxypyridin-3-yl)-2,2-difluoroethyl]-6-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[(1R)-1-(6-ethoxypyridin-3-yl)-2-fluoroethyl]-6-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-6-fluoro-N-[(1R)-2-fluoro-1-(2-methoxypyridin-4-yl)ethyl]-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[(2,6-dimethoxyphenyl)methyl]-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[2-(3-chlorophenyl)propan-2-yl]-6-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[(4S)-6,7-difluoro-3,4-dihydro-2H-1-benzopyran-4-yl]-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[(1R)-1-cyclohexyl-2,2-difluoroethyl]-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzopyran-1-carboxamide;exo-N-[(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-N-[(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-3-chloro-N-[(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-3-bromo-N-[(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-N-[(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]-5-(pyrimidin-5-yl)-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-2-acetyl-N-[(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]-1,1a,2,6b-tetrahydrocyclopropa[b]indole-1-carboxamide;exo-N-[(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]-6-methoxy-1a,6b-dihydro-1H-cyclopropa[4,5]furo[3,2-c]pyridine-1-carboxamide;exo-5-cyano-N-[(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-4-bromo-N-[(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-N-[(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]-4-methoxy-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-6-bromo-N-[(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-[(4R)-6-fluoro-3,4-dihydro-1H-2-benzopyran-4-yl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-N-[(1R)-1-cyclohexyl-2-hydroxyethyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzothiophene-1-carboxamide;exo-N-[1-(6-ethoxypyridin-3-yl)cyclobutyl]-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-N-[(4R)-6,7-dimethoxy-3,4-dihydro-1H-2-benzopyran-4-yl]-5-fluoro-1a,6b-dihydro-11H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-N-[(1R)-1-(6-ethoxypyridin-3-yl)-2,2-difluoroethyl]-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-[(4S)-7-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-N-[(4S)-6,7-difluoro-3,4-dihydro-2H-1-benzopyran-4-yl]-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-(6-methoxy-2,3-dihydro-1-benzofuran-3-yl)-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-(4-hydroxy-2,3-dihydro-1H-inden-1-yl)-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-(2-phenylethyl)-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide exo-5-fluoro-N-[1-(thiophen-2-yl)ethyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;methyl 2-(3-fluorophenyl)-2-[(exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carbonyl)amino]acetate;exo-N-[(5-chloro-2-fluorophenyl)methyl]-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-N-[(4-chloro-3-fluorophenyl)methyl]-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;2-{1-[(exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carbonyl)amino]propyl}pyridine;exo-5-fluoro-N-[(thiophen-2-yl)methyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;2-{[(exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carbonyl)amino]methyl}-6-(pyrrolidin-1-yl)pyridine;exo-N-{[2,6-bis(difluoromethyl)pyridin-4-yl]methyl}-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-N-[1-(1-benzofuran-2-yl)ethyl]-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-[(3-iodophenyl)methyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-N-[(2,5-difluorophenyl)methyl]-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-N-[(2,4-difluorophenyl)methyl]-5-fluoro-1a,6b-dihydro-H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-[(3-fluoro-5-methylphenyl)methyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-{[4-(1H-pyrrol-1-yl)phenyl]methyl}-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-[(4-hydroxyphenyl)methyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;6-{[(exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carbonyl)amino]methyl}quinoline;2-{[(exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carbonyl)amino]methyl}-1,3-benzothiazole;methyl 2-(3-chlorophenyl)-2-[(exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carbonyl)amino]acetate;exo-5-fluoro-N-[(1S)-1-(4-fluorophenyl)-3-hydroxypropyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-[(2-methylphenyl)methyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-[(3-phenyl-1,2-oxazol-5-yl)methyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;3-{[(exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carbonyl)amino]methyl}-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole;exo-5-fluoro-N-({4-[(pyridin-2-yl)oxy]phenyl}methyl)-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-{[3-(1,3-oxazol-2-yl)phenyl]methyl}-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;5-{(1S)-1-[(exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carbonyl)amino]ethyl}quinoline;exo-N-[1-(4-bromophenyl)ethyl]-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;6-{[(exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carbonyl)amino]methyl}isoquinoline;4-{[(exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carbonyl)amino](phenyl)methyl}pyridine;exo-N-{[2-(cyclopropylmethoxy)phenyl]methyl}-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-N-[(3-bromo-1,2,4-oxadiazol-5-yl)methyl]-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-N-[(3-benzyl-1,2,4-oxadiazol-5-yl)methyl]-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-[1-(1,2-oxazol-5-yl)ethyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-{[3-(4-methoxyphenyl)-1,2-oxazol-5-yl]methyl}-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-[(3-methoxy-1,2-oxazol-5-yl)methyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-{[3-(pyridin-2-yl)-1,2-oxazol-5-yl]methyl}-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-N-[(3-bromo-1,2-oxazol-5-yl)methyl]-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-[(3-phenyl-1,2-oxazol-5-yl)methyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide;exo-5-fluoro-N-{[3-(6-methoxypyridin-3-yl)-1,2,4-oxadiazol-5-yl]methyl}-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide; andexo-N-{[3-(4-chlorophenyl)-1,2-oxazol-5-yl]methyl}-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxamide.

In another embodiment of the invention, In one aspect, the present invention relates to a compound of formula Ia:

In other embodiments of the invention the compound of formula Ia have groups as provided in the general formula above, or as in the first through eleventh, fourteenth through seventeenth, and nineteenth through twenty-seventh embodiments previously disclosed for the compound of formula I where R5is hydrogen, w is 0 or 1, and R4is hydrogen.

In one embodiment of the invention of formula I, w is 0, 1, 2, or 3.

In another embodiment of formula I, w is 0, 1, or 2.

In another embodiment of formula I, w is 0 or 1.

In one embodiment of formula I, p is 1.

In one embodiment of formula I, p is 2.

In another embodiment of formula I, q is 0, 1, or 2.

In another embodiment of formula I, q is 0 or 1.

In another embodiment of formula I, q is 1.

In another embodiment of formula I, q is 0.

Other embodiments of the present invention include the following:(a) A pharmaceutical composition comprising a compound of formula I or Ia and a pharmaceutically acceptable carrier.(b) The pharmaceutical composition of (a), further comprising a second therapeutic agent selected from the group consisting of acetylcholinesterase inhibitors such as donepezil, rivastigmine, and galantamine; NMDA receptor antagonists such as memantine; beta-secretase inhibitors such as verubecestat, and AZD3293; M4 mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs; 5-HT6 antagonists such as idalopirdine, RVT-101, AVN-101, AVN322, SUVN-502, and SYN-120; histamine H3 receptor antagonists such as S38093; PDE4 inhibitors such as HT0712; PDE9 inhibitors such as B140936; HDAC6 inhibitors; antipsychotics; LRRK2 inhibitors; MAO-B inhibitors; and levodopa.(c) The pharmaceutical composition of (b), wherein the second therapeutic agent is an antipsychotic selected from the group consisting of clozapine, olanzapine, risperidone, aripiprazole, quetiapine, haloperidol, loxapine, thioridazine, molindone, thiothixene, fluphenazine, mesoridazine, trifluoperazine, chlorpromazine, and perphenazine.(d) A pharmaceutical combination that is (i) a compound of formula I or Ia and (ii) a second therapeutic agent selected from the group consisting of acetylcholinesterase inhibitors such as donepezil, rivastigmine, and galantamine; NMDA receptor antagonists such as memantine; beta-secretase inhibitors such as verubecestat, and AZD3293; M4 mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs; 5-HT6 antagonists such as idalopirdine, RVT-101, AVN-101, AVN322, SUVN-502, and SYN-120; histamine H3 receptor antagonists such as S38093; PDE4 inhibitors such as HT0712; PDE9 inhibitors such as B140936; HDAC6 inhibitors; antipsychotics; LRRK2 inhibitors; MAO-B inhibitors; and levodopa wherein the compound of formula I or Ia and the second therapeutic agent are each employed in an amount that renders the combination effective for treating cognitive impairments associated with Alzheimer's disease, Parkinson's disease, or schizophrenia.(e) The combination of (d), wherein the second therapeutic agent is an antipsychotic selected from the group consisting of clozapine, olanzapine, risperidone, aripiprazole, quetiapine, haloperidol, loxapine, thioridazine, molindone, thiothixene, fluphenazine, mesoridazine, trifluoperazine, chlorpromazine, and perphenazine.(f) A use of a compound of formula I or Ia in the preparation of a medicament for modulating α7 nAChR activity in a subject in need thereof.(g) A use of a compound of formula I or Ia in the preparation of a medicament for treating cognitive impairments associated with Alzheimer's disease, Parkinson's disease, and schizophrenia in a subject in need thereof.(h) A method of treating cognitive impairments associated with Alzheimer's disease, Parkinson's disease, and schizophrenia and/or reducing the likelihood or severity of symptoms of cognitive impairments associated with Alzheimer's disease, Parkinson's disease, and schizophrenia in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula I or Ia.(i) The method of (h), wherein the compound of formula I or Ia is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of acetylcholinesterase inhibitors such as donepezil, rivastigmine, and galantamine; NMDA receptor antagonists such as memantine; beta-secretase inhibitors such as verubecestat, and AZD3293; M4 mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs; 5-HT6 antagonists such as idalopirdine, RVT-101, AVN-101, AVN322, SUVN-502, and SYN-120; histamine H3 receptor antagonists such as S38093; PDE4 inhibitors such as HT0712; PDE9 inhibitors such as BI40936; HDAC6 inhibitors; antipsychotics; LRRK2 inhibitors; MAO-B inhibitors; and levodopa.(j) The method of (i), wherein the second therapeutic agent is an antipsychotic selected from the group consisting of clozapine, olanzapine, risperidone, aripiprazole, quetiapine, haloperidol, loxapine, thioridazine, molindone, thiothixene, fluphenazine, mesoridazine, trifluoperazine, chlorpromazine, and perphenazine.(k) A method of modulating α7 nAChR activity in a subject in need thereof, which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).(l) A method of treating cognitive impairments associated with Alzheimer's disease, Parkinson's disease, and schizophrenia and/or reducing the likelihood or severity of symptoms of cognitive impairments associated with Alzheimer's disease, Parkinson's disease, and schizophrenia in a subject in need thereof, which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).

In the embodiments of the compounds and salts provided above, it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination provides a stable compound or salt and is consistent with the description of the embodiments. It is further to be understood that the embodiments of compositions and methods provided as (a) through (l) above are understood to include all embodiments of the compounds and/or salts, including such embodiments as result from combinations of embodiments.

Additional embodiments of the invention include the pharmaceutical compositions, combinations, uses and methods set forth in (a) through (l) above, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the compounds described above. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate.

The present invention also includes a compound of the present invention for use (i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) preventing or treating cognitive impairments associated with Alzheimer's disease, Parkinson's disease, schizophrenia, and L-DOPA induced-dyskinesia, or (b) treating cognitive impairments associated with Alzheimer's disease, Parkinson's disease, schizophrenia, and L-DOPA induced-dyskinesia and/or reducing the likelihood or severity of symptoms of cognitive impairments associated with Alzheimer's disease, Parkinson's disease, schizophrenia, and L-DOPA induced-dyskinesia, or (c) use in medicine. In these uses, the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from acetylcholinesterase inhibitors such as donepezil, rivastigmine, and galantamine; NMDA receptor antagonists such as memantine; beta-secretase inhibitors such as verubecestat, and AZD3293; M4 mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs; 5-HT6 antagonists such as idalopirdine, RVT-101, AVN-101, AVN322, SUVN-502, and SYN-120; histamine H3 receptor antagonists such as 538093; PDE4 inhibitors such as HT0712; PDE9 inhibitors such as BI40936; HDAC6 inhibitors; antipsychotics; LRRK2 inhibitors; MAO-B inhibitors; and levodopa.

Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name and an ambiguity exists between the structure and the name, the structure is understood to predominate.

As used herein, the term “5-membered heteroaryl ring” refers to a stable unsaturated 5-membered ring that contains from 1 to 4 heteroatoms selected from the group consisting of O, N, and S. A 5-membered heteroaryl ring within the scope of this definition includes but is not limited to: furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and triazolyl.

As used herein, the term “6-membered heteroaryl ring” refers to a stable unsaturated 6-membered ring that contains from 1 to 4 heteroatoms selected from the group consisting of O, N, and S. A 6-membered heteroaryl ring within the scope of this definition includes but is not limited to: pyridazinyl, pyridyl, and pyrimidyl.

As used herein, the term “administration” and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means providing the compound to the individual in need of treatment. When a compound of the invention is provided in combination with one or more other active agents (e.g., cholinesterase inhibitors such as donepezil, rivastigmine, and galantamine), “administration” and its variants are each understood to include concurrent and sequential administration of the compound or salt and other agents.

The term “alkenyl” refers to a hydrocarbon radical straight or branched containing from 2 to 12 carbon atoms and at least one carbon to carbon double bond. Up to four carbon-carbon double bonds may be present. Thus, “C2-C6alkenyl” means an alkenyl radical having from 2 to 6 carbon atoms. Thus, “C2-C4alkenyl” means an alkenyl radical having from 2 to 4 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl, 3-methylbutenyl and so on. In one embodiment, an alkenyl group is linear. In another embodiment, an alkenyl group is branched.

The term “alkyl” refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond. An alkyl group may be straight or branched. An alkyl group contains from 1 to 8 carbon atoms [(C1-C8)alkyl] or from 1 to 6 carbon atoms [(C1-C6)alkyl] or from 1 to 4 carbon atoms [(C1-C4)alkyl]. Non-limiting examples of alkyl groups include methyl (Me), ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched.

The term “alkynyl” refers to a hydrocarbon radical straight or branched containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present. Thus, “C2-C6alkynyl” means an alkynyl radical having from 2 to 6 carbon atoms. Thus, “C2-C4alkynyl” means an alkynyl radical having from 2 to 4 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl and so on. In one embodiment, an alkynyl group is linear. In another embodiment, an alkynyl group is branched.

The term “alkoxy” refers to an alkyl (carbon and hydrogen chain) group singularly bonded to oxygen (R—O). Non-limiting examples of alkoxy are methoxy (CH3O—), ethoxy (CH3CH2O—) and butoxy (CH3CH2CH2O—).

The term “aryl” refers to mono- and poly-carbocyclic ring systems having at least one aromatic ring, wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond. Suitable aryl groups include phenyl, naphthyl, indanyl, and biphenyl.

In an embodiment, “aryl” is phenyl.

When “aryl” is substituted, said “aryl” includes aryl and O-aryl.

“Celite®” (Fluka) diatomite is diatomaceous earth, and can be referred to as “celite”.

The term “compound” refers to the free compound and, to the extent they are stable, any hydrate or solvate thereof. A hydrate is the compound complexed with water, and solvate is the compound complexed with an organic solvent.

The term “composition” is intended to encompass a product comprising the specified ingredients, as well as any product which results from combining the specified ingredients.

The term “cycloalkyl” as used herein, refers to any non-aromatic mono- and poly-carbocyclic ring systems comprising from 3 to 10 ring carbon atoms [(C3-C10)cycloalkyl], or from 3 to 6 ring carbon atoms [(C3-C6)cycloalkyl] wherein the individual carbocyclic rings in the polyring systems are fused, including spiro ring fusions, or attached to each other via a single bond. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Non-limiting examples of multicyclic cycloalkyls include bicyclo[4.1.0]heptyl, spiro[2.4]heptyl, spiro[3.3]heptyl, spiro[2.5]octyl, [1.1.1]-bicyclo pentane, 1-decalinyl, norbornyl, adamantyl and the like. A ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group. An illustrative example of such a cycloalkyl group (also referred to herein as a “cycloalkanoyl” group) includes, but is not limited to, cyclobutanoyl:

The term “effective amount” as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In one embodiment, the effective amount is a “therapeutically effective amount” for the alleviation of one or more symptoms of the disease or condition being treated. In another embodiment, the effective amount is a “prophylactically effective amount” for reduction of the severity or likelihood of one or more symptoms of the disease or condition. The term also includes herein the amount of active compound sufficient to modulate α7 nAChR activity and thereby elicit the response being sought (i.e., a “therapeutically effective amount”). When the active compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free acid or free base form of the compound.

The term “halogen” (or “halo”) refers to atoms of fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro (F), chloro (Cl), bromo (Br), and iodo (I)).

“Haloalkyl” refers to an alkyl group as described above wherein one or more (in particular 1 to 5) hydrogen atoms have been replaced by halogen atoms, with up to complete substitution of all hydrogen atoms with halo groups. C1-6haloalkyl, for example, includes —CF3, —CF2CF3, —CHFCH3, and the like.

The term “heteroalkyl” refers to an alkyl group where one or more of the carbon atoms is substituted by a heteroatom independently selected from N, O, or S.

“Hydroxyalkyl” refers to an alkyl group as described above in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by hydroxy groups. Examples include CH2OH, CH2CHOH and CHOHCH3.

The term “heteroaryl” generally refers a 5- or 6-membered monocyclic aromatic ring or a 7- to 12-membered bicyclic which consists of carbon atoms and one or more heteroatoms selected from N, O and S. For a bicyclic heteroaryl, only one of the rings need to be heteroaromatic, the second ring may be a heteroaromatic or an aromatic carbocyclic ring, and the point(s) of attachment to the rest of the molecule may be on either ring.

The term “heterocycloalkyl” as used herein refers to a stable and not fully aromatic 3- to 18-membered ring (i.e., C3-C18 heterocycloalkyl) radical that comprises two to twelve ring carbon atoms and from one to six ring heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range; e.g., “3 to 18 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, 5 ring atoms, etc., up to and including 18 ring atoms. In some embodiments, it is a C5-C10 heterocycloalkyl. In some embodiments, it is a C4-C10 heterocycloalkyl. In some embodiments, it is a C3-C10 heterocycloalkyl. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms, e.g. sulfur, in the heterocycloalkyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl may be attached to the rest of a molecule through any atom of the ring(s).

By “pharmaceutically acceptable” is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.

As used herein, the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur.

The term “preventing” as used herein with respect to Alzheimer's disease or other neurological diseases, refers to reducing the likelihood of disease progression.

The term “subject” (alternatively referred to herein as “patient”), as used herein, refers to an animal, preferably a mammal, most preferably a human.

The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom provided such substitution is chemically allowed and results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term “substituted with one or more” refers to substitution with the named substituent or substituents, multiple degrees of substitution, up to replacing all hydrogen atoms with the same or different substituents, being allowed unless the number of substituents is explicitly stated. Where the number of substituents is not explicitly stated, one or more is intended.

As used herein, “a compound of the invention” means a compound of formula I or Ia or Ia or a salt, solvate or physiologically functional derivative thereof.

The term “solvate” refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula I or Ia, or a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, acetone, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents included water, ethanol and acetic acid.

A “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

In the compounds of formula I or Ia, 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 formula I or Ia. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H or D). Protium 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 formula I or Ia 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.

Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heteroaryl ring described as containing from “1 to 3 heteroatoms” means the ring can contain 1, 2, or 3 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. The oxidized forms of the heteroatoms N and S are also included within the scope of the present invention.

It is understood by one skilled in the art that carbon atoms in organic molecules may often be replaced by silicon atoms to give analogous stable compounds. For example, carbon atoms in alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, groups may often be replaced by silicon atoms to provide stable compounds. All such compounds are within the scope of the present invention.

When any variable (for example, R) occurs more than one time in any constituent or in formula I or Ia or in any other formula depicting and describing compounds of the invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The compounds of formula I or Ia may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of formula I or Ia as well as mixtures thereof, including racemic mixtures, form part of the present invention. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.

Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated by chromatography employing columns with a chiral stationary phase. Also, some of the compounds of formula I or Ia may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.

Certain of the compounds of the present invention can exist as tautomers. For the purposes of the present invention a reference to a compound of formula I or Ia is a reference to the compound per se, or to any one of its tautomers per se, or to mixtures of two or more tautomers.

The compounds of formula I or Ia may have the ability to crystallize in more than one form, a characteristic known as polymorphism, and it is understood that such polymorphic forms (“polymorphs”) are within the scope of formula I or Ia. Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility and melting point.

The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the compounds of formula I or Ia.

The compounds of the present invention may have utility in preventing, treating, or ameliorating Alzheimer's disease. The compounds may also be useful in preventing, treating, or ameliorating other diseases mediated by the α7 nAChR, such as schizophrenia, sleep disorders, Parkinson's disease, autism, microdeletion syndrome, inflammatory diseases, pain disorders (including acute pain, inflammatory pain and neuropathic pain) and cognitive disorders (including mild cognitive impairment). Other conditions that may be prevented, treated, or ameliorated by the compounds of the invention include pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, 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, kidney diseases, cancer, and atherosclerosis.

In preferred embodiments, the compounds of the invention may be useful in preventing, treating, or ameliorating 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, ketamine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine) psychosispsychotic 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 preventing, treating, or ameliorating 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; primary hyperalgesia; secondary hyperalgesia; primary allodynia; secondary allodynia; or other pain caused by central sensitization.

Potential conditions or disorders that have a strong inflammatory component for which the compounds of the invention may be useful include one or more of the following conditions or diseases: diabetes (systemic inflammation in diabetes marked by increases in blood cytokines e.g. IL-6 and TNFα which may lead to insulin resistance); asthma; arthritis; cystic fibrosis; sepsis; ulcerative colitis; inflammatory bowel disease; atherosclerosis; neuroinflammation associated with neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jacob disease, frontotemporal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy, traumatic brain injury, Huntington's disease, amyotrophic lateral sclerosis).

Compounds of the invention may also be used to treat or prevent or ameliorate dyskinesia and protect against neurodegeneration in nigrostriatal neurons in Parkinson's disease. 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 administered in the form of pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to a salt that possesses the effectiveness of the parent compound and that is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Many of the compounds of the invention carry an acidic moiety, in which case suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (—COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.

For the purposes of preventing, treating, or ameliorating the cognitive impairments in Alzheimer's disease, Parkinson's disease, schizophrenia, L-DOPA induced-dyskinesia, and inflammation, the compounds of the present invention, optionally in the form of a salt, can be administered by any means that produces contact of the active agent with the agent's site of action. They can be administered by one or more conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but typically are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The compounds of the invention can, for example, be administered by one or more of the following: orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation (such as in a spray form), or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. Liquid preparations suitable for oral administration (e.g., suspensions, syrups, elixirs and the like) can be prepared according to techniques known in the art and can employ any of the usual media such as water, glycols, oils, alcohols and the like. Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as solubility aids. Injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further description of methods suitable for use in preparing pharmaceutical compositions of the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences, 18thedition (ed. A. R. Gennaro, Mack Publishing Co., 1990).

The compounds of this invention can be administered orally in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses. One dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses. Another dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses. For oral administration, the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 mg of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. 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, and the severity of the particular condition.

As noted above, the present invention also relates to a method of preventing, treating, or ameliorating the cognitive impairments in Alzheimer's disease, Parkinson's disease, schizophrenia, L-DOPA induced-dyskinesia, and inflammation with a compound of the present invention in combination with one or more therapeutic agents and a pharmaceutical composition comprising a compound of the present invention and one or more therapeutic agents selected from the group consisting of anti-Alzheimer's Disease agents, for example beta-secretase inhibitors; Ml mAChR agonist or PAMs; M4 mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs; ADAM 10 ligands or activators; gamma-secretase inhibitors, such as LY450139 and TAK 070; gamma secretase modulators; tau phosphorylation inhibitors; glycine transport inhibitors; LXR β agonists; ApoE4 conformational modulators; NR2B antagonists; androgen receptor modulators; blockers of Aβ 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-HT1a antagonists, such as lecozotan; p25/CDK5 inhibitors; NK1/NK3 receptor antagonists; COX-2 inhibitors; LRRK2 inhibitors; HMG-CoA reductase inhibitors; NSAIDs including ibuprofen; vitamin E; anti-amyloid antibodies (including anti-amyloid humanized monoclonal antibodies), such as bapineuzumab, ACC001, CAD106, 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 AVE1625; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) 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 H3 receptor antagonists such as ABT-834, ABT 829, GSK 189254 and CEP16795; 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; GSK30 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.

In another embodiment, the compounds of the instant invention 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, MAO-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA 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 compound of the instant invention 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 compounds of the instant invention may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine 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 compounds of the instant invention may be employed in combination with acetophenazine, alentemol, aripiprazole, amisuipride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, frihexyphenidyl, thioridazine, thiothixene, trifluoperazine or ziprasidone.

Compounds of the instant invention are useful for the treatment of moderate to severe dementia of the Alzheimer's type alone or in combination with an NMDA receptor antagonist, such as memantine, or in combination with an acetylcholinesterase inhibitor (AChEI) such as donepezil.

Compounds of the instant invention are useful for the treatment of mild to moderate dementia of the Alzheimer's type alone or in combination with either galantamine, rivastigmine, or donepezil.

Compounds of the instant invention are useful for the treatment of dementia associated with Parkinson's disease alone or in combination with rivastigmine.

Compounds of the instant invention are useful for the treatment of motor fluctuations in patients with advanced Parkinson's disease alone or in combination with carbidopa and levodopa.

When administering a combination therapy of the invention to a patient, therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). A compound of the invention and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like).

The α7 nAChR positive allosteric modulator (PAM) activity of the present compounds may be tested using assays known in the art. The α7 nAChR PAMs described herein have activities in an automated patch-clamp electrophysiology functional assay as described in the examples. The assay was performed using the IonFlux HT in a whole-cell, population patch configuration. See Golden et al.Assay Drug Dev. Technol. (2011) 9:608-619. The compounds were assessed for their ability to modulate the function of the human α7 nAChR stably expressed in a HEK cell line both in the presence, and in the absence of the natural α7 agonist acetylcholine. By performing a series of such measurements at different concentrations, the effective concentration of the α7 nAChR PAMs (EC50) was determined. See Spencer et al.Assay Drug Dev. Technol. (2012) 10:313-324.

The present invention also includes processes for making compounds of formula I or Ia. The compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above. The following reaction schemes and examples serve only to illustrate the invention and its practice.

It is understood that the compounds and intermediates in the foregoing reaction schemes may be employed as synthetic intermediates in other schemes that involve similar intermediates to produce alternative compounds of the present invention.

In some cases, the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. Additionally, various protecting group strategies familiar to one skilled in the art of organic synthesis may be employed to facilitate the reaction or to avoid unwanted reaction products.

In some cases, the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.

The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way. Wherein a racemic mixture is produced, the enantiomers may be separated using SFC (supercritical fluid chromatography) reverse or normal phase chiral resolution conditions either after isolation of the final product or at a suitable Intermediate, followed by processing of the single isomers individually. It is understood that alternative methodologies may also be employed in the synthesis of these key intermediates and examples. Asymmetric methodologies (e.g. chiral catalysis, auxiliaries) may be used where possible and appropriate.

The exact choice of reagents, solvents, temperatures, and other reaction conditions, depends upon the nature of the intended product.

Reaction Schemes

The compounds of the present invention can be prepared readily according to the following schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail. The general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following schemes.

Key benzylamine intermediates may be prepared according to Scheme 1, in which a Sharpless asymmetric aminohydroxylation of styrene 1.1 is carried out using dichlorohydantoin and potassium osmate(VI) dihydrate in the presence of hydroquinidine 1,4-phthalazinediyl diether. The resulting protected aminoalcohol 1.2 is methylated with Mel and Ag2O in CH3CN to afford the corresponding amino-ether 1.3. Alternatives reagents can be used to methylate 1.2 to 1.3. Compound 1.3 may be deprotected using, for example, HCl in dioxane to afford 1.4 as the hydrochloride salt. Other acidic conditions (for example HCl in diethyl ether (Et2O) or TFA) can be employed in the deprotection reaction.

Additional amines of interest may be prepared according to Scheme 2, in which the Ellman sulfinamide chiral auxiliary is used to prepare the amines in enantiomerically enriched form. For example, (R)-(+)-2-methyl-2-propanesulfinamide 2.1 and the protected glycolaldehyde 2.2 may be condensed using PPTS and MgSO4in dichloromethane to form sulfinimine 2.3. Other methods of forming the sulfinimine 2.3 may also be employed, such as treating a solution of 2.1 and 2.2 with CuSO4or Ti(OEt)4in DCM or THF. Reaction of the sulfinimine 2.3 with a lithiated pyridine, obtained via lithium-halogen exchange on bromide 2.4, leads to sulfinamide 2.5. Other organometallic reagents, such as Grignard reagents, may also be employed to give a variety of amine products of interest. Deprotection, for example using HCl, provides the desired amine intermediate 2.6 as the hydrochloride salt. Other acidic conditions (HCl in 1,4-dioxane or TFA for example) can be employed in the deprotection reaction.

Other useful amine intermediates may be prepared according to Scheme 3 wherein the circle represents a variety of cycloalkyl, heterocyclyl, aryl, or heteroaryl rings. Sulfinimine 3.2 can be obtained by treating aldehyde 3.1 with the Ellman sulfinamide chiral auxiliary in the presence of titanium(IV) ethoxide in tetrahydrofuran. A variety of other reagents and solvents may be used to promote this condensation reaction, including the use of MgSO4or CuSO4in dichloromethane. Monofluoromethyl and difluoromethyl phenyl sulfone anions, obtained by treatment of 3.3 (X=H or F) with LiHMDS (lithium bis(trimethylsilyl)amide), are reacted with sulfinimine 3.2 to give the corresponding sulfinamides 3.4 with good diastereoselectivity. Reductive removal of the phenyl sulfone moiety can be achieved using sodium-mercury amalgam to afford sulfinamide 3.5 and deprotection is carried out under acidic conditions (for example HCl in 1,4-dioxane) to provide the monofluoromethyl- or difluoromethyl-amine 3.6 (X=H or F).

Analogous amine intermediates to those in Scheme 3, in which the monofluoromethyl or difluoromethyl group is replaced by a trifluoromethyl group, may be prepared according to Scheme 4 wherein the circle represents a variety of cycloalkyl, heterocyclyl, aryl, or heteroaryl rings. In this case, the sulfinimine 3.2 is treated with the Ruppert-Prakash reagent in the presence of TBAT to provide the corresponding sulfinamide 4.1 with good diastereoselectivity. Deprotection under acidic conditions affords the desired amine intermediate 4.2.

A variety of aryl or heteroaryl cyclopropylamines may be prepared according to Scheme 5, in which the circle represents the aryl or heteroaryl ring. The cyano analogue 5.1 is reacted with ethylmagnesium bromide in the presence of titanium(IV) isopropoxide in tetrahydrofuran to give the corresponding cyclopropylamine 5.2.

A number of aryl or heteroaryl cyclobutylamine derivatives of interest may be prepared using the chemistry outlined in Scheme 6. Sulfinimine 6.2 can be obtained by treating cyclobutanone 6.1 with the racemic Ellman sulfinamide chiral auxiliary in the presence of titanium(IV) ethoxide in tetrahydrofuran. Reaction of sulfinimine 6.2 with the organolithium species 6.3 in an aprotic solvent such as tetrahydrofuran affords the sulfinamide 6.4. The organolithium reagent 6.3 may be available from commercial sources or may be obtained by lithium-halogen exchange on a suitable halide derivative. Finally, deprotection may be carried out under acidic conditions (for example HCl in 1,4-dioxane) to provide the cyclobutylamine 6.5.

A number of 3-hydroxycyclobutylamine intermediates of the present invention may be prepared according to Scheme 7. Reaction of arylacetic acid 7.1 with epichlorohydrin (7.2) in presence of isopropylmagnesium bromide can provide the corresponding 3-hydroxycyclobutyl acid derivative 7.3. Treatment of acid 7.3 with diphenyl phosphoryl azide affords an acyl azide intermediate that undergoes a Curtius rearrangement, leading to an isocyanate that reacts intramolecularly with the hydroxyl group to form the bicyclic carbamate intermediate 7.4. Hydrolysis of carbamate 7.4 using an aqueous base such as potassium hydroxide leads to the desired 3-hydroxycyclobutylamine intermediate 7.5.

Further intermediates in the present invention may be prepared according to Scheme 8. Alkylation of phenol 8.1 with 3-bromopropanoic acid in aqueous sodium hydroxide provides aryl ether 8.2, which may be converted to the chroman-4-one 8.3 by treatment with triflic acid. Sulfinimine 8.4 may be obtained by treating chroman-4-one 8.3 with (R)-(+)-2-methyl-2-propanesulfinamide in the presence of titanium (IV) ethoxide. Reduction of this sulfinimine may be carried out using L-Selectride® (Sigma Aldrich Corp., St. Louis, MO USA) to enhance diastereoselectivity and obtain, after standard acidic deprotection, the (S)-enantiomer of amine 8.5 as the major isomer. Alternatively, if the reduction of sulfinimine 8.4 is performed using NaBH4, the (R)-enantiomer of amine 8.5 is obtained as the major isomer.

4-Aminoisochromane intermediates in the present invention may be prepared according to Scheme 9. Reaction of the benzyl alcohol 9.1 with ethyl diazoacetate and rhodium diacetate dimer provides the ester 9.2, which can be saponified under standard conditions, for example the use of potassium hydroxide in aqueous methanol, to afford the corresponding acid 9.3. Acid 9.3 may be converted to the Weinreb amide 9.4 by reaction with N,O-dimethylhydroxylamine hydrochloride using HATU as the coupling reagent, and treatment of 9.4 with tert-butyllithium leads to cyclization to the isochroman-4-one 9.5. Following similar procedures to those outlined in Scheme 8, the sulfinimine 9.6 is obtained and reduced using L-Selectride© to afford, after standard acidic deprotection, the (R)-enantiomer of amine 9.7 as the major isomer. Alternatively, if the reduction of sulfinimine 9.6 is performed using NaBH4, the (S)-enantiomer of amine 9.7 is obtained as the major isomer.

Formation of a variety of tricyclic carboxylic acids may be accomplished using the methodology outlined in Scheme 10 or simple variants thereof. The bicyclic ketone 10.1 (X ═O, NR1, S, or CH2; Y=CH2or a bond) can be reduced, for example using sodium borohydride, to provide the alcohol 10.2. Other reducing agents, such as lithium aluminium hydride, may also be used for this step. Dehydration of alcohol 10.2 may be accomplished under acidic conditions, such as the use of p-toluenesulfonic acid in toluene, to afford the alkene 10.3, which may be reacted with ethyl diazoacetate in the presence of rhodium diacetate dimer to provide the tricyclic analogues 10.4 as a mixture of endo and exo isomers. Simple saponification under standard conditions, for example using lithium hydroxide, provides the carboxylic acid 10.5 (X=O, NR1, S, or CH2; Y=CH2or a bond). A variety of functional groups are compatible with this methodology and further modifications are possible depending on the nature of R. For example, when R is a halogen, various coupling reactions can be performed on an intermediate like 10.4, as understood by one skilled in the art of organic synthesis. Examples of such methodology include, but are not limited to, Heck coupling reactions, Sonogashira coupling reactions, Suzuki and Stille coupling methodology, and other coupling reactions like the Ullmann or Buchwald-Hartwig reactions.

The formation of aza analogues of these key tricyclic intermediates is illustrated in Scheme 11. Starting from the bicyclic pyridinone compound 11.1 (X=O, NR1, S, or CH2; Y=CH2or a bond), formation of the corresponding chloropyridine 11.2 is achieved using phosphorus oxychloride. Treatment of chloride 11.2 with a suitable metal alkoxide, for example sodium methoxide, can provide the ether analogue 11.3. Further elaboration of compound 11.3 to give the acid intermediate 11.5 (X=O, NR1, S, or CH2; Y=CH2or a bond) may be conducted in analogy with the methodology described in Scheme 10.

Many compounds of the present invention may be prepared according to Scheme 12, in which acid 10.5 (X═O, NR1, S, or CH2; Y=CH2or a bond) is coupled to an amine (WNH2) using HBTU and Hunig's base in dichloromethane to give the desired amide 12.1. Other coupling conditions, known to those skilled in the art of organic synthesis, including the use of reagents such as DCC, EDC, HATU, HOBt, HOAt and their combinations or T3P, can be employed to provide amide 12.1. Alternatively, the acid 10.5 can be activated by forming the corresponding acid chloride, using oxalyl chloride in the presence of catalytic DMF, or anhydride, using pivaloyl chloride, and the acid chloride or anhydride may be reacted with an amine of interest to afford the corresponding amide. Additionally, amide 12.1 may be obtained by treatment of ester 10.4 with an aluminum amide derived from treating amine WNH2with trimethylaluminum. If amide 12.1 is a mixture of enantiomers or diastereomers, the mixture may be separated by chromatography. Alternatively, acid 10.5 and/or amine WNH2(for example, amines 1.4, 2.6, 3.6 or 4.2) may be employed as single enantiomers or diastereomers to obtain 12.1 enriched in a single enantiomer or diastereomer.

It is understood that the compounds and intermediates in the foregoing reaction schemes may be employed as synthetic intermediates in other schemes that involve similar intermediates to produce alternative compounds of the present invention.

In some cases, the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. Additionally, various protecting group strategies familiar to one skilled in the art of organic synthesis may be employed to facilitate the reaction or to avoid unwanted reaction products.

In some cases, the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.

The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way. Wherein a racemic mixture is produced, the enantiomers may be separated using SFC (supercritical fluid chromatography) reverse or normal phase chiral resolution conditions either after isolation of the final product or at a suitable Intermediate, followed by processing of the single isomers individually. It is understood that alternative methodologies may also be employed in the synthesis of these key intermediates and examples. Asymmetric methodologies (e.g. chiral catalysis, auxiliaries) may be used where possible and appropriate. The exact choice of reagents, solvents, temperatures, and other reaction conditions, depends upon the nature of the intended product.

Unless otherwise indicated, when ratios of compounds (such as for examples solvents) are given, the ratio is on a volume to volume basis. For example, acetonitrile:water:formic acid—30:70:0.1 means a mixture of 30 parts by volume acetonitrile, 70 parts by volume water and 0.1 parts by volume formic acid. Additionally, unless otherwise specifically indicated, all reagents are commercially available, known in the literature, or readily synthesized by one skilled in the art. Straightforward protecting group strategies were applied in some routes.

The following abbreviations are used throughout the text:

The resulting mixture was allowed to stir at 0° C. for 10 min and then dichlorohydantoin (10.17 g, 51.62 mmol) was added portionwise. The resulting mixture was allowed to stir at 0° C. for 10 min and then a solution of hydroquinidine 1,4-phthalazinediyl diether (790 mg, 1.01 mmol) in n-propanol (100 mL) was added dropwise. The resulting mixture was allowed to stir at 0° C. for 15 min and then 4-ethoxystyrene (5.0 g, 33.74 mmol) was added, followed by a solution of potassium osmate(VI) dihydrate (250 mg, 0.67 mmol) in aqueous sodium hydroxide (0.5 M, 50 mL, 25.0 mmol). The reaction mixture was stirred at 0° C. for 6 h and then diluted with water (300 mL). The resulting mixture was extracted with diethyl ether (2×200 mL) and the combined organic extracts were washed with a saturated aqueous solution of sodium chloride (100 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes—0:100 to 100:0 to afford compound I1a. MS: m/z=304.3 [M+Na].

To a stirred solution of tert-butyl [(1R)-1-(4-ethoxyphenyl)-2-hydroxyethyl]carbamate (I1a, 2.10 g, 7.46 mmol) in acetonitrile (30 mL) at 0° C. was added silver(I) oxide (8.65 g, 37.32 mmol) portionwise followed by iodomethane (2.32 mL, 37.32 mmol) dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 60 h. The reaction mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes—0:100 to 50:50 to afford compound I1b. MS: m/z=318.3 [M+Na].

To a stirred solution of tert-butyl [(1R)-1-(4-ethoxyphenyl)-2-methoxyethyl]carbamate (2.76 g, 9.35 mmol) in 1,4-dioxane (20 mL) at ambient temperature was added a solution of hydrochloric acid in 1,4-dioxane (4.0 M, 34 mL, 136 mmol) dropwise. The reaction mixture was stirred for 4 h and then concentrated under reduced pressure. The residue was crystallized from diethyl ether to afford compound I1. MS: m/z=179.2 [M−NH2].

To a stirred solution of (S)—N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(6-ethoxypyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide (I2b, 2.0 g, 5.0 mmol) in methanol (20 mL) at ambient temperature was added a solution of hydrochloric acid in diethyl ether (2.0 M, 25 mL, 50.0 mmol) dropwise and the reaction mixture was stirred at ambient temperature for 18 h. The resulting mixture was adjusted to approximately pH 8 using a solution of ammonia in methanol (7.0 M) and was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ammonia in methanol (7.0 M):ethyl acetate—0:100 to 20:80, to afford compound I2a. MS: m/z=183.1 [M+H].

To a stirred solution of 6-ethoxynicotinaldehyde (480 mg, 3.17 mmol) and (S)-(−)-2-methyl-2-propanesulfinamide (385 mg, 3.17 mmol) in tetrahydrofuran (10 mL) at ambient temperature was added titanium(IV) ethoxide (1.4 mL, 6.35 mmol) dropwise. The reaction mixture was allowed to stir at ambient temperature for 24 h and was then diluted with a saturated aqueous solution of sodium chloride (20 mL). The resulting mixture was filtered through a pad of Celite® and the filtrate was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (20 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford compound I3a in sufficient purity for use in the next step.1H NMR (300 MHz, CDCl3): δ 8.55 (s, 1H); 8.51 (d, J 2.4 Hz, 1H); 8.12 (dd, J 8.6 Hz, 2.4 Hz, 1H); 6.81 (d, J 8.6 Hz, 1H); 4.43 (q, J 7.1 Hz, 2H); 1.42 (t, J 7.1 Hz, 3H); 1.24 (s, 9H).

To a stirred solution of (S)—N-[(6-ethoxypyridin-3-yl)methylidene]-2-methylpropane-2-sulfinamide (I3a, 700 mg, 2.75 mmol) and difluoromethyl phenyl sulfone (530 mg, 2.75 mmol) in tetrahydrofuran (15 mL) at −78° C. was added a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 3.0 mL, 3.0 mmol) dropwise, and the reaction mixture was stirred at −78° C. for 2 h. The mixture was diluted with a saturated aqueous solution of ammonium chloride (10 mL) and water (10 mL) and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (10 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes—0:100 to 50:50 to afford compound I3b. MS: m/z=447.3 [M+H].

To a stirred solution of (S)—N-[(1R)-1-(6-ethoxypyridin-3-yl)-2,2-difluoroethyl]-2-methylpropane-2-sulfinamide (I3c, 620 mg, 2.0 mmol) in methanol (15 mL) at ambient temperature was added a solution of hydrochloric acid in 1,4-dioxane (4.0 M, 2.5 mL, 10.0 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 6 h then concentrated under reduced pressure. The residue was crystallized from diethyl ether to afford compound I3. MS: m/z=203.2 [M+H].

To a stirred solution of (S)—N-[(6-ethoxypyridin-3-yl)methylidene]-2-methylpropane-2-sulfinamide (described in Intermediate 3) (260 mg, 1.02 mmol) and TBAT (607 mg, 1.12 mmol) in tetrahydrofuran (10 mL) at −55° C. was added a solution of (trifluoromethyl)trimethylsilane in tetrahydrofuran (2.0 M, 0.61 mL, 1.22 mmol) dropwise. The stirred reaction mixture was allowed to warm from −55° C. to −10° C. over 1 h, then a saturated solution of aqueous ammonium chloride (10 mL) was added. The resulting mixture was allowed to warm to ambient temperature and was extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (10 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes—0:100 to 100:0 to afford compound I5a. MS: m/z=325.2 [M+H].

Utilizing analogous procedures to those described for Intermediate 3, but substituting (S)—N-[(1R)-1-(6-ethoxypyridin-3-yl)-2,2,2-trifluoroethyl]-2-methylpropane-2-sulfinamide in place of (S)—N-[(1R)-1-(6-ethoxypyridin-3-yl)-2,2-difluoroethyl]-2-methylpropane-2-sulfinamide (I3c) to afford compound I5. MS: m/z=221.1 [M+H].

To a stirred solution of titanium(IV) ethoxide (1.65 mL, 5.55 mmol) in tetrahydrofuran (20 mL) at 50° C. was added 2-methoxy-5-cyanopyridine (500 mg, 3.7 mmol). A solution of ethylmagnesium bromide in tetrahydrofuran (1.0 M, 9.3 mL, 9.3 mmol) was then added dropwise to the solution. The reaction mixture was allowed to stir at 50° C. for 3 h. After cooling to ambient temperature, the mixture was acidified with an aqueous solution of hydrochloric acid (3 N, 10 mL, 30 mmol), washed with ethyl acetate (3×10 mL), and the organic extracts were discarded. The aqueous phase was then adjusted to a pH of approximately 10 by the addition of an aqueous solution of sodium hydroxide (1 N) and then extracted with ethyl acetate (3×10 mL). These combined organic extracts were washed with a saturated aqueous solution of sodium chloride (20 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes—0:100 to 100:0 to afford compound I7. MS: m/z=165.1 [M+H].

To a stirred solution of cyclobutanone (1.00 g, 14.1 mmol) and 2-methyl-2-propanesulfinamide (3.00 g, 24.2 mmol) in tetrahydrofuran (30 mL) at ambient temperature was added titanium(IV) ethoxide (6.2 mL, 29.2 mmol) dropwise. The reaction mixture was allowed to stir at ambient temperature for 24 h. The resulting mixture was diluted with a saturated aqueous solution of sodium chloride (20 mL), filtered through a pad of Celite®, and the filtrate was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (20 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford compound I8a in sufficient purity for use in the next step.1H NMR (300 MHz, CDCl3): δ 3.74 (br s, 1H); 3.57-3.42 (m, 1H); 3.34-3.15 (m, 1H); 3.15-3.05 (m, 2H); 2.17-2.03 (m, 2H); 1.22 (s, 9H).

To a stirred solution of 5-bromo-2-ethoxypyridine (467 mg, 2.31 mmol) in tetrahydrofuran (15 mL) at −78° C. was added a solution of n-butyllithium in cyclohexane (2.0 M, 1.16 mL, 2.32 mmol) dropwise. The resulting mixture was stirred at −78° C. for 15 min and then N-cyclobutylidene-2-methylpropane-2-sulfinamide (I8a, 400 mg, 2.31 mmol) was added dropwise. The stirred reaction mixture was allowed to warm from −78° C. to ambient temperature over 45 min, then a saturated solution of aqueous ammonium chloride (10 mL) was added. The resulting mixture was extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (10 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes—0:100 to 100:0 to afford compound I8b. MS: m/z=297.2 [M+H].

To a stirred solution of N-[1-(6-ethoxypyridin-3-yl)cyclobutyl]-2-methylpropane-2-sulfinamide (I8b, 88 mg, 0.30 mmol) in methanol (2 mL) at ambient temperature was added a solution of hydrochloric acid in 1,4-dioxane (4.0 M, 0.75 mL, 3.0 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 5 h then concentrated under reduced pressure. The residue was diluted with a saturated solution of aqueous sodium hydrogencarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (10 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford compound I8 in sufficient purity for use in the next step. MS: m/z=193.2 [M+H].

To a stirred solution of isopropylmagnesium bromide in tetrahydrofuran (1.0 M, 14.3 mL, 14.3 mmol) at 0° C. was added a solution of 4-fluorophenylacetic acid (1.0 g, 6.49 mmol) in tetrahydrofuran (5 mL) dropwise. This was followed by a dropwise addition of 2-(chloromethyl)oxirane (0.916 mL, 11.7 mmol). The stirred reaction mixture was allowed to warm to ambient temperature and then stirred for 45 min. Isopropylmagnesium bromide in tetrahydrofuran (1.0 M, 13.0 mL, 13.0 mmol) was added dropwise at ambient temperature and the stirred reaction mixture was heated at 60° C. for 18 h. After cooling to ambient temperature, the mixture was acidified with an aqueous solution of hydrochloric acid (6 N, 5 mL, 30 mmol) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were concentrated under reduced pressure and the residue was made basic by addition of a saturated aqueous solution of potassium carbonate (10 mL), washed with ethyl acetate (3×10 mL), and the organic extracts were discarded. The aqueous phase was then adjusted to approximately pH 2 by addition of an aqueous solution of hydrochloric acid (6 N) and extracted with ethyl acetate (3×10 mL). These combined organic extracts were washed with a saturated aqueous solution of sodium chloride (10 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford compound I10a in sufficient purity for use in the next step. MS: m/z=233.1 [M+Na].

To a stirred solution of 1-(4-fluorophenyl)-3-hydroxycyclobutane-1-carboxylic acid (I10a, 500 mg, 2.38 mmol) and triethylamine (0.332 mL, 2.38 mmol) in tert-butanol (5 mL) and 1,4-dioxane (5 mL) at ambient temperature was added diphenyl phosphoryl azide (655 mg, 2.38 mmol). The reaction mixture was warmed to 80° C. and stirred for 3 h. The resulting mixture was concentrated under reduced pressure and the residue was suspended in a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (10 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford compound I10b in sufficient purity for use in the next step. MS: m/z=208.1 [M+H].

To a stirred solution of 5-(4-fluorophenyl)-2-oxa-4-azabicyclo[3.1.1]heptan-3-one (I10b, 493 mg, 2.38 mmol) in 2-propanol (10 mL) at ambient temperature was added an aqueous solution of potassium hydroxide (4.0 M, 10 mL, 40 mmol). The stirred reaction mixture was heated at 100° C. for 3 h, then at ambient temperature for 18 h. The organic solvent was removed under reduced pressure and the residual mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford compound I10. MS: m/z=165.1 [M−NH2].

To a stirred solution of 3-fluorophenol (1.0 g, 8.9 mmol) and 3-bromopropionic acid (1.5 g, 9.8 mmol) in water (10 mL) at ambient temperature was added sodium hydroxide (713 mg, 17.8 mmol). The reaction mixture was allowed to stir at 100° C. for 18 h and was then allowed to cool to ambient temperature. The resulting mixture was adjusted to about pH 3 by addition of an aqueous solution of hydrochloric acid (3.0 N) and then was extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (10 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford compound I11a in sufficient purity for use in the next step.1H NMR (300 MHz, CDCl3): δ 7.21 (m, 1H); 6.71-6.60 (m, 3H); 4.24 (t J 6.2 Hz, 2H); 2.86 (t, J 6.2 Hz, 2H).

To a stirred solution of (R)—N-[(7-fluoro-2,3-dihydro-4H-chromen-4-ylidene]-2-methylpropane-2-sulfinamide (I11c, 110 mg, 0.41 mmol) in tetrahydrofuran (5 mL) at −78° C. was added a solution of lithium tri-sec-butylborohydride (1.0 M in tetrahydrofuran, 1.2 mL, 1.2 mmol) dropwise. The reaction mixture was allowed to warm to ambient temperature and was stirred at ambient temperature for 3 h. The resulting mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (10 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford compound I1c in sufficient purity for use in the next step.1H NMR (300 MHz, CDCl3): δ 7.26 (m, 1H); 6.61 (m, 1H); 6.50 (m, 1H); 4.47 (m, 1H); 4.23 (m, 2H); 3.44 (d, J=9.4 Hz, 1H); 2.39 (m, 1H); 2.16 (m, 1H); 1.25 (s, 9H).

To a stirred solution of ethyl [(2-bromo-4-fluorobenzyl)oxy]acetate (I12-a, 2.20 g, 7.55 mmol) in methanol (30 mL) at ambient temperature was added an aqueous solution of potassium hydroxide (4.0 M, 7.6 mL, 30.4 mmol). The reaction mixture was stirred at ambient temperature for 18 h, then the organic solvent was removed under reduced pressure. The resulting mixture was adjusted to approximately pH 2 by addition of an aqueous solution of hydrochloric acid (3.0 N) and was extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (10 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford compound I12-b in sufficient purity for use in the next step.1H NMR (300 MHz, CDCl3): δ 7.47 (dd, J=8.6, 6.0 Hz, 1H); 7.30 (dd, J=8.2, 2.6 Hz, 1H); 7.06 (m, 1H); 4.68 (s, 2H); 4.24 (s, 2H).

To a stirred solution of 2-[(2-bromo-4-fluorobenzyl)oxy]-N-methoxy-N-methylacetamide (I12-c, 2.0 g, 6.53 mmol) in tetrahydrofuran (40 mL) at −78° C. was added a solution of tert-butyllithium (1.7 M in pentane, 7.7 mL, 13.07 mmol) dropwise. The reaction mixture was stirred at −78° C. for 2 min and then a saturated aqueous solution of ammonium chloride (25 mL) was added. The resulting mixture was allowed to warm to ambient temperature and was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (25 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes—0:100 to 30:70, to afford compound I12-d. MS: m/z=167.1 [M+H].

Following analogous procedures to those described in Intermediate 11 but using 6-fluoro-1H-isochromen-4(3H)-one in place of 7-fluoro-2,3-dihydro-4H-chromen-4-one, compound I12 was obtained. MS: m/z=168.0 [M+H].

To a stirred solution of indene (500 mg, 4.30 mmol) and rhodium(II) acetate dimer (8 mg, 0.017 mmol) in dichloromethane (30 mL) at 50° C. was added ethyl diazoacetate (0.54 mL, 5.17 mmol) dropwise. The reaction mixture was allowed to stir at 50° C. for 1 h and then at ambient temperature for 3 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes—0:100 to 10:90, to afford compound I14-a as a mixture of diastereoisomers. MS: m/z=203.1 [M+H]

To a stirred solution of ethyl 1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylate (I14-a, 510 mg, 2.52 mmol) in ethanol (50 mL) and water (10 mL) at ambient temperature was added lithium hydroxide hydrate (529 mg, 12.61 mmol). The reaction mixture was stirred at ambient temperature for 18 h, then the organic solvent was removed under reduced pressure. The resulting mixture was adjusted to approximately pH 2 by addition of an aqueous solution of hydrochloric acid (3.0 N) and then was extracted with diethyl ether (3×25 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (10 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes—0:100 to 30:70, to afford compound I14 as a mixture of diastereoisomers. MS: m/z=175.1 [M+H].

The mixture of diastereomers of 1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid (Intermediate 14) was separated by semi-preparative reversed-phase HPLC, eluting with acetonitrile:water:formic acid—30:70:0.1. The first major peak to elute was endo-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid, compound I15, and the second major peak to elute was exo-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid. MS: m/z=175.1 [M+H].

The mixture of diastereomers of 1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid (Intermediate 14) was separated by semi-preparative reversed-phase HPLC, eluting with acetonitrile:water:formic acid—30:70:0.1. The first major peak to elute was endo-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid and the second major peak to elute was exo-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid, compound I16. MS: m/z=175.1 [M+H].

Following an analogous procedure as described in Intermediate 14, Step A, but using benzofuran in place of indene, compound I17-a was obtained. MS: m/z=205.1 [M+H].

The mixture of diastereomers of ethyl 1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxylate (I17-a) was separated by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes—0:100 to 10:90. The major peak to elute was exo-ethyl 1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxylate, compound I17-b. MS: m/z=205.1 [M+H].

Following an analogous procedure to that described in Intermediate 14, Step B, but using exo-ethyl 1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxylate in place of ethyl 1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylate, compound I17 was obtained. MS: m/z=177.1 [M+H].

A stirred solution of 5-fluorobenzofuran (5.0 g, 0.018 mol) and copper(I) trifluoromethanesulfonate benzene complex (234 mg, 0.46 mmol) in dichloromethane (75 mL) was heated at reflux and ethyl diazoacetate (22 mL, 0.21 mol) was added dropwise over a period of 10 min. The stirred reaction mixture was heated at 50° C. for 1 h and then cooled to ambient temperature and allowed to stir for 2 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by preparative reversed-phase HPLC, eluting with a gradient of acetonitrile:water:formic acid—5:95:0.1 to 95:5:0.1, to afford compound I18-a. MS: m/z=223.1 [M+H].

To a stirred solution of ethyl exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxylate (I18-a, 5.7 g, 0.026 mol) in ethanol (25 mL) and water (5 mL) was added lithium hydroxide monohydrate (5.32 g, 0.128 mol). The reaction mixture was stirred at ambient temperature for 14 h, then the organic solvent was removed under reduced pressure. The resulting mixture was adjusted to approximately pH 2 by addition of an aqueous solution of hydrochloric acid (3.0 N) and then was extracted with diethyl ether (3×50 mL). The combined organic extracts were dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford compound I18. MS: m/z=195.1 [M+H].

The racemic mixture of exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxylic acid (Intermediate 18) was further purified by SFC, utilizing a Lux A1 column and eluting with methanol:carbon dioxide—20:80. The first major peak to elute was exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxylic acid, diastereomer A, compound I19, and the second major peak to elute was exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxylic acid, diastereomer B. MS: m/z=195.1 [M−H].

The racemic mixture of exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxylic acid (Intermediate 18) was further purified by SFC, utilizing a Lux A1 column (Phenomenex®, Torrance, CA USA) and eluting with methanol:carbon dioxide—20:80. The first major peak to elute was exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxylic acid, diastereomer A, and the second major peak to elute was exo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxylic acid, diastereomer B, compound I20. MS: m/z=195.1 [M−H].

A stirred solution of exo-5-bromo-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxylic acid, diastereomer A (Intermediate A6) (150 mg, 0.59 mmol) and 3,5-dimethylisoxazole-4-boronic acid pinacol ester (145 mg, 0.65 mmol) in an aqueous solution of sodium carbonate (2.0 M, 0.89 mL, 1.77 mmol) and 1,2-dimethoxyethane (5 mL) at ambient temperature was deoxygenated with argon for 15 min. Tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.029 mmol) was added, the reaction vessel was sealed and the reaction mixture was heated at 80° C. for 18 h, then the organic solvent was removed under reduced pressure. The resulting mixture was poured into water (15 mL) and washed with ethyl acetate (2×10 mL). The aqueous layer was adjusted to approximately pH 4 by addition of a saturated aqueous solution of citric acid and the precipitate was isolated by filtration, washing with water, and dried to afford compound I23. MS: m/z=272.1 [M+H].

To a stirred solution of copper(I) cyanide (263 mg, 2.94 mmol) in 1-methyl-2-pyrrolidinone (6 mL) was added exo-5-bromo-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxylic acid, diastereomer A (Intermediate A6) (500 mg, 1.96 mmol). The reaction vessel was sealed and the reaction mixture was heated at 180° C. for 48 h. The resulting mixture was poured into water (50 mL) and the precipitate was isolated by filtration, washing with water, and dried to afford compound I24. MS: m/z=202.1 [M+H].

A stirred solution of exo-5-bromo-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxylic acid, diastereomer B (Intermediate A7) (400 mg, 1.56 mmol) and ethynyltrimethylsilane (0.56 mL, 3.90 mmol) in piperidine (5 mL) at ambient temperature was deoxygenated with argon for 15 min. Bis(triphenylphosphine)palladium(II) dichloride (56 mg, 0.079 mmol) was added, the reaction vessel was sealed and the reaction mixture was heated at 90° C. for 18 h, then the solvent was removed under reduced pressure. The resulting mixture was partitioned between water (15 mL) and ethyl acetate (10 mL). The aqueous layer was extracted further with ethyl acetate (2×10 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (10 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes—0:100 to 100:0, to afford compound I25. MS: m/z=273.1 [M+H].

A stirred suspension of furo[3,2-c]pyridin-4(5H)-one (2.0 g, 14.8 mmol) in phosphorus(V) oxychloride (10 mL) was heated at 120° C. for 1 h. The resulting mixture was concentrated under reduced pressure and then carefully added to ice-water (15 mL). The resulting mixture was adjusted to approximately pH 12 by addition of an aqueous solution of sodium hydroxide (4.0 M) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (10 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes—0:100 to 50:50, to afford compound I27-a.1H NMR (300 MHz, CDCl3): δ 8.26 (d, J=5.7 Hz, 1H); 7.69 (d, J=2.2 Hz, 1H); 7.39 (dd, J=5.7, 0.9 Hz, 1H); 6.88 (dd, J=2.2, 0.9 Hz, 1H).

Following analogous procedures to those described in Intermediate 14, but using 4-methoxyfuro[3,2-c]pyridine in place of indene, compound I27 was obtained. MS: m/z=208.0 [M+H].

Following an analogous procedure to that described in Intermediate 18, Step B, but using ethyl exo-6-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylate in place of ethyl 1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylate, compound I28 was obtained. MS: m/z=207.0 [M−H].

Intermediates IA1 through IA13 appearing in the following Table 1: TNT-A were prepared by analogy to the above Intermediates 1 through 30, as described or prepared as a result of similar transformations with modifications known to those skilled in the art. The requisite starting materials were described herein, commercially available, known in the literature, or readily synthesized by one skilled in the art. Straightforward protecting group strategies were applied in some routes.

Following an analogous procedure to that described in Example 1, but using exo-5-[(trimethylsilyl)ethynyl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-carboxylic acid, diastereomer B, (Intermediate 25) in place of exo-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid, compound 6-a was obtained. MS: m/z=450.2 [M+H].

Compounds A1 through A20, B1 through B19 and C1 through C53 appearing in Tables 2 through 4 were prepared by analogy to the above examples, as described or prepared as a result of similar transformations with modifications known to those skilled in the art. The requisite starting materials were described herein, commercially available, known in the literature, or readily synthesized by one skilled in the art. Straightforward protecting group strategies were applied in some routes.

The utility of the compounds in accordance with the present invention as positive allosteric modulators of α7 nicotinic acetylcholine receptor activity may be demonstrated by methodology known in the art. Direct activation of α7 (agonism), and potentiation of acetylcholine-evoked α7 currents was determined as follows:

Automated patch-clamp electrophysiology was performed using the IonFluxHT (Fluxion Biosciences Inc., San Francisco, CA) in the whole-cell, population patch configuration. Test compounds were assessed for their ability to modulate the function of the α7 nicotinic acetylcholine receptor both in the presence, and in the absence of the natural α7 agonist acetylcholine. A HEK cell line stably expressing both human RIC-3 and human α7 (PrecisION hnAChR α7/RIC-3, Eurofins Pharma, St. Charles, MO) was cultured in 175 cm2triple-layer tissue culture flasks to no more than 90% confluency in DMEM/F-12 growth media supplemented with 10% heat-inactivated fetal bovine serum, 1% non-essential amino acids, 0.625 μg/mL Puromycin, and 400 μg/mL Geneticin. Immediately prior to assay, cells were detached by first aspirating growth media, rinsing with Dulbecco's phosphate buffered saline, and then adding 10 mL of Accutase (Innovative Cell Technologies, San Diego, CA) to the flask and then incubating at 37° C. for 5 minutes. Detached cells were then recovered by the addition of 40 mL of CHO-serum-free media supplemented with 25 mM HEPES, and rocked gently in a 50 mL conical tube for 20 minutes prior to patch-clamp assay. After recovery, cells were pelleted by centrifugation at 1,000 RPM for 1 minute in a compact bench top centrifuge; recovery media was aspirated and cells were resuspended in external recording solution (150 mM NaCl, 5 mM KCl, 2 mM CaCl2), 1 mM MgCl2, 10 mM HEPES, 12 mM dextrose) to a density of 5.0×106cells/mL. The cell suspension was added to the cell inlet wells on an IonFlux HT population patch plate which had previously been rinsed and primed with deionized H2O. Test compounds were serially diluted in DMSO and then resuspended to the final test concentration in external recording solution, with, or without 40 μM acetylcholine added to the external recording solution; test compounds were then transferred to the IonFlux HT population patch plate. Internal recording solution (110 mM TrisPO4, 28 mM TrisBase, 0.1 mM CaCl2), 2 mM MgCl2, 11 mM EGTA, 4 mM MgATP) was added to the internal recording solution inlet wells on the IonFlux HT patch plate previously loaded with cells and test compounds, and the plate loaded into the IonFlux HT instrument. A protocol was executed on the IonFlux HT to trap the cells, break into the cells, and establish the whole-cell recording configuration; cells were voltage-clamped at a holding potential of −60 mV for the duration of the experiment, all experiments were conducted at room temperature, and the IonFlux HT injection pressure was 8 psi for solution applications. Upon establishing the whole-cell configuration, external recording solution was perfused into the recording chambers for 120 seconds and then 40 μM acetylcholine was applied for 1 second and immediately washed off with external recording solution for 60 seconds. The 40 μM acetylcholine-evoked α7 current served as the current response to which subsequent test compound effects, in the presence, or in the absence of 40 μM acetylcholine would be quantified relative to. Next, test compounds were evaluated at multiple concentrations for their ability to induce, or modulate α7 current responses; three concentrations of test compound were evaluated in ascending dose fashion per recording. To assess test compound agonist activity, test compound diluted in external recording solution was applied starting from the lowest concentration of test compound being tested in the concentration series, for 58 seconds; the first 20 seconds of the 58 second compound application period coincided with a data collection sweep which was 20 seconds in duration, and collected at a rate of 5,000 samples/second. To assess test compound positive allosteric modulator activity, immediately following the 58 second test compound only application period, the same concentration of test compound, diluted in external recording solution containing 40 μM acetylcholine was applied for 1 second; in this way, the test compound and the natural receptor agonist acetylcholine were co-applied, and potentiating effects of test compounds observed. The 1 second application of test compound diluted in external solution containing 40 μM acetylcholine coincided with a data collection sweep which was 20 seconds in duration, and collected at a rate of 5,000 samples/second, after which, external recording solution only was applied for 42 seconds. Following this 42 second wash with external recording solution only, the next highest concentration of the test compound in the concentration series was applied in the absence and then in the presence of acetylcholine as previously described, and data collected as previously described. After test compound agonist, and positive allosteric modulator activity were assessed at three ascending concentrations, the experiment was terminated and leak subtraction performed using the IonFlux HT data analysis software. Peak current amplitudes and the area under the curve (AUC) were both quantified for each current sweep using proprietary software and test compound effects where quantified as follows.

Test compound agonist activity was calculated as:

Test compound potentiator activity was calculated as:

X=Peak current amplitude (or AUC) evoked by 40 μM acetylcholine
Y=Peak current amplitude (or AUC) evoked by test compound diluted in external recording solution
Z=Peak current amplitude (or AUC) evoked by test compound diluted in external recording solution containing 40 μM acetylcholine

As such, test compounds which evoked the same current amplitude as 40 μM acetylcholine alone would exhibit a calculated % Agonism of 100%. Test compounds co-applied with 40 μM acetylcholine which evoked a current amplitude 2× the current evoked from 40 μM acetylcholine alone would exhibit a calculated % Potentiation of 100%, whereas test compounds co-applied with 40 μM acetylcholine which evoked the same current amplitude as 40 μM acetylcholine alone would be characterized as exhibiting no potentiation.

Agonist and potentiation data, derived by peak current amplitude or area under the curve (AUC) were graphed and fit using a 4-parameter logistic fit based on the Levenberg-Marquardt algorithm where y=A+((B−A)/(1+((C/x){circumflex over ( )}D))) where:

Potency data for selected compounds of the present invention in the automated patch-clamp electrophysiology functional assay (Assay A) are represented in the Table 5 below:

Electrophysiology EC50values for selected compounds of the present invention in the automated patch-clamp electrophysiology functional assay (Assay A) are provided in Table 6 below: