BR112018069456B1 - Compound useful as a modulator of a7 nAChR or a pharmaceutically acceptable salt thereof, its pharmaceutical composition and its use - Google Patents

Abstract

The present disclosure relates to compounds of formula (I) which are useful as modulators of a7 nAChR, to compositions comprising such compounds and to the use of such compounds to prevent, treat or ameliorate disease, particularly central nervous system disorders such as deficiencies. cognitive disorders in Alzheimer's disease, Parkinson's disease and schizophrenia, as well as for L-DOPA-induced dyskinesia and inflammation.

Description

FIELD OF INVENTION

[001] The present invention relates to compounds that are useful as modulators of α7 nAChR, to compositions comprising such compounds and to the use of such compounds to prevent, treat or ameliorate disease, particularly central nervous system disorders such as cognitive impairments in Alzheimer's disease, Parkinson's disease and schizophrenia.

BACKGROUND OF THE INVENTION

[002] The α7 nAChR is a fast desensitizing ligand-gated ion channel that has high permeability to Ca2+. In the 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 to 398. In neurons, α7 nAChRs are located in both presynaptic and postsynaptic structures, where receptor activation can modulate neurotransmitter release, neuronal excitability, and intracellular signaling, see, for example, Frazier et al. J. Neurosci. (1998) 18:1187 to 1195.

[003] Cognitive impairments are prevalent in many neurological and psychiatric diseases, including Alzheimer's disease (AD), schizophrenia and Parkinson's disease, and dysfunction in cholinergic signaling contributes to the cognitive impairments of these diseases, see, for example, Francis et al. al. J. Neurol. Neurosurg. Psychiatry (1999) 66:137 to 147. For example, a major feature of the pathogenesis in AD is the loss of cholinergic neurons in the basal forebrain nuclei, while increased cholinergic transmission through acetylcholine esterase inhibition is the standard of care for the cognitive symptoms of AD. More specifically for the α7 nAChR, encenicline, a partial agonist of the α7 nAChR, has recently been shown to enhance cognition in Alzheimer's disease, see, for example, Moebius H et al., 67th Annual Meeting. Am. Acad. Neurol. (AAN) 2015, Abst P7,100. Evidence implicating α7 nAChRs in the etiology of schizophrenia arises from studies demonstrating reduced expression of neuronal α7 nAChRs in the brains of schizophrenic patients and the observation that schizophrenics generally smoke, which is believed to be a form of self-medication. Furthermore, variants in the promoter region of the gene encoding the α7 nAChR, CHRNA7, which impacts α7 nAChR protein expression, are associated with symptoms of schizophrenia, see, for example, Sinkus et al. Neuropharmacology (2015) 96:274–288. Furthermore, accumulating evidence from clinical trials has indicated that activation of the 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 to 1073. Therefore, targeting the α7 nAChR represents a therapeutic strategy for the treatment of cognitive impairments associated with various cognitive disorders.

[004] 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 the 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 motor symptoms in PD. However, chronic L-DOPA treatment in PD patients also induces dyskinesia, a side effect of L-DOPA therapy. New lines of evidence indicate that activation of α7 nAChRs acutely alleviates dyskinesia in several animal models, see, for example, Zhang et al. J. Pharmacol. Exp. Ther. (2014) 351:25 to 32. Furthermore, accumulating evidence shows that pretreatment with α7 nAChR agonists can protect against neurodegeneration in nigrostriatal neurons, suggesting that α7 activation may also have disease-modifying properties, see , for example, Suzuki et al. J. Neurosci. Res. (2013) 91:462 to 471. Overall, α7 nAChR is an attractive target for both improving disease progression and managing dyskinesia.

[005] In addition to its expression in the central nervous system, the α7 nAChR is widely expressed in peripheral immune cells including macrophages, monocytes, dendritic cells, and B and T cells, see, for example, Rosas-Ballina et al. Science (2011) 334:98 to 101. Activation of peripheral α7 nAChRs is critical for inhibiting the release of pro-inflammatory cytokines via the cholinergic anti-inflammatory pathway, see, for example, Wang et al. Nature (2003) 421:384 to 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 to 929.

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

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

SUMMARY OF THE INVENTION

[008] The present invention relates to innovative compounds of formula I and pharmaceutically acceptable salts thereof. These compounds may be useful, as compounds or pharmaceutically acceptable salts thereof (where appropriate), in modulating the α7 nAChR, in preventing, treating or ameliorating disease, particularly central nervous system disorders such as cognitive impairments in Alzheimer's, Parkinson's disease and schizophrenia and/or as ingredients in pharmaceutical composition. As pharmaceutical composition ingredients, these compounds and salts thereof may be the principal active therapeutic agent, and, where appropriate, may be combined with other therapeutic agents including, but not limited to, acetylcholinesterase inhibitors, NMDA receptor antagonists, beta-secretase, M4 mAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs, 5-HT6 antagonists, histamine H3 receptor antagonists, PDE4 inhibitors, PDE9 inhibitors, HDAC6 inhibitors, antipsychotic, MAO inhibitors B and levodopa.

[009] In one aspect, the present invention relates to a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: Y is selected from 1 to 4 substituents, each independently selected from H, (C1-C4)alkyl, halogen and OH, wherein said alkyl is optionally substituted with one or more halogens or OH; A is a 5-membered heteroaryl ring that is substituted with 1 to 3 R groups each independently selected from OH, oxo, NR7R8, CN, alkoxy, halogen, aminoalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl , wherein said alkoxy, aminoalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF3, OCF3, CN, ( C1-C6)alkyl, O(C1-C4)alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C=O)NR7R8, (C=O)OR7, (C1- C4 )alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O(C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally and independently substituted with one or more halogen, CF3, OH and oxo; R1 is H or (C1-C4)alkyl; R2 is H or (C1-C4)alkyl; R3 is H, halogen or (C1-C4)alkyl, wherein said alkyl is optionally substituted with one or more halogens; R4 is H, halogen or (C1-C4)alkyl, wherein said alkyl is optionally substituted with one or more halogens; or, R3 and R4 may optionally join together to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring wherein said ring may be optionally substituted with one or more substituents independently selected from OH, halogen or (C1-C4) alkyl; R5 is H or (C1-C4)alkyl; R6 is H or (C1-C4)alkyl; R7 is H or (C1-C4)alkyl; R8 is H or (C1-C4)alkyl; and Ra is H or (C1-C4)alkyl.

[010] 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 for preventing, treating or ameliorating cognitive impairments associated with Alzheimer's disease, Parkinson's disease and schizophrenia.

[011] Other embodiments, aspects and features of the present invention are further described in or will be apparent from the description, examples and resulting appended claims. DETAILED DESCRIPTION OF THE INVENTION The present invention includes compounds of the above formula I and pharmaceutically acceptable salts thereof. The compounds of formula I are positive allosteric modulators of α7 nAChR.

[012] In a first embodiment of the invention, X is , and the other groups are as given in the general formula above.

[013] In a second embodiment of the invention, Y is H and the other groups are as provided in the general formula above or as in the first embodiment.

[014] In a third embodiment of the invention, A is selected from each substituted with 1 to 3 R groups independently selected from (C1-C4)alkyl, (C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each is optionally substituted with one or more substituents independently selected from of F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl, O(C1-C4)alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O(C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally and independently substituted with one or more F, Cl, CF3, OH and oxo; and the other groups are as provided in the general formula above, or as in the first or second embodiment.

[015] In a fourth embodiment of the invention, R5, R6, and Ra are independently H or methyl, and the other groups are as provided in the general formula above, or as in the first, second or third embodiments.

[016] In a fifth embodiment of the invention, R3 and R4 are independently H, F or methyl, and the other groups are as provided in the general formula above, or as in the first to fourth embodiments.

[017] In a sixth embodiment of the invention, the compound of the invention has the formula: or a pharmaceutically acceptable salt thereof, wherein; A is selected from each substituted with 1 to 2 R groups independently selected from (C1-C4)alkyl, (C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each is optionally substituted with one or more substituents independently selected from of F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl, O(C1-C4)alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O(C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally and independently substituted with one or more F, Cl, CF3, OH and oxo; and R3, R4, R5 and R6 are as provided in the first to fifth embodiments.

[018] In a seventh embodiment of the invention, the compound of the invention has the formula: or a pharmaceutically acceptable salt thereof, wherein; A is selected from each substituted with 1 to 2 R groups independently selected from (C1-C4)alkyl, (C3-C6)cycloalkyl, phenyl, indanyl, piperidinyl, pyridinyl, furanyl, oxazolyl, benzoxazinyl, cyclopentalpyrrolyl, thienopyrrolyl, thiazolyl, imidazolyl, azetidinyl, pyrrolyl, pyrazinyl, quinolinyl and benzothiazolyl wherein each is optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl, O (C1-C4)alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O (C3-C6)cycloalkyl, phenyl, O-phenyl, imidazolyl, pyrazinyl, furanyl, oxazolidinyl, pyrrolidinyl, and benzoxazolyl, wherein said alkyl, phenyl, oxazolidinyl, pyrrolidinyl and benzoxazolyl are optionally and independently substituted with one or more F, Cl, CF3 and oxo; R5 and R6 are independently H or methyl; and R3 and R4 are as provided in the first to fifth embodiments.

[019] In an eighth embodiment of the invention, the compound of the invention has the formula: or a pharmaceutically acceptable salt thereof, wherein; R is selected from (C1-C4)alkyl, (C3-C6)cycloalkyl, phenyl, indanyl, piperidinyl, pyridinyl, furanyl, oxazolyl, benzoxazinyl, cyclopentalpyrrolyl, thienopyrrolyl, thiazolyl, imidazolyl, azetidinyl, pyrrolyl, pyrazinyl, quinolinyl and benzothiazolyl in which each is optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl, O(C1-C4)alkyl, S (C1-C4)alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O(C3-C6)cycloalkyl, phenyl , O-phenyl, imidazolyl, pyrazinyl, furanyl, oxazolidinyl, pyrrolidinyl and benzoxazolyl, wherein said alkyl, phenyl, oxazolidinyl, pyrrolidinyl and benzoxazolyl are optionally and independently substituted with one or more F, Cl, CF3 and oxo; R3 and R4 are independently H, F or methyl; and R5 and R6 are independently H or methyl.

[020] The invention is also directed to a compound, or a pharmaceutically acceptable salt thereof, selected from the following exemplified compounds: 4-((1S,3S)-3-(3-(5-Fluoro-2-methylphenyl )-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl)-benzenesulfonamide; 4-((1S,3S)-3-(5-(2-Cyclopropylethyl)-1,2,4-oxadiazol-3-yl)-2,2-dimethylcyclopropyl)benzenesulfonamide; 4-((1S,3S)-2,2-Dimethyl-3-(5-(2,3,6-trifluorophenyl)-1,2,4-oxadiazol-3-yl)cyclopropyl)benzenesulfonamide; 4-((1R,2R)-2-(3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)benzenesulfonamide; 4-{(1R,3R)-3-[5-(2,4-Difluorophenyl)-1,3,4-thiadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(2,4-Difluorophenyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Difluoro-3-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(5-Phenyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(4-Phenyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-(2-phenyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-(3-phenylisoxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-(1-phenyl-1H-1,2,3-triazol-4-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[1-(3-Fluorophenyl)-1H-pyrazol-4-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[4-(3-Fluorophenyl)-1,3-thiazol-2-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(5-Methyl-4-phenyl-1,3-thiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(4-Methyl-5-phenyl-1,3-thiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(5-phenyl-1,3-thiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-{trans-2-[3-(Propan-2-yl)-1,2,4-thiadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(5-Chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-((1R,3R)-3-(3-Cyclohexyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl)benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]cyclopropyl}benzenesulfonamide; 4-(2-Methyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl)benzenesulfonamide; 4-{(1R,2R)-2-[1-(3-Fluorobenzyl)-1H-pyrazol-3-yl]cyclopropyl}benzenesulfonamide; 4-[trans-2-(2-Phenyl-1,3-oxazol-4-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(2-Phenyl-1,3-thiazol-4-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[1-(3-Fluorophenyl)-1H-1,2,3-triazol-4-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(2-Phenyl-1,3-thiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(2-Cyclohexyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[5-(Piperidin-1-yl)-1,2,4-thiadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]phenyl sulfamate; 4-[(1R,3R)-3-(4,5-Dicyclopropyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]-2-fluorobenzenesulfonamide; 5-{trans-2,2-Dimethyl-3-[4-(methylsulfonyl)phenyl]cyclopropyl}-3-phenyl-1,2,4-oxadiazole; 4-[trans-3-(5-Cyclopentilisoxazol-3-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[2-(3-Fluorophenyl)-1-methyl-1H-imidazol-4-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{trans-2,2-Dichloro-3-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[5-(Piperidin-1-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide 4-[trans-2,2-Dimethyl-3- (3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]-3-methylbenzenesulfonamide 4-{(1R,3R)-3-[3-(5-Chloro-2-methoxyphenyl)-1,2 ,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1R,3R)-3-{3-[4-Fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-{3-[5-Chloro-2-(propan-2-yloxy)phenyl]-1,2,4-oxadiazol-5-yl}-2,2-dimethyl cyclopropyl ]benzenesulfonamide; 4-[(1S,2S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[3-(5-Fluoro-2-methylphenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[3-(2,4-Difluorophenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,2S)-2-[3-(2,4-Difluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Difluoro-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[3-(2,6-Difluorophenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[3-(2-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-{3-[2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[3-(3-Bromophenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,2S)-2-[3-(5-Chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-2,2-Dimethyl-3-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[3-(5-Fluoropyridin-3-yl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1R,3R)-3-(3-Cyclobutyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,2S)-2-(3-Cyclohexyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{(1S,2S)-2-[3-(5-Fluoropyridin-3-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,2S)-2-[3-(2-Methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-{3-[5-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl} cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[3-(3,3-Difluorocyclobutyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1R,3R)-3-(3-Cyclopentyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[3-(Cyclopropylmethyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,3R)-2,2-Dimethyl-3-[3-(tetrahydrofuran-3-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-2,2-Dimethyl-3-[3-(tetrahydrofuran-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-2,2-Dimethyl-3-[3-(1-phenylcyclopropyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[3-(5-Fluoro-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazol-5-yl]- 2 ,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,3R)-2,2-Dimethyl-3-[3-(spiro[3.3]hept-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[3-(1-Acetylpiperidin-4-yl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-(3-tert-Butyl-1,2,4-oxadiazol-5-yl)-2,2-difluorocyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(3-Cyclopentyl-1,2,4-oxadiazol-5-yl)-2,2-difluorocyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[3-(5-Chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{3-[4-Fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-{3-[5-Chloro-2-(propan-2-yloxy)phenyl]-1,2,4-oxadiazol-5-yl}-2,2-dimethyl cyclopropyl ]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-{3-[2-(Trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-{3-[4-Fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-{3-[5-Fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[3-(2,6-Difluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(3-Bromophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2-Fluoro-6-methylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[3-(2,4-Difluorophenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2,4-Difluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2,3-Difluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2,5-Difluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2-Methylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(3-Methylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(4-Methylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2-Fluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,3R)-2,2-Difluoro-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-2,2-Difluoro-3-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{3-[4-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(3-Cyclohexyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[3-(5-Fluoropyridin-3-yl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-(3-Cyclobutyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(3-Cyclohexyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(3-tert-Butyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[3-(Propan-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(5-Fluoropyridin-3-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[3-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[3-(2-methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2-Methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{3-[5-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[3-(3,3-Difluorocyclobutyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(3,3-Difluorocyclobutyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-(3-Cyclopentyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(3-Cyclopentyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-{3-[5-(Trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[3-(1-Phenylcyclopropyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2-Cyclopropylpyridin-3-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-{3-[4-(Trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[3-(2,4-Difluorobenzyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[3-(Cyclopropylmethyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(Cyclopropylmethyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{3-[6-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{3-[2-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[3-(4-Methyl-1,3-oxazol-5-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[3-(2-Hydroxycyclohexyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[3-(1-methylcyclohexyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-2,2-Difluoro-3-[3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{trans-2-[3-(5-Chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{trans-3-[3-(5-Chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-2,2-difluorocyclopropyl}benzenesulfonamide; 4-{2-[3-(2,4-Difluorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylcyclopropyl}benzenesulfonamide; 4-{2-[3-(2,4-Difluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylcyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[5-(2,6-Difluorophenyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1R,3R)-3-{5-[5-Fluoro-2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-{5-[2-Fluoro-6-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-(5-phenyl-1,3,4-thiadiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-(5-phenyl-1H-1,2,4-triazol-3-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[5-(2-Cyclopropylpyridin-3-yl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1R,3R)-3-(5-Cyclohexyl-1,3,4-thiadiazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(5-phenyl-1,3,4-oxadiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[3-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(3-Fluorophenyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(2,6-Difluorophenyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[5-Fluoro-2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(5-phenyl-1,3,4-thiadiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(2,4-Difluorophenyl)-1,3,4-thiadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(propan-2-yl)-1,3,4-oxadiazol-2-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopentyl-1,3,4-oxadiazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(Cyclopropylmethyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(2-Cyclopropylpyridin-3-yl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclohexyl-1,3,4-thiadiazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopentyl-1,3,4-thiadiazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopropyl-1,3,4-thiadiazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(5-Cyclopentyl-1,3,4-thiadiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-{5-[2-Fluoro-6-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(5-phenyl-1,2,4-oxadiazol-3-yl)cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(2-Chloro-4-fluorophenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(2,4,6-trifluorophenyl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[4-Fluoro-3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(3-Fluorophenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(2-Fluoro-6-methylphenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[2-Fluoro-5-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-1,2,4-oxadiazol-3-yl }-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(2,6-Difluorophenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(3-Cyclopropylphenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(2,3,5-trifluorophenyl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(4-Ethynylphenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(4-Cyanophenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1,2,4-oxadiazol-3-yl}cyclopropyl ]benzenesulfonamide; 4-{(1R,2R)-2-[5-(3-Fluorophenyl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(2,4-Difluorobenzyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[1-(3-Chlorophenoxy)ethyl]-1,2,4-oxadiazol-3-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(5-Fluoro-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazol-3-yl]- 2 ,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[1-(2,5-Difluorophenyl)cyclobutyl]-1,2,4-oxadiazol-3-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-{5-[(5-Chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)methyl]-1,2,4-oxadiazol-3- yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(1,3-thiazol-4-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(4-methyl-1,3-oxazol-5-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl} benzenesulfonamide; 4-{(1S,3S)-3-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-1,2,4-oxadiazol-3-yl]-2,2-dimethyl cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(1-Cyclopropylpiperidin-4-yl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(1-methyl-1H-pyrrol-3-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[1-(1H-Imidazol-1-yl)ethyl]-1,2,4-oxadiazol-3-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[1-(pyrazin-2-yl)cyclopropyl]-1,2,4-oxadiazol-3-yl}cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[4-(trifluoromethyl)quinolin-2-yl]-1,2,4-oxadiazol-3-yl} cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-{5-[6-(2-Fluoroethoxy)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-2,2-dimethyl cyclopropyl]benzenesulfonamide ; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(tetrahydrofuran-2-ylmethyl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(1,1-Difluoroethyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[4-(4-Fluorophenyl)-1H-imidazol-2-yl]-1,2,4-oxadiazol-3-yl}-2,2-dimethyl cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(5-{2-[(2,2,2-trifluoroethyl)sulfanyl]-1,3-oxazol-5-yl}- 1,2 ,4-oxadiazol-3-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[3-(trifluoromethyl)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[4-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[2-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(4H-thieno[3,2-b]pyrrol-5-yl)-1,2,4-oxadiazol-3-yl] cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[1-(Cyclopropylcarbonyl)azetidin-3-yl]-1,2,4-oxadiazol-3-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(2-Cyclopentyl-1-oxo-octahydrocyclopenta[c]pyrrol-5-yl)- 1,2,4-oxadiazol-3-yl]-2 ,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopentyl-1,2,4-oxadiazol-3-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(spiro[2.5]oct-4-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(2,2,2-trifluoro-1-hydroxyethyl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(4-Hydroxycyclohexyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(3-Hydroxycyclobutyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)- 1,2, 4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(2-Hydroxy-1,3-benzothiazol-6-yl)-1,2,4-oxadiazol-3-yl]-2,2-dimethyl cyclopropyl} benzenesulfonamide; 4-{(1R,3R)-3-[5-(2-Cyclopropylethyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(5-Cyclohexyl-1,2,4-oxadiazol-3-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-{5-[1-(Trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}cyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[5-(5-Fluoropyridin-3-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[4-(2-Fluorophenyl)-1,3-oxazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[4-(2,4-Difluorophenyl)-1,3-oxazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[4-(2,5-Difluorophenyl)-1,3-oxazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1R,3R)-3-(4-tert-Butyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-(4-Cyclopropyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,2S)-2-(4-Phenyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-{(1S,2S)-2-[4-(3-Fluorophenyl)-1,3-thiazol-2-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,3R)-3-(4-Cyclopentyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-(5-Cyclopentyl-1,3-thiazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,2S)-2-[5-(3-Fluorophenyl)-1,3-thiazol-2-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopentyl-1,3-oxazol-2-yl)-2,2-difluorocyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[4-(2-Fluorophenyl)-1,3-oxazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[4-(2,5-Difluorophenyl)-1,3-oxazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[4-(2,4-Difluorophenyl)-1,3-oxazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(5-tert-Butyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(5-Cyclopropyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(4-Ethyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(4-tert-Butyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(4-Ethyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(4-Phenyl-1,3-thiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[4-(3-Fluorophenyl)-1,3-thiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[4-(propan-2-yl)-1,3-thiazol-2-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(4-Phenyl-1H-imidazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-(5-Cyclopentyl-1,3-oxazol-2-yl)-2,2-difluorocyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopentyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(5-Cyclopentyl-1,3-thiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopentyl-1,3-thiazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(4-Cyclopentyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[5-(3-Fluorophenyl)-1,3-thiazol-2-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(4-Cyclopentyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3S)-3-(4-Cyclohexyl-1,3-thiazol-2-yl)-2,2-difluorocyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(2-phenyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,2S)-2-(2-Phenyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(2-Phenyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(3-phenylisoxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[1-(3-Fluorophenyl)-1H-1,2,3-triazol-4-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[1-(3-Fluorophenyl)-1H-1,2,3-triazol-4-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(1-phenyl-1H-1,2,3-triazol-4-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-(1-Cyclopentyl-1H-pyrazol-4-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-(5-Ethoxy-1,2,4-thiadiazol-3-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[5-(3-Fluorophenyl)-1,2,4-thiadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(5-Cyclohexyl-1,2,4-thiadiazol-3-yl)cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-2,2-Difluoro-3-[5-(piperidin-1-yl)-1,2,4-thiadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Difluoro-3-(5-phenyl-1,2,4-thiadiazol-3-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(2-Cyclopentyl-1,3-thiazol-4-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(2-Cyclopentyl-1,3-thiazol-4-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-(5-Cyclohexyl-1,2,4-oxadiazol-3-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-(5-phenyl-1,2,4-oxadiazol-3-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[5-(3-Fluorophenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-{5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-2,2-Dimethyl-3-[5-(piperidin-1-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(2-Cyclopentyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,2S)-2-(2-Phenyl-1,3-thiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[trans-2,2-Difluoro-3-(5-phenyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[2-Methyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[trans-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)spiro[2.4]hept-1-yl]benzenesulfonamide; 4-{trans-2-[3-(3-Fluorophenyl)-1,2,4-thiadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[trans-2,2-Dichloro-3-(3-cyclopentyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{trans-3-[5-(3-Fluorophenyl)isoxazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]-3-fluorobenzenesulfonamide; 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]-2-methylbenzenesulfonamide; and 4-[trans-2,2-Dichloro-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide.

[021] Other embodiments of the present invention include the following:

[022] (a) A pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.

[023] (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 BI40936; HDAC6 inhibitors; antipsychotic; LRRK2 inhibitors; MAO-B inhibitors; and levodopa.

[024] (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.

[025] (d) A pharmaceutical combination that is (i) a compound of formula I 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 BI40936; HDAC6 inhibitors; antipsychotic; LRRK2 inhibitors; MAO-B inhibitors; and levodopa wherein the compound of formula I and the second therapeutic agent are each employed in an amount that makes the combination effective for treating cognitive impairments associated with Alzheimer's disease, Parkinson's disease and schizophrenia.

[026] (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.

[027] (f) A use of a compound of formula I in the preparation of a medicine to modulate α7 nAChR activity in an individual in need thereof.

[028] (g) A use of a compound of formula I in the preparation of a medicament for treating cognitive impairments associated with Alzheimer's disease, Parkinson's disease and schizophrenia in an individual in need thereof.

[029] (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 individual in need thereof, which comprises administering to the individual an effective amount of a compound of formula I.

[030] (i) The method of (h), wherein the compound of formula I 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; antipsychotic; LRRK2 inhibitors; MAO-B inhibitors; and levodopa.

[031] (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.

[032] (k) A method of modulating α7 nAChR activity in an individual in need thereof, which comprises administering to the individual the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (and).

[033] (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 an individual in need thereof, which comprises administering to the individual the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e).

[034] In the embodiments of the compounds and salts provided above, it should be understood that each embodiment can 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 should be further understood that the modalities of compositions and methods provided as (a) to (l) above are understood to be inclusive of all modalities of the compounds and/or salts, including such modalities as a result of combinations of modalities.

[035] Additional embodiments of the invention include the pharmaceutical compositions, combinations, uses and methods presented in (a) to (l) above, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes , subclasses 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.

[036] 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 the disease of Alzheimer's disease, Parkinson's disease, schizophrenia and L-DOPA-induced dyskinesia, or (b) treat cognitive impairments associated with Alzheimer's disease, Parkinson's disease, schizophrenia and L-DOPA-induced dyskinesia and/or reduce 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 may 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 S38093; PDE4 inhibitors such as HT0712; PDE9 inhibitors such as BI40936; HDAC6 inhibitors; antipsychotic; LRRK2 inhibitors; MAO-B inhibitors; and levodopa.

[037] Chemical names, common names and chemical structures can 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 there is an ambiguity between the structure and the name, it is understood that the structure is predominant.

[038] 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 variants thereof are each understood to include concomitant and sequential supply. of the compound or salt and other agents.

[039] As used herein, the term “5-membered heteroaryl ring” refers to a stable unsaturated 5-membered ring that contains 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.

[040] The term “alkoxy” refers to an “alkyl-O-” group. Alkoxy groups may be substituted as indicated.

[041] The term “alkyl” refers to an aliphatic hydrocarbon group that has one of its hydrogen atoms replaced with a bond. An alkyl group can be linear or branched and contain from 1 to 12 carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms [(C1-C6)alkyl] or from 1 to 4 carbon atoms [(C1-C4)alkyl] or from 1 to 3 carbon atoms [(C1 -C3)alkyl]. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neo- hexyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched.

[042] The term "aryl" (or "aryl ring system") refers to any mono- and polycarbocyclic ring systems in which the individual carbocyclic rings in the polyring systems are fused or fixed together through a single bond and in that at least one ring is aromatic. Suitable aryl groups include phenyl, indanyl, naphthyl, tetrahydronaphthyl and biphenyl. Aryl ring systems may include, if appropriate, an indication of the variable to which an atom in the particular ring is attached. Unless otherwise indicated, substituents for aryl ring systems may be attached to any atom in the ring, provided that such attachment results in the formation of a stable ring system.

[043] The term "composition" is intended to encompass a product that comprises the specified ingredients, as well as any product that results from the combination of the specified ingredients.

[044] The term "compound" is intended to encompass chemical agents described by generic formula I in all forms. Such chemical agents can be present in different forms such as hydrates, solvates and polymorphs.

[045] The term "cycloalkyl", as used herein, refers to a mono- or multicyclic non-aromatic ring system comprising 3 to 10 carbon atoms in the ring. In one embodiment, a cycloalkyl contains 5 to 10 carbon atoms in the ring. In another embodiment, a cycloalkyl contains 3 to 7 ring atoms. In another embodiment, a cycloalkyl contains 3 to 6 [(C3-C6) cycloalkyl] atoms in the ring. In another embodiment, a cycloalkyl contains 5 to 7 ring atoms. In another embodiment, a cycloalkyl contains 5 to 6 ring atoms. The term “cycloalkyl” also encompasses a cycloalkyl group, as defined above, that is fused to an aryl (e.g., benzene) or heteroaryl ring. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Non-limiting examples of multicyclic cycloalkyls include 1-decalinyl, norbornyl, bicyclo[3.1.0]hexyl, and adamantyl. The term “3- to 7-membered cycloalkyl” refers to a cycloalkyl group that has 3 to 7 carbon atoms in the ring. A carbon atom in the ring of a cycloalkyl group can 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:

[046] The term "effective amount" as used herein means the 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, general practitioner or other doctor. In one embodiment, the effective amount is a "therapeutically effective amount" for relieving one or more symptoms of the disease or condition being treated. In another embodiment, the effective amount is a "prophylactically effective amount" for reducing the severity or likelihood of one or more symptoms of the disease or condition. The term herein also includes 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.

[047] The term "halogen" (or “halo”) refers to atoms of fluorine, chlorine, bromine and iodine (alternatively called fluoro, chlorine, bromine and iodine).

[048] The term "heteroaryl" as used herein refers to any monocyclic or multicyclic ring system comprising 5 to 14 ring atoms, wherein 1 to 4 of the ring atoms are independently O, N, or S and the remaining ring atoms are carbon atoms, and wherein at least one ring is aromatic. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has. 5 or 6 ring atoms. In another embodiment, a heteroaryl group is bicyclic and has 9 or 10 ring atoms. A heteroaryl group is usually joined through a carbon atom in the ring, but can be joined through a non-ring atom. carbon as long as this results in a stable compound, and any nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide. The term “heteroaryl” also encompasses a heteroaryl group, as defined above, which is fused to a ring. benzene. The term "heteroaryl" also encompasses any fused polycyclic ring system containing at least one heteroatom ring selected from N, O, and S, wherein at least one ring of the fused polycyclic ring system is aromatic. For example, the term "9- to 10-membered bicyclic heteroaryl" encompasses a non-aromatic 5-membered heterocyclic ring that is fused to a benzene or pyridyl ring. Non-limiting examples of heteroaryls include benzimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, , isothiazolyl, isoxazolyl , naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzoimidazolyl, obenzofuranyl, di -hydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzoyl and the like, and all isomeric forms thereof. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like, as long as they contain at least one aromatic ring. In one embodiment, a heteroaryl group is a 5-membered heteroaryl. In another embodiment, a heteroaryl group is a 6-membered heteroaryl. In another embodiment, a heteroaryl group comprises a 5- to 6-membered heteroaryl group fused to a benzene ring.

[049] The term "heterocycle" or "heterocyclyl", as used herein, is intended to mean a 3- to 10-membered non-aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes monocyclic or bicyclic groups (fused, bridged or spirocyclic). Additional examples of "heterocyclyl" include, but are not limited to the following: oxazoline, isoxazoline, oxetanyl, tetrahydropyranyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl , dihydroimidazolyl, dihydroiso-oxazolyl, dihydroisothiazolyl, dihydro-oxadiazolyl, dihydro-oxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl , dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, tetrahydrofuranyl, and tetrahydrothienyl and N-oxides thereof. Attachment of a heterocyclyl substituent can occur through a carbon atom or through a heteroatom.

[050] The term "hydroxyalkyl", as used herein, refers to an alkyl group as defined above, in which one or more of the hydrogen atoms of the alkyl group has been replaced with an -OH group. In one embodiment, a hydroxyalkyl group has 1 to 6 carbon atoms. Non-limiting examples of hydroxyalkyl group include -CH2OH, -CH2CH2OH, -CH2CH2CH2OH and -CH2CH(OH)CH3. The term “C1-C6 hydroxyalkyl” refers to a hydroxyalkyl group that has 1 to 6 carbon atoms. The term “C1-C4 hydroxyalkyl” refers to a hydroxyalkyl group that has 1 to 4 carbon atoms. The term “C1-C3 hydroxyalkyl” refers to a hydroxyalkyl group that has 1 to 3 carbon atoms.

[051] As used herein, the term "oxo” or "=□" forms a carbonyl moiety with the carbon atom to which it is attached.

[052] "Pharmaceutically acceptable" means that the ingredients of the pharmaceutical composition must be compatible with each other and not harmful to their recipient.

[053] The term "prevent" as used herein in relation to Alzheimer's disease or other neurological diseases, refers to reducing the likelihood of disease progression.

[054] The term "individual" (alternatively referred to herein as "patient"), as used herein, refers to an animal, preferably a mammal, most preferably a human.

[055] 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 normal valence of the designated atom under existing circumstances is not exceeded, and that the substitution results in a compound stable. Unless expressly provided otherwise, substitution by a named substituent is permitted on any atom as long as such substitution is chemically permitted and results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. 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 permit use of the compound for the purposes described herein (e.g. example, therapeutic or prophylactic administration to an individual).

[056] In another embodiment of formula I, X is where R1 and R2 are H.

[057] In another embodiment of formula I, Y is selected from 1 to 4 substituents, each independently selected from H, (C1-C4)alkyl, halogen and OH, in which said alkyl is optionally substituted with one or more halogens or OH.

[058] In another embodiment of formula I, Y is selected from 1 to 4 substituents, where 2 substituents are H and the other substituents are independently selected from (C1-C4)alkyl, halogen and OH, in that said alkyl is optionally substituted with one or more halogens or OH.

[059] In another embodiment of formula I, Y is selected from 1 to 4 substituents, where 3 substituents are H and the other substituent is (C1-C4)alkyl or halogen.

[060] In another embodiment of formula I, Y is selected from 1 to 4 substituents, where 3 substituents are H and the other substituent is selected from methyl or fluorine.

[061] In another embodiment of formula I, Y is H.

[062] In another embodiment of formula I, A is a 5-membered heteroaryl ring that is substituted with 1 to 3 R groups each independently selected from alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl , cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C6)alkyl, O(C1-C4) alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O(C3-C6) cycloalkyl and phenyl, wherein said alkyl and phenyl are optionally and independently substituted with one or more halogen, CF3, OH and oxo.

[063] In another embodiment of formula I, A is a 5-membered heteroaryl ring selected from which are each substituted with 1 to 3 R groups independently selected from CN, alkoxy, halogen, aminoalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl, O(C1-C4)alkyl, S(C1-C4 )alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O(C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl , wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally and independently substituted with one or more F, Cl, CF3 and oxo.

[064] In another embodiment of formula I or Ia, A is a 5-membered heteroaryl ring selected from which are each substituted with 1 to 2 R groups independently selected from cyano, alkoxy, halogen, aminoalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl, O(C1-C4)alkyl, S(C1-C4 )alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O(C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl , wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally and independently substituted with one or more F, Cl, CF3 and oxo.

[065] In another embodiment of formula I or Ia, A is a 5-membered heteroaryl ring selected from which are each substituted with 1 R group selected from CN, alkoxy, halogen, aminoalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl, O(C1-C4)alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O(C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl, where said alkyl, aryl, heteroaryl and heterocyclyl are optionally and independently substituted with one or more F, Cl, CF3 and oxo.

[066] In another embodiment of formula I or Ia, A is a 5-membered heteroaryl ring selected from pyrazole, thiadiazole, triazole, isoxazole, oxazole, oxadiazole and thiazole, which are each substituted with 1 to 3 R groups independently selected from CN, alkoxy, halogen, aminoalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkoxy, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1- C4)alkyl, O(C1-C4)alkyl, S(C1-C4)alkyl, C=O(C1- C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O(C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally and independently substituted with one or more F, Cl, CF3 and oxo.

[067] In another embodiment of formula I or Ia, A is a 5-membered heteroaryl ring selected from pyrazole, thiadiazole, triazole, isoxazole, oxazole, oxadiazole and thiazole, which are each substituted with 1 to 2 R groups independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C3-C6)cycloalkyl, phenyl, indanyl, piperidinyl, pyridinyl, furanyl, oxazolyl, benzoxazinyl, cyclopentalpyrrolyl, thienopyrrolyl, thiazolyl, imidazolyl , azetidinyl, pyrrolyl, pyrazinyl, quinolinyl and benzothiazolyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl , O(C1-C4)alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C =O(C3-C6)cycloalkyl, phenyl, O-phenyl, heteroaryl and heterocyclyl, wherein said alkyl, phenyl, heteroaryl and heterocyclyl are optionally and independently substituted with one or more F, Cl, CF3 and oxo.

[068] In another embodiment of formula I or Ia, A is a 5-membered heteroaryl ring selected from pyrazole, thiadiazole, triazole, isoxazole, oxazole, oxadiazole and thiazole, which are each substituted with 1 R group selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C3-C6)cycloalkyl, phenyl, indanyl, piperidinyl, pyridinyl, furanyl, oxazolyl, benzoxazinyl, cyclopentalpyrrolyl, thienopyrrolyl, thiazolyl, imidazolyl, azetidinyl, pyrrolyl, pyrazinyl, quinolinyl and benzothiazolyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl, O( C1-C4)alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O( C3-C6)cycloalkyl, phenyl, O-phenyl, heteroaryl and heterocyclyl, wherein said alkyl, phenyl, heteroaryl and heterocyclyl are optionally and independently substituted with one or more F, Cl, CF3 and oxo.

[069] In another embodiment of formula I or Ia, A is a 5-membered heteroaryl ring selected from pyrazole, thiadiazole, triazole, isoxazole, oxazole, oxadiazole and thiazole, which are each substituted with 1 to 2 R groups independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C3-C6)cycloalkyl, phenyl, indanyl, piperidinyl, pyridinyl, furanyl, oxazolyl, benzoxazinyl, cyclopentalpyrrolyl, thienopyrrolyl, thiazolyl, imidazolyl , azetidinyl, pyrrolyl, pyrazinyl, quinolinyl and benzothiazolyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl , O(C1-C4)alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C =O(C3-C6)cycloalkyl, phenyl and O-phenyl.

[070] In another embodiment of formula I or Ia, A is a 5-membered heteroaryl ring selected from pyrazole, thiadiazole, triazole, isoxazole, oxazole, oxadiazole and thiazole, which are each substituted with 1 R group selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C3-C6)cycloalkyl, phenyl, indanyl, piperidinyl, pyridinyl, furanyl, oxazolyl, benzoxazinyl, cyclopentalpyrrolyl, thienopyrrolyl, thiazolyl, imidazolyl, azetidinyl, pyrrolyl, pyrazinyl, quinolinyl and benzothiazolyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl, O( C1-C4)alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O( C3-C6)cycloalkyl, phenyl and O-phenyl.

[071] In another embodiment of formula I or Ia, A is a 5-membered heteroaryl ring selected from furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl and triazolyl .

[072] In another embodiment of formula I, Ia or Ib, when the R groups are aryl, heteroaryl and heterocyclyl, said aryl, heteroaryl and heterocyclyl are independently selected from phenyl, indanyl, piperidinyl, pyridinyl, furanyl, oxazolyl , benzoxazinyl, cyclopentalpyrrolyl, thienopyrrolyl, thiazolyl, imidazolyl, azetidinyl, pyrrolyl, pyrazinyl, quinolinyl and benzothiazolyl, each optionally substituted with one or more F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4) alkyl, O(C1-C4)alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O(C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally and independently substituted with one or more F, Cl, CF3 and oxo.

[073] In another embodiment of formula I, Ia or Ib, when the R groups are aryl, heteroaryl and heterocyclyl, said aryl, heteroaryl and heterocyclyl are independently selected from phenyl, indanyl, piperidinyl, pyridinyl, furanyl, oxazolyl , benzoxazinyl, cyclopentalpyrrolyl, thienopyrrolyl, thiazolyl, imidazolyl, azetidinyl, pyrrolyl, pyrazinyl, quinolinyl and benzothiazolyl, each optionally substituted with one or more F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4) alkyl, O(C1-C4)alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl and C=O(C3-C6)cycloalkyl.

[074] In another embodiment of formula I, Ia or Ib, when the R groups are aryl, heteroaryl and heterocyclyl, said aryl, heteroaryl and heterocyclyl are independently selected from phenyl, indanyl, piperidinyl, pyridinyl, furanyl, oxazolyl , benzoxazinyl, cyclopentalpyrrolyl, thienopyrrolyl, thiazolyl, imidazolyl, azetidinyl, pyrrolyl, pyrazinyl, quinolinyl and benzothiazolyl, each optionally substituted with one or more F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4) alkyl, and O(C1-C4)alkyl.

[075] In another embodiment of formula I, Ia or Ib, the R groups are independently selected from alkyl, cycloalkyl and phenyl, said alkyl, cycloalkyl or phenyl are optionally substituted with one or more F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl, O(C1-C4)alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O(C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally and independently substituted with one or plus F, Cl, CF3 and oxo.

[076] In another embodiment of formula I, Ia or Ib, the R groups are independently selected from alkyl, cycloalkyl and phenyl, said alkyl, cycloalkyl or phenyl are optionally substituted with one or more F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl, O(C1-C4)alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl and C=O(C3-C6)cycloalkyl.

[077] In another embodiment of formula I, Ia or Ib, the R groups are independently selected from alkyl, cycloalkyl and phenyl, said alkyl, cycloalkyl or phenyl is optionally substituted with one or more F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl and O(C1-C4)alkyl.

[078] In another embodiment of formula I, Ia or Ib, the R groups are optionally substituted with one or more F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl, O( C1-C4)alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C1-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl and C=O( C3-C6)cycloalkyl.

[079] In another embodiment of formula I, Ia or Ib, the R groups are optionally substituted with one or more F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl and O( C1-C4)alkyl.

[080] In another embodiment of formula I, R1 is H or methyl.

[081] In another embodiment of formula I, R2 is H or methyl.

[082] In another embodiment of formula I, Ia or Ib, R3 is H, halogen or (C1-C4)alkyl, R4 is H, halogen or (C1-C4)alkyl, or R3 and R4 can optionally join together to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

[083] In another embodiment of formula I, Ia or Ib, R3 is H, F or methyl.

[084] In another embodiment of formula I, Ia or Ib, R4 is H, F or methyl.

[085] In another embodiment of formula I, Ia or Ib, R3 and R4 can optionally join together to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring in which said ring can be optionally substituted with one or more substituents independently selected from OH, halogen or (C1-C4)alkyl.

[086] In another embodiment of formula I, Ia or Ib, R3 and R4 can optionally join together to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

[087] In another embodiment of formula I, Ia or Ib, R5 is H or methyl.

[088] In another embodiment of formula I, Ia or Ib, R5 is H.

[089] In another embodiment of formula I, Ia or Ib, R6 is H or methyl.

[090] In another embodiment of formula I, Ia or Ib, R6 is H.

[091] In another embodiment of formula I, Ia or Ib, R7 is H or methyl.

[092] In another embodiment of formula I, Ia or Ib, R8 is H or methyl.

[093] In another embodiment of formula I, Ra is H or methyl.

[094] In another embodiment of formula I, Ra is H.

[095] In compounds of formula I, the natural isotopic abundances, or one or artificially enriched in a particular isotope that has the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in the nature. The present invention is intended to include all suitable isotopic variations of the compounds of formula I. 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. Enrichment for deuterium may provide certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. The isotopically enriched compounds within formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein with the use of appropriate isotopically enriched reagents and/or intermediates.

[096] Unless expressly stated otherwise, all tracks cited in this document are inclusive. For example, a heteroaryl ring described as containing "1 to 3 heteroatoms" means that the ring may contain 1, 2, or 3 heteroatoms. It is also understood that any range recited herein includes within its scope all subranges within that range. The oxidized forms of the N and S heteroatoms are also included within the scope of the present invention.

[097] It is understood by one skilled in the art that carbon atoms in organic molecules can often be replaced by silicon atoms to generate analogous stable compounds. For example, carbon atoms in alkoxy, alkyl, cycloalkyl, heteroaryl, heterocyclyl, and hydroxyalkyl groups can often be replaced with silicon atoms to provide stable compounds. All such compounds are included within the scope of the present invention.

[098] When any variable (for example, R) occurs more than once in any constituent or in formula I or in any other formula that presents and describes the compounds of the invention, its definition in each occurrence is independent of its definition in each another occurrence. Furthermore, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[099] Certain compounds of the present invention may have asymmetric centers and may occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, whether isolated or in mixtures, are included within the scope of the present invention.

[0100] Certain compounds of the present invention may exist as tautomers. For the purposes of the present invention, a reference to a compound of formula I is a reference to the compound itself or to any of its own tautomers, or to mixtures of two or more tautomers.

[0101] The compounds of the present invention may be useful in preventing, treating or improving Alzheimer's disease. The compounds may also be useful in preventing, treating, or ameliorating other α7 nAChR-mediated diseases, 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 can be prevented, treated or improved 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, hemorrhage Hereditary Cerebral 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 disease, cancer and atherosclerosis.

[0102] In preferred embodiments, the compounds of the invention may be useful for preventing, treating or improving 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.

[0103] 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 psychotic disorder (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants, and cocaine), 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 disorder (bipolar), Alzheimer's disease and post-traumatic stress), including both negative and positive symptoms of schizophrenia and other psychoses; cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, multiple 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, amnesic disorders or age-related cognitive decline.

[0104] Thus, in another specific embodiment, the present invention provides a method for preventing, treating or improving schizophrenia or psychosis that comprises administering to a patient in need thereof an effective amount of a compound of the present invention. Currently, the revised text 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 scientific and medical progress. Thus, the term "schizophrenia or psychosis" is intended to include similar disorders that are described in other diagnostic sources.

[0105] Potential sleep conditions or disorders for which the compounds of the invention may be useful include improving sleep quality; improve sleep quality; increase sleep maintenance; increase the value that is calculated from the time an individual sleeps divided by the time an individual tries to sleep; decrease sleep onset or latency (the time it takes to fall asleep); reduce difficulties falling asleep; increase sleep continuity; reduce the number of awakenings during sleep; reduce nighttime awakenings; decrease the time spent awake after the initial emergence of sleep; increase the total amount of sleep; reduce sleep fragmentation; alternate the timing, frequency, or duration of REM sleep events; alternating the timing, frequency, or duration of slow sleep events (i.e., stages 3 or 4); increase the amount and percentage of stage 2 sleep; promote slow sleep; improve EEG-delta activity during sleep; increase daytime alertness; reduce daytime drowsiness; treat or reduce excessive daytime sleepiness; insomnia; hypersomnia; narcolepsy; interrupted sleep; sleep apnea; wakefulness; nocturnal myoclonus; REM sleep interruptions; jet lag; sleep disorders of shift workers; dyssomnia; night terrors; insomnia associated with depression; emotional/mood disorders; as well as sleepwalking and enuresis; and sleep disorders that accompany aging; nighttime confusion due to Alzheimer's disease; conditions associated with circadian rhythm as well as physical and mental disorders associated with travel across time zones and rotating work shift schedules; conditions due to drugs that cause reductions in REM sleep as a side effect; syndromes that are manifested by non-restorative sleep and muscle pain or sleep apneas that are associated with breathing disorders during sleep; and conditions that result from decreased quality of sleep.

[0106] Pain disorders for which compounds of the invention may be useful include neuropathic pain (such as post-heretic neuralgia, nerve damage, "dynias", e.g., vulvodynia, phantom limb pain, root avulsions, diabetic neuropathy painful, painful traumatic mononeuropathy, painful polyneuropathy); central pain syndromes (potentially caused by virtually any injury at any level of the nervous system); post-surgical pain syndromes (e.g. post-mastectomy syndrome, post-thoracotomy syndrome, stump pain); bone and joint pain (osteoarthritis); repetitive motion pain; toothache; cancer pain; myofascial pain (muscle injury, fibromyalgia); perioperative pain (general, gynecological surgery); chronic pain; dysmenorrhea, as well as pain associated with angina, and inflammatory pain of varying origins (e.g., osteoarthritis, rheumatoid arthritis, rheumatic disease, tenosynovitis and gout); headache; migraine and cluster headache; primary hyperalgesia; secondary hyperalgesia; primary allodynia; secondary allodynia; or other pain caused by central sensitization.

[0107] Potential conditions or disorders that have a strong inflammatory component for which 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 can 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, head trauma, Huntington's disease, amyotrophic lateral sclerosis).

[0108] The compounds of the invention can also be used to treat or prevent or improve dyskinesia and protect against neurodegeneration in nigrostriatal neurons in Parkinson's disease. Furthermore, the compounds of the invention can be used to decrease tolerance and/or dependence to opioid pain treatment, and to treat withdrawal syndrome from, for example, alcohol, opioids and cocaine.

[0109] The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt that has the efficacy of the parent compound and that is not biologically or otherwise undesirable (e.g., is not toxic or otherwise harmful to the recipient thereof). . Suitable salts include acid addition salts which 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 acid. benzoic. Many of the compounds of the invention bear an acidic chemical moiety, in which cases pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium salts). or magnesium), and salts formed with suitable organic ligands, such as quaternary ammonium salts. Furthermore, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify or solubilize or hydrolyze the characteristics of the compound.

[0110] Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates ("mesylates"), naphthalenesulfonates , nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. Additionally, acids that are generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1):1 to 19; P. Gould, International J. of Pharmaceutics (1986) 33:201 to 217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on its website).

[0111] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g. organic amines) , such as dicyclohexylamine, tert-butyl amine, choline and salts with amino acids, such as arginine, lysine and the like. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain (for example, decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halide (for example, benzyl and phenethyl bromides) and others.

[0112] For the purpose of preventing, treating or improving 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 may be administered by one or more conventional means available for use in conjunction with pharmaceuticals, as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are typically administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice. The compounds of the invention may, for example, be administered by one or more of the following: orally, parenterally (including subcutaneous, intravenous, intramuscular, intrasternal infusion or injection techniques), by inhalation (as in a spray form), or via 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 (for example, 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) may be prepared according to techniques known in the art and may employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegration 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 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 salt 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, 18th Edition (ed. A. R. Gennaro, Mack Publishing Co., 1990).

[0113] The compounds of this invention can be administered orally in a dosage range of 0.001 to 1000 mg/kg of mammalian (e.g., human) body weight per day in a single dose or in divided doses. A 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 may 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 symptomatic dosage adjustment to the patient being treated. The specific dose level and dosing frequency for any particular patient can be varied and will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination and the severity of the particular condition.

[0114] As noted above, the present invention also relates to a method of preventing, treating or ameliorating 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; M1 mAChR or PAMs agonist; M4 or 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; tauphosphorylation inhibitors; glycine transport inhibitors; LXR β agonists; ApoE4 conformational modulators; NR2B antagonists; androgen receptor modulators; Aβ oligomer formation blockers; 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 humanized anti-amyloid 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; antibodies, 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 ibutamorene, ibutamorene 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; GSK3β inhibitors, including AZD1080, SAR502250, and CEP16805; neuronal nicotinic agonists; selective M1 agonists; HDAC inhibitors; and microtubule affinity-regulating kinase (MARK) ligands; or other drugs that affect receptors or enzymes that increase the effectiveness, safety, convenience or reduce unwanted side effects or toxicity of the compounds of the present invention.

[0115] Examples of combinations of the compounds of the present invention include combinations with agents for the treatment of schizophrenia, for example in combination with sedatives, hypnotics, anxiolytics, antipsychotics, anti-anxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, agonists and antagonists of melatonin, melatonergic agents, benzodiazepines, barbiturates, 5-HT2 antagonists and the like, such as: adinazolam, allobarbital, allonimide, aiprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbochloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, chlorethate, chlorpromazine, clozapine, ciprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, etc. etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midazole, oh, Nefazodone, Nisobamato, Nitrazepam, Nortriptyline, Olanzapine, Oxazepam, Paraldehyde, Paroxetine, Pentobarbital, Perlapine, Perfect, Phenelzine, Phenobarbital, Promethazine, Propofol, Protriptyline, Quazepam, Quetiapine, Complazepam, Risperidona, Roletamida, Roletamida Obarbital, Sertraline, Supproelona, Temazepam, thioridazine, thiothixene, tracazolate, tranylcypromainine, Trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimethozine, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem and salts thereof and combinations thereof and the like, or the The individual's compound may be administered in conjunction with the use of physical methods, such as with electrical stimulation or light therapy.

[0116] In another embodiment, the compounds of the present invention can be used in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics, such as biperiden (optionally as the hydrochloride or lactate salt of the same ) and trihexyphenidyl hydrochloride (benzhexol); 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.

[0117] In another embodiment, the compound of the present invention can be used in combination with a compound of 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 molindol. Other neuroleptic agents include loxapine, sulpiride, and risperidone. It will be appreciated that neuroleptic agents when used in combination with the compounds of the present invention may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, enatate of flurphenazine, 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 present invention can be used 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.

[0118] Examples of combinations of compounds of the present invention include combinations with agents for treating pain, for example, non-steroidal anti-inflammatory agents, such as aspirin, diclofenac, duflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac , naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2 inhibitors such as celecoxib, rofecoxib, valdecoxib, 406381 and 644784; CB-2 agonists such as 842166 and SAB378; VR-1 antagonists such as AMG517, 705498, 782443, PAC20030, V114380, and A425619; bradykinin B1 receptor antagonists such as SSR240612 and NVPSAA164; sodium channel blockers and antagonists, such as VX409 and SPI860; nitric oxide synthase (NOS) inhibitors (including iNOS and nNOS inhibitors) such as SD6010 and 274150; glycine site antagonists, including lacosamide; neuronal nicotinic agonists, such as ABT 894; NMDA antagonists such as AZD4282; potassium channel openers; AMPA/kainate receptor antagonists; calcium channel blockers such as ziconotide and NMED160; GABA-A receptor IO modulators (e.g., a GABA-A receptor agonist); matrix metalloprotease (MMP) inhibitors; thrombolytic agents; opiate analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene; neutrophil inhibitory factor (NIF); pramipexole, ropinirole; anticholinergics; amantadine; Bl5 monoamine oxidase inhibitors ("MAO-B"); 5-HT receptor agonists or antagonists; mGlu5 antagonists such as AZD9272; alpha agonists, such as AGN XX/YY; neuronal nicotinic agonists, such as ABT894; NMDA receptor agonists or antagonists, such as AZD4282; NKI antagonists; selective serotonin reuptake inhibitors ("SSRI") and/or selective serotonin and norepinephrine reuptake inhibitors ("SSNRI"), such as duloxetine; tricyclic antidepressant drugs, norepinephrine modulators; lithium; valproate; gabapentin; Pregabalin; rizatriptan; zolmitriptan; naratriptan and sumatriptan.

[0119] The compounds of the present invention can be administered in combination with compounds useful for improving sleep quality and preventing and treating sleep disorders and sleep disorders, including, for example, sedatives, hypnotics, anxiolytics, antipsychotics, anxiolytic agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, orexin antagonists, alpha-1 antagonists, GABA agonists, 5-HT2 antagonists including 5-HT2A antagonists and 5-HT2A/2C antagonists, histamine antagonists including histamine antagonists H3, histamine H3 inverse agonists, imidazopyridines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, other orexin antagonists, orexin agonists, prokineticin agonists and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, triazolopyridines and the like , such as: adinazolam, alobarbital, allonimide, alprazolam, amitriptyline, amobarbital, amoxapine, armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capromorelin, capuride, carbochloral, chloral betaine, chloral hydrate , chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepata, chlorethate, clozapine, conazepam, ciprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014, eplivanserin, estazolam, eszopiclone, ethlorinol, hay, bam, flunitrazepam , flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamorene, imipramine, indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline, MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate, me tiprilon , midaflur, midazolam, modafinil, nefazodone, NGD-2-73, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, ramelteon, reclazepam , routamide, secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracazolate, tranylcypromainine, Trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimethozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone, ask and salts thereof and combinations thereof and the like, or the compound of the present invention can be administered in conjunction with the use of physical methods such as light therapy or electrical stimulation.

[0120] The compounds of the present 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.

[0121] The compounds of the present invention are useful for the treatment of severe to moderate dementia of the Alzheimer's type alone or in combination with galantamine, rivastigmine or donepezil.

[0122] The compounds of the present invention are useful for the treatment of dementia associated with Parkinson's disease alone or in combination with rivastigmine.

[0123] The compounds of the present invention are useful for treating motor oscillations in patients with advanced Parkinson's disease alone or in combination with carbidopa and levodopa.

[0124] When administering a combination therapy of the invention to a patient, the therapeutic agents in the combination or a pharmaceutical composition or compositions comprising therapeutic agents, may be administered in any order such as, for example, in sequence, at the same time, together , simultaneously and similar. The amounts of the various active ingredients in such combination therapy may be different amounts (different dosage amounts) or the 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).

[0125] The α7 nAChR positive allosteric modulator (PAM) activity of the present compounds can be tested using assays known in the art. The α7 nAChR PAMs described herein have activities in an automated ion channel patch electrophysiological 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 to 619. Compounds were evaluated for their ability to modulate the function of the human α7 nAChR stably expressed in a HEK cell line in both the presence and absence of the natural α7 agonist acetylcholine. By carrying out a series of such measurements at different concentrations, the effective concentration of α7 nAChR PAMs (EC50) was determined. See Spencer et al. Assay Drug Dev. Technol. (2012) 10:313 to 324.

[0126] The present invention also includes processes for producing compounds of formula I. The compounds of the present invention can be readily prepared in accordance with the following examples and reaction schemes, 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 that are known to one skilled in the art, but are not mentioned in more detail. Furthermore, other methods for preparing the compounds of the invention will be readily apparent to the person skilled in the art in light of the following examples and reaction schemes. Unless otherwise noted, all variables are as defined above. The following examples and reaction schemes serve only to illustrate the invention and its practice.

General Schemes

[0127] The compounds of the present invention can be readily prepared according to the following specific examples and schemes 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 that are known to one skilled in the art, but are not mentioned in more detail. The general procedures for producing the compounds claimed in this invention can be readily understood and verified by one skilled in the art by viewing the following schemes.

[0128] Many compounds of the present invention can be prepared according to Scheme 1, in which acid 1.1 is reacted with CDI in 1,4-dioxane and then treated with amide oxime 1.2 in 1,4-dioxane at the temperature high to produce product 1.3. Other coupling reagents, such as EDC and HOAt and solvents, such as toluene, can be used in its transformation. If 1.3 is a mixture of enantiomers or diastereomers, the mixture can be separated by chiral chromatography. Alternatively, 1.1 and 1.2 can be employed as single enantiomers or diastereomers to obtain 1.3 enriched in a single enantiomer or diastereomer. Other methods of forming oxadiazole can also be used, such as the reaction of the corresponding ester of acid 1.1 with amide oxime 1.2 in the presence of potassium carbonate (or other bases) in ethanol (or other solvents) at elevated temperature or by the reaction of acid 1.1 with amide oxime 1.2 in the presence of EDC and HOAt followed by the addition of T3P to the reaction mixture or by treatment of the isolated intermediate with TBAF in tetrahydrofuran. SCHEME 1

[0129] In a similar manner, additional compounds of the present invention can be prepared according to Scheme 2, in which acid 2.1 is first reacted with CDI in 1,4-dioxane and then treated with amide oxime 1.2 in 1,4-dioxane at elevated temperature to produce product 2.2. If 2.2 is a mixture of enantiomers or diastereomers, the mixture can be separated by chiral chromatography. Alternatively, 2.1 and 1.2 can be employed as single enantiomers or diastereomers to obtain 2.2 enriched in a single enantiomer or diastereomer. Oxadiazole 2.2 is then sulfonylated by treatment with pure chlorosulfonic acid (or a mixture of a halogenated solvent and chlorosulfonic acid) followed by treatment of the resulting sulfonyl chloride with a solution of ammonia in a solvent (e.g., water, 1.4 -dioxane, tetrahydrofuran, methanol) to produce sulfonamide product 2.3. SCHEME 2

[0130] Additional compounds of the present invention can be prepared according to Scheme 3, wherein the cyclopropane intermediate 3.1 is an amide oxime. Acid 3.2 is reacted with CDI in 1,4-dioxane and then treated with amide oxime 3.1 and heated to elevated temperature to produce product 3.3. SCHEME 3

[0131] Furthermore, the compounds of the present invention can be prepared according to Scheme 4, in which acid 1.1 is reacted with acyl hydrazine 4.1 in the presence of HATU and NMM. Other coupling reagents and conditions can be employed to effect this transformation. The resulting hydrazide is then treated with Lawesson's reagent and heated to elevated temperature to produce thiadiazole product 4.2. Other thionation reagents, such as P4S10 and hexamethyldisiloxane or hexamethyldisilatian, and solvents, such as 1,4-dioxane, can be used for this transformation. Additionally, dehydration reagents, such as PTSA, can be employed to facilitate heterocycle formation after thiation. SCHEME 4

[0132] Other compounds of the present invention can be prepared according to Scheme 5, in which acid 1.1 is reacted with CDI in 1,4-dioxane and then treated with acyl hydrazine 5.1 at elevated temperature followed by dehydration of the amide resulting by treatment with phosphorus(V) oxychloride at elevated temperature to produce product 5.2. Other coupling reagents and conditions can be employed to effect this transformation. Other dehydration reagents, such as Burgess reagent or triflic anhydride, can also be used for this transformation. SCHEME 5

[0133] Certain oxazole-containing compounds of the present invention can be prepared according to Scheme 6, in which acid 1.1 is reacted with CDI in 1,4-dioxane and then treated with amino ketone 6.1 followed by cyclodehydration of the resulting amide by treatment with sulfuric acid to produce product 6.2. Other coupling and dehydration reagents and conditions can be employed to effect this transformation. SCHEME 6

[0134] In addition, other oxazole-containing compounds of the present invention can be prepared according to scheme 7, in which amide 7.1 is reacted with haloketone 7.2 in the presence of silver trifluoromethanesulfonate at elevated temperature to produce product 7.3. Other mild Lewis acids, such as boron trifluoride diethyl etherate, and halides, such as chloride or iodide, can be employed to effect this transformation. Additionally, Dehydration Reagents Can Be Employed To Complete The Formation Of Oxazole After Coupling 7.1 And 7.2. Scheme 7

[0135] Additional oxazole-containing compounds of the present invention can be prepared according to Scheme 8, in which the acid 8.1 is first treated with oxalyl chloride and DMF followed by reacting the resulting acid chloride with isocyanide 8.2 in the presence of 2 ,6-lutidine at elevated temperature and the resulting oxazole treated with trifluoroacetic acid to remove the tert-butyl and tert-butyl carbamate protecting groups to produce product 8.3. Other bases, coupling conditions and acids, such as HCl, can be used to effect these transformations. DIAGRAM 8

[0136] Furthermore, the compounds of the present invention can be prepared according to Scheme 9, in which alkyne 9.1 participates in a [3+2] cycloaddition with nitrile oxide (formed in situ by treating nitroalkane 9.2 with chloride of benzenesulfonyl in the presence of triethylamine) to produce isoxazole 9.3. Other nitrile oxide precursors, such as oximes or chloro-oximes, activation reagents for nitroalkanes, such as POCl3, and bases, such as pyridine, can be used to effect this transformation. DIAGRAM 9

[0137] Certain triazole-containing compounds of the present invention can be prepared according to Scheme 10, in which alkyne 9.1 participates in a copper-catalyzed dipolar [3+2] cycloaddition with azide 10.1 in the presence of a copper(I) source and a suitable ligand to produce triazole 10.2. DIAGRAM 10

[0138] Furthermore, the compounds of the present invention can be prepared according to Scheme 11, in which aldehyde 11.1 is reacted with hydrazine 11.2 in the presence of HCl in methanol at elevated temperature followed by removal of the formamidine protecting group by treatment with hydrazine hydrate to produce pyrazole 11.3. DIAGRAM 11

[0139] Additional compounds of the present invention can be prepared according to Scheme 12, in which thioamide 12.1 is reacted with haloketone 12.2 in ethanol at elevated temperature to produce product 12.3. Similar to Scheme 7, mild Lewis acids and other halides and solvents can also be employed to effect this transformation. Additionally, dehydration reagents can be employed to facilitate the formation of the heterocycle after coupling 12.1 and 12.2. DIAGRAM 12

[0140] Numerous compounds of the present invention can be prepared according to Scheme 13, in which boronic acid 13.1 is reacted with heteroaryl chloride 13.2 under palladium-catalyzed conditions to produce product 13.3. A variety of different catalysts (including those containing other metals such as nickel), ligands, bases and solvents can be employed in this reaction. Boronate esters or other boronic acid derivatives can also be used as alternatives to boronic acid 13.1 as can a variety of alternatives to heteroaryl chloride 13.2, including bromides, iodides, triflates or tosylates. Thiadiazole 13.3 is then sulfonylated by treatment with pure chlorosulfonic acid (or a mixture of a halogenated solvent and chlorosulfonic acid) followed by treatment of the resulting sulfonyl chloride with a solution of ammonia in a solvent (e.g., water, 1.4 -dioxane, tetrahydrofuran, methanol) to produce the sulfonamide product 13.4. If 13.4 is a mixture of enantiomers or diastereomers, the mixture can be separated by chiral chromatography. Alternatively, 13.1, 13.2 and 13.3 can be employed as single enantiomers or diastereomers to obtain 13.4 enriched in a single enantiomer or diastereomer. DIAGRAM 13

[0141] Other compounds of the present invention can be prepared according to Scheme 14, in which pyrazole 14.1 is treated with NaHMDS and then reacted with alkyl (or heteroalkyl or cycloalkyl or heterocyclyl) bromide 14.2 followed by treatment with hydrate. hydrazine to produce product 14.3. Alternatives to bromide 14.2 can be used in this procedure, including the corresponding chloride, iodide, mesylate, tosylate or triflate, and other bases, such as LDA, NaH or potassium tert-butoxide, can also be used in this transformation. DIAGRAM 14

[0142] Furthermore, certain compounds of the present invention can be prepared according to Scheme 15, in which boronate ester 15.1 is reacted with heteroaryl bromide 15.2 under palladium-catalyzed conditions followed by treatment with hydrazine hydrate to produce the product 15.3. Boronate esters or other boronic acid derivatives can also be used as alternatives to boronic acid 15.1 as can a variety of alternatives to heteroaryl chloride 15.2, including bromides, iodides, triflates or tosylates. A variety of different catalysts (including other metals such as nickel), ligands, bases and solvents can be employed in this reaction. DIAGRAM 15

[0143] Certain thiazole-containing compounds of the present invention can be prepared according to Scheme 16, in which haloketone 16.1 is reacted with thioamide 16.2 in ethanol at elevated temperature to produce product 16.3. Similar to Schemes 7 and 12, mild Lewis acids and other halides and solvents can also be employed to effect this transformation. Additionally, dehydration reagents can be employed to complete heterocycle formation after coupling of 16.1 and 16.2 and an amine base can be included to sequester acid formed during the reaction. The amidine variant of 16.2 could be employed to produce the corresponding imidazole, which could then be N-alkylated by treatment with an alkyl halide in the presence of a base. DIAGRAM 16

[0144] Furthermore, other thiazole-containing compounds of the present invention can be prepared according to Scheme 17, in which amine 17.1 is reacted with acyl chloride 17.2 in the presence of potassium carbonate and the resulting amide treated with Lawesson's reagent at elevated temperature followed by treatment with trifluoroacetic acid to produce thiazole 17.3. Other bases, thionation reagents and acids can be used in these transformations. DIAGRAM 17

[0145] Some useful synthetic intermediates such as amide oxime 1.2 can be prepared according to Scheme 18, in which nitrile 18.1 is treated with hydroxylamine at elevated temperature to produce amide oxime 1.2. Other solvents and forms of hydroxylamine (such as the hydrochloride salt; if this form is used, in addition to a suitable base, such as sodium carbonate, can also be included in the reaction mixture) can be used in this transformation. DIAGRAM 18

[0146] Useful synthetic intermediates such as 19.3 can be prepared according to Scheme 19. The sequence begins with sulfonylation of ester 19.1 by treatment with pure chlorosulfonic acid (or a mixture of a halogenated solvent and chlorosulfonic acid) followed by treatment of the chloride of resulting sulfonyl with a solution of ammonia in a solvent (e.g., water, 1,4-dioxane, tetrahydrofuran, methanol) and chiral separation of the isomeric mixture to produce enantiopure sulfonamide 19.2. Ester 19.2 can then be saponified by treatment with sodium hydroxide to produce acid 19.3. Other bases, such as lithium hydroxide or potassium trimethylsilanolate, can be used in this transformation. DIAGRAM 19

[0147] Another approach for intermediates such as 19.3 is illustrated in Scheme 20. The sequence begins with chiral separation of an isomeric mixture of acid 20.1 followed by esterification of the resulting enantiopure acid by treatment with thionyl chloride in ethanol to produce ester 20.2. Next, ester 20.2 is sulfonylated by treatment with pure chlorosulfonic acid (or a mixture of a halogenated solvent and chlorosulfonic acid) followed by treatment of the resulting sulfonyl chloride with a solution of ammonia in a solvent (e.g., water, 1. 4-dioxane, tetrahydrofuran, methanol). Saponification of the resulting sulfonamide then produces acid 19.3. Other esterification methods, such as using an alkyl halide and a base, and other bases for saponification can be employed in this sequence. DIAGRAM 20

[0148] Intermediates such as 8.1 can be prepared according to Scheme 21. Sulfonamide 19.2 is treated with di-tert-butyl dicarbonate in the presence of DMAP at elevated temperature followed by saponification of the resulting bis-protected sulfonamide to produce acid 8.1 . Other standard saponification conditions can be employed in this sequence. DIAGRAM 21

[0149] Intermediates such as amide oxime 3.1 can be prepared according to Scheme 22. This sequence begins with acid 1.1, which is converted to amide 7.1 by coupling with ammonium chloride in the presence of HATU and NMM (other coupling reagents and bases can also be used for this reaction). Amide 7.1 is then dehydrated with POCl3 (other dehydration reagents can also be employed) followed by treatment of the resulting nitrile with hydroxylamine to produce amide oxime 3.1. DIAGRAM 22

[0150] Intermediates such as 12.1 in the present invention can be prepared according to Scheme 23, in which amide 7.1 is treated with Lawesson's reagent to produce thioamide 12.1. Other tionation reagents can be used for this transformation. Thioamide 12.1 can be employed as an intermediate in schemes in the present invention involving compounds similar to 12.1. DIAGRAM 23

[0151] Intermediates such as alkyne 9.1 can be prepared according to Scheme 24. The ester 24.1 is reduced by treatment with LAH and the resulting alcohol oxidized by treatment with Dess-Martin periodinane to produce aldehyde 24.2. Other reducing agents (such as DIBAL) and oxidizing reagents (such as Collin's reagent, PCC or PDC) can be used in these transformations. Aldehyde 24.2 can then be reacted with dimethyl (1-diazo-2-oxopropyl)phosphonate in the presence of potassium carbonate to produce alkyne 9.1. Other bases can be used in this transformation. SCHEME 24

[0152] Intermediates such as 11.1 can be prepared according to Scheme 25. The sequence begins with treating (methoxymethyl)triphenylphosphonium chloride with n-butyllithium at low temperature and then reacting the resulting ylide with aldehyde 25.1 to produce enol ether 25.2. Enol ether 25.2 can then be treated with POCl3 in DMF to produce aldehyde 11.1. DIAGRAM 25

[0153] Other useful intermediates such as 26.5 can be prepared according to Scheme 26. The sequence begins with treatment of sulfonamide 26.1 with DMF-DMA at elevated temperature to produce aryl bromide 26.2. Aryl bromide 26.2 is then reacted with alkenyl boronate 26.3 under palladium-catalyzed conditions to produce styrenyl boronate 26.4. A variety of different catalysts (including other metals such as nickel), ligands, bases and solvents can be employed in this reaction. Styrenyl boronate 26.4 can then be treated with TMSD in the presence of palladium acetate followed by treatment of the resulting cyclopropane with triflic acid to produce cyclopropyl boronate 26.5. Other palladium catalysts (as well as copper and rhodium) can be used in the cyclopropanation reaction. DIAGRAM 26

[0154] Intermediates such as pyrazole 14.1 can be prepared according to Scheme 27. The sequence begins with treatment of acid 19.3 with N,O-dimethylhydroxylamine hydrochloride followed by reaction of the resulting Weinreb amide with methylmagnesium chloride and, then treating the resulting ketone with DMF-DMA to produce formamidine 27.1. Formamidin 27.1 can then be treated with hydrazine followed by DMF-DMA treatment to produce pyrazole 14.1. DIAGRAM 27

[0155] The haloketone intermediates of interest such as 16.1 can be prepared according to Scheme 28, in which the acid 1.1 is treated with sulfuric acid in the presence of methanol and then reacting the resulting ester with chloroiodomethane in the presence of LDA to produce haloketone 16.1. Other bases can be used in this transformation. DIAGRAM 28

[0156] Other useful intermediates such as 17.1 can be prepared according to Scheme 29. The sequence begins with reaction of ester 29.1 with chloroiodomethane in the presence of LDA followed by treatment of the resulting haloketone with sodium azide to produce azide 29.2. Azide 29.2 can then be reduced by treatment with triphenylphosphine in the presence of PTSA in a mixture of water and tetrahydrofuran to produce amine 17.1. Other reducing reagents, acids and solvents can be used in this transformation. DIAGRAM 29

[0157] Additional compounds in the present invention can be prepared according to Scheme 30, in which amide oxime 3.1 is first reacted with 1,1'-thiocarbonyldiimidazole and then treated with boron trifluoride diethyl etherate to form the corresponding thiadiazolone, which is then treated with phosphorus oxychloride to produce chlorothiadiazole 30.1. Other Lewis acids and halogenation reagents (such as PCl5, thionyl chloride and N-chlorosuccinimide) can be used for these transformations. Chlorothiadiazole 30.1 can be reacted with primary or secondary amine 30.2 at room or elevated temperature to produce amniothiadiazole 30.3. Alternatively, chlorothiadiazole 30.1 can be reacted with alcohols to form the corresponding alkoxythiadiazole.

[0158] Furthermore, the compounds in the present invention can be prepared according to Scheme 31, in which amine 17.1 is reacted with acyl chloride 17.2 in the presence of potassium carbonate and the resulting amide treated with phosphorus oxychloride at elevated temperature followed by treatment with trifluoroacetic acid to produce oxazole 31.1. Other bases, dehydration reagents and acids can be used in these transformations. DIAGRAM 31

[0159] Additional compounds in the present invention can be prepared according to Scheme 32, which begins with Wittig olefination of aldehyde 32.1 by reaction with phosphorane 32.2 at elevated temperature to produce cinnamate 32.3. Cinnamate 32.3 is then reacted with ylidene precursor 32.4 in the presence of n-butyllithium to produce cyclopropane 32.5. Cyclopropane 32.5 is then reacted with phenylmethanethiol in the presence of a palladium catalyst (such as tris(dibenzylideneacetone)dipalladium(0)), a ligand (such as Xantphos), and a base (such as N,N-diisopropylethylamine) to convert aryl bromide into the corresponding thioether, which is then treated with DCDMH followed by ammonium hydroxide to produce sulfonamide 32.6. Other palladium catalysts or precatalysts, ligands, bases and halogenation reagents (such as sulfuryl chloride) can be used in these transformations. Saponification of sulfonamide methyl ester 32.6 by treatment with lithium hydroxide then produces acid 32.7. DIAGRAM 32

[0160] Additional compounds in the present invention can be prepared according to Scheme 33, which begins with protection of aldehyde 33.1 as the acetal followed by treatment with a phase transfer catalyst (such as TBAB) in a mixture of chloroform and concentrated aqueous strong base (such as sodium hydroxide) to produce dichlorocyclopropane 33.2. Dichlorocyclopropane 33.2 is then treated with an acid (such as HCl) to remove the acetal, the resulting aldehyde oxidized with sodium chloride (or other suitable oxidants such as TPAP) to the corresponding carboxylic acid, and this acid converted to methyl ester 33.4 by treatment with trimethylsilyldiazomethane. Ester 33.4 is then treated with HCl in acetic acid to produce acid 33.5. DIAGRAM 33

[0161] Additional compounds in the present invention can be prepared according to Scheme 34, in which aldehyde 32.1 is first reacted with cyanoacetate 34.1 in the presence of piperidine and acetic acid to generate styrenyl ester 34.2. The ester 34.2 is then reacted with nitroalkane 34.3 in the presence of base at elevated temperature to produce cyclopropane 34.4. Cyclopropane 34.4 can then be saponified, decarboxylated, and the embedded nitrile hydrolyzed to generate methyl ester 34.5. Methyl ester 34.5 is then reacted with phenylmethanethiol in the presence of a palladium catalyst (such as tris(dibenzylideneacetone)dipalladium(0)), a ligand (such as Xantphos), and a base (such as diisopropylethylamine) to convert the bromide of aryl into the corresponding thioether, which is then treated with DCDMH followed by ammonium hydroxide to produce sulfonamide 34.6. Other palladium catalysts or precatalysts, ligands, bases and halogenation reagents (such as sulfuryl chloride) can be used in these transformations. Saponification of sulfonamide methyl ester 34.6 by treatment with lithium hydroxide then produces acid 34.7. DIAGRAM 34

[0162] It is understood that the compounds and intermediates in the preceding reaction schemes can be employed as synthetic intermediates in other schemes involving similar intermediates to produce alternative compounds of the present invention.

[0163] In some cases, the order of execution of the preceding reaction schemes can 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 can be employed to facilitate the reaction or to avoid unwanted reaction products.

[0164] In some cases, the final product can be additionally modified, for example, by manipulating substituents. Such manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation and hydrolysis reactions that are commonly known to those skilled in the art.

[0165] The following examples are provided so that the invention can be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any sense. Where a racemic mixture is produced, the enantiomers can be separated using chiral SFC normal or reverse phase separation conditions after isolation of the final product or in a suitable intermediate, followed by processing of the single isomers individually. It is understood that alternative methodologies can also be employed in the synthesis of these intermediates and key examples. Asymmetric methodologies (e.g., chiral catalysis, auxiliaries) can be used where possible and appropriate. The exact choice of reagents, solvents, temperatures, and other reaction conditions depends on the nature of the intended product.

[0166] The following abbreviations are used throughout the text: INTERMEDIATE 1 5-Fluoro-N l-hydroxy-2-methylbenzenecarboximidamide

[0167] 5-Fluoro-2-methylbenzonitrile (1.01 g, 7.47 mmol) was dissolved in ethanol (15 mL) at room temperature. Hydroxylamine (0.550 mL, 8.97 mmol) was added and the reaction mixture heated to 90 °C. The reaction mixture was allowed to stir for 12 h at 90 °C. The reaction mixture was allowed to cool and was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes - 0:100 to 35:65, to yield the title compound. MS: m/z = 169.1 [M+H]. INTERMEDIATE 2 (1R,2R)-2-(4-Sulfamoylphenyl)cyclopropanecarboxylic acid Step A: Ethyl (1R,2R)-2-(4-Sulfamoylphenyl)cyclopropanecarboxylate

[0168] To a stirred solution of ethyl trans-2-phenylcyclopropanecarboxylate (700 g, 3.68 mol) in chloroform (6 L) at 0 °C was added chlorosulfonic acid (2.45 L, 36.8 mol) in drops. The resulting mixture was allowed to warm to room temperature and stirring was continued for 2 h, then the reaction mixture was cooled to 0 °C and quenched by addition of water (3 L). The resulting mixture was extracted with dichloromethane (2 x 3 L) and the combined organic extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (15 L) and ammonium hydroxide solution (30%, 2.1 L, 18.0 mol) was added dropwise. The resulting mixture was allowed to stir for 30 min at room temperature and then diluted with water (10 L). The resulting mixture was extracted with ethyl acetate (3 x 5 L) and the combined organic extracts were washed with saturated aqueous sodium chloride (10 L), dried (sodium sulfate), filtered and concentrated under reduced pressure to give the compound racemic title. The enantiomers were separated by SFC, using a Chiralcel OD-H column and eluting with ethanol:carbon dioxide:diethylamine - 20:80:0.2. The first major elution peak was ethyl (1S,2S)-2-(4-sulfamoylphenyl)cyclopropanecarboxylate, and the second major elution peak was ethyl (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylate, the title compound. MS: m/z = 270.1 [M+H]. Step B: (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylic acid

[0169] To a stirred solution of ethyl (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylate (190 g, 0.705 mol) in tetrahydrofuran (3 L) and methanol (600 mL) at room temperature at 0 °C aqueous sodium hydroxide (2.12 M, 1.00 L, 2.12 mol) was added dropwise. The resulting mixture was allowed to stir at room temperature for 2 h and then concentrated under reduced pressure to remove organic solvents. The resulting mixture was adjusted to pH = 4 by addition of aqueous hydrochloric acid (2.0 M) and extracted with ethyl acetate (2 x 2 L) and the combined organic extracts were washed with saturated aqueous sodium chloride (1 L). , dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by recrystallization from diethyl ether to give the title compound. MS: m/z = 242.1 [M+H]. INTERMEDIATE 3 (1S,2S)-2-(4-sulfamoylphenyl)cyclopropanecarboxylic acid

[0170] Essentially following the procedures described in Intermediate 2, but using ethyl (1S,2S)-2-(4-sulfamoylphenyl)cyclopropanecarboxylate (described in Intermediate 2) instead of (1R,2R)-2- ethyl (4-sulfamoylphenyl)cyclopropanecarboxylate, the title compound was obtained. MS: m/z = 242.1 [M+H]. INTERMEDIATE 4 (1R,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid Step A: (1R,3R)-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid

[0171] The enantiomers of trans-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid (957 g, 5.03 mol) were separated by SFC, using a Lux-5u column and eluting with methanol:carbon dioxide - 30:70 . The first major elution peak was (1R,3R)-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid, the title compound, and the second major elution peak was (1S,3S)-2,2-dimethyl-3 acid. -phenylcyclopropanecarboxylic acid. MS: m/z = 191.1 [M+H]. Step B: Ethyl (1R,3R)-2,2-Dimethyl-3-phenylcyclopropanecarboxylate

[0172] To a stirred solution of (1R,3R)-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid (267 g, 1.40 mol) in ethanol (2.7 L) was added thionyl chloride (497 g, 4.21 mol) in drops at 0 °C. The resulting solution was allowed to stir for 1 h at room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2 L), washed with saturated aqueous sodium bicarbonate (2 x 1.5 L) and saturated aqueous sodium chloride (3 L), dried (magnesium sulfate) and concentrated under reduced pressure to produce the title compound. MS: m/z = 219.1 [M+H]. Step C: Ethyl (1R,3R)-2,2-Dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate

[0173] To a stirred solution of ethyl (1R,3R)-2,2-dimethyl-3-phenylcyclopropanecarboxylate (245 g, 1.12 mol) in chloroform (2.5 L) at 0 °C was added chlorosulfonic acid (1564 g, 13.48 mol) in drops. The resulting solution was allowed to stir for 30 min at 0 °C, warmed to room temperature, and allowed to stir for 2 h. The reaction mixture was cooled to 0 °C, water (2 L) was added, and the resulting solution was extracted with ethyl acetate (2 x 3 L). The organic extracts were combined, washed with saturated aqueous sodium chloride (3 L), dried (magnesium sulfate) and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (9 L), cooled to 5 °C, and ammonium hydroxide solution (30%, 1.75 L, 13.5 mol) was added. The resulting solution was allowed to stir for 30 min at room temperature, diluted with water (5 L), and the resulting solution extracted with ethyl acetate (3 x 3 L). The combined organic extracts were washed with saturated aqueous sodium chloride (5 L), dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:petroleum ether - 17:83 to 33:67 to give the title compound. MS: m/z = 298.0 [M+H]. Step D:(1R,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid

[0174] To a solution of (1R,3R)-ethyl 2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate (15 g, 50.4 mmol) in tetrahydrofuran (400 mL) and methanol (100 mL ) at room temperature sodium hydroxide (1.0 M, 150 mL, 150 mmol) was added. The reaction mixture was heated to 60 °C and allowed to stir for 2.5 h. The reaction mixture was cooled to 0 °C, hydrochloric acid (1.00 M, 12.5 mL, 151 mmol) slowly added, and the resulting mixture concentrated under reduced pressure to remove methanol, tetrahydrofuran and a small amount of water. . The mixture was extracted with ethyl acetate (3 x 200 mL) and the combined organic extracts were washed with saturated aqueous sodium chloride (150 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure to give the title compound. . MS: m/z = 270.1 [M+H]. INTERMEDIATE 5 (1S,3S)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid

[0175] Essentially following the procedures described in Intermediate 4, but using (1S,3S)-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid (described in Intermediate 4) instead of (1R,3R)-2 acid ,2-dimethyl-3-phenylcyclopropanecarboxylic acid, the title compound was obtained. MS: m/z = 270.2 [M+H]. INTERMEDIATE 6 (1S,3S)-2,2-Difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid Step A: Ethyl (1S,3S)-2,2-Difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylate

[0176] To chlorosulfonic acid (35.5 mL, 530 mmol) at 0 °C was added ethyl trans-2,2-difluoro-3-phenylcyclopropanecarboxylate (10.0 g, 44.2 mmol) (Dolbier et al. J. Fluorine Chem. (2004) 125:459 to 469) in drops. The reaction mixture was allowed to stir at 0 °C for 30 min, then warmed to room temperature, and allowed to stir for 2 h. The reaction mixture was slowly added to slowly stirred ice/water (500 mL) over the course of 5 min. The resulting suspension was then diluted with ethyl acetate (400 mL) and allowed to stir for 5 min. The layers were separated and the aqueous layer extracted with ethyl acetate (2 x 400 mL). The combined organic extracts were washed with water (400 mL), dried (magnesium sulfate) and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (400 mL) and ammonium hydroxide (30%, 92 mL, 1.36 mol) was added. The reaction mixture was allowed to stir at room temperature for 2.5 h and then it was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes - 0:100 to 40:60 to yield the racemic title compound. The racemate was separated by SFC, using an AD-H ChiralPak column, eluting with isopropanol:carbon dioxide:diethylamine - 20:80:0.1. The first major peak for elution was ethyl (1R,3R)-2,2-difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylate and the second major peak for elution was (1S,3S)-2,2-difluoro-3 Ethyl -(4-sulfamoylphenyl)cyclopropanecarboxylate, the title compound. MS: m/z = 306.2 [M+H]. Step B:(1S,3S)-2,2-difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid

[0177] To a solution of ethyl (1S,3S)-2,2-difluoro-3-(4-sulfamoylphenyl)cyclopropane carboxylate, (500 mg, 1.64 mmol) in acetonitrile (8.2 mL) was added aqueous lithium hydroxide (1.0 M, 4.9 mL, 4.9 mmol) and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and the aqueous layer acidified with aqueous HCl (1 M). The mixture was then extracted with ethyl acetate (3 x 20 mL) and the combined organic extracts washed with saturated aqueous sodium chloride (20 mL), dried (magnesium sulfate) and concentrated under reduced pressure to yield the title compound. . MS: m/z = 278.1 [M+H]. INTERMEDIATE 7 (1R,3R)-2,2-difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid

[0178] Essentially following the procedures described in Intermediate 6, but with the use of (1R,3R)-2,2-difluoro-3-(4-sulfamoylphenyl) ethyl cyclopropanecarboxylate (described in Intermediate 6) in place of (1S ethyl,3S)-2,2-difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylate, the title compound was obtained. MS: m/z = 278.1 [M+H]. INTERMEDIATE 8 (1R,3R)-3-{4-[(tert-butoxycarbonyl)(tert-butyl)sulfamoyl]phenyl}-2,2-dimethylcyclopropanecarboxylic acid Step A: (1R,3R)-3-{4-[(tert Ethyl -butoxycarbonyl)(tert-butyl)sulfamoyl]phenyl}-2,2-dimethylcyclopropanecarboxylate

[0179] To a stirred solution of ethyl (1R,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate (described in Intermediate 4) (2.00 g, 6.73 mmol) in tetra- hydrofuran (24 mL) at room temperature were added di-tert-butyl dicarbonate (7.34 g, 33.6 mmol) and DMAP (82 mg, 0.67 mmol). The resulting mixture was allowed to stir at room temperature for 18 h, then at 50 °C for 7 h, then allowed to cool to room temperature. Di-tert-butyl dicarbonate (1.50 g, 6.87 mmol) was added and the reaction mixture was allowed to stir at 50 °C for 3 h, then allowed to cool to room temperature. Di-tert-butyl dicarbonate (3.00 g, 13.7 mmol) and DMAP (82 mg, 0.67 mmol) were added and the reaction mixture was allowed to stir at 50 °C for 3 h, then allowed to cool to room temperature. 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 30:70 to give the title compound. MS: m/z = 517.3 [M + CH3CN + Na]. Step B:(1R,3R)-3-{4-[(tert-butoxycarbonyl)(tert-butyl)sulfamoyl]phenyl}-2,2-dimethylcyclopropanecarboxylic acid

[0180] To a stirred solution of ethyl (1R,3R)-3-{4-[(tert-butoxycarbonyl)(tert-butyl)sulfamoyl]phenyl}-2,2-dimethylcyclopropanecarboxylate (2.36 g, 5. 19 mmol) in tetrahydrofuran (15 mL) and methanol (15 mL) at room temperature was added aqueous sodium hydroxide (2.0 M, 9.47 mL, 18.9 mmol) dropwise. The resulting mixture was allowed to stir at room temperature for 18 h and then poured into water (50 mL). The resulting mixture was adjusted to pH = 4 by addition of aqueous hydrochloric acid (1.0 M) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (40 mL), dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the title compound, which was used without further purification. MS: m/z = 489.2 [M + CH3CN + Na]. INTERMEDIATE 9 (1S,3S)-3-{4-[(tert-butoxycarbonyl)(tert-butyl)sulfamoyl]phenyl}-2,2-dimethylcyclopropanecarboxylic acid

[0181] Essentially following the procedures described in Intermediate 8, but with the use of (1S,3S)-2,2-dimethyl-3-(4-sulfamoylphenyl) ethyl cyclopropanecarboxylate (described in Intermediate 5) instead of (1R ethyl ,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate, the title compound was obtained. MS: m/z = 489.4 [M + CH3CN + Na]. INTERMEDIATE 10 (1S,3S)-N'-Hydroxy-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboximidamide Step A: (1S,3S)-2,2-Dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

[0182] (1S,3S)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 5) (4.0 g, 14.85 mmol) was dissolved in dichloromethane (34 mL) and sodium sulfoxide dimethyl (3.8 mL) at room temperature. N-Methylmorpholine (3.3 mL, 30.0 mmol), HATU (5.85 g, 15.39 mmol), and ammonium chloride (1.59 g, 29.7 mmol) were added sequentially. The reaction mixture was allowed to stir for 14 h at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 5:95:0.1 to 55:45:0.1 to give the title compound. MS: m/z = 269.1 [M+H]. Step B: 4-[(1S,3S)-3-Cyano-2,2-dimethylcyclopropyl]benzenesulfonamide

[0183] (1S,3S)-2,2-Dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide (3.23 g, 12.04 mmol) was dissolved in acetonitrile (60 mL) at room temperature. Phosphorus oxychloride (2.24 mL, 24.07 mmol) was added and the reaction mixture was heated to 80 °C and allowed to stir for 45 min. The reaction mixture was allowed to cool and saturated aqueous sodium bicarbonate (20 mL) was added slowly. The resulting mixture was adjusted to pH 8 by addition of saturated aqueous sodium carbonate (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (15 mL) and saturated aqueous sodium chloride (15 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:ethanol:hexanes - 3:1:96 to 21:7:72 to give the title compound. MS: m/z = 251.1 [M+H]. Step C:(1S,3S)-N'-Hydroxy-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboximidamide

[0184] To a stirred solution of 4-[(1S,3S)-3-cyano-2,2-dimethylcyclopropyl]benzenesulfonamide (2.63 g, 10.51 mmol) in ethanol (52 mL) was added hydroxylamine (6 .44 mL, 105 mmol). The reaction mixture was heated to 60 °C and allowed to stir for 13 h. The reaction mixture was allowed to cool and was concentrated under reduced pressure. The residue was co-evaporated with methanol (2x) and acetonitrile (4x) to produce the title compound in sufficient purity for use in the next step. MS: m/z = 284.1 [M+H]. INTERMEDIATE 11 (1R,3R)-N'-Hydroxy-2,2-dimethyl-3-(4-sulfamoylphenyl) cyclopropanecarboximidamide

[0185] Essentially following the procedures described in Intermediate 10, but with the use of (1R,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (described in Intermediate 4) instead of (1S ,3S)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid, the title compound was obtained. MS: m/z = 284.1 [M + H]. INTERMEDIATE 12 (1R,2R)-2-(4-Sulfamoylphenyl)cyclopropanecarbothioamide Step A: (1R,2R)-2-(4-Sulfamoylphenyl)cyclopropanecarboxamide

[0186] To a solution of (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 2) (3.00 g, 12.4 mmol) in dichloromethane (37 mL) and dimethyl sulfoxide (4. 1 mL) at room temperature were added HATU (5.20 g, 13.7 mmol), N-methylmorpholine (5.5 mL, 49.7 mmol) and ammonium chloride (2.00 g, 37.3 mmol) sequentially and the reaction mixture was allowed to stir for 15 h. The reaction mixture was concentrated under reduced pressure and the residue purified by silica gel column chromatography, eluting with a gradient of ethyl acetate:ethanol:hexanes - 0:0:100 to 67:33:0. The product-containing fractions were combined and concentrated under reduced pressure. Further purification was achieved by washing the solid residue with dichloromethane to give the title compound. MS: m/z = 241.1 [M+H]. Step B: (1R,2R)-2-(4-Sulfamoylphenyl)cyclopropanecarbothioamide

[0187] To a suspension of (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxamide (1.15 g, 4.79 mmol) in tetrahydrofuran (19 mL) at room temperature was added Lawesson's reagent (1 .94 g, 4.79 mmol) and the reaction mixture was allowed to stir for 5 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with a gradient of ethyl acetate:ethanol:hexanes - 0:0:100 to 67:33:0. The product-containing fractions were combined and concentrated under reduced pressure. Further purification was achieved by washing the solid residue with dichloromethane to give the title compound. MS: m/z = 257.2 [M+H]. INTERMEDIATE 13 4-[(1R,3S)-3-Ethynyl-2,2-dimethylcyclopropyl]benzenesulfonamide Step A:4-[(1R,3R)-3-(Hydroxymethyl)-2,2-dimethylcyclopropyl]benzenesulfonamide

[0188] To a solution of ethyl (1R,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate (described in Intermediate 4) (3.0 g, 10.1 mmol) in tetrahydrofuran (30 mL) at 0 °C was added a 1.0 M solution of diisobutylaluminum hydride (1.0 M in hexane, 60.5 mL, 60.5 mmol). The reaction mixture was allowed to stir for 1 h and then water (3 mL) was added. The resulting mixture was filtered through a Celite filter, washed with methanol (3 x 50 mL), and concentrated under reduced pressure to yield the title compound. MS: m/z = 278.1 [M+Na]. Step B: 4-[(1R,3R)-3-Formyl-2,2-dimethylcyclopropyl]benzenesulfonamide

[0189] To a solution of 4-[(1R,3R)-3-(hydroxymethyl)-2,2-dimethylcyclopropyl]benzenesulfonamide (100 mg, 0.39 mmol) in dichloromethane (3.9 mL) at 0 °C Dess-Martin periodinane (199 mg, 0.47 mmol) was added and the reaction mixture was allowed to stir for 30 min. The reaction mixture was allowed to warm to room temperature and allowed to stir for 6 h. The reaction mixture was cooled with saturated aqueous sodium bicarbonate (2 mL) and saturated aqueous sodium thiosulfate (2 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 5 ml). The combined organic extracts were 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 yield the title compound. MS: m/z = 254.1 [M+H]. Step C: 4-[(1R,3S)-3-Ethynyl-2,2-dimethylcyclopropyl]benzenesulfonamide

[0190] Dimethyl (1-Diazo-2-oxopropyl)phosphonate (53.7 mg, 0.279 mmol) was added to a solution of 4-[(1R,3R)-3-formyl-2,2-dimethylcyclopropyl]benzenesulfonamide and potassium carbonate (64.4 mg, 0.466 mmol) in methanol (0.35 mL) and the solution was allowed to stir for 18 h at room temperature. The reaction mixture was then diluted with diethyl ether (4 mL), washed with saturated aqueous sodium bicarbonate (4 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 yield the title compound. MS: m/z = 250.1 [M+H]. INTERMEDIATE 14 N-[(Dimethylamino)methylidene]-4-{(1R,3R)-3-[1-(dimethylamino)-3-oxoprop-1-en-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide

[0191] To a solution of (methoxymethyl) triphenylphosphonium chloride (5.68 g, 16.6 mmol) in tetrahydrofuran (25 mL) at -78 ° C was added n-butyllithium (2.5 M in tetrahydrofuran, 6.63 mL, 16.6 mmol). The reaction mixture was warmed to 0 °C and allowed to stir for 30 min and then cooled to -78 °C. 4-((1R,3R)-3-Formyl-2,2-dimethylcyclopropyl)benzenesulfonamide (described in Intermediate 13) (1.40 g, 5.53 mmol) was added to this solution and the reaction mixture warmed to room temperature and allowed to stir for 30 min. The reaction mixture was diluted with water (50 mL) and ethyl acetate (50 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (25 mL), dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate:hexanes - 25:75. The product-containing fractions were combined and concentrated under reduced pressure. The resulting solid was added to a flask containing a solution [prepared by treating a solution of N,N-dimethylformamide (0.550 mL, 7.11 mmol) in chloroform (5 mL) at 0 °C with phosphorus oxychloride (0.663 mL , 7.11 mmol) followed by heating the resulting mixture to 40 °C, then cooling it back to 0 °C] at 0 °C and the reaction mixture heated to 55 °C and allowed to stir for 30 min. The reaction mixture was cooled to 0 °C and potassium carbonate (1.97 g, 14.2 mmol) in water (10 mL) was added. The reaction mixture was diluted with water (20 mL) and dichloromethane (30 mL). The phases were separated and the aqueous phase extracted with dichloromethane (2 x 30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (25 ml), dried (magnesium sulfate), filtered and concentrated under reduced pressure to give the title compound. MS: m/z = 378.2 [M+H]. INTERMEDIATE 15 2-Methyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid, diastereomer 4 Step A: Methyl 2-Methyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate, diastereomer 4

[0192] To a solution of 2-methyl-3-phenylcyclopropanecaboxylic acid (2.64 g, 15.0 mmol) in dichloromethane (30 mL) and methanol (7.5 mL) was slowly added a solution of TMS-diazomethane in ether (2 M, 9.00 mL, 18.0 mmol). After gas evolution ceased, the reaction mixture was allowed to stir for 10 minutes, it was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes. - 0:100 to 20:80. The residue was added dropwise to chlorosulfonic acid (12.0 mL, 179 mmol) at 0 °C and the reaction mixture was allowed to stir for 30 min. The reaction mixture was allowed to warm to room temperature and allowed to stir for 30 min. The reaction mixture was then poured onto ice, diluted with water (15 mL), stirred vigorously, and the aqueous phase decanted. The remaining residue was dissolved in 1,4-dioxane (12 mL), ammonium hydroxide was added (6.00 mL, 43.1 mmol) and the reaction mixture was allowed to stir for 30 min. The reaction mixture was filtered (washing with ethyl acetate) and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes - 5:95 to 50:50 and then chirally separated by SFC, first using an AS-H column, eluting with isopropanol: carbon dioxide:diethylamine - 12:88:0.1 and then, using an OD-H column, eluting with methanol:carbon dioxide:diethylamine - 30:70:0.1. The fourth major peak for elution, diastereomer 4, (as determined by analytical SFC using an AS-H column eluting with isopropanol:carbon dioxide:diethylamine - 20:80:0.1) was the title compound. MS: m/z = 270.2 [M+H]. Step B: 2-Methyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid, diastereomer 4

[0193] To a solution of methyl 2-methyl-3-(4-sulfamoylphenyl)cyclopropanecaboxylate, diastereomer 4, (121 mg, 0.449 mmol) in tetrahydrofuran (2.80 mL) was added aqueous sodium hydroxide (1 M, 1.40 mL, 1.40 mmol) and the reaction mixture was allowed to stir at room temperature for 4 h. The reaction mixture was then acidified to pH 1 with aqueous HCl (1N, 3.0 mL, 3.0 mmol), extracted with ethyl acetate (2 x 10 mL), and the combined organic extracts washed with ethyl chloride. saturated aqueous sodium and concentrated under reduced pressure to give the title compound. MS: m/z = 256.1 [M+H]. INTERMEDIATE 16 N-[(Dimethylamino)methylidene]-4-[trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]benzenesulfonamide Step A: 4-Bromo-N -[(dimethylamino)methylidene]benzenesulfonamide

[0194] A stirred solution of 4-bromobenzenesulfonamide (5.00 g, 21.2 mmol) in N,N-dimethylformamide dimethyl acetal (113 mL) was heated to 110 °C for 18 h, then allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure to generate the title compound in sufficient purity for use in the next step. MS: m/z = 291.0 [M+H]. Step B: N-[(Dimethylamino)methylidene]-4-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]benzenesulfonamide

[0195] To a stirred solution of 4-bromo-N-[(dimethylamino)methylidene]benzenesulfonamide (6.10 g, 21.0 mmol) in toluene (70 mL) at room temperature was added vinylboronic acid pinacol ester ( 7.11 mL, 41.9 mmol), bis(tri-tert-butylphosphine)palladium(0) (535 mg, 1.05 mmol) and triethylamine (6.42 mL, 46.1 mmol). The resulting mixture was heated at 80 °C for 18 h, then poured into water (100 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried (sodium 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 give the title compound. MS: m/z = 365.3 [M+H]. Step C: N-[(Dimethylamino)methylidene]-4-[trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trimethylsilyl)cyclopropyl] benzenesulfonamide

[0196] To a stirred solution of N-[(dimethylamino)methylidene]-4-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl ]benzenesulfonamide (6.00 g, 16.5 mmol) in tetrahydrofuran (82 mL) at room temperature were added palladium(II) acetate (924 mg, 4.12 mmol) and (trimethylsilyl)diazomethane (2.0 M in diethyl ether, 24.7 mL, 49.4 mmol), sequentially. The reaction mixture was allowed to stir at room temperature for 18 h, then acetic acid (12 mL) was added and the resulting mixture was poured into water (200 mL) and extracted with dichloromethane (3 x 200 mL). The combined organic extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes - 10:90 to 60:40 to give the title compound. MS: m/z = 451.3 [M+H]. Step D: N-[(Dimethylamino)methylidene]-4-[trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]benzenesulfonamide

[0197] To a stirred solution of N-[(dimethylamino)methylidene]-4-[trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- (trimethylsilyl)cyclopropyl]benzenesulfonamide (1.25 g, 2.77 mmol) in dichloromethane (22 mL) at 0 °C trifluoromethanesulfonic acid (0.801 mL, 9.02 mmol) was added. The reaction mixture was allowed to warm to room temperature and allowed to stir for 2 h, then it was poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane (2 x 100 mL). The combined organic extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of methanol:dichloromethane - 0:100 to 4:96 to give the title compound. MS: m/z = 379.3 [M+H]. INTERMEDIATE 17 N-[(Dimethylamino)methylidene]-4-[(1R,2R)-2-(1H-pyrazol-3yl)cyclopropyl] benzenesulfonamide Step A(1R,2R)-N-Methoxy-N-methyl-2-(4 -sulfamoylphenyl)cyclopropanecarboxamide

[0198] To a suspension of (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 2) (1.9 g, 7.9 mmol) in dichloromethane (16 mL) was added triethylamine (3.29 mL, 23.6 mmol) and HATU (3.59 g, 9.45 mmol) sequentially. The reaction mixture was allowed to stir for 5 min and then N,O-dimethylhydroxylamine hydrochloride (0.922 g, 9.45 mmol) was added. The reaction mixture was allowed to stir for 18 h and then it was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate (2 x 20 mL). The organic phase was concentrated under reduced pressure and the residue suspended in dichloromethane and filtered. The resulting solid was washed with water to yield the title compound. MS: m/z = 285.1 [M+H]. Step B: 4-[(1R,2R)-2-Acetylcyclopropyl]benzenesulfonamide

[0199] To a solution of (1R,2R)-N-methoxy-N-methyl-2-(4-sulfamoylphenyl)cyclopropanecarboxamide in tetrahydrofuran (28 mL) at -15 °C was added a solution of methylmagnesium chloride (3.0 M, 22.7 mL, 67.9 mmol) in tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and allowed to stir for 18 h. The reaction mixture was cooled to 0 °C and saturated aqueous ammonium chloride (50 mL) added slowly. The resulting mixture was extracted with ethyl acetate (3 x 40 mL) and the combined organic extracts washed with saturated aqueous sodium chloride (2 mL), dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:ethanol:hexanes - 0:0:100 to 60:20:20 to give the title compound. MS: m/z = 240.1 [M+H]. Step C: N-[(Dimethylamino)methylidene]-4-{(1R,2R)-2-[3-(dimethylamino)prop- 2-enoyl]cyclopropyl}benzenesulfonamide

[0200] 4-[(1R,2R)-2-acetylcyclopropyl]benzenesulfonamide (0.825 g, 3.45 mmol) was suspended in N,N-dimethylformamide dimethylacetal (9.23 mL, 69.0 mmol) in a sealable container . The container was sealed and the reaction mixture was heated to 110 °C and allowed to stir for 18 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The organic phase was washed with water (3 x 10 mL), dried (sodium sulfate) and concentrated under reduced pressure to give the title compound. MS: m/z = 350.2 [M+H]. Step D: 4-[(1R,2R)-2-(1H-Pyrazol-3-yl)cyclopropyl]benzenesulfonamide

[0201] To a solution of N-[(dimethylamino)methylidene]-4-{(1R,2R)-2-[3-(dimethylamino)prop-2-enoyl]cyclopropyl}benzenesulfonamide (1.21 g, 3, 45 mmol) in methanol (17 mL) at room temperature, hydrazine (2.17 mL, 69.0 mmol) was added and the reaction mixture was allowed to stir for 18 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in ethyl acetate (30 ml) and the organic phase washed with saturated aqueous sodium bicarbonate (2 x 20 ml), dried (sodium sulfate) and concentrated under reduced pressure to give the title compound. MS: m/z = 264.1 [M+H]. Step E: N-[(Dimethylamino)methylidene]-4-[(1R,2R)-2-(1H-pyrazol-3-yl)cyclopropyl]benzenesulfonamide

[0202] 4-[(1R,2R)-2-(1H-pyrazol-3-yl)cyclopropyl]benzenesulfonamide (749 mg, 2.84 mmol) was suspended in DMF-DMA (7.62 mL, 56.9 mmol) in a sealable container. The container was sealed and the reaction mixture was heated to 110 °C and allowed to stir for 18 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water (3 x 50 mL), dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:ethanol:hexanes - 0:0:100 to 67:33:0 to give the title compound. MS: m/z = 319.2 [M+H]. INTERMEDIATE 18 4-[(1R,2R)-2-(2-Chloroacetyl)cyclopropyl]benzenesulfonamide Step A: Methyl (1R,2R)-2-(4-Sulfamoylphenyl)cyclopropanecarboxylate

[0203] To a solution of (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 2) (2.0 g, 8.29 mmol) in methanol (20 mL) was added concentrated sulfuric acid (0.044 mL, 0.83 mmol) and the reaction mixture was heated to 60 °C and allowed to stir for 14 h. The reaction mixture was concentrated under reduced pressure and dichloromethane (20 mL) was added. The mixture was washed with saturated aqueous sodium bicarbonate (20 ml), dried (sodium sulfate) and concentrated under reduced pressure to give the title compound. MS: m/z = 255.8 [M+H]. Step B: 4-[(1R,2R)-2-(2-Chloroacetyl)cyclopropyl]benzenesulfonamide

[0204] To a solution of methyl (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylate (600 mg, 2.35 mmol) in tetrahydrofuran (8 mL) at -70 °C was added chloroiodomethane (2 .07 g, 11.8 mmol) and a solution of lithium diisopropylamide (2.0 M in tetrahydrofuran/heptane/ethylbenzene, 8.23 mL, 16.5 mmol), sequentially, and allowed to the reaction mixture was stirred for 1 h. Acetic acid (1.5 mL) was added and the reaction mixture was allowed to warm to room temperature and stir for 1 h. The reaction mixture was poured into water (5 mL) and the aqueous phase was extracted with ethyl acetate (2 x 5 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by preparatory silica gel thin layer chromatography, eluting with ethyl acetate:petroleum ether - 33:67 to give the title compound. 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.4 Hz, 2 H); 7.24 (d, J = 8.4 Hz, 2 H); 4.83 (s, 1 H); 4.82 (s, 1H); 3.74 (s, 2H); 2.59 (m, 1 H); 1.98 (m, 1H); 1.71 (m, 1H); 1.38 (m, 1 H). INTERMEDIATE 19 4-[(1R,2R)-2-Ethynylcyclopropyl]benzenesulfonamide Step A: 4-[(1R,2R)-2-(Hydroxymethyl)cyclopropyl]benzenesulfonamide

[0205] To a solution of (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 2) (3.0 g, 12 mmol) in tetrahydrofuran (50 mL) at 0 °C was added a borane solution (1.0 M in tetrahydrofuran, 24.9 mL, 24.9 mmol). The reaction mixture was allowed to warm to room temperature and stir for 3 h. The reaction mixture was poured into water (50 mL) and the mixture extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under reduced pressure to yield the title compound. 1H NMR (400 MHz, CD3OD): δ 7.76 (d, J = 8.0 Hz, 2 H); 7.24 (d, J = 8.0 Hz, 2 H); 3.62 (dd, J = 11.2, 6.0 Hz, 1 H); 3.49 (dd, J = 11.2, 6.8 Hz, 1 H); 1.92 (m, 1H); 1.45 (m, 1H); 1.02 (m, 2H). Step B: 4-[(1R,2R)-2-Ethynylcyclopropyl]benzenesulfonamide

[0206] To a solution of 4-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]benzenesulfonamide (1.00 g, 4.40 mmol) in tetrahydrofuran (20 mL) was added pyridinium chlorochromate (1 .90 g, 8.80 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stir for 5 h. The reaction mixture was diluted with water (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried (sodium sulfate) and concentrated under reduced pressure. The residue was taken up in methanol (30 mL) and treated with potassium carbonate (2.76 g, 20.0 mmol) and (1-diazo-2-oxopropyl)dimethyl phosphonate (921 mg, 4.79 mmol), sequentially. The reaction mixture was allowed to stir for 1 h, then heated to 60 °C and allowed to stir for 2 h. The reaction mixture was concentrated under reduced pressure, water (30 ml) was added and the mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic extracts were dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 50:50 to yield the title compound. 1H NMR (400 MHz, CD3OD): δ 7.79 (d, J = 8.0 Hz, 2 H); 7.26 (d, J = 8.0 Hz, 2 H); 2.30 (m, 1 H); 2.25 (s, 1 H); 1.61 (m, 1 H); 1.34 (m, 2H). INTERMEDIATE 20 Tert-Butyl[(4-{(1R,2R)-2-[(R)-glycyl]cyclopropyl}phenyl)sulfonyl]carbamate Step A:(1R,2R)-2-{4-[( methyl tert-Butoxycarbonyl)(tert-butyl)sulfamoyl]phenyl}cyclopropanecarboxylate

[0207] To a solution of methyl (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylate (described in Intermediate 18) (1.1 g, 4.3 mmol) in tetrahydrofuran (10 mL) at temperature 4-dimethylaminopyridine (0.158 g, 1.29 mmol) and di-tert-butyl dicarbonate (10.0 mL, 43.1 mmol) were added to the environment. The reaction mixture was heated to 70 °C and allowed to stir for 10 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 25:75 to give the title compound. 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.4 Hz, 2 H); 7.16 (d, J = 8.4 Hz, 2 H); 3.71 (s, 3H); 2.55 (m, 1 H); 1.94 (m, 1H); 1.55 (s, 1H); 1.49 (s, 9H); 1.43 (s, 9H); 1.35 (m, 1 H). Step B tert-Butyl({4-[(1R,2R)-2-(chloroacetyl)cyclopropyl]phenyl}sulfonyl)carbamate

[0208] To a solution of methyl (1R,2R)-2-{4-[(tert-butoxycarbonyl)(tert-butyl)sulfamoyl]phenyl}cyclopropanecarboxylate (200 mg, 0.49 mmol) in tetrahydrofuran ( 5 mL) at -78 °C chloroiodomethane (300 mg, 1.70 mmol) and lithium diisopropylamide (2.0 M in tetrahydrofuran/heptane/ethylbenzene, 0.97 mL, 1.9 mmol) were added. sequentially. The reaction mixture was allowed to stir for 20 min and then it was heated to -40 °C and allowed to stir for 10 min. An aqueous HCl solution (1 M, 10 mL, 10 mmol) was added to the reaction mixture. The reaction mixture was concentrated under reduced pressure and the resulting residue purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 25:75 to yield the title compound. 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.4 Hz, 2 H); 7.14 (d, J = 8.4 Hz, 2 H); 4.19 (s, 2H); 2.59 (m, 1 H); 2.44 (m, 1H); 1.76 (m, 1 H); 1.45 (s, 9 H); 1.39 (s, 9 H); 1.20 (m, 1 H). Step C tert-Butyl[(4-{(1R,2R)-2-[(R)-glycyl]cyclopropyl}phenyl)sulfonyl]carbamate

[0209] To a solution of tert-butyl({4-[(1R,2R)-2-(chloroacetyl)cyclopropyl]phenyl}sulfonyl)tert-butylcarbamate (1.2 g, 2.8 mmol) in tetra -hydrofuran (10 mL) and water (0.5 mL) at room temperature were added sodium azide (0.36 g, 5.6 mmol). The reaction mixture was allowed to stir for 10 h and then it was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (25 mL), dried (sodium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 20:80. The product-containing fractions were combined and concentrated under reduced pressure. The residue was taken up in tetrahydrofuran (5 mL) and water (0.5 mL) at room temperature and treated with triphenylphosphine (264 mg, 1.01 mmol) and p-toluenesulfonic acid (192 mg, 1.01 mmol). sequentially. The reaction mixture was allowed to stir for 1 h. The reaction mixture was concentrated under reduced pressure to yield the title compound. MS: m/z = 821.4 [2M+H]. INTERMEDIATE 21 2-Amino-1,2-dicyclopropylethanone Step A: 2-Bromo-1,2-dicyclopropylethanone

[0210] To a solution of 1,2-dicyclopropylethanone (400 mg, 3.22 mmol) in methanol (3 mL) at 0 °C was added bromine (0.199 mL, 3.87 mmol) in drops. The mixture was warmed to room temperature and allowed to stir for 1 h. Saturated aqueous sodium sulfite (10 mL) was added and the resulting mixture extracted with ethyl acetate (30 mL). The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure to yield the title compound in sufficient purity for use in the next step. 1H NMR (400 MHz, CDCl3): δ 3.73 (d, J = 10.4 Hz, 1 H), 2.24 (m, 1 H), 1.55 (m, 1 H), 1.13 (m, 2 H), 1.02 (m, 2 H), 0.86 (m, 2 H), 0.48 (m, 2 H). Step B: N-(1,2-Dicyclopropyl-2-oxoethyl)formamide

[0211] To a stirred solution of 2-bromo-1,2-dicyclopropyletan-1-one (50 mg, 0.25 mmol) in acetonitrile (2 mL) at room temperature was added sodium N-formylformamide (47 mg, 0.49 mmol) and potassium carbonate (68 mg, 0.49 mmol). The reaction mixture was heated to 80 °C and allowed to stir for 2 h. The reaction mixture was diluted with water (5 mL) and dichloromethane (10 mL). The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure to yield the title compound in sufficient purity for use in the next step. MS: m/z = 168.0 [M+H]. Step C: 2-Amino-1,2-dicyclopropylethanone

[0212] To a stirred solution of N-(1,2-dicyclopropyl-2-oxoethyl)formamide (48 mg, 0.29 mmol) in methanol (3 mL) at room temperature was added an aqueous solution of HCl (12 N , 0.3 mL, 3.60 mmol). The reaction mixture was heated to 30 °C and allowed to stir for 12 h. The reaction mixture was concentrated under reduced pressure to yield the title compound. MS: m/z = 140.0 [M+H]. INTERMEDIATE 22 (1R,2R)-N'-Hydroxy-2-(4-sulfamoylphenyl)cyclopropanecarboximidamide Step A: 4-[(1R,2R)-2-Cyanocyclopropyl]benzenesulfonamide

[0213] (1R,2R)-2-(4-Sulfamoylphenyl)cyclopropanecarboxamide (described in Intermediate 12) (1.72 g, 7.16 mmol) was dissolved in acetonitrile (36 mL) at room temperature. Phosphorus oxychloride (1.33 mL, 14.3 mmol) was added, the reaction mixture heated to 80 °C and allowed to stir for 30 min. To the reaction mixture was slowly added cold saturated aqueous sodium bicarbonate (50 mL) and the aqueous phase extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated aqueous sodium chloride (15 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 6 0:40 to give the title compound. MS: m/z = 223.1 [M+H]. Step B(1R,2R)-N'-Hydroxy-2-(4-sulfamoylphenyl)cyclopropanecarboximidamide

[0214] To a stirred solution of 4-[(1R,2R)-2-cyanocyclopropyl]benzenesulfonamide (960 mg, 4.32 mmol) in ethanol (22 mL) was added hydroxylamine (2.65 mL, 43.2 mmol ). The reaction mixture was heated to 60 °C and allowed to stir for 1 h. The reaction mixture was allowed to cool and was concentrated under reduced pressure. The residue was co-evaporated with methanol (2x) and acetonitrile (4x) to produce the title compound in sufficient purity for use in the next step. MS: m/z = 256.1 [M+H]. INTERMEDIATE 23 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]phenol Step A: 5-[trans-3-(4-Bromophenyl)-2 ,2-dimethylcyclopropyl]-3-phenyl-1,2,4-oxadiazole

[0215] To a solution of isopropyltriphenylphosphonium iodide (15.3 g, 35.3 mmol) in tetrahydrofuran (30 mL) at -50 °C was added a solution of n-butyllithium in hexane (2.5 M, 12.9 mL, 32.3 mmol). The reaction mixture was allowed to stir for 30 min and then warmed to room temperature and allowed to stir for 2 h. The reaction mixture was cooled to -50 °C and ethyl (2E)-3-(4-bromophenyl)prop-2-enoate (3.00 g, 11.8 mmol) was added. The reaction mixture was warmed to room temperature and allowed to stir for 12 h. Water (50 mL) was added and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in ethanol (20 mL) and water (4 mL) and lithium hydroxide (1.21 g, 50.5 mmol) was added. The reaction mixture was heated to 50 °C and allowed to stir for 4 h. The reaction mixture was then extracted with ethyl acetate (2 x 5 mL). The aqueous layer was adjusted to pH 1 by adding aqueous HCl (3 M, ca 20 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organic extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5 mL) and HATU (2.68 g, 7.06 mmol), diisopropylethylamine (3.70 mL, 21.2 mmol) and N-hydroxybenzenecarboximidamide (1.92 g, 14.1 mmol) were added. The reaction mixture was allowed to stir at room temperature for 30 min and then it was heated to 100 °C and allowed to stir for 5 h. The reaction mixture was diluted with water (50 mL) and the aqueous layer extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 9:91 to yield the title compound. MS: m/z = 371.5 [M+H]. Step B: 5-{trans-2,2-Dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}-3-phenyl -1,2,4-oxadiazole

[0216] To a solution of 5-[trans-3-(4-bromophenyl)-2,2-dimethylcyclopropyl]-3-phenyl-1,2,4-oxadiazole (50 mg, 0.14 mmol) in 1, 4-dioxane (2 mL) at room temperature was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (51 .6 mg, 0.203 mmol), potassium acetate (39.9 mg, 0.406 mmol) and PdCl2(dppf) (9.9 mg, 0.014 mmol). The reaction mixture was heated to 90 °C and allowed to stir for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 9:91 to yield the title compound. 1H NMR (400 MHz, CDCl3): δ 8.08 (dd, J = 3.0, 4.6 Hz, 2 H), 7.77 (d, J = 7.6 Hz, 2 H), 7, 45-7.48 (m, 3 H), 7.25 (d, J = 8.0 Hz, 2 H), 3.05 (d, J = 6.0 Hz, 1 H), 2.60 ( d, J = 6.0 Hz, 1 H), 1.41 (s, 3 H), 1.34 (s, 12 H), 1.03 (s, 3 H). Step C: 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]phenol

[0217] To a solution of 5-{trans-2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl} -3-phenyl-1,2,4-oxadiazole (45 mg, 0.11 mmol) in tetrahydrofuran (5 mL) at 0 °C was added sodium hydroxide (25.9 mg, 0.649 mmol) followed by addition in drops of an aqueous solution of hydrogen peroxide (30%, 0.066 mL, 0.65 mmol). The reaction mixture was allowed to stir for 1 h. A saturated aqueous solution of sodium sulfite (10 mL) was added and the mixture extracted with ethyl acetate (2 x 5 mL). The combined organic extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure to yield the title compound. MS: m/z = 307.1 [M+H]. INTERMEDIATE 24 Ethyl (1S,3S)-2,2-Dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate

[0218] Essentially following the procedures described in Intermediate 4, but using (1S,3S)-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid instead of (1R,3R)-2,2-dimethyl-3 - phenylcyclopropanecarboxylic acid, the title compound was obtained. MS: m/z = 298.0 [M+H]. INTERMEDIATE 25 Methyl trans-3-(2-Fluoro-4-sulfamoylphenyl)-2,2-dimethylcyclopropanecarboxylate Step A: Methyl (2E)-3-(4-Bromo-3-fluorophenyl)prop-2-enoate

[0219] To a stirred solution of 4-bromo-3-fluorobenzaldehyde (1.00 g, 4.93 mmol) in toluene (20 mL) was added methyl (2E)-(tritylphosphanylidene) ethanoate (2.47 g, 7.39 mmol). The reaction mixture was heated to 80 °C and allowed to stir for 16 h. The reaction mixture was concentrated under reduced pressure and water (50 mL) was added. The aqueous layer was extracted with ethyl acetate (3 x 80 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (150 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:petroleum ether - 0:100 to 10:90, to yield the title compound. 1H NMR (400 MHz, CDCl3): δ 7.53-7.59 (m, 2 H), 7.24 (d, J = 9.2 Hz, 1 H), 7.16 (d, J = 8 .4 Hz, 1 H), 6.41 (d, J = 16.0 Hz, 1 H), 3.79 (s, 3 H). Step B:N-({[trans-3-(3-Fluoro-4-sulfamoylphenyl)-2,2-dimethylcyclopropyl]carbonyl}oxy)benzenecarboximidamide

[0220] To a stirred suspension of isopropyltriphenylphosphonium iodide (3.50 g, 8.11 mmol) in tetrahydrofuran (20 mL) at -50 °C was added a solution of n-butyllithium in hexane (2. 5 M, 2.97 mL, 7.43 mmol) in drops. The reaction mixture was allowed to stir for 30 min, then it was heated to 15 °C and allowed to stir for 4 h. The reaction mixture was then cooled to -50 °C and methyl (2E)-3-(4-bromo-3-fluorophenyl)prop-2-enoate (700 mg, 2.70 mmol) was added. The reaction mixture was heated to 15 °C and allowed to stir for 2 h. The reaction mixture was diluted with diethyl ether (50 mL), an aqueous hydrogen peroxide solution (10%, 30 mL) was added, and the layers separated. The organic layer was washed with water (50 mL), saturated aqueous sodium sulfite solution (50 mL) and saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate: petroleum ether - 0:100 to 5:95, to generate the title compound. 1H NMR (400 MHz, CDCl3): δ 7.42-7.48 (m, 1 H), 6.94 (dd, J = 9.54, 1.76 Hz, 1 H), 6.85 (d , J = 8.28 Hz, 1 H), 3.74 (s, 3 H), 2.64 (d, J = 5.77 Hz, 1 H), 1.93 (d, J = 5.77 Hz, 1 H), 1.37 (s, 3 H), 0.94 (s, 3 H). Step C: methyl trans-3-[4-(Benzylsulfanyl)-3-fluorophenyl]-2,2-dimethylcyclopropanecarboxylate

[0221] To a stirred solution of N-({[trans-3-(3-fluoro-4-sulfamoylphenyl)- 2,2-dimethylcyclopropyl]carbonyl}oxy)benzenecarboximidamide (150 mg, 0.498 mmol) in 1,4- dioxane (3 mL) were added phenylmethanethiol (0.088 mL, 0.75 mmol), diisopropylethylamine (0.174 mL, 0.996 mmol), Pd2(dba)3 (45.6 mg, 0.0498 mmol) and Xantphos (86 mg , 0.15 mmol). The reaction mixture was deoxygenated with nitrogen, heated to 100 °C, and allowed to stir for 16 h. The reaction mixture was cooled, diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 5:95, to generate the title compound. 1H NMR (400 MHz, CDCl3): δ 7.11-7.28 (m, 6 H), 6.77-6.90 (m, 2 H), 4.05 (s, 2 H), 3, 73 (s, 3 H), 2.63 (d, J = 5.95 Hz, 1 H), 1.92 (d, J = 5.95 Hz, 1 H), 1.36 (s, 3 H ), 0.91 (s, 3H). Step D: methyl trans-3-(2-Fluoro-4-sulfamoylphenyl)-2,2-dimethylcyclopropanecarboxylate

[0222] To a stirred solution of methyl trans-3-[4-(benzylsulfanyl)-3-fluorophenyl]-2,2-dimethylcyclopropanecarboxylate (190 mg, 0.552 mmol) in acetonitrile (2 mL) at 0 °C was added acetic acid (0.05 mL), water (0.04 mL) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (326 mg, 1.66 mmol). The reaction mixture was allowed to stir for 90 min and then aqueous ammonium hydroxide (14.8 M, 0.373 mL, 5.52 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirring was continued for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with water (20 mL), and the aqueous layer extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 50:50, to provide the title compound. MS: m/z = 301.7 [M+H]. 1H NMR (400 MHz, CD3OD): δ 7.75-7.81 (m, 1 H); 7.15-7.18 (m, 2H); 3.72 (s, 3H); 2.69 (d, J = 5.87 Hz, 1 H); 2.20 (d, J = 5.87 Hz, 1 H); 1.35 (s, 3H); 0.93 (s, 3H). INTERMEDIATE 26 methyl trans-3-(2-Fluoro-4-sulfamoylphenyl)-2,2-dimethylcyclopropanecarboxylate

[0223] Essentially following the procedures described in Intermediate 25, but with the use of 4-bromo-2-fluorobenzaldehyde in place of 4-bromo-3-fluorobenzaldehyde, the title compound was obtained. MS: m/z = 343.1 [M+H+CH3CN]. INTERMEDIATE 27 Trans-2,2-dimethyl-3-(3-methyl-4-sulfamoylphenyl)cyclopropanecarboxylic acid

[0224] Essentially following the procedures described in Intermediate 25, but with the use of 4-bromo-3-methylbenzaldehyde in place of 4-bromo-3-fluorobenzaldehyde, the title compound was obtained. MS: m/z = 325.1 [M+H+CH3CN]. INTERMEDIATE 28 Methyl trans-2,2-Dimethyl-3-(4-(methylthio)phenyl)cyclopropanecarboxylate Step A: Methyl 3-(4-(Methylthio)phenyl)acrylate

[0225] To a stirred solution of 4-(methylthio)benzaldehyde (3.00 g, 19.7 mmol) in tetrahydrofuran (30 mL) at room temperature was added methyl 2-(triphenylphosphoranylidene)acetate (9.88 g, 29.6 mmol). The reaction mixture was heated to 70 °C and allowed to stir for 12 h. The reaction mixture was cooled to room temperature, water (50 mL) was added and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried (sodium sulfate), filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 20:80, to produce the title compound. MS: m/z = 209.0 [M+H]. Step B: methyl trans-2,2-Dimethyl-3-(4-(methylthio)phenyl)cyclopropanecarboxylate

[0226] To a stirred suspension of isopropyltriphenylphosphonium iodide (9.34 g, 21.6 mmol) in tetrahydrofuran (50 mL) at -50 °C was added n-butyllithium in hexane (2.5 M, 7.92 mL, 19.8 mmol) in drops. The reaction mixture was allowed to stir for 30 min, then allowed to warm to room temperature and stir for 4 h. The reaction mixture was cooled to -50 °C, methyl 3-(4-(methylthio)phenyl)acrylate (1.5 g, 7.2 mmol) was added, and the reaction mixture was allowed to warm to temperature environment and stirred for 2 h. Water (20 mL) was added and the reaction mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried (sodium sulfate), filtered and the filtrate concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 60:40:0.1 to 90:10:0.1, to yield the title compound. 1H NMR (400 MHz, CDCl3): δ 7.17 (d, J = 7.6 Hz, 2 H); 7.08 (d, J = 8.2 Hz, 2 H); 3.72 (s, 3H); 2.64 (d, J = 5.7 Hz, 1 H); 2.46 (s, 3H); 1.91 (d, J = 6.0 Hz, 1 H); 1.36 (s, 3H); 0.91 (s, 3H). INTERMEDIATE 29 Tert-butyl((4-((1S,3S)-3-(2-chloroacetyl)-2,2 dimethylcyclopropyl)phenyl)sulfonyl)carbamate Step A: (1S,3S)-3-(4- Ethyl (N-(tert-Butoxycarbonyl)-N-(tert-butyl)sulfamoyl)phenyl)-2,2-dimethylcyclopropanecarboxylate

[0227] To a stirred solution of ethyl (1S,3S)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate (Intermediate 24) (2.00 g, 6.73 mmol) in tetrahydrofuran ( 20 mL) at room temperature were added di-tert-butyl dicarbonate (14.68 g, 67.3 mmol) and 4-(dimethylamino)pyridine (0.25 g, 2.0 mmol). The reaction mixture was heated to 70 °C and allowed to stir for 12 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue purified by silica gel column chromatography, eluting with ethyl acetate:petroleum ether - 17:83, to generate the title compound. MS: m/z = 476.3 [M+Na]. Step B: tert-Butyl((4-((1S,3S)-3-(2-chloroacetyl)-2,2-dimethylcyclopropyl)phenyl)sulfonyl)carbamate

[0228] To a stirred solution of ethyl (1S,3S)-3-(4-(N-(tert-butoxycarbonyl)-N-(tert-butyl)sulfamoyl)phenyl)-2,2-dimethylcyclopropanecarboxylate (2, 5 g, 5.5 mmol) in tetrahydrofuran (10 mL) at -78 °C were added chloroiodomethane (2.92 g, 16.5 mmol) and a solution of LDA in tetrahydrofuran/heptane/ethylbenzene (2 .0 M, 11 L, 22 mmol). The reaction mixture was allowed to stir for 30 min and then it was heated to -40 °C and allowed to stir for 20 min. An aqueous HCl solution (1 M, 22 mL, 22 mmol) was added and the mixture extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:petroleum ether - 5:95 to 9:91, to produce the title compound. 1H NMR (400 MHz, CDCl3, rotamer ratio 1:1, asterisks denote rotamer peaks): δ 7.96 (d, J = 8.40 Hz, 2 H); 7.26-7.29 (m, 2H); 4.20 (d, J = 3.60 Hz, 1 H); 3.88-3.99 (m, 1H); 2.97* (d, J = 6.0 Hz, 0.5 H); 2.93* (d, J = 6.0 Hz, 0.5 H); 2.59* (d, J = 6.0 Hz, 0.5 H); 2.46* (d, J = 6.0 Hz, 0.5 H); 1.51 (s, 9 H), 1.47 (s, 9 H); 1.30* (s, 1.5H); 1.26* (s, 1.5H); 1.01* (s, 1.5H); 0.98* (s, 1.5H). INTERMEDIATE 30 Trans-2,2-dichloro-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid Step A: (3,3-Diethoxyprop-1-en-1-yl)benzene

[0229] To a stirred solution of cinnamaldehyde (1.00 g, 7.57 mmol) and triethylorthoformate (1.68 g, 11.4 mmol) in ethanol (12 mL) at room temperature was added NBS (0.013 g, 0.076 mmol) and the reaction mixture was allowed to stir for 30 min. The reaction mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 1:50, to generate the title compound. 1H NMR (400 MHz, CD3OD): δ 7.39-7.43 (m, 2 H); 7.29-7.31 (m, 2H); 7,227.27 (m, 1H); 6.68 (d, J = 16.0 Hz, 1 H); 6.16 (dd, J = 16.0, 5.2 Hz, 1 H); 5.03 (d, J = 5.2 Hz, 1 H); 3.67 (q, J = 7.2 Hz, 2 H); 3.53 (q, J = 7.2 Hz, 2 H); 1.14-1.22 (m, 6 H). Step B: (trans-2,2-Dichloro-3-(diethoxymethyl)cyclopropyl)benzene

[0230] To a stirred solution of (3,3-diethoxyprop-1-en-1-yl)benzene (17 g, 82 mmol) in chloroform (120 mL) at room temperature was added an aqueous solution of sodium hydroxide ( 50%, 100 mL, 1.9 mol) and N-benzyl-N,N-diethylethanaminium chloride (2.44 g, 10.7 mmol) and the reaction mixture was allowed to stir for 16 h. The reaction mixture was filtered and the filtrate was extracted with dichloromethane (2 x 100 mL). The combined organic extracts were dried (sodium sulfate), filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 1:10, to generate the title compound. 1H NMR (400 MHz, CD3OD): δ 7.25-7.33 (m, 5 H); 4.57 (d, J = 7.6 Hz, 1 H); 3.67-3.79 (m, 4H); 2.92 (d, J = 8.8 Hz, 1 H); 2.35 (dd, J = 8.8, 7.2 Hz, 1 H); 1.26 (t, J = 7.2 Hz, 3H); 1.15 (J = 7.2 Hz, 3 H). Step C: trans-2,2-Dichloro-3-phenylcyclopropanecarbaldehyde

[0231] To a stirred solution of (trans-2,2-dichloro-3-(diethoxymethyl)cyclopropyl)benzene (9.00 g, 31.1 mmol) in acetone (100 mL) at room temperature was added an aqueous solution of hydrogen chloride (3 M, 10 mL, 30 mmol) and the reaction mixture was allowed to stir for 16 h. The aqueous layer was extracted with ethyl acetate (2 x 100 mL) and the combined organic extracts were dried (sodium sulfate), filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate: petroleum ether - 10:90 to 20:80, to generate the title compound. 1H NMR (400 MHz, CD3OD): δ 9.48 (d, J = 4.4 Hz, 1 H); 7.24-7.47 (m, 5H); 3.55 (d, J = 8.0 Hz, 1 H); 2.91 (d, J = 8.4 Hz, 1 H). Step D: methyl trans-2,2-Dichloro-3-phenylcyclopropanecarboxylate

[0232] To a stirred solution of trans-2,2-dichloro-3-phenylcyclopropanecarbaldehyde (4.50 g, 20.9 mmol) in n-butanol (5.00 mL) at 0 °C was added 2-methylpent- 2-ene (8.80 g, 105 mmol) and a solution of sodium chloride (5.68 g, 62.8 mmol) and sodium dihydrogen phosphate (10.04 g, 84 mmol) in water (5 mL ). The reaction mixture was allowed to warm to room temperature and stir for 1 h. The reaction mixture was adjusted to pH 4 and the aqueous layer extracted with ethyl acetate (2 x 5 mL). The combined organic extracts were dried (sodium sulfate), filtered, and the filtrate concentrated under reduced pressure. The residue was dissolved in methanol (3 mL) at room temperature, thionyl chloride (1.61 mL, 22.1 mmol) was added, and the reaction mixture was allowed to stir for 30 min. The reaction mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 10:90, to generate the title compound. 1H NMR (400 MHz, CD3OD): δ 7.23-7.37 (m, 5 H); 3.83 (s, 3H); 3.46 (d, J = 8.4 Hz, 1 H); 2.84 (d, J = 8.4 Hz, 1 H). Step E: methyl trans-2,2-Dichloro-3-(4-sulfamoylphenyl)cyclopropanecarboxylate

[0233] To a stirred solution of methyl trans-2,2-dichloro-3-phenylcyclopropanecarboxylate (1.0 g, 4.1 mmol) in chloroform (15 mL) at 0 °C was added chlorosulfonic acid (5.37 mL, 82 mmol) and the reaction mixture was allowed to stir for 2 h. The reaction mixture was poured into water (30 mL) and the aqueous phase extracted with dichloromethane (2 x 30 mL). The combined organic extracts were dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue (1.2 g, 3.5 mmol) was dissolved in 1,4-dioxane (20 mL) and ammonia (0.24 g, 14.0 mmol) was added. The reaction mixture was allowed to warm to room temperature and allowed to stir for 30 min. The reaction mixture was poured into water (15 mL) and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate: petroleum ether - 10:90 to 50:50, to generate the title compound. 1H NMR (400MHz, CDCl3): δ 7.92 (d, J = 8.4 Hz, 2 H); 7.40 (d, J = 8.4 Hz, 2 H); 4.90 (s, 2H); 3.85 (s, 3H); 3.51 (d, J = 8.0 Hz, 1 H); 2.90 (d, J = 8.4 Hz, 1 H). Step F: Trans-2,2-dichloro-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid

[0234] To a stirred solution of methyl trans-2,2-dichloro-3-(4-sulfamoylphenyl)cyclopropanecarboxylate (200 mg, 0.62 mmol) in acetic acid (2 mL) was added an aqueous solution of HCl ( 3M, 1 mL, 3 mmol) and the reaction mixture was heated to 100 °C and allowed to stir for 2 h. The reaction mixture was cooled, poured into water (5 mL), and the aqueous phase extracted with ethyl acetate (2 x 5 mL). The combined organic extracts were dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure to produce the title compound in sufficient purity for use in the next step. 1H NMR (400 MHz, CD3OD): δ 7.84 (d, J = 8.4 Hz, 2 H); 7.35 (d, J = 8.4 Hz, 2 H); 3.40 (d, J = 8.4 Hz, 1 H); 2.86 (d, J = 8.4 Hz, 1 H). INTERMEDIATE 31 (1R,2R)-2-(4-{[(Dimethylamino)methylidene]sulfamoyl}phenyl)-N'-hydroxycyclopropanecarboximidamide Step A: (1R,2R)-2-(4-Sulfamoylphenyl)cyclopropanecarboxamide

[0235] A stirred solution of (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 2) (1.00 g, 4.14 mmol) in tetrahydrofuran (20 mL) at room temperature was 1,1'-carbonyldiimidazole (0.806 g, 4.97 mmol) was added. The reaction mixture was heated to 35 °C and allowed to stir for 1 h. The reaction mixture was allowed to cool to room temperature, then aqueous ammonium hydroxide (14.8 M, 5.6 mL, 83 mmol) was added and the mixture was allowed to stir for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting mixture was adjusted to pH 3 by addition of an aqueous HCl solution (1 M). The resulting precipitate was isolated by filtration, washed with water and dried to give the title compound. MS: m/z = 241.2 [M+H]. Step B:4-[(1R,2R)-2-Cyanocyclopropyl]-N-[(dimethylamino)methylidene]benzenesulfonamide

[0236] To a stirred solution of (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxamide (1.0 g, 4.2 mmol) in N,N-dimethylformamide (8 mL) was added thionyl chloride (3 .3 g, 27 mmol) in drops at 0 °C. The resulting solution was allowed to stir for 1 h at 15 °C and then diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (25 ml), dried (sodium sulfate) and concentrated under reduced pressure to give the title compound. MS: m/z = 278.1 [M+H]. Step C: (1R,2R)-2-(4-{[(Dimethylamino)methylidene]sulfamoyl}phenyl)-N‘-hydroxycyclopropanecarboximidamide

[0237] To a stirred solution of 4-[(1R,2R)-2-cyanocyclopropyl]-N-[(dimethylamino)methylidene]benzenesulfonamide (950 mg, 3.43 mmol) in ethanol (7 mL) was added hydrochloride hydroxylamine (476 mg, 6.85 mmol) and triethylamine (1.39 g, 13.7 mmol). The reaction mixture was heated at reflux for 15 h. The reaction mixture was allowed to cool and was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:petroleum ether - 0:100 to 25:75, to yield the title compound. MS: m/z = 310.9 [M+H]. INTERMEDIATE 32 Methyl trans-2,2-Dimethyl-3-(2-methyl-4-sulfamoylphenyl)cyclopropanecarboxylate Step A: Ethyl 3-(4-Bromo-2-methylphenyl)-2-cyanoprop-2-enoate

[0238] To a stirred solution of 4-bromo-2-methylbenzaldehyde (500 mg, 2.51 mmol) and ethyl 2-cyanoacetate (284 mg, 2.51 mmol) in toluene (20 mL) was added piperidine (42 .8 mg, 0.502 mmol) and acetic acid (151 mg, 2.51 mmol). The reaction mixture was heated to 130 °C and allowed to stir for 18 h with continuous removal of water. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:petroleum ether - 0:100 to 10:90, to yield the title compound. 1H NMR (400 MHz, CDCl3): δ 8.47 (s, 1 H), 7.97-8.07 (m, 1 H), 7.48 (br, 2 H), 4.40 (q, J = 7.04 Hz, 2 H), 2.44 (s, 3 H), 1.41 (t, J = 7.04 Hz, 3 H). Step B: ethyl trans-3-(4-Bromo-2-methylphenyl)-1-cyano-2,2-dimethylcyclopropanecarboxylate

[0239] To a stirred solution of ethyl trans-3-(4-bromo-2-methylphenyl)-2-cyanoprop-2-enoate (100 mg, 0.340 mmol) in ethanol (5 mL) was added 2-nitropropane ( 36.3 mg, 0.408 mmol) and potassium carbonate (56.4 mg, 0.408 mmol). The reaction mixture was heated to 90 °C and allowed to stir for 6 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 17:83, to generate the title compound. 1H NMR (400 MHz, CD3OD) δ 7.39 (s, 1 H), 7.33 (d, J = 8.38 Hz, 1 H), 7.21 (d, J = 8.16 Hz, 1 H), 4.34 (q, J = 7.20 Hz, 2 H), 3.07 (s, 1 H), 2.27 (s, 3 H), 1.50 (s, 3 H), 1.39 (t, J = 7.06 Hz, 3 H), 1.33 (s, 3 H). Step C: Trans-3-(4-bromo-2-methylphenyl)-1-cyano-2,2-dimethylcyclopropanecarboxylic acid

[0240] To a stirred solution of potassium carbonate (147 mg, 1.06 mmol) in water (1 mL) was added a solution of trans-3-(4-bromo-2-methylphenyl)-1-cyano-2 Ethyl ,2-dimethylcyclopropanecarboxylate (235 mg, 0.699 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL). The reaction mixture was heated to reflux and allowed to stir for 1 h and then it was heated to 85 °C and allowed to stir for 14 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with water (50 mL) and washed with ethyl acetate (2 x 30 mL). The layers were separated and the aqueous layer was adjusted to pH ~ 3 by adding an aqueous HCl solution (3 M) and then extracted with ethyl ether (3 x 50 mL). The organic extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure to generate the title compound. 1H NMR (400 MHz, CDCl3): δ 7.39 (s, 1 H), 7.32 (d, J = 7.94 Hz, 1 H), 7.20 (d, J = 8.16 Hz, 1 H), 3.10 (s, 1 H), 2.27 (s, 3 H), 1.57 (s, 3 H), 1.34 (s, 3 H). Step D trans-3-(4-Bromo-2-methylphenyl)-2,2-dimethylcyclopropanecarbonitrile

[0241] To a stirred solution of trans-3-(4-bromo-2-methylphenyl)-1-cyano-2,2-dimethylcyclopropanecarboxylic acid (210 mg, 0.68 mmol) in DMSO (3 mL) at room temperature lithium chloride (165 mg, 3.90 mmol), sodium bicarbonate (82 mg, 0.98 mmol) and water (0.070 mL, 3.9 mmol) were added. The reaction mixture was allowed to stir for 30 min and then it was heated to 175 °C and allowed to stir for 5 h. The reaction mixture was cooled, diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (3 x 50 mL) and saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), filtered, and the solvent concentrated under reduced pressure to give the title compound. 1H NMR (400 MHz, CD3OD): δ 7.37 (d, J = 1.2 Hz, 1 H), 7.30 (d, J = 1.6 Hz, 1 H), 7.01 (d, J = 8.2 Hz, 1 H), 2.41 (d, J = 5.9 Hz, 1 H), 2.30 (s, 3 H), 1.95-1.99 (m, 1 H ), 1.51 (s, 3 H), 0.83 (s, 3 H). Step E: methyl trans-3-(4-Bromo-2-methylphenyl)-2,2-dimethylcyclopropanecarboxylate

[0242] To a vial containing trans-3-(4-bromo-2-methylphenyl)-2,2-dimethylcyclopropanecarbonitrile (300 mg, 1.14 mmol) was added a solution of HCl in methanol (4 M, 10 mL, 40.0 mmol) and the reaction mixture was heated to 80 °C and allowed to stir for 24 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with water (10 mL). The aqueous layer was adjusted to pH ~ 8 by adding a saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (30 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 9:91, to generate the title compound. 1H NMR (400 MHz, CDCI3) δ 7.32 (s, 1 H), 7.25 (d, J = 8.22 Hz, 1 H), 6.91 (d, J = 8.22 Hz, 1 H), 3.75 (s, 3 H), 2.51 (d, J = 5.48 Hz, 1 H), 2.29 (s, 3 H), 1.94 (d, J = 5, 87 Hz, 1 H), 1.43 (s, 3 H), 0.85 (s, 3 H). Step F: methyl trans-3-[4-(Benzylsulfanyl)-2-methylphenyl]-trans-2,2-dimethylcyclopropanecarboxylate

[0243] To a stirred solution of methyl trans-3-(4-bromo-2-methylphenyl)-2,2-dimethylcyclopropanecarboxylate (130 mg, 0.437 mmol) in 1,4-dioxane (3 mL) was added phenylmethanethiol ( 0.077 mL, 0.66 mmol), DIEA (0.153 mL, 0.875 mmol), Pd2(dba)3 (80 mg, 0.087 mmol), and Xantphos (152 mg, 0.262 mmol). The reaction mixture was heated to 110 °C and allowed to stir for 16 h. The reaction mixture was cooled, diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 5:95, to generate the title compound. 1H NMR (400 MHz, CD3OD): δ 7.09-7.21 (m, 7 H); 6.90-7.04 (m, 1 H); 4.06 (s, 2H); 3.70 (s, 3H); 2.46 (d, J = 5.2 Hz, 1 H); 2.21(s, 3H); 1.98 (d, J = 6.0 Hz, 1 H); 1.37 (s, 3H); 0.80 (s, 3H). Step G: methyl trans-2,2-Dimethyl-3-(2-methyl-4-sulfamoylphenyl)cyclopropanecarboxylate

[0244] To a stirred solution of methyl trans-3-(4-(benzylthio)-2-methylphenyl)-2,2-dimethylcyclopropanecarboxylate (122 mg, 0.358 mmol) in acetonitrile (4 mL) at 0 °C was added acetic acid (0.1 mL), water (0.08 mL) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (212 mg, 1.08 mmol) and the mixture was allowed to reaction was stirred for 90 min. Ammonium hydroxide (14.8 M, 0.243 mL, 3.60 mmol) was added and the reaction mixture was allowed to warm to room temperature and allowed to stir for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 50:50, to generate the title compound. 1H NMR (400 MHz, CDCI3): δ 7.74 (s, 1 H), 7.69 (dd, J = 8.16, 1.88 Hz, 1 H), 7.19 (d, J = 8 .03 Hz, 1 H), 4.75 (s, 2 H), 3.77 (s, 3 H), 2.61 (d, J = 6.02 Hz, 1 H), 2.39 (s , 3 H), 2.05 (s, 1 H), 1.46 (s, 3 H), 0.85 (s, 3 H). INTERMEDIATE 33 4-[(1S,3S)-3-(5-Chloro-1,2,4-thiadiazol-3-yl)-2,2-difluorocyclopropyl] benzenesulfonamide

[0245] Essentially following the procedures described in Example 29, but with the use of (1S,3S)-2,2-difluoro-N'-hydroxy-3-(4-sulfamoylphenyl)cyclopropanecarboximidamide (Intermediate 36) instead of ( 1R,2R)-N'-hydroxy-2-(4-sulfamoylphenyl)cyclopropanecarboximidamide, the title compound was obtained. MS: m/z = 352.0 [M+H]. INTERMEDIATE 34 4-[(1S,2S)-2-(Chloroacetyl)cyclopropyl]benzenesulfonamide

[0246] Essentially following the procedures described in Intermediate 29, but using ethyl (1S,2S)-2-(4-sulfamoylphenyl)cyclopropanecarboxylate (described in Intermediate 2) in place of (1S,3S)-2, Ethyl 2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate, the title compound was obtained. 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.6 Hz, 2 H); 7.20 (d, J = 8.6 Hz, 2 H); 4.24 (s, 2H); 2.59-2.73 (m, 1H); 2.47-2.55 (m, 1 H); 1.78-1.88 (m, 1 H); 1.50-1.53 (m, 9 H); 1.45-1.48 (m, 10 H). INTERMEDIATE 35 (1R,3R)-2,2-Dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

[0247] Essentially following the procedures described in Intermediate 10, but with the use of (1R,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 4) instead of (1S,3S )-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid, the title compound was obtained. MS: m/z = 269.1 [M+H]. INTERMEDIATE 36 (1S,3S)-2,2-difluoro-N'-hydroxy-3-(4-sulfamoylphenyl) cyclopropanecarboximidamide

[0248] Essentially following the procedures described in Intermediate 10, but using (1S,3S)-2,2-difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 4) instead of (1S,3S )-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid, the title compound was obtained. MS: m/z = 292.0 [M+H]. INTERMEDIATE 37 4-(trans-3-((Hydroxy-imino)methyl)-trans-2,2-dimethylcyclopropyl) benzenesulfonamide Step A: ethyl trans-2,2-Dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate

[0249] Essentially following the procedures described in Intermediate 4, but with the use of trans-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid in place of (1R,3R)-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid, the title compound was obtained. MS: m/z = 298.0 [M+H]. Step B:4-(trans-3-(Hydroxymethyl)-2,2-dimethylcyclopropyl)benzenesulfonamide

[0250] Essentially following the procedures described in Intermediate 13, but with the use of ethyl trans-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate in place of (1R,3R)-2,2-dimethyl- Ethyl 3-(4-sulfamoylphenyl)cyclopropanecarboxylate, the title compound was obtained. MS: m/z = 278.1 [M+Na]. Step C: 4-(trans-3-Formyl-2,2-dimethylcyclopropyl)benzenesulfonamide

[0251] Essentially following the procedures described in Intermediate 13, but with the use of 4-(trans-3-(hydroxymethyl)-2,2-dimethylcyclopropyl)benzenesulfonamide instead of 4-[(1R,3R)-3-( hydroxymethyl)-2,2-dimethylcyclopropyl]benzenesulfonamide, the title compound was obtained. MS: m/z = 254.1 [M+H]. Step D 4-(trans-3-((Hydroxyimino)methyl)-2,2-dimethylcyclopropyl)benzenesulfonamide

[0252] To a stirred solution of 4-(trans-3-formyl-2,2-dimethylcyclopropyl)benzenesulfonamide (300 mg, 1.18 mmol) in ethanol (10 mL) at room temperature was added sodium carbonate (377 mg , 3.55 mmol) and hydroxylamine hydrochloride (254 mg, 3.55 mmol) and the reaction mixture was allowed to stir for 16 h. The reaction mixture was concentrated under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (60 mL), dried (sodium sulfate), filtered, and the filtrate concentrated under reduced pressure to yield the title compound in sufficient purity for use in the next step. MS: m/z = 269 [M+H].

[0253] The intermediates appearing in the following tables were prepared in analogy to the above intermediates, as described or prepared as a result of similar transformations with modifications known to those skilled in the art. The required starting materials have been described in this document, are commercially available, known in the literature or readily synthesized by one skilled in the art. Simplified protecting group strategies were applied in some pathways. INT-A TABLE INT-B TABLE EXAMPLE 1 4-((1S,3S)-3-(3-(5-Fluoro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl)-benzenesulfonamide

[0254] To a solution of (1S,3S)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 5) (150 mg, 0.558 mmol) in 1,4-dioxane (2.8 mL ) 1,1'-carbonyldiimidazole (101 mg, 0.624 mmol) was added. The reaction mixture was heated to 45 °C and allowed to stir for 2 h. The reaction mixture was cooled to room temperature and 5-fluoro-N'-hydroxy-2-methylbenzimidamide (Intermediate 1) (104 mg, 0.617 mmol) in 1,4-dioxane (1.5 mL) was added. The reaction mixture was heated to 110 °C, allowed to stir for 5 h, then allowed to cool, and was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes - 0:100 to 40:60 to give the title compound. MS: m/z = 402.2 [M+H]. 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J = 7.9 Hz, 2 H); 7.73 (d, J = 9.6 Hz, 1 H); 7.41 (d, J = 8.0 Hz, 2 H); 7.07-7.10 (m, 1 H); 4.94 (s, 2H); 3.07 (d, J = 6.0 Hz, 1 H); 2.64 (d, J = 6.0 Hz, 1 H); 2.60 (s, 3H); 1.06 (s, 3H). EXAMPLE 2 4-((1S,3S)-3-(5-(2-Cyclopropylethyl)-1,2,4-oxadiazol-3-yl)-2,2-dimethylcyclopropyl)benzenesulfonamide

[0255] To a solution of 3-cyclopropylpropanoic acid (59.8 mg, 0.524 mmol) in 1,4-dioxane (2.40 mL) was added 1,1'-carbonyldiimidazole (85 mg, 0.52 mmol ). The reaction mixture was heated to 85 °C and allowed to stir for 20 min. The reaction mixture was cooled to room temperature and (1S,3S)-N'-hydroxy-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropane-carboximidamide (Intermediate 10) (135 mg, 0.476 mmol) was added. The reaction mixture was heated to 130 ° C, allowed to stir for 1 h, and then allowed to cool and concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 10:90:0.1 to 95:5:0.1. Product-containing fractions were concentrated under reduced pressure to remove acetonitrile. The remaining solution was made basic with saturated aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (10 mL), dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound. MS: m/z = 362.2 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 7.75 (d, J = 8.0 Hz, 2 H); 7.50 (d, J = 8.0 Hz, 2 H); 7.31 (s, 2H); 2.98 (t, J = 7.3 Hz, 2 H); 2.71 (m, 2H); 1.64 (q, J = 7.2 Hz, 2 H); 1.21 (s, 3H); 0.93 (s, 3H); 0.74 (d, J = 8.5 Hz, 1 H); 0.35-0.38 (m, 2H); 0.04 (d, J = 5.0 Hz, 2 H). EXAMPLE 3 4-((1S,3S)-2,2-Dimethyl-3-(5-(2,3,6-trifluorophenyl)-1,2,4-oxadiazol-3-yl)cyclopropyl)benzenesulfonamide

[0256] To a solution of 2,3,6-trifluorobenzoic acid (73.2 mg, 0.416 mmol) in 1,4-dioxane (1.80 mL) at room temperature was added 1,1'-carbonyldiimidazole ( 75 mg, 0.46 mmol). The reaction mixture was heated to 85 °C and allowed to stir for 20 min. The reaction mixture was cooled to room temperature and (1S,3S)-N'-hydroxy-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboximidamide (Intermediate 10) (105.1 mg, 0.371 mmol) in 1. 4-dioxane (1.5 mL) was added. The reaction mixture was heated to 130 ° C, allowed to stir for 1.5 h, and then allowed to cool and concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 15:85:0.1 to 90:10:0.1. Product-containing fractions were concentrated under reduced pressure. The residue was taken up in methanol (5 mL) and treated with MP-carbonate. The mixture was allowed to stir for 20 min. The mixture was filtered and concentrated under reduced pressure to yield the title compound. MS: m/z = 424.2 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 7.92 (qd, J = 9.4, 4.8 Hz, 1 H); 7.77 (d, J = 8.1 Hz, 2 H); 7.55 (d, J = 8.1 Hz, 2 H); 7.48 (t, J = 9.6 Hz, 1 H); 7.32 (s, 2H); 2.84-2.89 (m, 2H); 1.28 (s, 3H); 0.99 (s, 3H). EXAMPLE 4 4-((1R,2R)-2-(3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)benzenesulfonamide

[0257] To a solution of (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 2) (1.40 g, 5.80 mmol) in 1,4-dioxane (29 mL) at room temperature 1,1'-carbonyldiimidazole (1.04 g, 6.41 mmol) was added. The reaction mixture was heated to 85 °C and allowed to stir for 20 min. The reaction mixture was cooled to room temperature and 3-fluoro-N'-hydroxybenzimidamide (1.08 g, 7.01 mmol) was added. The reaction mixture was heated to 135 °C and allowed to stir for 1.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 10:90:0.1 to 90:10:0.1. The product-containing fractions were made basic with saturated aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (10 ml), dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound. MS: m/z = 360.2. 1H NMR (500 MHz, DMSO-d6): δ 7.85 (d, J = 7.7 Hz, 1 H); 7.75 (m, 3H); 7.63 (q, J = 7.2 Hz, 1 H); 7.48 (d, J = 7.7 Hz, 2 H); 7.44-7.46 (m, 1 H); 7.33 (s, 2H); 2.85-2.92 (m, 2H); 1.86-1.94 (m, 2 H). EXAMPLE 5 4-{(1R,3R)-3-[5-(2,4-Difluorophenyl)-1,3,4-thiadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide

[0258] To a solution of (1R,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 4) (103 mg, 0.383 mmol) in dimethyl sulfoxide (1.90 mL) at At room temperature N-methylmorpholine (0.084 mL, 0.77 mmol), HATU (165 mg, 0.433 mmol) and 2,4-difluorobenzohydrazide (82.4 mg, 0.479 mmol) were added sequentially. The reaction mixture was allowed to stir for 10 min, then it was poured into saturated aqueous ammonium chloride (10 mL), and the mixture extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with saturated aqueous ammonium chloride (2 x 15 mL) and saturated aqueous sodium chloride (15 mL), dried (sodium sulfate) and concentrated under reduced pressure. The residue was taken up in tetrahydrofuran (1.9 mL) and then treated with Lawesson's reagent (557 mg, 1.38 mmol). The reaction mixture was heated to 65 °C, allowed to stir for 1 h, and then concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 15:85:0.1 to 95:5:0.1. The product-containing fractions were made basic with saturated aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (10 ml), dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound. MS: m/z = 422.3. 1H NMR (500 MHz, DMSO-d6): δ 8.37-8.42 (m, 1 H); 7.90 (d, J = 8.0 Hz, 2 H); 7.42 (d, J = 8.0 Hz, 3 H); 7.05-7.08 (m, 1H); 6.97-7.01 (m, 1 H); 4.83 (s, 2H); 3.13 (d, J = 6.1 Hz, 1 H); 2.76 (d, J = 6.1 Hz, 1 H); 1.57 (s, 3H); 1.30 (s, 3H); 1.05 (s, 3H). EXAMPLE 6 4-{(1S,3S)-3-[5-(2,4-Difluorophenyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide

[0259] To a solution of (1S,3S)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 5) (152 mg, 0.342 mmol) in 1,4-dioxane (1.70 mL ) at room temperature 1,1-carbonyldiimidazole (63.7 mg, 0.393 mmol) was added. The reaction mixture was heated to 75 °C and allowed to stir for 20 min. The reaction mixture was then cooled to room temperature, 2,4-difluorobenzohydrazide (71.8 mg, 0.417 mmol) was added, and the reaction mixture heated to 130 °C. The reaction mixture was allowed to stir for 3 h. The reaction mixture was cooled to room temperature, phosphorus oxychloride (0.318 mL, 3.42 mmol) was added, and the reaction mixture was heated to 70 °C and allowed to stir for 18 h. The reaction mixture was cooled to room temperature, slowly poured into cold saturated aqueous sodium bicarbonate (15 mL), and the mixture extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (15 mL), dried (sodium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes - 0:100 to 45:55 to give the title compound. MS: m/z = 406.3. 1H NMR (500 MHz, DMSO-d6): δ 8.06-8.11 (m, 1 H); 7.90 (d, J = 8.1 Hz, 2 H); 7.41 (d, J = 8.0 Hz, 2 H); 6.99-7.07 (m, 2H); 4.80 (s, 2H); 3.01 (d, J = 6.1 Hz, 1 H); 2.58 (d, J = 6.1 Hz, 1 H); 1.39 (s, 3H); 1.05 (s, 3H). EXAMPLE 7 4-{(1S,3S)-2,2-Difluoro-3-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide

[0260] To a solution of (1S,3S)-2,2-difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 6) (50 mg, 0.18 mmol) in 1,4-dioxane (0. 90 mL) 1,1'-carbonyldiimidazole (35.1 mg, 0.216 mmol) was added and the mixture was allowed to stir at room temperature for 2 h. N'-Hydroxyisobutyrimidamide (23.3 mg, 0.216 mmol) was added in one portion and the mixture was allowed to stir for 30 min, then it was heated to 90 °C, and allowed to stir for 2 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with ethyl acetate (15 mL), washed with saturated aqueous sodium chloride (2 x 10 mL), dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:ethanol:hexanes - 3:1:96 to 30:10:60 to give the title compound. MS: m/z = 344.2 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 7.83 (d, J = 8.4 Hz, 2 H); 7.67 (d, J = 8.3 Hz, 2 H); 7.40 (s, 2H); 4.34 (dd, J = 12.1, 8.25 Hz, 1 H); 4.05 (dd, J = 13.4, 8.06 Hz, 1 H); 3.10 (m, 1H); 1.28 (d, J = 6.98 Hz, 6 H). EXAMPLE 8 4-[(1R,2R)-2-(5-Phenyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide Step A(1R,2R)-N-(2-Oxo-2-phenylethyl)-2 -(4-sulfamoylphenyl)cyclopropanecarboxamide

[0261] To a suspension of (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 2) (233 mg, 0.967 mmol) in tetrahydrofuran (4.0 mL) was added 1,1'- carbonyldiimidazole (188 mg, 1.16 mmol) and the reaction mixture was allowed to stir at room temperature for 2 h. The resulting suspension was then added to a stirred solution of 2-amino-1-phenylethanone hydrobromide (230 mg, 1.06 mmol) and triethylamine (0.148 mL, 1.06 mmol) in tetrahydrofuran (0.8 mL) and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and the residues washed with dichloromethane and water and the resulting solid dried under reduced pressure to give the title compound. MS: m/z = 359.2 [M+H]. Step B 4-[(1R,2R)-2-(5-Phenyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide

[0262] To a vial containing (1R,2R)-N-(2-oxo-2-phenylethyl)-2-(4-sulfamoylphenyl) cyclopropanecarboxamide (100 mg, 0.279 mmol) sulfuric acid (concentrated, 0.297 mL, 5.58 mmol) and the resulting mixture was allowed to stir at room temperature for 4 h. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with aqueous sodium bicarbonate (10%, 15 mL), dried (magnesium sulfate), and concentrated under reduced pressure. The resulting solid was recrystallized from acetone. MS: m/z = 341.2 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 7.75 (d, J = 7.9 Hz, 2 H); 7.71 (d, J = 8.0 Hz, 2 H); 7.58 (s, 1 H), 7.43-7.47 (m, 4 H), 7.36 (t, J = 7.25 Hz, 1 H), 7.32 (br s, 2 H ), 2.70 (m, 1 H), 2.60 (m, 1 H), 1.80 (m, 1 H), 1.67 (m, 1 H). EXAMPLE 9 4-[(1R,2R)-2-(4-Phenyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide

[0263] To a suspension of (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxamide (described in Intermediate 12) (100 mg, 0.416 mmol) in ethyl acetate (4.2 mL) 2-bromo- 1- phenylethanone (83 mg, 0.42 mmol) and silver trifluoromethanesulfonate (107 mg, 0.416 mmol) and the reaction mixture heated to 50 °C and allowed to stir for 16 h. The reaction mixture was diluted with ethyl acetate (10 mL) and filtered. To the filtrate was added saturated aqueous sodium chloride (15 mL) and the mixture was allowed to stir for 2 h. The mixture was filtered and the phases separated. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:ethanol:hexanes -3:1:96 to 45:15:40 to give the title compound. MS: m/z = 341.2 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 8.49 (s, 1 H), 7.73-7.76 (m, 4 H); 7.41-7.45 (m, 4 H), 7.29-7.34 (m, 3 H), 2.662.70 (m, 1 H), 2.58-2.62 (m, 1 H ), 1.75-1.79 (m, 1 H), 1.64-1.68 (m, 1 H). EXAMPLE 10 4-[(1R,3R)-2,2-Dimethyl-3-(2-phenyl-1,3-oxazol-5-yl)cyclopropyl] benzenesulfonamide Step A: tert-Butyl({4-[(1R,3R tert-butyl )-2,2-dimethyl-3-(2-phenyl-1,3-oxazol-5-yl)cyclopropyl]phenyl}sulfonyl)carbamate

[0264] To a suspension of (1R,3R)-3-{4-[(tert-butoxycarbonyl)(tert-butyl)sulfamoyl]phenyl}-2,2-dimethylcyclopropanecarboxylic acid (Intermediate 8) (150 mg, 0.352 mmol ) in dichloromethane (1.76 mL) at 0°C was added N,N-dimethylformamide (0.0328 mL, 0.423 mmol) followed by oxalyl chloride (0.705 mL, 1.41 mmol). The reaction mixture was allowed to stir at 0 °C for 5 min and then it was warmed to room temperature and allowed to stir for 4 h. The reaction mixture was concentrated under reduced pressure and co-evaporated with toluene (2x). The resulting residue was diluted with toluene (3.2 mL) and to the mixture (isocyanomethyl)benzene (0.0383 mL, 0.352 mmol) and 2,6-lutidine (0.0411 mL, 0.352 mmol) were added. The reaction mixture was heated to 80 °C and allowed to stir for 2.5 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were washed with saturated aqueous ammonium chloride (3 x 10 mL), dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes - 0:100 to 20:80, to yield the title compound. MS: m/z = 525.5 [M+H]. Step B:4-[(1R,3R)-2,2-Dimethyl-3-(2-phenyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide

[0265] To a solution of tert-butyl({4-[(1R,3R)-2,2-dimethyl-3-(2-phenyl-1,3-oxazol-5-yl)cyclopropyl]phenyl}sulfonyl) tert-butyl carbamate (125 mg, 0.238 mmol) in dichloromethane (1.65 mL) trifluoroacetic acid (0.551 mL, 7.15 mmol) was added and the mixture was allowed to stir at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes - 0:100 to 40:60, to yield the title compound. MS: m/z = 369.3 [M+H]. 1H NMR (500 MHz, CDCl3): δ 8.02 (d, J = 7.8 Hz, 2 H), 7.84 (d, J = 8.2 Hz, 2 H), 7.44-7, 48 (m, 3 H), 7.41 (d, J = 7.72 Hz, 2 H), 6.96 (s, 1 H), 4.78 (s, 2 H), 2.52 (d , J = 5.9 Hz, 1 H) 2.37 (d, J = 6.02 Hz, 1 H), 1.24 (s, 3 H), 1.00 (s, 3 H). EXAMPLE 11 4-[(1R,3R)-2,2-Dimethyl-3-(3-phenylisoxazol-5-yl)cyclopropyl]benzenesulfonamide

[0266] To a stirred solution of 4-[(1R,3S)-3-ethynyl-2,2-dimethylcyclopropyl]benzenesulfonamide (Intermediate 13) (9.8 mg, 0.039 mmol), (nitromethyl)benzene (5.4 mg, 0.039 mmol), and benzenesulfonyl chloride (13.9 mg, 0.079 mmol) triethylamine (11.0 μl, 0.079 mmol) was added at -10 °C. The reaction mixture was allowed to warm to room temperature and allowed to stir for 16 h. The reaction mixture was concentrated under a stream of nitrogen gas. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes - 0:100 to 25:75. The product-containing fractions were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of methanol:dichloromethane - 0:100 to 10:90 to give the title compound. MS: m/z = 369.3 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 7.85 (d, J = 7.0 Hz, 2 H); 7.78 (d, J = 8.0 Hz, 2 H); 7.52 (m, 5H); 7.32 (s, 2H); 6.95 (s, 1H); 2.78 (d, J = 6.0 Hz, 1 H); 2.76 (d, J = 6.0 Hz, 1 H); 1.20 (s, 3H); 0.96 (s, 3H). EXAMPLE 12 4-[(1R,3R)-2,2-Dimethyl-3-(1-phenyl-1H-1,2,3-triazol-4-yl)cyclopropyl] benzenesulfonamide

[0267] To a solution of 4-[(1R,3S)-3-ethynyl-2,2-dimethylcyclopropyl]benzenesulfonamide (Intermediate 13) (30 mg, 0.120 mmol), cupric sulfate (3.84 mg, 0.024 mmol) and sodium 2-(1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-3-olate (4.8 mg, 0.024 mmol) in methanol (1. 0 mL) at room temperature was added a solution of azidobenzene (0.5 M in methyl tert-butyl ether, 0.722 mL, 0.361 mmol). The reaction mixture was allowed to stir at room temperature for 1 h and was heated to 50 °C and allowed to stir for 1 h. The reaction mixture was diluted with water (30 mL) and ethyl acetate (30 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (15 mL), dried (magnesium sulfate), and concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 35:65:0.1 to 65:35:0.1 to give the title compound. MS: m/z = 369.1 [M+H]. 1H NMR (400 MHz, CD3OD): δ 8.45 (s, 1 H); 7.86 (m, 4H); 7.58 (m, 2H); 7.48 (m, 3H); 2.72 (d, J = 6.0 Hz, 1 H); 2.57 (d, J = 6.0 Hz, 1 H); 1.17 (s, 3H); 1.00 (s, 3 H). EXAMPLE 13 4-{(1R,3R)-3-[1-(3-Fluorophenyl)-1H-pyrazol-4-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide Step A: N-[(Dimethylamino)methylidene]-4- {(1R,3R)-3-[1-(3-fluorophenyl)-1H-pyrazol-4-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide

[0268] To the solution of N-[(dimethylamino)methylidene]-4-{(1R,3R)-3-[1-(dimethylamino)-3-oxoprop-1-en-2-yl]-2,2- dimethylcyclopropyl}benzenesulfonamide (Intermediate 14) (200 mg, 0.530 mmol) and (3-fluorophenyl)hydrazine (100 mg, 0.795 mmol) in methanol (3 mL) was added aqueous HCl (3 M, 0.530 mL, 1.59 mmol) at room temperature. The reaction mixture was heated to 60 °C and allowed to stir for 30 min. The reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate and diluted with water (20 mL) and dichloromethane (20 mL). The phases were separated and the aqueous phase extracted with dichloromethane (2 x 20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (15 ml), dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound. MS: m/z = 441.2 [M+H]. Step B 4-{(1R,3R)-3-[1-(3-Fluorophenyl)-1H-pyrazol-4-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide

[0269] To a solution of N-[(dimethylamino)methylidene]-4-{(1R,3R)-3-[1-(3-fluorophenyl)-1H-pyrazol-4-yl]-2,2-dimethylcyclopropyl }benzenesulfonamide (200 mg, 0.454 mmol) in methanol (1 mL) at room temperature was added hydrazine hydrate (114 mg, 2.27 mmol) and the reaction mixture was allowed to stir for 1 h. The reaction mixture was directly purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 40:60:0.1 to 60:40:0.1 to generate the title compound. MS: m/z = 386.1 [M+H]. 1H NMR (400 MHz, CD3OD): δ 8.18 (s, 1 H); 7.84 (d, J = 8.0 Hz, 2 H); 7.66 (s, 1 H); 7.55 (t, J = 8.0 Hz, 2 H); 7.46 (m, 3H); 7.02 (t, J = 8.0 Hz, 1 H); 2.41 (d, J = 6.0 Hz, 1 H); 2.34 (d, J = 6.0 Hz, 1 H); 1.13 (s, 3H); 0.94 (s, 3H). EXAMPLE 14 4-{(1R,2R)-2-[4-(3-Fluorophenyl)-1,3-thiazol-2-yl]cyclopropyl} benzenesulfonamide

[0270] To a solution of (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarbothioamide (Intermediate 12) (100 mg, 0.39 mmol) in ethanol (3.9 mL) was added 2-bromo-1- (3-fluorophenyl)ethanone (85 mg, 0.39 mmol) and the reaction mixture heated to 75 °C and allowed to stir for 2 h. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate (5 mL) was added, and the resulting mixture extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 15:85:0.1 to 95:5:0.1 to give the title compound. MS: m/z = 375.2 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 8.04 (s, 1 H); 7.80 (d, J = 7.9 Hz, 1 H); 7.73-7.76 (m, 4H); 7.46-7.50 (m, 1 H); 7.43 (d, J = 8.0 Hz, 2 H); 7.30 (s, 2H); 7.15-7.19 (m, 1 H); 2.88-2.92 (m, 1 H); 2.70-2.73 (m, 1 H); 1.84-1.88 (m, 1 H); 1.73-1.76 (m, 1 H). EXAMPLE 15 4-[(1R,2R)-2-(5-Methyl-4-phenyl-1,3-thiazol-2-yl)cyclopropyl]benzenesulfonamide

[0271] To a solution of (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarbothioamide (Intermediate 12) (50 mg, 0.20 mmol) in ethanol (2.0 mL) was added 2-bromo-1- phenylpropan-1-one (30 μl, 0.20 mmol) and the reaction mixture heated to 75 °C and allowed to stir for 15 h. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate (5 mL) was added, and the resulting mixture extracted with ethyl acetate (3 x 5 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 15:85:0.1 to 95:5:0.1. The product-containing fractions were combined and concentrated under reduced pressure. Further purification was achieved by washing the solid residue with dichloromethane to give the title compound. MS: m/z = 371.2 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 7.73 (d, J = 8.0 Hz, 2 H); 7.65 (d, J = 7.7 Hz, 2 H); 7.46 (t, J = 7.6 Hz, 2 H); 7.41 (d, J = 8.1 Hz, 2 H); 7.34-7.37 (m, 1H); 7.30 (s, 1H); 2.75-2.78 (m, 1 H); 2.60-2.64 (m, 1 H); 1.75-1.79 (m, 1H); 1.67-1.70 (m, 1 H). EXAMPLE 16 4-[(1R,2R)-2-(4-Methyl-5-phenyl-1,3-thiazol-2-yl)cyclopropyl]benzenesulfonamide

[0272] To a solution of (1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarbothioamide (Intermediate 12) (50 mg, 0.20 mmol) in ethanol (2.0 mL) was added 1-bromo-1- phenylpropan-2-one (37.4 mg, 0.176 mmol) and the reaction mixture heated to 75 ° C and allowed to stir for 22 h. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate (5 mL) was added, and the resulting mixture extracted with ethyl acetate (3 x 5 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 15:85:0.1 to 95:5:0.1 to give the title compound. MS: m/z = 371.2 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 7.73 (d, J = 8.0 Hz, 2 H); 7.45-7.46 (m, 4H); 7.41 (d, J = 8.2 Hz, 3 H); 7.38 (s, 1 H); 7.29 (s, 2H); 2.76-2.80 (m, 1 H); 2.61-2.64 (m, 1H); 2.38 (s, 3H); 1.76-1.80 (m, 1 H); 1.68-1.72 (m, 1 H). EXAMPLE 17 4-[(1S,3S)-2,2-Dimethyl-3-(5-phenyl-1,3-thiazol-2-yl)cyclopropyl] benzenesulfonamide Step A: (1S,2S)-2,2-Dimethyl- N-(2-oxo-2-phenylethyl)-3-(4-sulfamoylphenyl) cyclopropanecarboxamide

[0273] To a solution of (1S,3S)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 5) (100 mg, 0.371 mmol) in dichloromethane (1.1 mL) and sodium sulfoxide dimethyl (0.12 mL) at room temperature were added HATU (155 mg, 0.408 mmol), 2-amino-1-phenylethanone hydrogen chloride (67 mg, 0.39 mmol), and N-methylmorpholine (0.12 mL , 1.1 mmol) sequentially and the reaction mixture was allowed to stir for 2 h. saturated aqueous sodium bicarbonate (5 mL) was added and the resulting mixture extracted with ethyl acetate (3 x 5 mL). The combined organic extracts were dried (sodium 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 75:25 to give the title compound. MS: m/z = 387.3 [M+H]. Step B 4-r(1S,3S)-2,2-Dimethyl-3-(5-1enyl-1,3-thiazol-2-yl)cyclopropyl]benzenesulfonamide

[0274] To a solution of (1S,3S)-2,2-dimethyl-N-(2-oxo-2-phenylethyl)-3-(4-sulfamoylphenyl)cyclopropanecarboxamide (90 mg, 0.23 mmol) in toluene (1.9 mL) and tetrahydrofuran (0.47 mL) Lawesson's reagent (99 mg, 0.25 mmol) was added and the reaction mixture was heated to 100 °C and allowed to stir for 3.5 H. Water (2 mL) was added and the resulting mixture extracted with ethyl acetate (3 x 5 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified first by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes - 0:100 to 75:25 and then by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 15:85:0.1 to 95:5:0.1 to produce the title compound. MS: m/z = 385.3 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 8.10 (s, 1 H); 7.77 (d, J = 8.0 Hz, 2 H); 7.64 (d, J = 7.6 Hz, 2 H); 7.53 (d, J = 8.0 Hz, 2 H); 7.44 (t, J = 7.6 Hz, 2 H); 7.35 (t, J = 7.6 Hz, 1 H); 7.32 (s, 2H); 3.06 (d, J = 6.1 Hz, 1 H); 2.92 (d, J = 6.1 Hz, 1 H); 1.22 (s, 3H); 0.97 (s, 3H). EXAMPLE 18 4-{trans-2-[3-(Propan-2-yl)-1,2,4-thiadiazol-5-yl]cyclopropyl} benzenesulfonamide, enantiomer B Step A: 5-(2-Phenylcyclopropyl)-3-( propan-2-yl)-1,2,4-thiadiazole

[0275] To a solution of 5-chloro-3-isopropyl-1,2,4-thiadiazole (1.00 g, 6.15 mmol) in 1,4-dioxane (22 mL) was added (2-phenylcyclopropyl) boronic acid (1.49 g, 9.22 mmol) and cesium carbonate (4.01 g, 12.3 mmol). The mixture was deoxygenated with nitrogen and PdCl2(dppf)-CH2Cl2 adduct (753 mg, 0.922 mmol) was added. The reaction mixture was heated to 100 °C and allowed to stir for 3.5 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, rinsing with ethyl acetate. The filtrate was concentrated under reduced pressure and the resulting residue purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes - 0:100 to 90:10 to give the title compound. MS: m/z = 245.1 [M+H]. Step B:4-{trans-2-[3-(Propan-2-yl)-1,2,4-thiadiazol-5-yl]cyclopropyl}benzenesulfonamide, enantiomer B

[0276] To a solution of 5-(2-phenylcyclopropyl)-3-(propan-2-yl)-1,2,4-thiadiazole (1.01 g, 4.13 mmol) in methylene chloride (8, 0 mL) at 0 °C chlorosulfonic acid (4.0 mL, 60 mmol) was added and the mixture was allowed to slowly warm to room temperature and stir for 1.5 h. The reaction mixture was added dropwise to ice water and the organic layer separated and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (8.0 mL) and cooled to 0 °C. Ammonium hydroxide (2.9 mL, 20.7 mmol) was added slowly and the reaction mixture was allowed to stir at room temperature for 30 min. Water (10 mL) was added and the resulting mixture extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were dried (sodium sulfate) or concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes - 0:100 to 100:10 to give the title compound. The racemate was separated by SFC, using an AD-H ChiralPak column, eluting with ethanol:carbon dioxide:isopropylamine - 55:45:0.3. The first main peak to elute was 4-{trans-2-[3-(propan-2-yl)-1,2,4-thiadiazol-5-yl]cyclopropyl}benzenesulfonamide, enantiomer A, and the second compound to elute 4-{trans-2-[3-(propan-2-yl)-1,2,4-thiadiazol-5-yl]cyclopropyl}benzenesulfonamide, enantiomer B, was the title compound. MS: m/z = 324.1 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 7.74 (d, J = 8.0 Hz, 2 H); 7.42 (d, J = 8.0 Hz, 2 H); 7.31 (s, 2H); 3.16-3.22 (m, 1 H); 3.09-3.14 (m, 1 H); 2.71-2.75 (m, 1 H); 1.80-1.85 (m, 2H); 1.30 (d, J = 6.9 Hz, 6 H). EXAMPLE 19 4-{(1R,2R)-2-[3-(5-Chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide Step A: 3-(5-Chloro-2 -methoxyphenyl)-5-(trans-2-phenylcyclopropyl)-1,2,4-oxadiazole

[0277] To a solution of trans-2-phenylcyclopropanecarboxylic acid (487 mg, 3.00 mmol) in 1,4-dioxane (10 mL) was added 1,1'-carbonyldiimidazole (535 mg, 3.30 mmol ). The reaction mixture was heated to 45 °C and allowed to stir for 2 h. 5-Chloro-N'-hydroxy-2-methoxybenzimidamide (Intermediate A1) (602 mg, 3.00 mmol) was then added and the reaction mixture heated to 100 ° C and allowed to stir for 18 h. The reaction mixture was allowed to cool and then it was 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 give the title compound. MS: m/z = 327.4 [M+H]. Step B: 4-{(1R,2R)-2-[3-(5-Chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide

[0278] A vial containing 3-(5-chloro-2-methoxyphenyl)-5-(trans-2-phenylcyclopropyl)-1,2,4-oxadiazole (732 mg, 2.24 mmol) at 0 °C was cold chlorosulfonic acid (3.00 mL, 44.8 mmol) was added. The reaction mixture was allowed to warm to room temperature and stir for 1 h. The reaction mixture was poured into ice water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were concentrated under reduced pressure, the residue dissolved in 1,4-dioxane (20 mL), and ammonium hydroxide (30%, 7.00 mL, 50.3 mmol) was added. The reaction mixture was allowed to stir for 2 h and then concentrated under reduced pressure. The residue was taken up in ethyl acetate (30 ml), washed with water (20 ml), dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes - 5:95 to 100:0 to give the title compound. MS: m/z = 406.2 [M+H]. The racemate was separated by SFC, using an AD-H ChiralPak column, eluting with methanol:carbon dioxide - 50:50. The first main peak for elution was 4-{(1S,2S)-2-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide and the second peak Main elution was 4-{(1R,2R)-2-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide, the title compound. MS: m/z = 406.2 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 7.82 (d, J = 2.7 Hz, 1 H); 7.75 (d, J = 8.5 Hz, 2 H); 7.61 (dd, J = 2.7, 9.0 Hz, 1 H); 7.48 (d, J = 8.5 Hz, 2 H); 7.33 (s, 2H); 7.27 (d, J = 9.0 Hz, 1 H); 3.89 (s, 3 H), 2.91 - 2.83 (m, 2 H); 1.91 - 1.84 (m, 2 H). EXAMPLE 20 4-((1R,3R)-3-(3-Cyclohexyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl) benzenesulfonamide

[0279] A solution of (1R,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 4) (162 mg, 0.602 mmol) in 1,4-dioxane (3 mL) was 1,1'-carbonyldiimidazole (107 mg, 0.660 mmol) was added. The reaction mixture was heated to 45 °C and allowed to stir for 2 h. N'-Hydroxycyclohexanecarboximidamide (85 mg, 0.600 mmol) was then added and the reaction mixture heated to 105 °C and allowed to stir for 4 h. The reaction mixture was cooled to room temperature and purified directly by silica gel chromatography, eluting with a gradient of ethyl acetate: ethanol: hexanes - 3:1:96 to 36:13:51 to produce the title compound. MS: m/z = 376.3 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 7.78 (d, J = 8.3 Hz, 2 H); 7.53 (d, J = 8.3 Hz, 2 H); 7.34 (s, 2H); 2.95 (d, J = 6.1 Hz, 1 H); 2.90 (d, J = 6.1 Hz, 1 H); 2.80 - 2.74 (m, 1 H); 1.93 (br d, J = 12 Hz, 2 H); 1.73 (br d, J = 13 Hz, 2 H); 1.65 (br d, J = 9.0 Hz, 1 H); 1.49 (br q, J = 12 Hz, 2 H); 1.37 (br q, J = 12 Hz, 2 H); 1.28 - 1.22 (m, 1 H); 1.26 (s, 3H); 0.96 (s, 3H). EXAMPLE 21 4-{(1S,3S)-2,2-Dimethyl-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]cyclopropyl} benzenesulfonamide Step A: (1S,3S)- 2,2-Dimethyl-N-(3-methyl-2-oxobutyl)-3-(4-sulfamoylphenyl) cyclopropanecarboxamide

[0280] To a solution of (1S,3S)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 5) (100 mg, 0.371 mmol) in dichloromethane (1.14 mL) and sodium sulfoxide dimethyl (124 μl) were added HATU (155 mg, 0.408 mmol), 1-amino-3-methylbutan-2-one hydrochloride (53.6 mg, 0.390 mmol) and N-methylmorpholine (122 μl, 1.11 mmol ). The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 15:85:0.1 to 95:5:0.1 to give the title compound. MS: m/z = 353.3 [M+H]. Step B:4-{(1S,3S)-2,2-Dimethyl-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]cyclopropyl}benzenesulfonamide

[0281] To a solution of (1S,3S)-2,2-dimethyl-N-(3-methyl-2-oxobutyl)-3-(4-sulfamoylphenyl)cyclopropanecarboxamide (95 mg, 0.27 mmol) in toluene (2.2 mL) and tetrahydrofuran (0.54 mL) Lawesson reagent (114 mg, 0.283 mmol) was added. The reaction mixture was heated to 100 °C and allowed to stir for 2 h. The reaction mixture was cooled, water added (10 mL), and the resulting mixture extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 15:85:0.1 to 95:5:0.1 and the product-containing fractions were concentrated under reduced pressure. The residue was taken up in methanol (5 mL) and treated with MP-carbonate. The mixture was allowed to stir for 20 min. The mixture was filtered and concentrated under reduced pressure to yield the title compound. MS: m/z = [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 7.75 (d, J = 8.0 Hz, 2 H); 7.49 (d, J = 8.0 Hz, 2 H); 7.41 (s, 1H); 7.30 (s, 2H); 3.18 (m, 1H); 2.93 (d, J = 6.1 Hz, 1 H); 2.81 (d, J = 6.1 Hz, 1 H); 1.27 (d, J = 6.8 Hz, 6 H); 1.16 (s, 3H); 0.92 (s, 3H). EXAMPLE 22 4-(2-Methyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl)benzenesulfonamide, diastereomer 4

[0282] To a solution of 2-methyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid, diastereomer 4 (Intermediate 15) (25 mg, 0.098 mmol) in 1,4-dioxane (0.5 mL) was added 1, 1'-carbonyldiimidazole (19.1 mg, 0.118 mmol) and the reaction mixture heated to 50 °C and allowed to stir for 2 h. N'-hydroxybenzimidamide (14.7 mg, 0.108 mmol) was then added and the reaction mixture heated to 120 °C and allowed to stir for 4 h. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure, and the resulting residue purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes - 5:95 to 50:50 to yield the title compound. MS: m/z = 356.2 [M+H]. 1H NMR (500 MHz, d6-DMSO): δ 7.99 (d, J = 6.4 Hz, 2 H); 7.79 (d, J = 8.2 Hz, 2 H); 7.63 - 7.55 (m, 5 H); 7.35 (s, 2H); 3.11 (dd, J = 9.8, 5.2 Hz, 1 H); 3.01 (t, J = 5.0 Hz, 1 H); 2.12 - 2.07 (m, 1 H); 1.00 (d, J = 6.1 Hz, 3 H). EXAMPLE 23 4-{(1R,2R)-2-[1-(3-Fluorobenzyl)-1H-pyrazol-3-yl]cyclopropyl} benzenesulfonamide

[0283] To a solution of N-[(dimethylamino)methylidene]-4-[(1R,2R)-2-(1H-pyrazol-3-yl)cyclopropyl]benzenesulfonamide (Intermediate 17) (25 mg, 0.079 mmol) in N,N-dimethylformamide (0.785 mL) at room temperature were added a solution of NaHMDS (1.0 M in tetrahydrofuran, 0.079 mL, 0.079 mmol) in toluene and 3-fluorobenzyl chloride (14 mg, 0.094 mmol) sequentially. The reaction mixture was allowed to stir for 18 h. The reaction mixture was concentrated under reduced pressure and the resulting residue treated with a hydrazine hydrate solution (28% in ethanol/water, 1.0 mL, 8.8 mmol) and allowed to stir for 1.5 h. The reaction mixture was concentrated under reduced pressure and the resulting residue purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 5:95:0.1 to 55:45:0.1 to generate the title compound. MS: m/z = 372.5 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 7.74 (s, 1 H); 7.69 (d, J = 8.1 Hz, 2 H); 7.38 (m, 1 H); 7.31 (d, J = 7.9 Hz, 2 H); 7.26 (s, 2H); 7.11 (m, 1H); 7.03 (m, 2H); 6.12 (s, 1 H); 5.27 (s, 2H); 2.25 (m, 2H); 1.45 (m, 2H). EXAMPLE 24 4-[trans-2-(2-Phenyl-1,3-oxazol-4-yl)cyclopropyl]benzenesulfonamide

[0284] To a solution of N-[(dimethylamino)methylidene]-4-[trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]benzenesulfonamide ( Intermediate 16) (30 mg, 0.079 mmol) in toluene (0.79 mL) were added 4-bromo-2-phenyloxazole (31 mg, 0.12 mmol), chloro[(di(1-adamantyl)-N-butylphosphine )-2-(2-aminobiphenyl)]palladium(II) (5.3 mg, 0.0079 mmol) and an aqueous solution of tribasic potassium phosphate (1 M, 0.238 mL, 0.238 mmol) sequentially. The reaction mixture was heated to 100 °C and allowed to stir for 18 h. The reaction mixture was diluted with ethyl acetate (3 mL), filtered through an SPE cartridge containing celite, and the filtrate concentrated under reduced pressure. The residue was treated with a hydrazine hydrate solution (37% in water/ethanol, 1.5 mL, 17.6 mmol) and allowed to stir for 1.5 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 20:80:0.1 to 60:40:0.1 to generate the title compound. . MS: m/z = 341.1 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 8.07 (s, 1 H); 7.95 (s, 2H); 7.23 (d, J = 7.9 Hz, 2 H); 7.53 (m, 3H); 7.37 (d, J = 8.3 Hz, 2 H); 7.28 (s, 2H); 6.12 (s, 1H); 5.27 (s, 2H); 2.54 (m, 2H); 1.45 (m, 2H); 2.42 (m, 1H); 2.32 (m, 1 H); 1.60 (m, 1 H), 1.50 (m, 1 H). EXAMPLE 25 4-[(1R,2R)-2-(2-Phenyl-1,3-thiazol-4-yl)cyclopropyl]benzenesulfonamide

[0285] To a solution of 4-[(1R,2R)-2-(2-chloroacetyl)cyclopropyl]benzenesulfonamide (Intermediate 18) (100 mg, 0.37 mmol) in ethanol (5 mL) was added benzenecarbothioamide (60 mg, 0.44 mmol) and the reaction mixture was heated to 60 °C and allowed to stir for 30 min. The reaction mixture was concentrated under reduced pressure and the resulting residue purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:ammonium hydroxide - 10:90:0.05 to 90:10:0.05 to produce the title compound. . MS: m/z = 357.1 [M+H]. 1H NMR (400 MHz, CD3OD): δ 7.90-7.92 (m, 2 H), 7.79 (d, J = 7.60 Hz, 2 H), 7.43-7.45 (m , 3 H), 7.33 (d, J = 8.8 Hz, 2 H), 7.19 (s, 1 H), 2.40-2.51 (m, 2 H), 1.66- 1.72 (m, 1 H), 1.56-1.62 (m, 1 H). EXAMPLE 26 4-{(1R,2R)-2-[1-(3-Fluorophenyl)-1H-1,2,3-triazol-4-yl]cyclopropyl} benzenesulfonamide

[0286] To a solution of 4-[(1R,2R)-2-ethynylcyclopropyl]benzenesulfonamide (Intermediate 19) (50 mg, 0.226 mmol) in methanol (2 mL) at room temperature was added copper(II) sulfate ( 7.2 mg, 0.045 mmol), sodium 2-(1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-3-olate (9.0 mg, 0.045 mmol) and 1-azido-3-fluorobenzene (31 mg, 0.23 mmol) sequentially. The reaction mixture was allowed to stir for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and the resulting residue purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:ammonium hydroxide - 26:74:0.05 to 56:44:0, 05 to produce the title compound. MS: m/z = 359.1 [M+H]. 1H NMR (400 MHz, CD3OD): δ 8.34 (s, 1 H); 7.83 (m, 4H); 7.32 (m, 4H); 2.47 (m, 1H); 2.42 (m, 1H); 1.69 (m, 1H); 1.59 (m, 1 H). EXAMPLE 27 4-[(1R,2R)-2-(2-Phenyl-1,3-thiazol-5-yl)cyclopropyl]benzenesulfonamide Step A:tert-Butyl[(4-{(1R,2R)-2-[( tert-butyl 2-oxo-2-phenylethyl)carbamoyl]cyclopropyl}phenyl)sulfonyl]carbamate

[0287] To a stirred mixture of tert-butyl[(4-{(1R,2R)-2-[(R)-glycyl]cyclopropyl}phenyl)sulfonyl]tert-butyl]carbamate (Intermediate 20) (125 mg, 0.304 mmol) and potassium carbonate (842 mg, 6.09 mmol) in ethyl acetate (5 mL) and water (5 mL) at room temperature benzoyl chloride (856 mg, 6.09 mmol) was added dropwise. The reaction mixture was allowed to stir for 10 min and then it was diluted with water (50 mL) and ethyl acetate (50 mL). The organic layer was separated and concentrated under reduced pressure. The residue was purified by thin layer chromatography on preparatory silica gel, eluting with ethyl acetate:petroleum ether - 50:50 to give the title compound. MS: m/z = 537.1 [M+Na]. Step B: tert-Butyl({4-[(1R,2R)-2-(2-phenyl-1,3-thiazol-5-yl)cyclopropyl] phenyl}sulfonyl)carbamate

[0288] To a stirred solution of tert-butyl[(4-{(1R,2R)-2-[(R)-N-(phenylcarbonyl)glycyl]cyclopropyl}phenyl)sulfonyl]carbamate tert-butyl (92 mg , 0.18 mmol) in toluene (3 mL) at room temperature was added Lawesson's reagent (72.3 mg, 0.179 mmol). The reaction mixture was heated to 70 °C and allowed to stir for 1 h. The solvent was removed under reduced pressure to produce the title compound in sufficient purity for use in the next step. MS: m/z = 513.2 [M+H]. Step C 4-[(1R,2R)-2-(2-Phenyl-1,3-thiazol-5-yl)cyclopropyl]benzenesulfonamide

[0289] To a solution of tert-butyl({4-[(1R,2R)-2-(2-phenyl-1,3-thiazol-5-yl)cyclopropyl]phenyl}sulfonyl) tert-butylcarbamate ( 92 mg, 0.18 mmol) in dichloromethane (1 mL) at room temperature was added trifluoroacetic acid (2.00 mL, 26.0 mmol) dropwise. The reaction mixture was allowed to stir for 1 h. The reaction mixture was concentrated under reduced pressure and saturated aqueous sodium bicarbonate (10 mL) and dichloromethane (5 mL) were added. The combined organic extracts were washed with saturated aqueous sodium chloride (15 mL), dried (magnesium sulfate), and concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:ammonium hydroxide - 10:90:0.05 to 90:10:0.05 to produce the title compound. MS: m/z = 357.1 [M+H]. 1H NMR (CD3OD, 400MHz): δ 7.83 (m, 4 H); 7.61 (s, 1 H); 7.44 (m, 3H); 7.33 (d, J = 8.4 Hz, 2 H); 2.52 (m, 1 H); 2.39 (m, 1 H); 1.67 (m, 1H); 1.61 (m, 1 H). EXAMPLE 28 4-[(1R,2R)-2-(2-Cyclohexyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide Step A: tert-Butyl[(4-{(1R,2R)-2- tert-butyl [(R)-N-(cyclohexylcarbonyl)glycyl]cyclopropyl}phenyl)sulfonyl]carbamate

[0290] To a stirred mixture of tert-butyl[(4-{(1R,2R)-2-[(R)-glycyl]cyclopropyl}phenyl)sulfonyl]tert-butyl]carbamate (Intermediate 20) (300 mg, 0.73 mmol) and potassium carbonate (2.02 g, 14.6 mmol) in ethyl acetate (5 mL) and water (5 mL) at room temperature cyclohexanecarbonyl chloride (2.14 g, 14.6 mmol) in drops. The mixture was allowed to stir for 10 min, then diluted with water (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 50:50 to yield the title compound. MS: m/z = 543.0 [M+Na]. Step B: N-tert-Butyl-4-[(1R,2R)-2-(2-cyclohexyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide

[0291] To a stirred solution of tert-butyl[(4-{(1R,2R)-2-[(R)-N-(cyclohexylcarbonyl)glycyl]cyclopropyl}phenyl)sulfonyl]tert-butylcarbamate ( 120 mg, 0.23 mmol) in tetrahydrofuran (1 mL) at room temperature was added phosphoryl chloride (0.64 mL, 6.9 mmol) dropwise. The mixture was heated to 70 °C and allowed to stir for 1 h. Saturated aqueous sodium bicarbonate (10 mL) was added and the resulting mixture extracted with ethyl acetate (5 mL). The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure to yield the title compound in sufficient purity for use in the next step. MS: m/z = 543.0 [M+H]. Step C:4-[(1R,2R)-2-(2-Cyclohexyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide

[0292] To a stirred solution of N-tert-butyl-4-[(1R,2R)-2-(2-cyclohexyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide (90 mg, 0 .22 mmol) in dichloromethane (1 mL) at room temperature trifluoroacetic acid (2.0 mL, 26.0 mmol) was added dropwise. The mixture was heated to 30 °C and allowed to stir for 1 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with saturated aqueous sodium bicarbonate (10 ml) and dichloromethane (5 ml). The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:ammonium hydroxide - 10:90:0.05 to 90:10:0.05 to yield the title compound MS: m/z = 347.2 [M+H]. 1H NMR (400 MHz, CD3OD): δ 7.81 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 8.4 Hz, 2 H), 6.77 (s, 1 H), 2.76- 2.78 (m, 1 H), 2.33-2.39 (m, 2 H), 2.01-2.03 (m, 2 H), 1.80- 1.83 (m, 2 H), 1.71-1.74 (m, 1 H), 1.49-1.58 (m, 4 H), 1.26-1.47 (m, 3 H ). EXAMPLE 29 4-{(1R,2R)-2-[5-(Piperidin-1-yl)-1,2,4-thiadiazol-3-yl]cyclopropyl} benzenesulfonamide Step A:4-[(1R,2R)-2 -(5-Oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)cyclopropyl]benzenesulfonamide

[0293] To a stirred mixture of (1R,2R)-N'-hydroxy-2-(4-sulfamoylphenyl)cyclopropanecarboximidamide (Intermediate 22) (0.83 g, 3.25 mmol) in tetrahydrofuran (33 mL) at room temperature di-1H-imidazol-1-ylmethanethione (0.869 g, 4.88 mmol) was added. The reaction mixture was allowed to stir for 30 min. Water (25 mL) was added and the resulting mixture extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (33 mL) and boron trifluoride diethyl etherate (3.29 mL, 25.9 mmol) was added dropwise. The reaction mixture was allowed to stir for 6 h. Water (25 mL) was added and the resulting mixture extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (15 mL), dried (sodium sulfate), and concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 5:95:0.1 to 95:5:0.1 to generate the title compound. MS: m/z = 298.0 [M+H]. Step B 4-[(1R,2R)-2-(5-Chloro-1,2,4-thiadiazol-3-yl)cyclopropyl]benzenesulfonamide

[0294] To a stirred mixture of 4-[(1R,2R)-2-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)cyclopropyl]benzenesulfonamide (157 mg , 0.528 mmol) in acetonitrile (4.64 mL) at room temperature was added phosphorus oxychloride (2.00 mL, 21.5 mmol). The reaction mixture was heated to 100 °C and allowed to stir for 2 h. The reaction mixture was cooled and added dropwise to a cold saturated aqueous sodium bicarbonate solution (30 mL). The resulting mixture was extracted with ethyl acetate (5 x 20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (30 mL) and saturated aqueous sodium chloride (30 mL), dried (sodium sulfate) 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 give the title compound. MS: m/z = 316.0 [M+H]. Step C 4-{(1R,2R)-2-[5-(Piperidin-1-yl)-1,2,4-thiadiazol-3-yl]cyclopropyl}benzenesulfonamide

[0295] To a solution of 4-[(1R,2R)-2-(5-chloro-1,2,4-thiadiazol-3-yl)cyclopropyl]benzenesulfonamide (20 mg, 0.063 mmol) in tetrahydrofuran ( 0.2 mL) at room temperature piperidine (31 μL, 0.32 mmol) was added. The reaction mixture was allowed to stir for 1 h. The reaction mixture was purified directly by silica gel chromatography, eluting with a gradient of ethyl acetate:hexanes - 0:100 to 70:30 to yield the title compound. MS: m/z = 365.2 [M+H]. 1H NMR (600 MHz, CD3OD): δ 7.80 (d, J = 8.1 Hz, 2 H), 7.31 (d, J = 8.2 Hz, 2 H), 3.50 (d, J = 5.5 Hz, 4 H), 3.32 (br s, 1 H), 2.56-2.59 (m, 1 H), 2.31-2.34 (m, 1 H), 1.74-1.78 (m, 1 H), 1.68-1.70 (m, 5 H), 1.48-1.51 (m, 1 H). EXAMPLE 30 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]phenyl sulfamate Step A: ({4-[trans-2,2-Dimethyl- tert-butyl 3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]phenoxy}sulfonyl)carbamate

[0296] To a solution of 4-[trans-2,2-dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]phenol (Intermediate 23) (30 mg, 0.098 mmol ) in dichloromethane (3 mL) at room temperature were added triethylamine (0.14 mL, 0.98 mmol) and tert-butyl (chlorosulfonyl)carbamate (106 mg, 0.492 mmol). The reaction mixture was allowed to stir for 30 min. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (2 x 5 mL). The combined organic extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure to yield the title compound. MS: m/z = 386.1 [M+H-CO2C(CHs)3]. Step B:4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]phenyl sulfamate

[0297] To a solution of tert-butyl ({4-[trans-2,2-dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]phenoxy}sulfonyl)carbamate (30 mg, 0.062 mmol) in dichloromethane (2 mL) at room temperature was added trifluoroacetic acid (2.00 mL, 26.0 mmol). The reaction mixture was allowed to stir for 3 h. A saturated aqueous solution of sodium bicarbonate (10 mL) was added and the aqueous layer extracted with dichloromethane (3 x 10 mL). The combined organic extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:ammonium hydroxide - 50:50:0.05 to 80:20:0.05 to yield the title compound. MS: m/z = 386.0 [M+H]. 1H NMR (400 MHz, CDCl3): δ 8.06-8.08 (m, 2 H), 7.47-7.50 (m, 3 H), 7.28-7.29 (m, 4 H ), 5.03 (br s, 2 H), 3.01 (d, J = 6.0 Hz, 1 H), 2.53 (d, J = 6.4 Hz, 1 H), 1.41 (s, 3 H), 1.05 (s, 3 H). EXAMPLE 31 4-[(1R,3R)-3-(4,5-Dicyclopropyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl] benzenesulfonamide Step A: tert-butyl[(4-{(1R, tert-butyl 3R)-3-[(1,2-dicyclopropyl-2-oxoethyl)carbamoyl]-2,2-dimethylcyclopropyl}phenyl)sulfonyl]carbamate

[0298] To a stirred solution of (1R,3R)-3-{4-[(tert-butoxycarbonyl)(tert-butyl)sulfamoyl]phenyl}-2,2-dimethylcyclopropanecarboxylic acid (Intermediate 8) (50 mg, 0.117 mmol) in dichloromethane (2 mL) at room temperature were added HATU (89 mg, 0.24 mmol) and triethylamine (0.049 mL, 0.35 mmol). 2-Amino-1,2-dicyclopropylethanone (49 mg, 0.14 mmol) was added and the reaction mixture was heated to 30 °C and allowed to stir for 30 min. The reaction mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 33:67 to give the title compound. MS: m/z = 547.1 [M+H]. Step B: tert-Butyl({4-[(1R,3R)-3-(4,5-dicyclopropyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]phenyl}sulfonyl)carbamate - butyl

[0299] To a solution of tert-butyl[(4-{(1R,3R)-3-[(1,2-dicyclopropyl-2-oxoethyl)carbamoyl]-2,2-dimethylcyclopropyl}phenyl)sulfonyl]carbamate tert-butyl (40 mg, 0.073 mmol) in tetrahydrofuran (2 mL) at room temperature was added phosphorus oxychloride (0.068 mL, 0.73 mmol). The reaction mixture was heated to 70 °C and allowed to stir for 2 h. The reaction mixture was concentrated under reduced pressure to produce the title compound in sufficient purity for use in the next step. MS: m/z = 529.3 [M+H]. Step C 4-[(1R,3R)-3-(4,5-Dicyclopropyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide

[0300] To a solution of tert-butyl((4-((1R,3R)-3-(4,5-dicyclopropyloxazol-2-yl)-2,2-dimethylcyclopropyl)phenyl)sulfonyl) tert-butylcarbamate (40 mg, 0.076 mmol) in dichloromethane (2 mL) at room temperature was added trifluoroacetic acid (2 mL, 26.0 mmol). The reaction mixture was heated to 30 °C and allowed to stir for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:ammonium hydroxide - 10:90:0.05 to 90:10:0.05 to yield the title compound. . MS: m/z = 373.2 [M+H]. 1H NMR (400 MHz, CD3OD): δ 7.83 (d, J = 8.4 Hz, 2 H), 7.41 (d, J = 8.4 Hz, 2 H), 2.76 (d, J = 6.4 Hz, 1 H), 2.42 (d, J = 6.0 Hz, 1 H), 1.95-1.97 (m, 1 H), 1.81-1.83 ( m, 1 H), 1.17 (s, 3 H), 0.94-0.96 (m, 2 H), 0.92 (s, 3 H), 0.81-0.86 (m, 4 H), 0.74-0.76 (m, 2 H). EXAMPLE 32 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]-2-fluorobenzenesulfonamide, enantiomer A Step A:N-({[trans-3 -(3-Fluoro-4-sulfamoylphenyl)-2,2-dimethylcyclopropyl]carbonyl}oxy)benzenecarboximidamide

[0301] To a stirred solution of methyl trans-3-(2-fluoro-4-sulfamoylphenyl)-2,2-dimethylcyclopropanecarboxylate (Intermediate 25) (130 mg, 0.431 mmol) in methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) lithium hydroxide (181 mg, 4.31 mmol) was added and the reaction mixture was allowed to stir for 16 h. The reaction mixture was concentrated under reduced pressure and water (30 mL) was added. The resulting mixture was adjusted to pH 5 by adding an aqueous HCl solution (1 M) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 mL), HATU (160 mg, 0.421 mmol), and diisopropylethylamine (0.201 mL, 1.15 mmol) was added, and the reaction mixture was allowed to stir for 10 min. N-Hydroxybenzimidamide (104 mg, 0.766 mmol) was added and the reaction mixture was allowed to stir for 2 h. The reaction mixture was concentrated under reduced pressure to produce the title compound in sufficient purity for use in the next step. MS: m/z = 406.2 [M+H]. Step B: 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]-2-fluorobenzenesulfonamide, enantiomer A

[0302] A solution of N-({[trans-3-(3-fluoro-4-sulfamoylphenyl)-2,2-dimethylcyclopropyl]carbonyl}oxy)benzenecarboximidamide (125 mg, 0.308 mmol) in N,N-dimethylformamide ( 3 mL) was heated to 100 °C and allowed to stir for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:ammonium hydroxide - 40:60:0.05 to 70:30:0.05, to produce the title compound. The racemate was separated by SFC, using an AD-H ChiralPak column, eluting with a gradient of ethanol:CO2:ammonium hydroxide - 40:60:0.1 to 100:0:0.1. The first major peak for elution was 4-[2,2-dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]-2-fluorobenzenesulfonamide, enantiomer A, the title compound. MS: m/z = 388.0 [M+H]. 1H NMR (400 MHz, CD3OD): δ 8.04-8.06 (m, 2 H), 7.86 (app t, J = 4.2 Hz, 1 H), 7.51-7.54 ( m, 3 H), 7.28-7.33 (m, 2 H), 3.10 (d, J = 5.6 Hz, 1 H), 2.89 (d, J = 6.4 Hz, 1 H), 1.40 (s, 3 H), 1.08 (s, 3 H). EXAMPLE 33 5-(trans-2,2-Dimethyl-3-(4-(methylsulfonyl)phenyl)cyclopropyl)-3-phenyl-1,2,4-oxadiazole Step A: 5-(trans-2,2-Dimethyl-3 -(4-(methylthio)phenyl)cyclopropyl)-3-phenyl-1,2,4-oxadiazole

[0303] To a stirred solution of methyl trans-2,2-dimethyl-3-(4-(methylthio)phenyl)cyclopropanecarboxylate (Intermediate 28) (750 mg, 3.00 mmol) in methanol (9 mL) and water (3 mL) at room temperature was added sodium hydroxide (240 mg, 5.99 mmol). The reaction mixture was heated to 50 °C and allowed to stir for 5 h. The reaction mixture was cooled, concentrated under reduced pressure, and the mixture was adjusted to pH ~ 3 by adding an aqueous HCl solution (3 M). The aqueous layer was extracted with ethyl acetate (3 x 15 mL) and the combined organic extracts were dried (sodium sulfate), filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 mL) at room temperature and triethylamine (0.35 mL, 2.54 mmol), HATU (354 mg, 0.93 mmol) and N-hydroxybenzimidamide (173 mg, 1 .27 mmol) were added. The reaction mixture was allowed to stir for 20 min, heated to 100 °C, and allowed to stir for 3 h. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were dried (sodium sulfate), filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate:petroleum ether - 10:90, to produce the title compound. MS: m/z = 337.1 [M+H]. Step B: 5-(trans-2,2-Dimethyl-3-(4-(methylsulfonyl)phenyl)cyclopropyl)-3-phenyl-1,2,4-oxadiazole

[0304] To a stirred solution of 5-(trans-2,2-dimethyl-3-(4-(methylthio)phenyl)cyclopropyl)-3-phenyl-1,2,4-oxadiazole (50 mg, 0.15 mmol) in dichloromethane (1 mL) at room temperature m-CPBA (80%, 51.3 mg, 0.30 mmol) was added and the reaction mixture was allowed to stir for 1 h. A saturated aqueous sodium sulfite solution (1 mL) and a saturated aqueous potassium carbonate solution (1 mL) were added and the aqueous layer was extracted with dichloromethane (3 x 5 mL). The combined organic extracts were dried (sodium sulfate), filtered and the filtrate concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:ammonium hydroxide - 45:55:0.05 to 75:25:0.05, to generate the title compound. MS: m/z = 369.0 [M+H]. 1H NMR (400 MHz, CD3OD): δ 8.03-8.08 (m, 2 H); 7.93 (d, J = 8.4 Hz, 2 H); 7.60 (d, J = 8.2 Hz, 2 H); 7.48-7.56 (m, 3H); 3.11-3.15 (m, 4H); 2.90 (d, J = 6.2 Hz, 1 H); 1.42 (s, 3H); 1.06 (s, 3 H). EXAMPLE 34 4-(trans-3-(5-Cyclopentilisoxazol-3-yl)-2,2-dimethylcyclopropyl) benzenesulfonamide

[0305] To a stirred solution of 4-(trans-3-((hydroxy-imino)methyl)-trans-2,2-dimethylcyclopropyl)benzenesulfonamide (Intermediate 37) (75 mg, 0.28 mmol) and ethinylcyclopentane (52 .6 mg, 0.559 mmol) in methanol (2.4 mL) and water (0.6 mL) at room temperature was added [bis(trifluoroacetoxy)iodo]benzene (240 mg, 0.56 mmol) and allowed to the reaction mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure and the residue purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 47:53:0.1 to 67:33:0.1, to generate the title compound. MS: m/z = 361.1 [M+H]. 1H NMR (400 MHz, CD3OD): δ 7.85 (d, J = 8.0 Hz, 2 H); 7.44 (d, J = 8.0 Hz, 2 H); 6.16 (s, 1 H); 3.19-3.28 (m, 1 H); 2.66 (d, J = 6.0 Hz, 1 H); 2.42 (d, J = 6.4 Hz, 1 H); 2.10 (d, J = 6.0 Hz, 2 H); 1,671.84 (m, 6H); 1.17 (s, 3H); 0.96 (s, 3H). EXAMPLE 35 4-{(1S,3S)-3-[2-(3-Fluorophenyl)-1-methyl-1H-imidazol-4-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide Step A: tert-Butyl((4- tert-butyl ((1S,3S)-3-(2-(3-fluorophenyl)-1H-imidazol-5-yl)-2,2-dimethylcyclopropyl)phenyl)sulfonyl)carbamate

[0306] To a stirred solution of tert-butyl((4-((1S,3S)-3-(2-chloroacetyl)-2,2-dimethylcyclopropyl)phenyl)sulfonyl) tert-butylcarbamate (Intermediate 29) ( 100 mg, 0.22 mmol) in N,N-dimethylformamide (3 mL) 3-fluorobenzimidamide (39.2 mg, 0.28 mmol) and DIEA (0.11 mL, 0.66 mmol) were added. The reaction mixture was heated to 80 °C and allowed to stir for 20 min. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (10 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure to yield the title compound in sufficient purity for use in the next step. MS: m/z = 542.7 [M+H]. Step B 4-((1S,3S)-3-(2-(3-Fluorophenyl)-1H-imidazol-5-yl)-2,2-dimethylcyclopropyl)benzenesulfonamide

[0307] To a stirred solution of tert-butyl((4-((1S,3S)-3-(2-(3-fluorophenyl)- 1H-imidazol-5-yl)-2,2-dimethylcyclopropyl)phenyl) tert-butylsulfonyl)carbamate (30 mg, 0.055 mmol) in dichloromethane (2 mL) at room temperature was added trifluoroacetic acid (2 mL, 0.055 mmol) and the reaction mixture was allowed to stir for 2 h. The reaction mixture was concentrated under reduced pressure and the residue purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:ammonium hydroxide - 40:60:0.05 to 70:30:0.05, to generate the title compound. . MS: m/z = 386.0 [M+H]. 1H NMR (400 MHz, CD3OD): δ 7.85 (d, J = 8.2 Hz, 2 H); 7.67-7.69 (m, 1 H); 7.60-7.63 (m, 1 H); 7.42-7.49 (m, 3H); 7,077.12 (m, 1H); 6.96 (s, 1H); 2.50 (d, J = 6.3 Hz, 1 H); 2.41 (d, J = 6.3 Hz, 1 H); 1.13 (s, 3H); 0.97 (s, 3H). Step C: tert-butyl[(4-{(1S,3S)-3-[2-(3-fluorophenyl)-1-methyl-1H-imidazol-5-yl]-2,2-dimethylcyclopropyl}phenyl)sulfonyl ]tert-butyl and tert-butyl carbamate[(4-{(1S,3S)-3-[2-(3-fluorophenyl)-1-methyl-1H-imidazol-4-yl]-2,2 dimethylcyclopropyl} tert-butyl phenyl)sulfonyl]carbamate

[0308] To a stirred solution of tert-butyl((4-((1S,3S)-3-(2-(3-fluorophenyl)- 1H-imidazol-5-yl)-2,2-dimethylcyclopropyl)phenyl) tert-butylsulfonyl)carbamate (30 mg, 0.055 mmol) in N,N-dimethylformamide (2 mL) at room temperature were added potassium carbonate (15.3 mg, 0.11 mmol) and iodomethane (11.8 mg , 0.083 mmol) and the reaction mixture was allowed to stir for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (10 mL), dried (sodium sulfate), filtered, and the filtrate concentrated under reduced pressure to yield the title compounds in sufficient purity for use in the next step. MS: m/z = 556.7 [M+H]. Step D: 4-{(1S,3S)-3-[2-(3-Fluorophenyl)-1-methyl-1H-imidazol-4-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide

[0309] To a stirred solution of tert-butyl[(4-{(1S,3S)-3-[2-(3-fluorophenyl)-1-methyl-1H-imidazol-5-yl]-2,2- tert-butyl dimethylcyclopropyl}phenyl)sulfonyl]carbamate and tert-butyl[(4-{(1S,3S)-3-[2-(3-fluorophenyl)-1-methyl-1H-imidazol-4-yl]- tert-Butyl 2,2-dimethylcyclopropyl}phenyl)sulfonyl]carbamate (30 mg, 0.054 mmol) in dichloromethane (2 mL) at room temperature was added trifluoroacetic acid (2 mL, 0.055 mmol) and the reaction mixture was allowed to was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with methanol:dichloromethane - 9:91, and then by preparatory HPLC, eluting with a gradient of acetonitrile:water:ammonium hydroxide - 30:70:0.05 to 60:40:0.05, to generate the title compound. MS: m/z = 400.0 [M+H]. 1H NMR (400 MHz, CD3OD): δ 7.85 (d, J = 8.2 Hz, 2 H); 7.50-7.58 (m, 1 H); 7.43-7.49 (m, 3H); 7.39-7.42 (m, 1 H); 7.18-7.26 (m, 1 H); 7.04 (s, 1H); 3.75 (s, 3H); 2.47 (d, J = 6.3 Hz, 1 H); 2.38 (d, J = 6.7 Hz, 1 H); 1.15 (s, 3H); 0.96 (s, 3H). EXAMPLE 36 4-{trans-2,2-Dichloro-3-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide

[0310] To a stirred solution of trans-2,2-dichloro-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid (Intermediate 30) (20 mg, 0.064 mmol) in dichloromethane (1 mL) at room temperature was added oxalyl dichloride (16.37 mg, 0.13 mmol) and N,N-dimethylformamide (0.00050 mL, 0.00645 mmol) and the reaction mixture was allowed to stir for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (2 mL) at room temperature, triethylamine (0.018 mL, 0.13 mmol) and 3-fluoro-N'-hydroxybenzimidamide (19.89 mg, 0.13 mmol) were added, and allowed to stir the reaction mixture for 10 min. Water (5 mL) was added and the aqueous layer was extracted with ethyl acetate (2 x 5 mL). The combined organic extracts were dried (sodium sulfate), filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1 mL), heated to 100 °C and allowed to stir for 10 h. The reaction mixture was cooled to room temperature and purified by preparatory HPLC, eluting with a gradient of acetonitrile: water: trifluoroacetic acid - 43:57:0.1 to 73:27:0.1, to generate the title compound. MS: m/z = 427.8 [M+H]. 1H NMR (400 MHz, CDCl3): δ 7.95-7.97 (m, 2 H); 7.81-7.83 (m, 1 H); 7.79-7.80 (m, 1 H); 7.42-7.51 (m, 3H); 7.15-7.20 (m, 1 H); 4.90 (s, 2H); 3.89 (d, J = 8.4 Hz, 1 H); 3.48 (d, J = 8.4 Hz, 1 H). EXAMPLE 37 4-{(1R,2R)-2-[5-(Piperidin-1-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl} benzenesulfonamide Step A: N-[(Dimethylamino)methylidene]-4 -{(1R,2R)-2-[5-(piperidin-1-yl)- 1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide

[0311] A mixture of (1R,2R)-2-(4- {[(dimethylamino)methylidene]sulfamoyl}phenyl)-N'-hydroxycyclopropanecarboximidamide (Intermediate 31) (50 mg, 0.161 mmol), 1-piperidinecarbonitrile (11 .9 mg, 0.108 mmol) and zinc(II) chloride (22.0 mg, 0.161 mmol) in N,N-dimethylformamide (5 mL) was heated to 80 °C and allowed to stir for 2 h. To the resulting mixture was added 4-toluenesulfonic acid monohydrate (30.6 mg, 0.161 mmol) and the reaction mixture was heated to 85 ° C and allowed to stir for 1 h. The reaction mixture was cooled and then diluted with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (20 ml), dried (sodium sulfate) and concentrated under reduced pressure to give the title compound. MS: m/z = 404.1 [M+H]. Step B 4-{(1R,2R)-2-[5-(Piperidin-1-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide

[0312] To a stirred solution of N-[(dimethylamino)methylidene]-4-{(1R,2R)- 2-[5-(piperidin-1-yl)-1,2,4-oxadiazol-3-yl ]cyclopropyl}benzenesulfonamide (20 mg, 0.050 mmol) in tetrahydrofuran (2 mL) at room temperature was added hydrazine hydrate (2.5 mg, 0.050 mmol). The reaction mixture was allowed to stir for 30 min then water (5 mL) was added and the resulting mixture extracted with ethyl acetate (3 x 5 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid - 15:85:0.1 to 95:5:0.1, and the product-containing fractions were concentrated under reduced pressure to yield the compound title. MS: m/z = 349.1 [M+H]. 1H NMR (400 MHz, CD3OD): δ 7.81 (d, J = 8.4 Hz, 2 H); 7.33 (d, J = 8.4 Hz, 2 H); 3.55-3.58 (m, 4H); 2.53 (m, 1H); 2.19 (m, 1 H); 1.63-1.68 (m, 7H); 1.54 (m, 1 H). EXAMPLE 38 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]-3-methylbenzenesulfonamide, enantiomer A Step A:trans-2,2-dimethyl acid -3-(2-methyl-4-sulfamoylphenyl)cyclopropanecarboxylic acid

[0313] To a stirred solution of methyl trans-2,2-dimethyl-3-(2-methyl-4-sulfamoylphenyl)cyclopropanecarboxylate (Intermediate 32) (110 mg, 0.370 mmol) in methanol (2 mL), tetra- hydrofuran (2 mL), and water (1 mL) at room temperature, lithium hydroxide (155 mg, 4.31 mmol) was added and the reaction mixture was allowed to stir for 16 h. The reaction mixture was concentrated under reduced pressure, water (30 mL) was added, and the aqueous layer adjusted to pH ~ 5 by addition of an aqueous HCl solution (1 M).

[0314] The mixture was extracted with ethyl acetate (3 x 30 mL), the combined organic extracts washed with saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under pressure reduced to generate the title compound in sufficient purity for use in the next step. Step B: 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]-3-methylbenzenesulfonamide, enantiomer A

[0315] To a stirred solution of trans-2,2-dimethyl-3-(2-methyl-4-sulfamoylphenyl)cyclopropanecarboxylic acid (103 mg, 0.364 mmol) in N,N-dimethylformamide (3 mL) at room temperature were HATU (138 mg, 0.364 mmol) and DIEA (0.190 mL, 1.091 mmol) were added and the reaction mixture was allowed to stir for 10 min. N-Hydroxybenzimidamide (99 mg, 0.73 mmol) was added and the reaction mixture was allowed to stir for 2 h. The reaction mixture was then heated to 100 °C and allowed to stir for 5 h. The reaction mixture was cooled to room temperature and purified by preparatory HPLC, eluting with a gradient of acetonitrile: water: ammonium hydroxide - 30:70:0.05 to 60:40:0.05 to generate the racemic title compound. The racemate was separated by SFC, using an IC column, eluting with ethanol:CO2:ammonium hydroxide - 45:55:0.1 to 100:0:0.1. The first major peak for elution was 4-[trans-2,2-dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]-3-methylbenzenesulfonamide, enantiomer A, the title compound . MS: m/z = 384.0 [M+H]. 1H NMR (400 MHz, CD3OD): δ 8.04-8.09 (m, 2 H), 7.78 (s, 1 H), 7.72 (d, J = 8.02 Hz, 1 H) , 7.50-7.56 (m, 3 H), 7.39 (d, J = 8.22 Hz, 1 H), 3.00 (d, J = 6.06 Hz, 1 H), 2 .85 (d, J = 6.26 Hz, 1 H), 2.48 (s, 3 H), 1.47 (s, 3 H), 0.99 (s, 3 H).

[0316] The examples appearing in the following tables were prepared in analogy to the examples above, as described or prepared as a result of similar transformations with modifications known to those skilled in the art. The required starting materials have been described in this document, are commercially available, known in the literature or readily synthesized by one skilled in the art. Simplified protecting group strategies were applied in some pathways.

[0317] The usefulness of the compounds according to the present invention as positive allosteric modulators of α7 nicotinic acetylcholine receptor activity can be demonstrated by methodology known in the art. The direct activation of α7 (agonism) and the potentiation of α7 currents caused by acetylcholine were determined as follows:

FUNCTIONAL TEST OF AUTOMATED ELECTROPHYSIOLOGY BY PATCH-CLAMP OF ION CHANNELS (TEST A)

[0318] Automated patch-clamp electrophysiology of ion channels was performed using the IonFlux HT (Fluxion Biosciences Inc., San Francisco, CA) in the whole cell population patch configuration. Test compounds were analyzed for their ability to modulate the function of the α7 nicotinic acetylcholine receptor in both the presence and absence of the natural α7 acetylcholine agonist. A HEK cell line stably expressing both human RIC-3 and human α7 (PreciSION hnAChR α7/RIC-3, Eurofins Pharma, St. Charles, MO) was grown in 175 cm triple-layer tissue culture flasks to prevent greater 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 before the assay, cells were detached by first aspirating the growth media, rinsing with phosphate-buffered Dulbecco's saline, and then adding 10 ml of Accutase (Innovative Cell Technologies, San Diego, CA, USA) to the vial and then incubation at 37 °C for 5 minutes. Detached cells were then recovered by adding 40 ml of CHO serum-free media supplemented with 25 mM HEPES, and moderately shaking in a 50 ml conical tube for 20 min before ion channel patch-clamp assay. After recovery, cells were pelleted by centrifugation at 1,000 RPM for 1 minute in a compact tabletop centrifuge; recovery media were 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 x 106 cells/ml. The cell suspension was added to the cell entry wells on an IonFlux HT population patch plate that had been previously 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; The 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 in the IonFlux HT patch plate previously loaded with cells and test compounds, and the plate loaded into the IonFlux HT instrument. A protocol was run on the IonFlux HT to trap cells, disrupt cells, and establish the whole-cell recording setup; 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 (55.2 kPa) for solution applications. . Upon establishment of the whole cell configuration, the external recording solution was perfused into the recording chambers for 120 seconds and then 40 μM acetylcholine was applied for 1 second and immediately removed by washing with the external recording solution for 60 seconds. . The α7 current elicited by 40 μM acetylcholine served as the current response to which the subsequent effects of the test compound, in the presence or absence of 40 μM acetylcholine, would be relatively quantified. 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 an ascending dose manner by recording. To analyze the agonist activity of test compound, the test compound diluted in external recording solution was applied starting from the lowest concentration of test compound that is tested in the concentration series, for 58 seconds; wherein the first 20 seconds of the 58 second compound application period coincided with a data collection sweep that was 20 seconds long, and was collected at a rate of 5,000 samples/second. To analyze the positive allosteric modulator activity of test compound, immediately after the 58 second application period of test compound alone, 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 the potentiating effects of test compounds observed. The 1-second application of the test compound diluted in external solution containing 40 μM acetylcholine coincided with a data collection sweep that was 20 seconds long, and was collected at a rate of 5,000 samples/second, after which the solution external registration was only applied for 42 seconds. After this 42 second wash with external recording solution only, the next highest concentration of 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 the positive allosteric modulator and agonist activities of the test compound were analyzed at three ascending concentrations, the experiment was terminated and flow subtraction performed using IonFlux HT data analysis software. Peak current amplitudes and area under the curve (AUC) were both quantified for each current sweep with the use of particular software and test compound effects where quantified as follows.

[0319] The agonist activity of the test compound was calculated as: % Agonism = (Y/X) x 100 The potentiating activity of the test compound was calculated as: % Potentiation = [(Z/X) x 100] - 100 ) caused by test compound diluted in external recording solution containing 40 μM acetylcholine

[0320] As such, test compounds that elicited the same current amplitude as 40 μM acetylcholine alone would exhibit a calculated % agonism of 100%. Test compounds co-applied with 40 μM acetylcholine that elicited a current amplitude 2x the current elicited by 40 μM acetylcholine alone would exhibit a calculated % Potentiation of 100%, whereas test compounds co-applied with 40 μM acetylcholine that elicited the same current amplitude as 40 μM acetylcholine alone would be characterized as not exhibiting potentiation.

[0321] Agonism and potentiation data, derived by peak current amplitude or area under the curve (AUC) were graphed and fitted using 4-parameter logic tuning based on the Levenberg-Marquardt algorithm in which y = A + ((B-A)/(1+((C/x)AD))) where: A = Minimum B = Maximum C = EC50 D = Angular coefficient x = Concentration of test compound y = % Agonism or % Empowerment

[0322] Potency data for selected compounds of the present invention in the patch-clamp automated electrophysiology functional assay (Assay A) are represented in the table below: *Potency defined as A (EC50 < 0.1 μM); B (0.1 μM < EC50 < 0.5 μM); C (0.5 μM < EC50 < 5 μM); D (5 μM < EC50 < 50 μM)

[0323] Electrophysiology EC50 values for selected compounds of the present invention in the patch-clamp automated electrophysiology functional assay (Assay A) are provided in the table below:

[0324] It will be appreciated that several of the features and functions discussed above and other features and functions, or alternatives thereto, may desirably be combined in many other different systems or applications. Furthermore, these various alternatives, modifications, variations or improvements not presently foreseen or not anticipated therein may subsequently be made by those skilled in the art which are also intended to be covered by the following claims.

Claims (14)

1. Compound or a pharmaceutically acceptable salt thereof, characterized by the fact that it has formula I: where: X is selected from Y is selected from hydrogen, (C1-C4)alkyl and halogen; A is a 5-membered heteroaryl ring selected from: wherein each is substituted with 1 to 3 R groups independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, piperidinyl, pyridinyl, cyclopropylmethyl, tetrahydrofuran, indanyl, spiro[3.3 ]heptyl, phenoxymethyl, 2,3-dihydrobenzyl[d]oxazilyl, thiazolyl, oxazolyl, imidazolyl, pyrrolyl, imidazolylmethyl, tetrahydrofuranylmethyl, quinolinyl, thieno[2,3-b]pyrrolyl, azetidinyl, octahydrocyclopenta[b ]pyrrolyl, spiro[2.5]octanyl, hydroxymethyl, 3,4-dihydro-2H-benzo[b][1.4]oxazinyl, benzo[b]thiazolyl, cyclopropylethyl, ethoxy, each of which is optionally substituted with one or plus substituents independently selected from F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C6)alkyl, O(C1-C4)alkyl, S(C1-C4)alkyl, C=O( C1-C4)alkyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O(C3-C6)cycloalkyl, phenyl, oxazolidinyl, wherein said one or more substituents are optionally independently substituted with one or more of halogen, CF3, OH and oxo; R1 is H; R2 is H; R3 is H, halogen or (C1-C4)alkyl; R4 is H, halogen or (C1-C4)alkyl; or R3 and R4 may optionally join together to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring, wherein said ring may be optionally substituted with one or more substituents independently selected from OH, halogen or (C1-C4) alkyl; R5 is H or (C1-C4)alkyl; and R6 is H or (C1-C4)alkyl; 2. Compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized by the fact that X is the 3. Compound or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that Y is H. 4. Compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that R5 and R6 are independently H or methyl. 5. Compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that R3 and R4 are independently H, F or methyl. 6. Compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it has formula Ib: where: R is selected from (C1-C4)alkyl, (C3-C6)cycloalkyl, phenyl, indanyl, piperidinyl, pyridinyl, furanyl, oxazolyl, benzoxazinyl, cyclopentalpyrrolyl, thienopyrrolyl, thiazolyl, imidazolyl, azetidinyl, pyrrolyl, pyrazinyl , quinolinyl and benzothiazolyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl, O(C1-C4 )alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C=O(C3-C6 )cycloalkyl, phenyl, O-phenyl, imidazolyl, pyrazinyl, furanyl, oxazolidinyl, pyrrolidinyl and benzoxazolyl, wherein said alkyl, phenyl, oxazolidinyl, pyrrolidinyl and benzoxazolyl are optionally independently substituted with one or more F, Cl, CF3 and oxo; R3 and R4 are independently H, F or methyl; and R5 and R6 are independently H or methyl. 7. Compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that it is: 4-((1S,3S)-3-(3-(5-Fluoro-2-methylphenyl )-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl)-benzenesulfonamide; 4-((1S,3S)-3-(5-(2-Cyclopropylethyl)-1,2,4-oxadiazol-3-yl)-2,2-dimethylcyclopropyl)benzenesulfonamide; 4-((1S,3S)-2,2-Dimethyl-3-(5-(2,3,6-trifluorophenyl)-1,2,4-oxadiazol-3-yl)cyclopropyl)benzenesulfonamide; 4-((1R,2R)-2-(3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)benzenesulfonamide; 4-{(1R,3R)-3-[5-(2,4-Difluorophenyl)-1,3,4-thiadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(2,4-Difluorophenyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Difluoro-3-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(5-Phenyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(4-Phenyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-(2-phenyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-(3-phenylisoxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-(1-phenyl-1H-1,2,3-triazol-4-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[1-(3-Fluorophenyl)-1H-pyrazol-4-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[4-(3-Fluorophenyl)-1,3-thiazol-2-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(5-Methyl-4-phenyl-1,3-thiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(4-Methyl-5-phenyl-1,3-thiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(5-phenyl-1,3-thiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-{trans-2-[3-(Propan-2-yl)-1,2,4-thiadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(5-Chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-((1R,3R)-3-(3-Cyclohexyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl)benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]cyclopropyl}benzenesulfonamide; 4-(2-Methyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl)benzenesulfonamide; 4-{(1R,2R)-2-[1-(3-Fluorobenzyl)-1H-pyrazol-3-yl]cyclopropyl}benzenesulfonamide; 4-[trans-2-(2-Phenyl-1,3-oxazol-4-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(2-Phenyl-1,3-thiazol-4-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[1-(3-Fluorophenyl)-1H-1,2,3-triazol-4-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(2-Phenyl-1,3-thiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(2-Cyclohexyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[5-(Piperidin-1-yl)-1,2,4-thiadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]phenyl sulfamate; 4-[(1R,3R)-3-(4,5-Dicyclopropyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]-2-fluorobenzenesulfonamide; 5-{trans-2,2-Dimethyl-3-[4-(methylsulfonyl)phenyl]cyclopropyl}-3-phenyl-1,2,4-oxadiazole; 4-[trans-3-(5-Cyclopentilisoxazol-3-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[2-(3-Fluorophenyl)-1-methyl-1H-imidazol-4-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{trans-2,2-Dichloro-3-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[5-(Piperidin-1-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]-3-methylbenzenesulfonamide; 4-{(1R,3R)-3-[3-(5-Chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide; 4-[(1R,3R)-3-{3-[4-Fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-{3-[5-Chloro-2-(propan-2-yloxy)phenyl]-1,2,4-oxadiazol-5-yl}-2,2-dimethylcyclopropyl] benzenesulfonamide; 4-[(1S,2S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[3-(5-Fluoro-2-methylphenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[3-(2,4-Difluorophenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,2S)-2-[3-(2,4-Difluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Difluoro-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[3-(2,6-Difluorophenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[3-(2-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-{3-[2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[3-(3-Bromophenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,2S)-2-[3-(5-Chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-2,2-Dimethyl-3-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[3-(5-Fluoropyridin-3-yl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1R,3R)-3-(3-Cyclobutyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,2S)-2-(3-Cyclohexyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{(1S,2S)-2-[3-(5-Fluoropyridin-3-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,2S)-2-[3-(2-Methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-{3-[5-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[3-(3,3-Difluorocyclobutyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide; 4-[(1R,3R)-3-(3-Cyclopentyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[3-(Cyclopropylmethyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,3R)-2,2-Dimethyl-3-[3-(tetrahydrofuran-3-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-2,2-Dimethyl-3-[3-(tetrahydrofuran-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-2,2-Dimethyl-3-[3-(1-phenylcyclopropyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[3-(5-Fluoro-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazol-5-yl]- 2 ,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,3R)-2,2-Dimethyl-3-[3-(spiro[3.3]hept-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[3-(1-Acetylpiperidin-4-yl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-(3-tert-Butyl-1,2,4-oxadiazol-5-yl)-2,2-difluorocyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(3-Cyclopentyl-1,2,4-oxadiazol-5-yl)-2,2-difluorocyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[3-(5-Chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{3-[4-Fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-{3-[5-Chloro-2-(propan-2-yloxy)phenyl]-1,2,4-oxadiazol-5-yl}-2,2-dimethylcyclopropyl] benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-{3-[2-(Trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-{3-[4-Fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-{3-[5-Fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[3-(2,6-Difluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(3-Bromophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2-Fluoro-6-methylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[3-(2,4-Difluorophenyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2,4-Difluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2,3-Difluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2,5-Difluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2-Methylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(3-Methylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(4-Methylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2-Fluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,3R)-2,2-Difluoro-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-2,2-Difluoro-3-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{3-[4-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(3-Cyclohexyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[3-(5-Fluoropyridin-3-yl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-(3-Cyclobutyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(3-Cyclohexyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(3-tert-Butyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[3-(Propan-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(5-Fluoropyridin-3-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[3-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[3-(2-methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2-Methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{3-[5-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[3-(3,3-Difluorocyclobutyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide; 4-{(1R,2R)-2-[3-(3,3-Difluorocyclobutyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-(3-Cyclopentyl-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(3-Cyclopentyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-{3-[5-(Trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[3-(1-Phenylcyclopropyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(2-Cyclopropylpyridin-3-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl} benzenesulfonamide; 4-[(1R,2R)-2-{3-[4-(Trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[3-(2,4-Difluorobenzyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[3-(Cyclopropylmethyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1R,2R)-2-[3-(Cyclopropylmethyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{3-[6-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl} cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{3-[2-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[3-(4-Methyl-1,3-oxazol-5-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[3-(2-Hydroxycyclohexyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl}cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[3-(1-methylcyclohexyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-2,2-Difluoro-3-[3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{trans-2-[3-(5-Chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-{trans-3-[3-(5-Chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-2,2-difluorocyclopropyl} benzenesulfonamide; 4-{2-[3-(2,4-Difluorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylcyclopropyl}benzenesulfonamide; 4-{2-[3-(2,4-Difluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylcyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[5-(2,6-Difluorophenyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1R,3R)-3-{5-[5-Fluoro-2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-{5-[2-Fluoro-6-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-2,2-dimethyl cyclopropyl]benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-(5-phenyl-1,3,4-thiadiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-(5-phenyl-1H-1,2,4-triazol-3-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[5-(2-Cyclopropylpyridin-3-yl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1R,3R)-3-(5-Cyclohexyl-1,3,4-thiadiazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(5-phenyl-1,3,4-oxadiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[3-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(3-Fluorophenyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(2,6-Difluorophenyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[5-Fluoro-2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-2,2-dimethyl cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(5-phenyl-1,3,4-thiadiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(2,4-Difluorophenyl)-1,3,4-thiadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(propan-2-yl)-1,3,4-oxadiazol-2-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopentyl-1,3,4-oxadiazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(Cyclopropylmethyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(2-Cyclopropylpyridin-3-yl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclohexyl-1,3,4-thiadiazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopentyl-1,3,4-thiadiazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopropyl-1,3,4-thiadiazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(5-Cyclopentyl-1,3,4-thiadiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-{5-[2-Fluoro-6-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-2,2-dimethyl cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(5-phenyl-1,2,4-oxadiazol-3-yl)cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(2-Chloro-4-fluorophenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(2,4,6-trifluorophenyl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[4-Fluoro-3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2,2-dimethyl cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(3-Fluorophenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(2-Fluoro-6-methylphenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[2-Fluoro-5-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-1,2,4-oxadiazol-3-yl }-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(2,6-Difluorophenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(3-Cyclopropylphenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(2,3,5-trifluorophenyl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(4-Ethynylphenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(4-Cyanophenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}cyclopropyl] benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1,2,4-oxadiazol-3-yl}cyclopropyl ]benzenesulfonamide; 4-{(1R,2R)-2-[5-(3-Fluorophenyl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(2,4-Difluorobenzyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[1-(3-Chlorophenoxy)ethyl]-1,2,4-oxadiazol-3-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(5-Fluoro-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazol-3-yl]- 2 ,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[1-(2,5-Difluorophenyl)cyclobutyl]-1,2,4-oxadiazol-3-yl}-2,2-dimethyl cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-{5-[(5-Chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)methyl]-1,2,4-oxadiazol-3- yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(1,3-thiazol-4-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(4-methyl-1,3-oxazol-5-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl} benzenesulfonamide; 4-{(1S,3S)-3-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-1,2,4-oxadiazol-3-yl]-2,2-dimethyl cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(1-Cyclopropylpiperidin-4-yl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(1-methyl-1H-pyrrol-3-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[1-(1H-Imidazol-1-yl)ethyl]-1,2,4-oxadiazol-3-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[1-(pyrazin-2-yl)cyclopropyl]-1,2,4-oxadiazol-3-yl}cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[4-(trifluoromethyl)quinolin-2-yl]-1,2,4-oxadiazol-3-yl}cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-{5-[6-(2-Fluoroethoxy)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-2,2-dimethyl cyclopropyl]benzenesulfonamide ; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(tetrahydrofuran-2-ylmethyl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(1,1-Difluoroethyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[4-(4-Fluorophenyl)-1H-imidazol-2-yl]-1,2,4-oxadiazol-3-yl}-2,2-dimethyl cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(5-{2-[(2,2,2-trifluoroethyl)sulfanyl]-1,3-oxazol-5-yl}- 1,2 ,4-oxadiazol-3-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[3-(trifluoromethyl)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[4-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-3-yl} cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-{5-[2-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-3-yl} cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(4H-thieno[3,2-b]pyrrol-5-yl)-1,2,4-oxadiazol-3-yl] cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-{5-[1-(Cyclopropylcarbonyl)azetidin-3-yl]-1,2,4-oxadiazol-3-yl}-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[5-(2-Cyclopentyl-1-oxo-octahydrocyclopenta[c]pyrrol-5-yl)- 1,2,4-oxadiazol-3-yl]-2 ,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopentyl-1,2,4-oxadiazol-3-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(spiro[2.5]oct-4-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl} benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(2,2,2-trifluoro-1-hydroxyethyl)-1,2,4-oxadiazol-3-yl]cyclopropyl} benzenesulfonamide; 4-{(1S,3S)-3-[5-(4-Hydroxycyclohexyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide; 4-{(1S,3S)-3-[5-(3-Hydroxycyclobutyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)- 1,2, 4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-{(1S,3S)-3-[5-(2-Hydroxy-1,3-benzothiazol-6-yl)-1,2,4-oxadiazol-3-yl]-2,2-dimethyl cyclopropyl} benzenesulfonamide; 4-{(1R,3R)-3-[5-(2-Cyclopropylethyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide; 4-[(1R,2R)-2-(5-Cyclohexyl-1,2,4-oxadiazol-3-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-{5-[1-(Trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}cyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[5-(5-Fluoropyridin-3-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-{(1R,3R)-3-[4-(2-Fluorophenyl)-1,3-oxazol-2-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide; 4-{(1R,3R)-3-[4-(2,4-Difluorophenyl)-1,3-oxazol-2-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide; 4-{(1R,3R)-3-[4-(2,5-Difluorophenyl)-1,3-oxazol-2-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide; 4-[(1R,3R)-3-(4-tert-Butyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-(4-Cyclopropyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,2S)-2-(4-Phenyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-{(1S,2S)-2-[4-(3-Fluorophenyl)-1,3-thiazol-2-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,3R)-3-(4-Cyclopentyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-(5-Cyclopentyl-1,3-thiazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1S,2S)-2-[5-(3-Fluorophenyl)-1,3-thiazol-2-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopentyl-1,3-oxazol-2-yl)-2,2-difluorocyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[4-(2-Fluorophenyl)-1,3-oxazol-2-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide; 4-{(1S,3S)-3-[4-(2,5-Difluorophenyl)-1,3-oxazol-2-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide; 4-{(1S,3S)-3-[4-(2,4-Difluorophenyl)-1,3-oxazol-2-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide; 4-[(1R,2R)-2-(5-tert-Butyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(5-Cyclopropyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(4-Ethyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(4-tert-Butyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(4-Ethyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(4-Phenyl-1,3-thiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-3-[4-(3-Fluorophenyl)-1,3-thiazol-2-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide; 4-{(1S,3S)-2,2-Dimethyl-3-[4-(propan-2-yl)-1,3-thiazol-2-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(4-Phenyl-1H-imidazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-(5-Cyclopentyl-1,3-oxazol-2-yl)-2,2-difluorocyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopentyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(5-Cyclopentyl-1,3-thiazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(5-Cyclopentyl-1,3-thiazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(4-Cyclopentyl-1,3-oxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[5-(3-Fluorophenyl)-1,3-thiazol-2-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(4-Cyclopentyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3S)-3-(4-Cyclohexyl-1,3-thiazol-2-yl)-2,2-difluorocyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(2-phenyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,2S)-2-(2-Phenyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(2-Phenyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(3-phenylisoxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[1-(3-Fluorophenyl)-1H-1,2,3-triazol-4-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide; 4-{(1S,3S)-3-[1-(3-Fluorophenyl)-1H-1,2,3-triazol-4-yl]-2,2-dimethylcyclopropyl} benzenesulfonamide; 4-[(1S,3S)-2,2-Dimethyl-3-(1-phenyl-1H-1,2,3-triazol-4-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-(1-Cyclopentyl-1H-pyrazol-4-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-(5-Ethoxy-1,2,4-thiadiazol-3-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-{(1R,2R)-2-[5-(3-Fluorophenyl)-1,2,4-thiadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(5-Cyclohexyl-1,2,4-thiadiazol-3-yl)cyclopropyl]benzenesulfonamide; 4-{(1S,3S)-2,2-Difluoro-3-[5-(piperidin-1-yl)-1,2,4-thiadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-[(1S,3S)-2,2-Difluoro-3-(5-phenyl-1,2,4-thiadiazol-3-yl)cyclopropyl]benzenesulfonamide; 4-[(1R,2R)-2-(2-Cyclopentyl-1,3-thiazol-4-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,3S)-3-(2-Cyclopentyl-1,3-thiazol-4-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,3R)-3-(5-Cyclohexyl-1,2,4-oxadiazol-3-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-(5-phenyl-1,2,4-oxadiazol-3-yl)cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-3-[5-(3-Fluorophenyl)-1,2,4-oxadiazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[(1R,3R)-2,2-Dimethyl-3-{5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}cyclopropyl]benzenesulfonamide; 4-{(1R,3R)-2,2-Dimethyl-3-[5-(piperidin-1-yl)-1,2,4-oxadiazol-3-yl]cyclopropyl}benzenesulfonamide; 4-[(1R,2R)-2-(2-Cyclopentyl-1,3-oxazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[(1S,2S)-2-(2-Phenyl-1,3-thiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[trans-2,2-Difluoro-3-(5-phenyl-1,3-oxazol-2-yl)cyclopropyl]benzenesulfonamide; 4-[2-Methyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-[trans-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)spiro[2.4]hept-1-yl]benzenesulfonamide; 4-{trans-2-[3-(3-Fluorophenyl)-1,2,4-thiadiazol-5-yl]cyclopropyl}benzenesulfonamide; 4-[trans-2,2-Dichloro-3-(3-cyclopentyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; 4-{trans-3-[5-(3-Fluorophenyl)isoxazol-3-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide; 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]-3-fluorobenzenesulfonamide; 4-[trans-2,2-Dimethyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]-2-methylbenzenesulfonamide; and 4-[trans-2,2-Dichloro-3-(3-phenyl-1,2,4-oxadiazol-5-yl)cyclopropyl]benzenesulfonamide; or a pharmaceutically acceptable salt thereof. 8. Compound according to any one of claims 1 to 7, characterized in that it is selected from the group consisting of: a pharmaceutically acceptable salt thereof. 9. Compound according to claim 8, characterized by the fact that it is in the form of a pharmaceutically acceptable salt thereof. 10. Pharmaceutical composition, characterized in that it comprises at least one compound defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 11. Pharmaceutical composition according to claim 10, characterized in that it comprises at least one secondary therapeutic agent that is selected from the group consisting of acetylcholinesterase inhibitors, NMDA receptor antagonists, antipsychotics, MAO-B inhibitors and levodopa, wherein the acetylcholinesterase inhibitor is selected from the group consisting of donepezil, rivastigmine, galantamine; the NMDA receptor antagonist is memantine; the antipsychotic is selected from the group consisting of clozapine, olanzapine, risperidone, aripiprazole, quetiapine, haloperidol, loxapine, thioridazine, molindone, thiothixene, fluphenazine, mesoridazine, trifluoperazine, chlorpromazine and perphenazine; and the MAO-B inhibitor is selected from the group consisting of selegiline, rasagiline and safinamide. 12. Pharmaceutical composition according to claim 10 or 11, characterized in that it provides an amount of a compound defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, which is sufficient to provide a therapeutic response in an individual in need of therapy for the treatment of Alzheimer's disease, Parkinson's disease or schizophrenia. 13. Use of a compound defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof and, optionally, one or more secondary therapeutic agent(s), characterized by the fact that it is for the preparation of a single composition or separate compositions for the treatment of Alzheimer's disease, Parkinson's disease or schizophrenia. 14. Use according to claim 13, characterized in that at least one secondary therapeutic agent is selected from the group consisting of acetylcholinesterase inhibitors, NMDA receptor antagonists, antipsychotics, MAO-B inhibitors and levodopa, in that the acetylcholinesterase inhibitor is selected from the group consisting of donepezil, rivastigmine, galantamine; the NMDA receptor antagonist is memantine; the antipsychotic is selected from the group consisting of clozapine, olanzapine, risperidone, aripiprazole, quetiapine, haloperidol, loxapine, thioridazine, molindone, thiothixene, fluphenazine, mesoridazine, trifluoperazine, chlorpromazine and perphenazine; and the MAO-B inhibitor is selected from the group consisting of selegiline, rasagiline and safinamide.