Spiroperidine allosteric modulators of nicotinic acetylcholine receptors

Abstract

The present disclosure relates to compounds of formula I useful as α7 nAChR modulators, compositions comprising such compounds, and uses of such compounds for preventing, treating or ameliorating diseases, particularly central nervous system disorders such as Alzheimer's disease, Parkinson's disease and cognitive impairment in schizophrenia, and for L-DOPA-induced movement disorders and inflammation.

Description

Technical Field

[0001] The present disclosure relates to compounds useful as α7 nAChR modulators, compositions comprising such compounds, and the use of such compounds for preventing, treating or ameliorating diseases, particularly central nervous system disorders such as Alzheimer's disease, Parkinson's disease, and cognitive impairment in schizophrenia. Background Art

[0002] α7 nAChR is a rapidly desensitizing ligand-gated ion channel that is sensitive to Ca 2+ It has high permeability. In the human brain, α7nAChR is highly expressed in the cortical layer and hippocampus associated with cognition, see, for example, Breese et al., J. Comp. Neurol. (1997) 387: 385-398. In neurons, α7 nAChR is located in presynaptic and postsynaptic structures, where receptor activation can regulate neurotransmitter release, neuronal excitability, and intracellular signaling, see, for example, Frazier et al., J. Neurosci. (1998) 18: 1187-1195.

[0003] Cognitive impairment is common in many neurological and psychiatric diseases, including Alzheimer's disease (AD), schizophrenia and Parkinson's disease, and cholinergic signaling disorders contribute to cognitive impairment in these diseases, see, e.g., Francis et al., J. Neurol. Neurosurg. Psychiatry (1999) 66: 137-147. For example, a major feature of AD pathogenesis is the loss of cholinergic neurons in the basal forebrain nuclei, and increasing cholinergic transmission by inhibiting acetylcholinesterase is the standard of care for AD cognitive symptoms. More specifically to α7nAChR, it has recently been demonstrated that Encenicline (an α7 nAChR partial agonist) improves cognition in Alzheimer's disease, see, e.g., Moebius H et al., 67 thAnnual Meeting. Am. Acad. Neurol. (AAN) 2015, Abst P7.100. Evidence that α7 nAChR is involved in the etiology of schizophrenia comes from studies showing that the expression of neuronal α7 nAChR in the brains of schizophrenia patients is reduced and observations that schizophrenia patients often smoke, which is believed to be a form of self-medication. In addition, variations in the promoter region of the gene CHRNA7 encoding α7 nAChR (which affects the expression of α7 nAChR protein) are associated with symptoms of schizophrenia, see, for example, Sinkus et al., Neuropharmacology (2015) 96: 274-288. In addition, increasing evidence from clinical trials has shown that activation of α7 nAChR with agonists may have beneficial effects on cognition, see, e.g., Keefe et al., Neuropsychopharmacology (2015) 40:3053-3060 and Bertrand et al., Pharmacology Reviews (2015) 67:1025-1073. Therefore, targeting α7 nAChR represents a therapeutic strategy for treating cognitive impairment associated with various cognitive disorders.

[0004] Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive motor deficits such as tremor, bradykinesia, rigidity, and impaired postural reflexes. The main pathological finding associated with the disease is the degeneration of dopaminergic neurons in the substantia nigra, which leads to the loss of dopaminergic tone in the striatum. L-DOPA is the current standard treatment for motor symptoms in PD. However, long-term treatment with L-DOPA in PD patients can also induce dyskinesias, which are side effects of L-DOPA therapy. New evidence suggests that activation of α7 nAChRs can acutely relieve dyskinesias in several animal models, see, for example, Zhang et al., J. Pharmacol. Exp. Ther. (2014) 351: 25-32. In addition, there is growing evidence that pretreatment with α7 nAChR agonists prevents neurodegeneration in nigrostriatal neurons, suggesting that α7 activation may also have disease-modifying properties, see, e.g., Suzuki et al., J. Neurosci. Res. (2013) 91:462-471. Overall, α7 nAChR is an attractive target for amelioration of disease progression and management of movement disorders.

[0005] In addition to being expressed in the central nervous system, α7 nAChR is also widely expressed in peripheral immune cells, including macrophages, monocytes, dendritic cells, and B and T cells, see, e.g., Rosas-Ballina et al., Science (2011) 334:98-101. Activation of peripheral α7 nAChRs is crucial for inhibiting the release of proinflammatory cytokines via the cholinergic anti-inflammatory pathway, see, e.g., Wang et al., Nature (2003) 421:384-388. Therefore, α7 nAChR is a potential target for several inflammatory diseases such as rheumatoid arthritis and atherosclerosis, see, e.g., WJ de Jonge et al., British J. Pharmacol. (2007) 151:915-929.

[0006] In recent years, α7 selective positive allosteric modulators (PAMs) have been proposed as a treatment for cognitive impairment in AD, PD and schizophrenia, as well as L-DOPA-induced movement disorders and inflammation. Compared to α7 agonists (whether endogenous agonists or not) that activate channels, PAMs increase the potency of endogenous agonists without interfering with the temporal and spatial integrity of neurotransmission. There are two types of α7 PAMs: type I and type II, which differ according to the functional properties of the modulation. Type I PAMs (e.g., NS1738, see, e.g., Timmermann et al., J. Pharmacol. Exp. Ther. (2007) 323: 294-307) mainly affect peak currents, with little or no effect on receptor passivation, while type II PAMs (e.g., PNU120596, see, e.g., Hurst et al., J. Neurosci. (2005) 25: 4396-4405) significantly delay receptor passivation. Additionally, it is speculated that by binding to non-conserved regions of the receptor, α7 nAChR PAMs may have improved selectivity over related channel targets.

[0007] The present invention relates to a novel class of compounds that exhibit positive allosteric modulation of the α7 nAChR. Summary of the invention

[0008] The present disclosure relates to novel compounds of formula I and II and pharmaceutically acceptable salts thereof. These compounds can be used to regulate α7 nAChR as a compound or as a pharmaceutically acceptable salt thereof (when appropriate), prevent, treat or improve diseases, particularly central nervous system disorders such as cognitive impairment in Alzheimer's disease, Parkinson's disease and schizophrenia, and / or as a pharmaceutical composition component. As a pharmaceutical composition component, these compounds and their salts can be the main active therapeutic agent, and can be combined with other therapeutic agents when appropriate, including but not limited to acetylcholinesterase inhibitors, NMDA receptor antagonists, β-secretase inhibitors, M4 mAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs, 5-HT6 antagonists, histamine H3 receptor antagonists, PDE4 inhibitors, PDE9 inhibitors, HDAC6 inhibitors, antipsychotics, MAO-B inhibitors and levodopa.

[0009] In one aspect, the present invention relates to compounds of formula I:

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein:

[0012] n is 0, 1 or 2;

[0013] X is S(O) 2 or C(O);

[0014] R 1 Selected from NR a R b and R c ;

[0015] R a Selected from H, (C 1 -C 4 ) alkyl, (C 3 -C 6 ) cycloalkyl, aryl, heteroaryl and heterocyclic radicals, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radicals are optionally substituted by one or more independently selected R 8 substituted by a substituent;

[0016] R b H or (C 1 -C 4 )alkyl;

[0017] R c For (C 1 -C 4 ) alkyl, wherein the alkyl is optionally replaced by R 9 replaced by; or R cis a heteroaryl group, wherein the heteroaryl group is optionally substituted by one or more R 10 replaced by;

[0018] A is a 5-membered heteroaryl ring, which is substituted by 1 to 3 R groups, each of which is independently selected from OH, oxo, NR 6 R 7 , CN, alkoxy, halogen, aminoalkyl, hydroxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein the R group selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally replaced by one or more independently selected from R 11 substituted by a substituent;

[0019] R 2 are independently halogen, (C 1 -C 4 )alkyl or O(C 1 -C 4 ) alkyl, wherein the alkyl is optionally substituted with one or more halogens;

[0020] Or, when both are (C 1 -C 4 ) alkyl and attached to the same carbon atom, the two R 2 Optionally, they may form a cyclopropyl, cyclobutyl or cyclopentyl ring together, or, when both are (C 1 -C 4 ) alkyl and are not attached to the same carbon atom, the two R 2 Optionally, they may be combined to form a bridged ring, wherein the cyclopropyl, cyclobutyl, cyclopentyl or bridged ring may be optionally substituted by one or more independently selected from OH, halogen or (C 1 -C 4 ) is substituted by an alkyl substituent;

[0021] R 3 is H, halogen or (C 1 -C 4 ) alkyl, wherein the alkyl is optionally substituted with one or more halogens;

[0022] R 4 is H, halogen or (C 1 -C 4 ) alkyl, wherein the alkyl is optionally substituted with one or more halogens;

[0023] Or, R 3 and R 4 Optionally, they may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring, wherein the ring may be optionally substituted by one or more independently selected from OH, halogen or (C 1 -C 4) is substituted by an alkyl substituent;

[0024] R 5 H or (C 1 -C 4 )alkyl;

[0025] R 6 H or (C 1 -C 4 )alkyl;

[0026] R 7 H or (C 1 -C 4 )alkyl;

[0027] R 8 OH, (C 1 -C 4 ) alkyl, aryl, heteroaryl or heterocyclic group;

[0028] R 9 is aryl, heteroaryl or heterocyclic;

[0029] R 10 is methyl or hydroxyl;

[0030] R 11 Halogen, OH, oxo, CF 3 、OCF 3 、CN、(C 1 -C 6 ) alkyl, O(C 1 -C 6 )alkyl, S(C 1 -C 4 )alkyl, C=O(C 1 -C 4 ) alkyl, NR 12 R 13 、(C=O)NR 6 R 7 、(C=O)OR 6 , (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, (C 3 -C 6 )cycloalkyl, O(C 3 -C 6 )cycloalkyl, C=O(C 3 -C 6 ) cycloalkyl, aryl, O-aryl, heteroaryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted by one or more halogen, (C 1 -C 4) alkyl, (C 3 -C 6 )cycloalkyl, CF 3 、OCF 3 、OCH 3 , CN, OH and oxo-substituted;

[0031] R 12 For (C 1 -C 4 )alkyl, heterocyclyl, cycloalkyl, heteroaryl, aryl or (C=O)R 6 , each of which is optionally substituted by one or more independently selected from halogen, (C 1 -C 4 ) alkyl and OH substituents; and

[0032] R 13 For (C 1 -C 4 )alkyl, heterocyclyl, cycloalkyl, heteroaryl, aryl or (C=O)R 6 , each of which is optionally substituted by one or more independently selected from halogen, (C 1 -C 4 ) is substituted by an alkyl group and an OH substituent.

[0033] The present invention also includes pharmaceutical compositions containing the compounds of the present invention and methods for preparing such pharmaceutical compositions. The present invention also includes methods for preventing, treating or ameliorating cognitive impairment associated with Alzheimer's disease, Parkinson's disease and schizophrenia.

[0034] Other embodiments, aspects, and features of the present invention will be further described in or will be apparent from the ensuing description, examples, and accompanying claims. DETAILED DESCRIPTION

[0035] The present invention includes compounds of the above formula I and pharmaceutically acceptable salts thereof. The compounds of formula I and II are positive allosteric modulators of α7 nAChR.

[0036] In a first embodiment of the present invention, -XR 1 for Other groups are as provided in the above formula.

[0037] In a second embodiment of the present invention, R 2 is independently methyl, ethyl or F, and the other groups are as provided in the above formula or in the first embodiment.

[0038] In a third embodiment of the present invention, A is a 5-membered heteroaryl ring substituted with 1 R group independently selected from OH, oxo, NR6 R 7 , CN, alkoxy, halogen, aminoalkyl, hydroxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein the R group selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally replaced by one or more independently selected from R 11 The other groups are as provided in the above general formula or in the first and second embodiments.

[0039] In a fourth embodiment of the present invention, R is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one or more independently selected from R 11 The other groups are as provided in the above general formula or in the first, second and third embodiments.

[0040] In a fifth embodiment of the present invention, R is cyclohexyl, phenyl, pyrazolyl, pyridinyl or isoxazolyl, each of which is optionally substituted by one or more independently selected from R 11 The other groups are as provided in the above general formula or in the first to fourth embodiments.

[0041] In a sixth embodiment of the present invention, R 3 and R 4 are independently selected from H, F and methyl, and the other groups are as provided in the above formula or in the first to fifth embodiments.

[0042] In a seventh embodiment of the present invention, the compound of the present invention has formula (II):

[0043]

[0044] or a pharmaceutically acceptable salt thereof, wherein:

[0045] m is 0, 1, 2 or 3;

[0046] Z is independently selected from F, Cl, Br, methyl, methoxy, ethyl, ethoxy, propyl, -CH 2 OH, -CH 2 CH 2 OH, -CF 3 、-CH 2 CF 3 、-OCF 3 、-OCHF 2 、-OCH 2 CF 3 and cyclopropyl;

[0047] Ring A is oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, isothiazolyl, thiazolyl, pyrazolyl or imidazolyl;

[0048] Ring B is cyclohexyl, phenyl, pyrazolyl, pyridinyl or isoxazolyl;

[0049] R 3 H, F or (C 1 -C 4 )alkyl, wherein the alkyl is optionally substituted with one or more halogens; and

[0050] R 4 H, F or (C 1 -C 4 )alkyl, wherein the alkyl is optionally substituted with one or more halogens.

[0051] In an eighth embodiment of the present invention, the compound of the present invention has the formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0052] m is 0, 1 or 2;

[0053] Z is independently selected from F, Cl, Br, methyl, methoxy, ethyl, ethoxy, propyl, -CH 2 OH, -CH 2 CH 2 OH, -CF 3 、-CH 2 CF 3 、-OCF 3 、-OCHF 2 、-OCH 2 CF 3 and cyclopropyl;

[0054] Ring A is oxadiazolyl, oxazolyl, isoxazolyl or thiazolyl;

[0055] Ring B is phenyl, pyrazolyl, pyridinyl or isoxazolyl; and

[0056] R 3 and R 4 All are H or R 3 and R 4 All are F.

[0057] The present invention also relates to a compound selected from the following exemplary compounds or a pharmaceutically acceptable salt thereof:

[0058] (1R)-1-{5-[2-methyl-5-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0059] (1R)-1-[5-(2,5-dimethylphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0060] 4,4-difluoro-1-{3-[3-(2,2,2-trifluoroethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer C;

[0061] 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide; diastereomer E;

[0062] (1R)-1-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0063] 1-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-4-methyl-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer D;

[0064] (1R)-1-{2-[3-(trifluoromethoxy)phenyl]-1,3-thiazol-4-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0065] (1R)-1-{5-[4-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0066] (2R)-2-[5-(1,4-dimethyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0067] (2R)-2-{5-[2-(difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0068] (2R)-2-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0069] (2R)-1,1-difluoro-2-{3-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0070] (2R)-2-{5-[2-(difluoromethoxy)-5-methylpyridin-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0071] (2R)-1,1-difluoro-2-{5-[1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0072] (1R)-1-{1-[3-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0073] (2R)-2-[5-(1-cyclopropyl-1H-pyrazol-5-yl)-1,3,4-oxadiazol-2-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0074] (2S)-2-[5-(1-cyclopropyl-1H-pyrazol-5-yl)-1,3,4-thiadiazol-2-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0075] (2R)-2-[5-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-3-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0076] (2R)-1,1-difluoro-2-{5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0077] (2R)-1,1-difluoro-2-[5-(2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0078] 1,1-Difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-(methylsulfonyl)-6-azaspiro[2.5]octane;

[0079] (2R)-1,1-difluoro-2-[5-(1,3,4-trimethyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0080] (1R)-1-[4-(3-cyclopropylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0081] (2R)-1,1-difluoro-2-{2-[4-fluoro-2-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0082] (2R)-2-[5-(1-cyclopropyl-4-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0083] 1-[5-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]-6-(methylsulfonyl)-6-azaspiro[2.5]octane, enantiomer A;

[0084] (1R)-1-[5-(1-ethyl-5-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0085] (1R)-1-[5-(3-cyclopropyl-5-methylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0086] (2R)-2-{5-[1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0087] (2R)-2-[5-(2-cyclopropyl-5-methylphenyl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane 6-sulfonamide;

[0088] (2R)-2-[2-(3-cyclopropylisoxazol-4-yl)-1,3-oxazol-4-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0089] 2-[3-(2,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-(methylsulfonyl)-6-azaspiro[2.5]octane;

[0090] (1R)-1-[5-(2-methylphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0091] (2R)-2-[5-(2,5-dimethylphenyl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0092] (2R)-2-{2-[2-(difluoromethoxy)pyridin-4-yl]-1,3-oxazol-4-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0093] 1,1-Difluoro-2-{1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0094] 1,1-Difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0095] (1R)-1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0096] (2R)-1,1-difluoro-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[2.5]octane-6-sulfonamide;

[0097] (2R)-1,1-difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0098] (1R)-1-{3-[5-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0099] (1R)-1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0100] (2R)-1,1-difluoro-2-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0101] (2R)-2-[3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0102] (2R)-1,1-difluoro-2-{3-[4-(2-hydroxypropan-2-yl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0103] 1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-[(pyridin-2-ylmethyl)sulfonyl]-6-azaspiro[2.5]octane;

[0104] 1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-(thiophen-3-ylsulfonyl)-6-azaspiro[2.5]octane;

[0105] 1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-[(tetrahydro-2H-pyran-2-ylmethyl)sulfonyl]-6-azaspiro[2.5]octane;

[0106] 1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]-6-azaspiro[2.5]octane;

[0107] 1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-[(2-phenylethyl)sulfonyl]-6-azaspiro[2.5]octane;

[0108] 4-({1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]oct-6-yl}sulfonyl)-2,1,3-benzoxadiazole;

[0109] 6-({1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]oct-6-yl}sulfonyl)-1,3-benzothiazole;

[0110] 4-({1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]oct-6-yl}sulfonyl)-5-hydroxy-3-methyl-1,2,3-oxadiazol-3-ium trifluoroacetate;

[0111] N-tert-butyl-1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-carboxamide;

[0112] 1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-N-cyclohexyl-6-azaspiro[2.5]octane-6-carboxamide;

[0113] 1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-N-(pyridin-2-ylmethyl)-6-azaspiro[2.5]octane-6-sulfonamide;

[0114] 1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-N-(isothiazol-5-ylmethyl)-6-azaspiro[2.5]octane-6-carboxamide;

[0115] N-Benzyl-1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-carboxamide;

[0116] 1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-(methylsulfonyl)-6-azaspiro[2.5]octane;

[0117] 1-{3-[2-(methylamino)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0118] 1-{3-[2-(Pyrrolidin-1-yl)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0119] 2-[3-(3,5-dimethylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0120] (1R)-1-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0121] (2R)-2-[3-(3-cyclopropyl-5-methylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0122] (2R)-2-(3-cyclohexyl-1,2,4-oxadiazol-5-yl)-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0123] (2R)-1,1-difluoro-2-[3-(2-methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0124] (2R)-1,1-difluoro-2-{3-[2-(trifluoromethyl)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0125] (2R)-2-{3-[2-(difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0126] (2R)-2-[3-(1-cyclopropyl-4-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0127] (2R)-1,1-difluoro-2-[3-(imidazo[1,2-a]pyridin-7-yl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0128] (1R)-1-{3-[5-cyclopropyl-3-(trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0129] 1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0130] (2R)-2-[3-(1-cyclopropyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0131] (2R)-2-{3-[3-cyclopropyl-5-(trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0132] (2R)-2-{3-[5-cyclopropyl-3-(trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0133] 1,1-Dichloro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0134] (1R)-1-{5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0135] (1R)-1-[5-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0136] (1R)-1-[5-(2-cyanophenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0137] (1R)-1-{5-[2-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0138] (1R)-1-{5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0139] (1R)-1-{5-[5-bromo-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0140] (1R)-1-{5-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0141] (1R)-1-(5-phenyl-1,2,4-oxadiazol-3-yl)-6-azaspiro[2.5]octane-6-sulfonamide;

[0142] (1R)-1-{5-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0143] (1R)-1-{5-[4-chloro-2-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0144] (1R)-1-{5-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0145] (1R)-1-{5-[2-fluoro-6-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0146] (1R)-1-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0147] (1R)-1-{5-[4-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0148] (1R)-1-[5-(2,4-difluorophenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0149] (1R)-1-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0150] (1R)-1-{5-[2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0151] (1R)-1-{5-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0152] (1R)-1-[5-(2,4-dimethylphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0153] (1R)-1-{5-[2-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0154] (1R)-1-{5-[5-fluoro-2-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0155] (1R)-1-{5-[5-chloro-2-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0156] (1R)-1-{5-[4-(2-hydroxypropan-2-yl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0157] (1R)-1-{5-[2-(difluoromethoxy)-4-fluorophenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0158] (1R)-1-[5-(2,4,5-trimethylphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0159] (2R)-2-[5-(2-Cyclopropylphenyl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0160] (1R)-1-[5-(5-fluoro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0161] (1R)-1-[5-(1-cyclopropyl-3-methyl-1H-indol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0162] (1R)-1-[5-(2-methylpyridin-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0163] (1R)-1-{5-[3-(propan-2-yl)cyclobutyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0164] (1R)-1-{5-[2-fluoro-6-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0165] (1R)-1-{5-[2-fluoro-5-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0166] (1R)-1-[5-(2,6-dimethylbenzyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0167] (1R)-1-[5-(3-methylcyclohexyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0168] (1R)-1-{5-[1-(2-chlorophenyl)ethyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0169] (1R)-1-{5-[5-fluoro-2-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0170] (1R)-1-{5-[1-(2,5-difluorophenyl)cyclobutyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0171] (1R)-1-[5-(Spiro[2.5]octane-4-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0172] (1R)-1-{5-[4-fluoro-2-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0173] (1R)-1-[5-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0174] (1R)-1-(5-{1-[3-(trifluoromethyl)phenyl]cyclopropyl}-1,2,4-oxadiazol-3-yl)-6-azaspiro[2.5]octane-6-sulfonamide;

[0175] (1R)-1-[5-(3-phenylcyclobutyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0176] (1R)-1-[5-(3,6-dimethylpyridin-2-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0177] (1R)-1-{5-[6-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0178] (1R)-1-{5-[2-(2,2,2-trifluoroethoxy)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0179] (1R)-1-{5-[3-methyl-6-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0180] (1R)-1-[5-(Spiro[3.3]hept-2-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0181] (1R)-1-[5-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0182] (1R)-1-{5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0183] (1R)-1-{5-[4-(trifluoromethyl)-1,3-oxazol-5-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0184] (1R)-1-[5-(4-ethyl-1,3-oxazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0185] (1R)-1-{5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0186] (1R)-1-[5-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0187] (1R)-1-[5-(4,5-dimethylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0188] (1R)-1-{5-[(3,5-dimethylisoxazol-4-yl)methyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0189] (1R)-1-{5-[3-(trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0190] (1R)-1-[5-(1-cyclopropyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0191] (1R)-1-{5-[2-(1H-imidazol-1-yl)-5-(trifluoromethyl)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0192] (1R)-1-{5-[1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0193] (2R)-2-{5-[2-(cyclopropyloxy)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0194] (2R)-2-[5-(1-cyclopropyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0195] (2R)-2-[5-(1-tert-butyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0196] (2R)-1,1-difluoro-2-[5-(3-methylimidazo[1,2-a]pyridin-7-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0197] (2R)-2-[5-(3-cyclopropyl-1-ethyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0198] (2R)-1,1-difluoro-2-{5-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0199] (2R)-2-{5-[1-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0200] (2R)-1,1-difluoro-2-[5-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0201] (2R)-2-[5-(1-cyclopropyl-4-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0202] (2R)-2-[5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0203] (2R)-1,1-difluoro-2-[5-(1-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0204] (2R)-1,1-difluoro-2-[5-(1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0205] (2R)-1,1-difluoro-2-{5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0206] (2R)-2-{5-[1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0207] (2R)-2-[5-(2-cyclopropyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0208] (2R)-2-{5-[1-cyclopropyl-4-(trifluoromethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0209] (2R)-2-[5-(3-cyclopropylpyridazin-4-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0210] (1R)-1-[5-(3-cyclopropylpyridazin-4-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0211] (2R)-1,1-difluoro-2-{5-[2-(propane-2-oxy)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0212] (1R)-1-[5-(1,4-dimethyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0213] (2R)-1,1-difluoro-2-[5-(4H-pyrazolo[1,5-c][1,3]thiazol-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0214] (2R)-2-{5-[1-cyclopropyl-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0215] (2R)-2-{5-[3-cyclopropyl-5-(trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0216] (2R)-1,1-difluoro-2-[5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0217] (1R)-1-{5-[4-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0218] (1R)-1-{5-[2-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0219] (1R)-1-{5-[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0220] (1R)-1-{5-[5-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0221] (1R)-1-{5-[2-methyl-5-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0222] (1R)-1-{5-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0223] (1R)-1-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0224] (1R)-1-[5-(1-cyclopropyl-4-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0225] (1R)-1-[5-(2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0226] (2R)-1,1-difluoro-2-[5-(2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0227] (2R)-1,1-difluoro-2-[5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0228] (2R)-1,1-difluoro-2-{5-[3-(trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0229] (1R)-1-[5-(2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0230] (1R)-1-(5-{3-[5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1,2,4-oxadiazol-3-yl)-6-azaspiro[2.5]octane-6-sulfonamide;

[0231] (1R)-1-[5-(2-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0232] (1R)-1-[5-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0233] (1R)-1-{5-[2-(1H-pyrrol-1-yl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0234] (1R)-1-[5-(4'-fluorobiphenyl-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0235] (1R)-1-{5-[2-(1-cyanocyclopropyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0236] (1R)-1-{5-[2-(pyrimidin-2-yl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0237] (1R)-1-{5-[2-(1H-pyrazol-1-yl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0238] (1R)-1-{5-[3-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0239] (1R)-1-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0240] (1R)-1-{5-[3-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0241] (1R)-1-{5-[3-(trifluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0242] (1R)-1-[5-(2,5-difluorophenyl)-1,3,4-thiadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0243] (1R)-1-[5-(5-fluoro-2-methylphenyl)-1,3,4-oxadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0244] (1R)-1-{5-[2-(2,2,2-trifluoroethoxy)phenyl]-1,3,4-oxadiazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0245] (1R)-1-{5-[2-(2,2,2-trifluoroethoxy)phenyl]-1,3,4-thiadiazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0246] (1R)-1-[5-(2-methylphenyl)-1,3,4-thiadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0247] (1R)-1-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0248] (1R)-1-{5-[3-(difluoromethoxy)phenyl]-1,3,4-thiadiazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0249] (1R)-1-[5-(3-cyclopropyl-5-methylisoxazol-4-yl)-1,3,4-oxadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0250] (1R)-1-[5-(3-cyclopropyl-5-methylisoxazol-4-yl)-1,3,4-thiadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0251] (2R)-1,1-difluoro-2-[5-(2-methylphenyl)-1,3,4-oxadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0252] (2R)-1,1-difluoro-2-[5-(2-methylphenyl)-1,3,4-thiadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0253] (1R)-1-(4-phenyl-1,3-oxazol-2-yl)-6-azaspiro[2.5]octane-6-sulfonamide;

[0254] (1R)-1-[2-(3-cyclopropylisoxazol-4-yl)-1,3-thiazol-4-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0255] (1R)-1-[1-(3,5-dimethylisoxazol-4-yl)-1H-pyrazol-4-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0256] (2R)-2-[2-(3-cyclopropylisoxazol-4-yl)-1,3-thiazol-4-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0257] (2R)-2-{3-[2-(difluoromethoxy)pyridin-4-yl]isoxazol-5-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0258] (2R)-2-[4-(3-cyclopropylisoxazol-4-yl)-1-methyl-1H-imidazol-2-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0259] (2R)-2-(3'-cyclopropyl-3,4'-bisisoxazol-5-yl)-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0260] (2R)-1,1-difluoro-2-{4-[4-fluoro-2-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0261] (1S)-1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0262] (2S)-1,1-difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0263] (2S)-2-(3-cyclohexyl-1,2,4-oxadiazol-5-yl)-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0264] (2S)-1,1-difluoro-2-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0265] (2S)-1,1-difluoro-2-[5-(2-methylphenyl)-1,3,4-oxadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0266] (2R)-1,1-difluoro-2-[5-(2-methylphenyl)-1,3,4-thiadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0267] 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0268] 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0269] 4,4-difluoro-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[2.5]octane-6-sulfonamide;

[0270] 1-[3-(2,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl]-4,4-difluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0271] 4-methyl-1-{3-[2-(2,2,2-trifluoroethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0272] 1-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0273] 1-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0274] 1-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0275] 1-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0276] 1-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0277] 2-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1,4-trifluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0278] 2-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1,4-trifluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0279] 2-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1,4-trifluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0280] 2-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1,4-trifluoro-6-azaspiro[2.5]octane-6-sulfonamide;

[0281] 1,1,4-Trifluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0282] 1,1,4-Trifluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0283] 1,1,4-Trifluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0284] 1,1-Difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0285] 1-Fluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0286] 1-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-2-methyl-6-azaspiro[2.5]octane-6-sulfonamide;

[0287] 2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-1,1-dimethyl-6-azaspiro[2.5]octane-6-sulfonamide;

[0288] 1,1-Difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide;

[0289] 1-[5-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]-6-(methylsulfonyl)-6-azaspiro[2.5]octane;

[0290] 1,1-Difluoro-2-[5-(piperidin-1-yl)-1,2,4-thiadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0291] 1,1-Difluoro-2-[5-(piperidin-1-yl)-1,2,4-thiadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide;

[0292] 3'-[5-(2,5-dimethylphenyl)-1,2,4-oxadiazol-3-yl]-2',2'-difluoro-3-azaspiro[bicyclo[3.2.1]octane-8,1'-cyclopropane]-3-sulfonamide; and

[0293] 2-[5-(2,5-Dimethylphenyl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-5-methyl-6-azaspiro[2.5]octane-6-sulfonamide.

[0294] Other embodiments of the present invention include the following:

[0295] (a) A pharmaceutical composition comprising a compound of formula I or II and a pharmaceutically acceptable carrier.

[0296] (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; β-secretase inhibitors such as vilrostat and AZD3293; M4 mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs; 5-HT6 antagonists such as idalopirdine, RVT-101, AVN-101, AVN322, SUVN-502 and SYN-120; histamine H3 receptor antagonists such as S38093; PDE4 inhibitors such as HT0712; PDE9 inhibitors such as BI40936; HDAC6 inhibitors; antipsychotics; LRRK2 inhibitors; MAO-B inhibitors; and levodopa.

[0297] (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.

[0298] (d) a pharmaceutical combination of (i) a compound of Formula I or II and (ii) a second therapeutic agent selected from: an acetylcholinesterase inhibitor such as donepezil, rivastigmine and galantamine; an NMDA receptor antagonist such as memantine; a β-secretase inhibitor such as viroxetine and AZD3293; M4 mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs; 5-HT6 antagonists such as idalopirdine, RVT-101, AVN-101, AVN322, SUVN-502 and SYN-120; histamine H3 receptor antagonists such as S38093; PDE4 inhibitors such as HT0712; PDE9 inhibitors such as BI40936; HDAC6 inhibitors; antipsychotics; LRRK2 inhibitors; MAO-B inhibitors; and levodopa, wherein the compound of Formula I or II and the second therapeutic agent are each employed in an amount that imparts a combination effective treatment for cognitive impairment associated with Alzheimer's disease, Parkinson's disease or schizophrenia.

[0299] (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.

[0300] (f) Use of a compound of formula I or II in the preparation of a medicament for modulating α7 nAChR activity in a subject in need thereof.

[0301] (g) Use of a compound of formula I or II for the preparation of a medicament for treating cognitive impairment associated with Alzheimer's disease, Parkinson's disease and schizophrenia in a subject in need thereof.

[0302] (h) A method of treating cognitive impairment associated with Alzheimer's disease, Parkinson's disease and schizophrenia and / or reducing the likelihood or severity of symptoms of cognitive impairment associated with Alzheimer's disease, Parkinson's disease and schizophrenia in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I or II.

[0303] (i) The method of (h), wherein the compound of Formula I or II is administered in combination with an effective amount of at least one second therapeutic agent selected from: acetylcholinesterase inhibitors such as donepezil, rivastigmine and galantamine; NMDA receptor antagonists such as memantine; β-secretase inhibitors such as vilrostat and AZD3293; M4 mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs; 5-HT6 antagonists such as idalopirdine, RVT-101, AVN-101, AVN322, SUVN-502 and SYN-120; histamine H3 receptor antagonists such as S38093; PDE4 inhibitors such as HT0712; PDE9 inhibitors such as BI40936; HDAC6 inhibitors; antipsychotics; LRRK2 inhibitors; MAO-B inhibitors; and levodopa.

[0304] (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.

[0305] (k) A method of modulating α7 nAChR activity in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of (a), (b) or (c) or a combination of (d) or (e).

[0306] (l) A method of treating cognitive impairment associated with Alzheimer's disease, Parkinson's disease and schizophrenia and / or reducing the likelihood or severity of symptoms of cognitive impairment associated with Alzheimer's disease, Parkinson's disease and schizophrenia in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of (a), (b) or (c) or a combination of (d) or (e).

[0307] In the embodiments of compounds and salts provided above, it is understood that each embodiment can be combined with one or more other embodiments to the extent that this combination provides a stable compound or salt and is consistent with the description of the embodiment. It is also understood that the embodiments of the compositions and methods provided above in (a) to (l) are understood to include all embodiments of compounds and / or salts, including such embodiments resulting from combinations of embodiments.

[0308] Additional embodiments of the present invention include the pharmaceutical compositions, combinations, uses and methods described above in (a) to (l), wherein the compound of the present invention employed is a compound of one of the embodiments, aspects, classes, subclasses or features of the above-mentioned compounds. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate.

[0309] The present invention also includes compounds of the present invention for (i) use in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) preventing or treating cognitive impairment associated with Alzheimer's disease, Parkinson's disease, schizophrenia and L-DOPA-induced dyskinesia, or (b) treating cognitive impairment associated with and / or reducing the likelihood or severity of symptoms of cognitive impairment associated with Alzheimer's disease, Parkinson's disease, schizophrenia and L-DOPA-induced dyskinesia, or (c) for use in medicine. In these uses, the compounds of the 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; β-secretase inhibitors such as vilrostat and AZD3293; M4 mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs; 5-HT6 antagonists such as idalopirdine, RVT-101, AVN-101, AVN322, SUVN-502 and SYN-120; histamine H3 receptor antagonists such as S38093; PDE4 inhibitors such as HT0712; PDE9 inhibitors such as BI40936; HDAC6 inhibitors; antipsychotics; LRRK2 inhibitors; MAO-B inhibitors; and levodopa.

[0310] Chemical names, common names, and chemical structures are used interchangeably to describe the same structure. If both a chemical structure and a chemical name are used to refer to a chemical compound and there is an ambiguity between the structure and the name, the structure should be considered dominant.

[0311] As used herein, the term "5-membered heteroaryl ring" refers to a stable unsaturated 5-membered ring containing 1 to 4 heteroatoms selected from O, N and S. 5-membered heteroaryl rings within the scope of this definition include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl and triazolyl.

[0312] In another embodiment, the "5-membered heteroaryl ring" is furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl and triazolyl.

[0313] As used herein, the term "administration" and variations thereof (e.g., "administering" a compound) with respect to a compound of the invention refers to providing the compound to an 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 variations thereof are each understood to include both simultaneous and sequential administration of the compound or salt and the other agent.

[0314] The term "alkenyl" refers to a straight or branched hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Up to four carbon-carbon double bonds may be present. Thus, "C 2 -C 6 "Alkenyl" refers to an alkenyl radical having 2 to 6 carbon atoms. Thus, "C 2 -C 4 "Alkenyl" refers to an alkenyl radical having 2 to 4 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl, 3-methylbutenyl, and the like. In one embodiment, the alkenyl group is straight-chained. In another embodiment, the alkenyl group is branched.

[0315] The term "alkyl" refers to an aliphatic hydrocarbon group in which one of the hydrogen atoms is replaced by a bond. The alkyl group may be straight chain or branched. The alkyl group contains 1 to 8 carbon atoms [(C 1 -C 8 ) alkyl] or 1 to 6 carbon atoms [(C 1 -C 6 ) alkyl] or 1 to 4 carbon atoms [(C 1 -C 4 ) alkyl]. Non-limiting examples of alkyl groups include methyl (Me), ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In one embodiment, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched.

[0316] When the "alkyl" is substituted, the "alkyl" includes alkyl, O-alkyl, S-alkyl and (C=O)-alkyl.

[0317] The term "alkynyl" refers to a straight or branched hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Up to three carbon-carbon triple bonds may be present. Thus, "C 2 -C 6"Alkynyl" refers to an alkynyl radical having 2 to 6 carbon atoms. Thus, "C 2 -C 4 "Alkynyl" refers to an alkynyl radical having 2 to 4 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like. In one embodiment, the alkynyl group is straight-chained. In another embodiment, the alkynyl group is branched.

[0318] The term "aryl" refers to any mono- and poly-carbocyclic ring systems, wherein the individual carbocyclic rings in the polycyclic system are fused or connected to each other via a single bond, and wherein at least one ring is aromatic. Suitable aryl groups include phenyl, indanyl, naphthyl, tetrahydronaphthyl and biphenyl. Where appropriate, an aryl ring system may include an indication of the variables to which a particular ring atom is attached. Unless otherwise indicated, substituents of an aryl ring system may be attached to any ring atom, as long as such attachment results in the formation of a stable ring system.

[0319] In one embodiment, "aryl" is phenyl.

[0320] When the "aryl" is substituted, the "aryl" includes an aryl group and an O-aryl group.

[0321] The term "composition" is intended to encompass a product comprising the specified ingredients, as well as any product resulting from combining the specified ingredients.

[0322] The term "compound" is intended to encompass all forms of a chemical agent described by the general formula I or II. Such a chemical agent may exist in different forms, such as hydrates, solvates and polymorphs.

[0323] As used herein, the term "cycloalkyl" refers to a group containing 3 to 10 ring carbon atoms [(C 3 -C 10 )cycloalkyl] or 3 to 6 ring carbon atoms [(C 3 -C 6 )cycloalkyl] non-aromatic mono- and poly-carbocyclic ring systems, wherein the individual carbocyclic rings in the polycyclic system are fused (including spiro-fused) or connected to each other via a single bond. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[4.1.0]heptyl, spiro[2.4]heptyl, spiro[3.3]heptyl, spiro[2.5]octyl and cycloheptyl. The ring carbon atoms of the cycloalkyl group can be functionalized as a carbonyl group. Illustrative examples of such cycloalkyl groups (also referred to herein as "cycloalkanoyl" groups) include, but are not limited to, cyclobutanoyl:

[0324]

[0325] When the "cycloalkyl" is substituted, the "cycloalkyl" includes cycloalkyl, O-cycloalkyl and (C=O)-cycloalkyl.

[0326] In one embodiment, "cycloalkyl" is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0327] As used herein, the term "effective amount" refers to the amount of an active compound or agent that elicits a biological or medical response in a tissue, system, animal, or human that is being sought by a researcher, veterinarian, physician, or other clinician. In one embodiment, an effective amount is a "therapeutically effective amount" that alleviates one or more symptoms of the disease or condition being treated. In another embodiment, an effective amount is a "prophylactically effective amount" that reduces the severity or likelihood of one or more symptoms of the disease or condition. The term also includes herein the amount of active compound sufficient to modulate α7 nAChR activity and thereby elicit the response being sought (i.e., a "therapeutically effective amount"). When the active compound (i.e., active ingredient) is administered in salt form, the amount of active ingredient referred to is with respect to the free acid or free base form of the compound.

[0328] The term "halogen" (or "halo") refers to fluorine, chlorine, bromine, and iodine atoms (alternatively referred to as fluoro (F), chloro (Cl), bromo (Br), and iodo (I)).

[0329] As used herein, the term "heteroaryl" refers to any monocyclic or polycyclic ring system comprising 5 to 14 ring atoms, wherein 1 to 4 ring atoms are independently O, N or S, the remaining ring atoms are carbon atoms, and wherein at least one ring is aromatic. In one embodiment, the heteroaryl group has 5 to 10 ring atoms. In another embodiment, the heteroaryl group is monocyclic and has 5 to 6 ring atoms. In another embodiment, the heteroaryl group is bicyclic and has 9 or 10 ring atoms. The heteroaryl group is usually joined via a ring carbon atom, but can also be joined via a non-carbon atom, as long as a stable compound is produced, and any nitrogen atom of the heteroaryl group can be optionally oxidized to the corresponding N-oxide. The term "heteroaryl" also encompasses a heteroaryl group as defined above fused to a benzene ring. The term "heteroaryl" also encompasses any fused polycyclic ring system containing at least one ring heteroatom 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 fused to a benzene or pyridine ring. Non-limiting examples of heteroaryl include benzimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, naphthazinyl, furanyl, imidazolyl, indolinyl, indolyl, indolizinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthopyridinyl, oxadiazolyl, oxazolyl , pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolyl pyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydroindole, dihydroquinolyl and methylenedioxybenzoyl etc. and all isomeric forms thereof. The term "heteroaryl" also refers to partially saturated heteroaryl moieties, such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl etc., as long as they contain at least one aromatic ring. In one embodiment, the heteroaryl group is a 5-membered heteroaryl. In another embodiment, the heteroaryl group is a 6-membered heteroaryl. In another embodiment, the heteroaryl group comprises a 5- to 6-membered heteroaryl group fused to a benzene ring.

[0330] In one embodiment, "heteroaryl" is benzimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolyl, naphthazinyl, furanyl, imidazolyl, dihydroindolinyl, indolyl, indolizinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridinyl, thiadiazolyl, thiazolyl, thienyl or triazolyl.

[0331] In another embodiment, "heteroaryl" is carbazolyl, carbolyl, naphthazinyl, furanyl, imidazolyl, indolinyl, indolyl, indolizinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridinyl, thiadiazolyl, thiazolyl, thienyl or triazolyl.

[0332] In another embodiment, "heteroaryl" is furanyl, imidazolyl, indolinyl, indolyl, indolizinyl, indazolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl.

[0333] As used herein, the term "heterocycle" or "heterocyclyl" is intended to refer to a 3- to 10-membered non-aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from O, N and S, and includes monocyclic or bicyclic groups (fused, bridged or spiro). Other 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, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotriazolyl, tetrahydrofuranyl, and tetrahydrothiophenyl and N-oxides thereof. Attachment of heterocyclyl substituents may be via a carbon atom or via a heteroatom.

[0334] In one embodiment, "heterocycle" or "heterocyclyl" is oxazoline, isoxazoline, oxetanyl, tetrahydropyranyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl.

[0335] In one embodiment, the "heterocycle" or "heterocyclyl" is dihydrofuranyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotriazolyl, tetrahydrofuranyl or tetrahydrothiophenyl.

[0336] "Pharmaceutically acceptable" means the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.

[0337] As used herein, the term "preventing" with respect to Alzheimer's disease or other neurological diseases means reducing the likelihood of disease progression.

[0338] As used herein, the term "subject" (alternatively referred to herein as "patient") refers to an animal, preferably a mammal, most preferably a human.

[0339] The term "substituted" means that one or more hydrogens on the designated atom are replaced with a group selected from the indicated group, as long as the normal valence of the designated atom in the existing situation is not exceeded and the substitution results in a stable compound. Unless explicitly stated to the contrary, substitutions may be made with designated substituents on any atom, as long as such substitutions are chemically permitted and result in a stable compound. Combinations of substituents and / or variables are permitted only if such combinations result in stable compounds. A "stable" compound is one that can be prepared and isolated and whose structure and properties remain substantially unchanged or can be left substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

[0340] In another embodiment of Formula I, X is S(O) 2 .

[0341] In another embodiment of Formula I, X is C(O).

[0342] In another embodiment of Formula I, R 1 NR a R b .

[0343] In another embodiment of Formula I, R 1 For R c .

[0344] In another embodiment of Formula I, R a H, (C 1 -C 4 ) alkyl or (C 3 -C 6 )cycloalkyl, wherein the alkyl is optionally substituted with phenyl, pyridyl or isothiazolyl.

[0345] In another embodiment of Formula I, R a H or (C 1 -C 4 )alkyl.

[0346] In another embodiment of Formula I, R a It is H or methyl.

[0347] In another embodiment of Formula I, R a For H.

[0348] In another embodiment of Formula I, R b It is H or methyl.

[0349] In another embodiment of Formula I, R b For H.

[0350] In another embodiment of Formula I, R c For (C 1 -C 4 )alkyl, thienyl, pyrazolyl, benzoxadiazolyl, benzothiazolyl or oxadiazolyl, wherein the thienyl, pyrazolyl, benzoxadiazolyl and oxadiazolyl are optionally substituted with one or more methyl or hydroxy groups, and wherein the alkyl is optionally substituted with pyridyl, tetrahydropyranyl, isothiazolyl or phenyl.

[0351] In another embodiment of Formula I, R c It is methyl.

[0352] In another embodiment of Formula I, -XR 1 -(C=O)-R 1 .

[0353] In another embodiment of Formula I, -XR 1 for

[0354]

[0355] In another embodiment of Formula I or II, A (or Ring A) is oxadiazolyl, thiazolyl, pyrazolyl, thiadiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, furanyl, thienyl, triazolyl or pyrrolyl.

[0356] In another embodiment of Formula I or II, A (or Ring A) is oxadiazolyl, thiazolyl, pyrazolyl, thiadiazolyl, oxazolyl, isoxazolyl, or imidazolyl.

[0357] In another embodiment of Formula I or II, A (or Ring A) is oxadiazolyl, thiazolyl, oxazolyl, pyrazolyl, isoxazolyl or thiadiazolyl.

[0358] In another embodiment of Formula I or II, A (or Ring A) is oxadiazolyl, oxazolyl, isoxazolyl or thiazolyl.

[0359] In another embodiment of Formula I, the R group is selected from OH, oxo, NR 6 R 7 , CN, alkoxy, halogen, aminoalkyl, hydroxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein the R group selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally replaced by one or more independently selected from R 11 substituted by a substituent.

[0360] In another embodiment of Formula I, the R groups are independently selected from NR 6 R 7 、CN、(C 1 -C 4 ) alkoxy, halogen, (C 1 -C 4 ) alkyl, (C 3 -C 8 ) cycloalkyl, phenyl, indanyl, tetrahydronaphthyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, tetrahydrocyclopentapyrazolyl, imidazopyridinyl, indolyl, tetrahydropyrazolopyridinyl, dihydropyrrolopyrazolyl, pyridazinyl, pyrazolothiazolyl and piperidinyl, wherein the alkoxy, alkyl, cycloalkyl, indanyl, tetrahydronaphthyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, tetrahydrocyclopentapyrazolyl, imidazopyridinyl, indolyl, tetrahydropyrazolopyridinyl, dihydropyrrolopyrazolyl, pyridazinyl, pyrazolothiazolyl and piperidinyl are optionally substituted by one or more independently selected from R 11 substituted by a substituent.

[0361] In another embodiment of Formula I, R is selected from (C 3 -C 8 )cycloalkyl, phenyl, indanyl, tetrahydronaphthyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, tetrahydrocyclopentapyrazolyl, imidazopyridinyl, indolyl, tetrahydropyrazolopyridinyl, dihydropyrrolopyrazolyl, pyridazinyl, pyrazolothiazolyl and piperidinyl, each of which is optionally substituted by one or more independently selected R 11 substituted by a substituent.

[0362] In another embodiment of Formula I, R is cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazolyl, pyridinyl or isoxazolyl, each of which is optionally substituted by one or more independently selected from F, Cl, Br, methyl, methoxy, ethyl, ethoxy, propyl, CF 3 , CH 2 CF 3 、OCH 3 , OCHF 2 、OCH 2 CF 3 , cyclopropyl, NR 6 R 7 and CN substituents.

[0363] In another embodiment of Formula I, R is selected from phenyl, pyrazolyl, pyridinyl and isoxazolyl, wherein the phenyl, pyrazolyl, pyridinyl and isoxazolyl are optionally substituted by one or more independently selected from F, Cl, Br, methyl, methoxy, ethyl, ethoxy, propyl, CF 3 , CH 2 CF 3 、OCH 3 , OCHF 2 、OCH 2 CF 3 , cyclopropyl, NR 6 R 7 and CN substituents.

[0364] In another embodiment of Formula I, n is 0, 1 or 2.

[0365] In another embodiment of Formula I, n is 0 or 1.

[0366] In another embodiment of Formula I, n is 0.

[0367] In another embodiment of Formula I, R 2 are independently halogen or (C 1 -C 4 ) alkyl, wherein the alkyl is optionally substituted with one or more halogens;

[0368] Or, when both are (C 1 -C 4 ) alkyl and attached to the same carbon atom, the two R 2 Optionally, they may form a cyclopropyl, cyclobutyl or cyclopentyl ring together, or, when all are (C 1 -C 4 ) alkyl and are not attached to the same carbon atom, optionally together may form a bridged ring, wherein the cyclopropyl, cyclobutyl, cyclopentyl or bridged ring may be optionally substituted by one or more independently selected from OH, halogen or (C 1-C 4 ) is substituted by an alkyl substituent.

[0369] In another embodiment of Formula I, R 2 are independently halogen, methyl or ethyl, wherein the methyl or ethyl is optionally substituted with one or more halogens;

[0370] Alternatively, when both are methyl or ethyl and are attached to the same carbon atom, the two R 2 Optionally they may be taken together to form a cyclopropyl, cyclobutyl or cyclopentyl ring or, when both are methyl or ethyl and are not attached to the same carbon atom, may be taken together to form a bridged ring.

[0371] In another embodiment of Formula I, R 2 is F or methyl.

[0372] In another embodiment of Formula I or II, R 3 is H, F or methyl.

[0373] In another embodiment of Formula I or II, R 4 is H, F or methyl.

[0374] In another embodiment of Formula I or II, R 3 and R 4 The cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl rings may be optionally substituted with one or more cycloalkyl radicals independently selected from OH, halogen or (C 1 -C 4 ) is substituted by an alkyl substituent.

[0375] In another embodiment of Formula I or II, R 3 and R 4 Optionally, they may be joined together to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

[0376] In another embodiment of Formula I, R 5 It is H or methyl.

[0377] In another embodiment of Formula I, R 5 For H.

[0378] In another embodiment of Formula I, R 6 It is H or Me.

[0379] In another embodiment of Formula I, R 7 It is H or Me.

[0380] In another embodiment of Formula I, R 8 OH, (C 1 -C 4)alkyl, phenyl, pyridyl or isothiazolyl.

[0381] In another embodiment of Formula I, R 8 is phenyl, pyridyl or isothiazolyl.

[0382] In another embodiment of Formula I, R 9 It is pyridyl, tetrahydropyranyl or phenyl.

[0383] In another embodiment of Formula I, R 10 is methyl or hydroxy.

[0384] In another embodiment of Formula I, R 11 Halogen, OH, oxo, CF 3 、OCF 3 、CN、(C 1 -C 4 ) alkyl, O(C 1 -C 4 )alkyl, S(C 1 -C 4 )alkyl, C=O(C 1 -C 4 ) alkyl, NR 12 R 13 、(C=O)NR 6 R 7 、(C=O)OR 6 , (C 2 -C 4 ) alkynyl, (C 3 -C 6 )cycloalkyl, O(C 3 -C 6 )cycloalkyl, C=O(C 3 -C 6 ) cycloalkyl, aryl, O-aryl, heteroaryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally independently substituted with one or more halogen, (C 1 -C 4 ) alkyl, (C 3 -C 6 )cycloalkyl, CF 3 、OCF 3 、OCH 3 , CN, OH and oxo.

[0385] In another embodiment of Formula I, R 11 F, Cl, Br, OH, NR 12 R 13 CF 3 、OCF 3 、CN、(C1 -C 4 ) alkyl, O(C 1 -C 4 ) alkyl, (C 3 -C 6 )cycloalkyl, O(C 3 -C 6 ) cycloalkyl, phenoxy, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl or imidazolyl, wherein the alkyl, cycloalkyl, phenoxy, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl and imidazolyl are optionally substituted by one or more independently selected from halogen, (C 1 -C 4 )alkyl, CN and OH, wherein the alkyl is optionally substituted with one or more fluorine.

[0386] In another embodiment of Formula I, R 11 F, Cl, Br, OH, NR 12 R 13 CF 3 、OCF 3 、CN、(C 1 -C 4 ) alkyl, O(C 1 -C 4 ) alkyl, (C 3 -C 6 )cycloalkyl, O(C 3 -C 6 ) cycloalkyl, phenoxy, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl or imidazolyl, wherein the alkyl, cycloalkyl, phenoxy, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl and imidazolyl are optionally substituted by one or more independently selected from halogen, (C 1 -C 4 )alkyl, CN and OH, wherein the alkyl is optionally substituted with one or more fluorine.

[0387] In another embodiment of Formula I, R 11 F, Cl, Br, methyl, methoxy, ethyl, ethoxy, propyl, CF 3 , CH 2 CF 3 、OCH 3 , OCHF 2 、OCH 2 CF 3 , cyclopropyl, NR 12 R 13 or CN.

[0388] In another embodiment of Formula I, R 11F, Cl, Br, methyl, methoxy, ethyl, ethoxy, propyl, -CH 2 OH, -CH 2 CH 2 OH, -CF 3 、-CH 2 CF 3 、-OCF 3 、-OCHF 2 、-OCH 2 CF 3 Or cyclopropyl.

[0389] In another embodiment of Formula I, R 12 H or (C 1 -C 4 )alkyl.

[0390] In another embodiment of Formula I, R 13 H or (C 1 -C 4 )alkyl.

[0391] In another embodiment of Formula II, m is 0, 1, 2 or 3.

[0392] In another embodiment of Formula II, m is 0, 1 or 2.

[0393] In another embodiment of Formula II, m is 0 or 1.

[0394] In the compounds of Formula I or II, the atoms may have their natural isotopic abundance, or one or more atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is intended to include all suitable isotopic variants of the compounds of Formula I or II. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H or D). Protium is the main isotope of hydrogen found in nature. Enrichment with deuterium can provide certain therapeutic advantages, such as increasing half-life in vivo or reducing dosage requirements, or can provide compounds that can be used as standards for characterizing biological samples. Isotopically enriched compounds within Formula I or II can be prepared without undue experimentation using suitable isotopically enriched reagents and / or intermediates by conventional techniques known to those skilled in the art or by methods similar to those described in the schemes and embodiments herein.

[0395] Unless expressly indicated to the contrary, all ranges cited herein 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 cited herein includes within its scope all subranges within that range. Oxidized forms of the heteroatoms N and S are also included within the scope of the present invention.

[0396] It will be appreciated by those skilled in the art that carbon atoms in organic molecules can often be replaced by silicon atoms to obtain similar stable compounds. For example, carbon atoms in alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl groups can often be replaced by silicon atoms to provide stable compounds. All such compounds are within the scope of the present invention.

[0397] When any variable (e.g., R) occurs more than one time in any constituent or in Formula I or in any other formula depicting and describing compounds of the invention, its definition on each occurrence is independent of its definition at every other occurrence. Additionally, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0398] Certain compounds of the present invention may have asymmetric centers and may exist as mixtures of stereoisomers or as individual diastereomers or enantiomers. All isomeric forms of these compounds, whether separated or in mixture, are within the scope of the present invention.

[0399] Certain compounds of the present invention may exist as tautomers. For purposes of the present invention, reference to a compound of Formula I or II is a reference to the compound itself, or any one of its tautomers itself, or a mixture of two or more tautomers.

[0400] The compounds of the present invention may be useful in preventing, treating or improving Alzheimer's disease. The compounds may also be used to prevent, treat or improve other diseases mediated by α7 nAChR, such as schizophrenia, sleep disorders, Parkinson's disease, autism, microdeletion syndrome, inflammatory diseases, pain disorders (including acute pain, inflammatory pain and neuropathic pain) and cognitive disorders (including mild cognitive impairment). Other conditions that the compounds of the present invention may prevent, treat or improve include pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, trisomy 21 (Down syndrome), cerebral amyloid angiopathy, degenerative dementia, hereditary cerebral hemorrhage with Dutch amyloidosis (HCHWA-D), Creutzfeldt-Jakob disease, prion disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, kidney disease, cancer and atherosclerosis.

[0401] In a preferred embodiment, the compounds of the present invention may be used to prevent, treat or improve Alzheimer's disease, cognitive disorders, schizophrenia, pain disorders and sleep disorders. For example, the compounds may be used to prevent Alzheimer's dementia, and to treat early, middle or late stage Alzheimer's dementia.

[0402] Potential schizophrenia conditions or disorders for which the compounds of the invention may be useful include one or more of the following conditions or diseases: schizophrenia or psychosis, including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamines and other psychostimulants and cocaine) psychotic disorder, psychotic disorder associated with affective disorder, brief reactive psychosis, schizophrenia. Affective psychoses, "schizophrenia spectrum" disorders such as schizophreniform or schizotypal personality disorders, or disorders related to psychosis (such as major depression, manic-depressive (bipolar) disorder, Alzheimer's disease, and post-traumatic stress syndrome), including positive and negative symptoms of schizophrenia and other psychoses; Cognitive disorders, including dementia (related to Alzheimer's disease, ischemic, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, perinatal hypoxia, other general medical conditions, or substance abuse); Delirium, amnesia, or age-related cognitive decline.

[0403] Therefore, in another specific embodiment, the present invention provides a method for preventing, treating or ameliorating schizophrenia or psychosis, comprising administering an effective amount of a compound of the present invention to a patient in need thereof. Currently, the text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington, DC) provides a diagnostic tool that includes paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorders. As used herein, the term "schizophrenia or psychosis" includes treatments for those mental disorders as described in the DSM-IV-TR. Those skilled in the art will recognize that there are alternative nomenclatures, nosologies, and classification systems for mental disorders, and that these systems develop as medicine and science advance. Therefore, the term "schizophrenia or psychosis" is intended to include similar conditions described in other diagnostic sources.

[0404] Potential sleep conditions or disorders for which the compounds of the invention may be useful include enhancing sleep quality; improving sleep quality; enhancing sleep maintenance; increasing the value calculated from the time a subject sleeps divided by the time a subject attempts to sleep; reducing sleep latency or onset (the time it takes to fall asleep); reducing difficulty falling asleep; increasing sleep continuity; reducing the number of awakenings during sleep; reducing nighttime awakenings; reducing the time spent awake after the initial onset of sleep; reducing sleep latency or onset (the time it takes to fall asleep); reducing difficulty falling asleep; increasing sleep continuity; reducing the number of awakenings during sleep; reducing nighttime awakenings; reducing the time spent awake after sleep onset; increasing the total amount of sleep; reducing sleep fragmentation; altering the timing, frequency, or duration of REM sleep episodes; altering the timing, frequency, or duration of slow wave (i.e., stage 3 or 4) sleep episodes; increasing stage 2 sleep The invention relates to the treatment of: a) reducing the amount and percentage of sleep; b) promoting slow-wave sleep; c) enhancing EEG-delta activity during sleep; c) increasing daytime alertness; c) reducing daytime sleepiness; d) treating or reducing excessive daytime sleepiness; d) insomnia; drowsiness; d) narcolepsy; d) disrupted sleep; d) sleep apnea; d) wakefulness; d) nocturnal myoclonus; d) REM sleep disruption; d) jet lag; d) shift worker sleep disorder; d) sleep disturbances; d) night terrors; d) insomnia associated with depression; d) affective / mood disorders; and d) somnambulism and enuresis; d) sleep disorders associated with aging; d) Alzheimer's disease sundowning syndrome; d) conditions related to circadian rhythms and mental and physical disorders associated with travel across time zones and shift work schedules; d) conditions caused by medications that cause a decrease in REM sleep as a side effect; d) syndromes associated with breathing disorders during sleep, manifested as non-restorative sleep and muscle pain or sleep apnea; and d) conditions caused by decreased sleep quality.

[0405] Pain disorders for which the compounds of the invention may be useful include neuropathic pain (e.g., post-herpetic neuralgia, nerve injury, dynias such as vulvodynia, phantom limb pain, radicular avulsions, painful diabetic neuropathy, painful traumatic mononeuropathy, painful polyneuropathy); central pain syndromes (which may be caused by virtually any lesion at any level of the nervous system); postoperative pain syndromes (e.g., post-mastectomy syndrome, post-thoracotomy syndrome, stump pain); bone and joint pain (osteoarthritis); repetitive motion pain; dental pain; cancer pain; myofascial pain (muscle injury, fibromyalgia); perioperative pain (general surgery, obstetrics and gynecology); chronic pain; dysmenorrhea, as well as pain associated with angina, and inflammatory pain of various origins (e.g., osteoarthritis, rheumatoid arthritis, rheumatism, tenosynovitis, and gout); headaches; migraine and cluster headaches; primary hyperalgesia; secondary hyperalgesia; primary allodynia; secondary allodynia; or other pain caused by central sensitization.

[0406] Potential conditions or disorders with a strong inflammatory component for which the compounds of the invention may be useful include one or more of the following conditions or diseases: diabetes (systemic inflammation in diabetes is characterized by increased blood cytokines such as IL-6 and TNFα, which may lead to insulin resistance); asthma; arthritis; cystic fibrosis; sepsis; ulcerative colitis; inflammatory bowel disease; atherosclerosis; neuroinflammation associated with neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, frontotemporal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy, traumatic brain injury, Huntington's disease, amyotrophic lateral sclerosis).

[0407] The compounds of the present invention can also be used to treat or prevent or improve movement disorders and prevent neurodegeneration in nigrostriatal neurons in Parkinson's disease. In addition, the compounds of the present invention can be used to reduce tolerance and / or dependence on opioids for pain treatment and for the treatment of withdrawal syndromes such as alcohol, opioids and cocaine.

[0408] 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 is biologically or otherwise undesirable (e.g., non-toxic and harmless to its recipient). Suitable salts include acid addition salts, which can be formed, for example, by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or benzoic acid. Many compounds of the present invention have an acidic moiety, in which case a suitable pharmaceutically acceptable salt thereof can include an alkali metal salt (e.g., sodium or potassium salt), an alkaline earth metal salt (e.g., calcium or magnesium salt) and a salt formed with a suitable organic ligand such as a quaternary ammonium salt. In addition, in the presence of an acid (-COOH) or alcohol group, a pharmaceutically acceptable ester can be used to change the solubility or hydrolysis characteristics of the compound.

[0409] Exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate ("mesylate"), naphthylate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), and the like. In addition, acids generally considered suitable for forming pharmaceutically acceptable salts from basic drug compounds are discussed in, for example, P. Stahl et al., Camille G. (ed.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1): 1-19; P. Gould, International J. of Pharmaceutics (1986) 33: 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC, on its website).

[0410] Exemplary basic salts include ammonium salts, alkali metal salts (such as sodium salts, lithium salts and potassium salts), alkaline earth metal salts (such as calcium salts and magnesium salts), salts with organic bases (e.g., organic amines) (such as dicyclohexylamine, tert-butylamine, choline) and salts with amino acids (such as arginine, lysine, etc.). Basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides (e.g., methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl and dibutyl sulfate), long chain halides (e.g., decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like.

[0411] For the purpose of preventing, treating or improving Alzheimer's disease, Parkinson's disease, cognitive impairment in schizophrenia, L-DOPA-induced dyskinesia and inflammation, the compounds of the present invention can be administered by any means that will produce contact between the active agent and the site of action of the active agent, optionally in the form of a salt. They can be administered as a single therapeutic agent or as a combination of therapeutic agents by one or more conventional measures that can be used in combination with drugs. They can be administered alone, but are usually administered together with a pharmaceutical carrier selected based on the selected route of administration and standard pharmaceutical practice procedures. The compounds of the present invention can be administered, for example, in the form of a unit dose of a pharmaceutical composition by one or more of the following: orally, parenterally (including subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion technology), by inhalation (such as in the form of a spray), or rectally, wherein the pharmaceutical composition contains an effective amount of the compound and conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Liquid preparations suitable for oral administration (e.g., suspensions, syrups, elixirs, etc.) can be prepared according to techniques known in the art and can use any common medium such as water, glycols, oils, alcohols, etc. Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can use solid excipients such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc. Parenteral compositions can be prepared according to techniques known in the art and usually use sterile water (as a carrier) and optionally other ingredients such as cosolvents. Injectable solutions can be prepared according to methods known in the art, wherein the carrier comprises a salt solution, a glucose solution or a solution containing a mixture of salt and glucose. Further descriptions of methods suitable for preparing the pharmaceutical compositions of the present invention and ingredients suitable for use in the compositions are described in Remington's Pharmaceutical Sciences, 18 th edition (ed. AR Gennaro, Mack Publishing Co., 1990).

[0412] The compounds of the present invention can be orally administered in a dosage range of 0.001 to 1000 mg / kg mammal (e.g., human) body weight / day in a single dose or divided dose. One dosage range is 0.01 to 500 mg / kg body weight / day orally in a single dose or divided dose. Another dosage range is 0.1 to 100 mg / kg body weight / day orally in a single dose or divided dose. For oral administration, the composition can be provided in the form of tablets or capsules containing 1.0 to 500 mg of active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400 and 500 mg of active ingredient to adjust the dosage of the patient to be treated according to the symptoms. The specific dosage level and frequency of administration for any particular patient may vary and will depend on a variety of factors, including the activity of the specific compound employed, the metabolic stability and duration of action of the 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.

[0413] As described above, the present invention also relates to a method for preventing, treating or ameliorating Alzheimer's disease, Parkinson's disease, cognitive impairment in schizophrenia, L-DOPA-induced movement disorders and inflammation using a combination of the compounds of the present invention and one or more therapeutic agents, as well as a pharmaceutical composition comprising the compounds of the present invention and one or more therapeutic agents, wherein the therapeutic agent is selected from: anti-Alzheimer's disease drugs, such as β-secretase inhibitors; M1mAChR agonists or PAMs; M4mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs; ADAM 10 ligands or activators; γ-secretase inhibitors, such as LY450139 and TAK 070; γ-secretase modulators; τ phosphorylation inhibitors; glycine transport inhibitors; LXRβ 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 zaliproden; 5-HT1a antagonists such as lecozotan; p25 / CDK5 inhibitors; NK1 / NK3 receptor antagonists; COX-2 inhibitors; LRRK2 inhibitors; HMG-CoA reductase inhibitors; NSAIDs, including ibuprofen; vitamin E; anti-amyloid antibodies (including anti-amyloid humanized monoclonal antibodies), such as bapineuzumab, ACC001, CAD106, AZD3102, H12A11V1; anti-inflammatory compounds, such as (R)-flurbiprofen, nitroflurbiprofen, ND-1251, VP-0 25, HT-0712 and EHT-202; PPARγ agonists such as pioglitazone and rosiglitazone; CB-1 receptor antagonists or CB-1 receptor inverse agonists such as AVE1625; antibiotics such as doxycycline and rifampicin; N-methyl-D-aspartate (NMDA) receptor antagonists such as memantine, neramexane and EVT101; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, tacrine, fiserin, radotigib and ABT-089; growth hormone secretagogues such as ibuprofen, ibuprofen mesylate and caprorelin; 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, which may improve the efficacy, safety, convenience or reduce the adverse side effects or toxicity of the compounds of the present invention. .

[0414] Examples of combinations of the compounds of the present invention include combinations with agents for the treatment of schizophrenia, such as sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolone, imidazopyridine, pyrazolopyrimidine, weak tranquilizers, melatonin agonists and antagonists, melatonergic drugs, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as adizalam, allobarbital, spironaphthalene, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, alevetrile, and the like. Prazole, benzazepam, benzotamine, brotizolam, bupropion, buspirone, butalbital, ethylvaleryl urea, carbochloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, chlorpiperaquinone, chlordiazepoxide, methotrexate, chlorpromazine, clozapine, ciproazepam, norimipramine, cypromazine, diazepam, dichloralphenazone, divalproex sodium, diphenhydramine, doxepin, estazolam, etomidate, fenobant, flunitrazepam, flupentixol, fluphenazine Naijing, flurazepam, fluvoxamine, fluoxetine, fosazepam, phenacetin, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, chloroquine, melatonin, methylphenobarbital, aminopropyl ester, methaqualone, midaflutol, midazolam, nefazodone, nisolbamate, nitrazepam, nortriptyline, olanzapine, oxazepam, trimethoprim, paroxetine, pentobarbital, perampapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, Quazepam, quetiapine, resclozepam, risperidone, loremide, secobarbital, sertraline, thiopropanone, temazepam, thioridazine, thiothixene, tracazolate, tranylcypromine, trazodone, triazolam, bismethoxybenzazepam, trimethoxyphenylacetamide, trichloroethyl phosphate, trifluoperazine, trimetozine, trimipramine, udazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem and salts thereof and combinations thereof, etc., or the subject compounds can be administered in combination with physical methods such as the use of light therapy or electrical stimulation.

[0415] In another embodiment, the compounds of the present invention can be used in combination with the following drugs: levodopa (with or without selective extracerebral decarboxylase inhibitors such as carbidopa or benserazide), anticholinergics such as biperiden (optionally in the form of its hydrochloride or lactate) and trihexyphenidyl hydrochloride (benhexyphenidyl); COMT inhibitors such as entacapone; MAO-B inhibitors; antioxidants; A2a adenosine receptor antagonists; cholinergic agonists; NMDA receptor antagonists; 5-hydroxytryptamine receptor antagonists and dopamine receptor agonists such as alentimod, bromocriptine, fenoldopam, lisuride, nagolide, pergolide and pramipexole. It should be understood that the dopamine agonist can be in the form of a pharmaceutically acceptable salt, for example, alentimod hydrobromide, bromocriptine mesylate, fenoldopam mesylate, nagolide hydrochloride and pergolide mesylate.

[0416] In another embodiment, the compounds of the present invention can be used in combination with compounds from the class of phenothiazines, thioxanthenes, heterocyclic dibenzazepines, butyrophenones, diphenylbutylpiperidines and indolones. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of dibenzazepines is clozapine. An example of butyrophenones is haloperidol. An example of diphenylbutylpiperidines is pimozide. An example of indolones is molindone. Other neuroleptics include loxapine, sulpiride and risperidone. It should be understood that when used in combination with the compounds of the present invention, the neuroleptic agent may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, fluphenazine enanthate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are usually used in non-salt form. Thus, the compounds of the present invention may be used in combination with acetophenazine, alentimol, aripiprazole, amisulpride, trihexyphenidyl, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa and benserazide, levodopa and carbidopa, lisuride, loxapine, mesoridazine, molindone, nagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene, trifluoperazine or ziprasidone.

[0417] Examples of combinations of the compounds of the present invention include combinations with agents for treating pain, such as nonsteroidal 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 664784; CB-2 agonists, such as 842166 and SAB378; VR-1 antagonists, such as A MG517, 705498, 782443, PAC20030, V114380, and A425619; bradykinin Bl receptor antagonists, such as SSR240612 and NVPSAA16; 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., GABA-A receptor agonists); matrix metalloproteinase (MMP) inhibitors; thrombolytics; opioid analgesics, such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, dextropropoxyphene; neutrophil inhibitory factor (NIF); pramipexole, ropinirole; anticholinergics; amantadine; monoamine oxidase Bl5 ("MAO-B") inhibitors; 5HT 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 ("SSRIs") and / or selective serotonin and norepinephrine reuptake inhibitors ("SSNRIs"), such as duloxetine; tricyclic antidepressants, norepinephrine modulators; lithium; valproate; gabapentin; pregabalin; rizatriptan; zolmitriptan; naratriptan and sumatriptan.

[0418] The compounds of the present invention can be administered in combination with compounds useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disorders, including, for example, sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, ciclopirox, orexin antagonists, alpha-1 antagonists, GABA agonists, 5HT-2 antagonists (including 5HT-2A antagonists and 5HT-2A / 2C antagonists), histamine antagonists (including histamine H3 antagonists, histamine H3 inverse agonists), imidazopyridines, weak tranquilizers, melatonin agonists and antagonists, melatonergic drugs, other orexin antagonists, orexin agonists, pro-agonists Actinomycin agonists and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, triazolopyridines, etc., such as: adizalam, alobarbital, spironaphthalene, alprazolam, amitriptyline, amobarbital, amoxapine, armodafinil, APD-125, benzazepam, benzotamine, brotizolam, bupropion, buspirone, butabarbital, butalbital, caprorelin, ethylvaleryl urea, carbochloral, chloral betaine, chloral hydrate, methylaminodiazepine, clomipramine, clonazepam, chlorpiperazine, chlordiazepoxide, chlorethyldimethacrylate, clozapine, canazepam, ciprofloxacin, norimipramine, cyproconazole, diazepam, dichloralphenazone, sodium divalproex, diphenhydramine Ming, doxepin, EMD-281014, eliserin, estazolam, eszopiclone, ethclopentyl alcohol, etomidate, fenobant, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol, phenethylperidone, halazepam, hydroxyzine, ibumolem, imipramine, indiprolon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline, MDL-100907, chloroquine, melatonin, methylphenobarbital, aminopropylamine, methaqualone, methyperidone, midaflutol, midazolam, modafinil, nefazodone, NGD-2-73, nisolamide, nitrazepam, nortriptyline, oxazepam, trimerone Aldehyde, paroxetine, pentobarbital, perrapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, ramelteon, resclorazepam, loremide, secobarbital, sertraline, sulprotone, TAK-375, temazepam, thioridazine, thiogabine, tracazolate, tranylcypromine, trazodone, triazolam, bismethoxybenzazepam, trimethoxyphenylacetamide, trichloroethyl phosphate, trifluoperazine, trimetozine, trimipramine, udazepam, venlafaxine, zaleplon, zolazepam, zolpidem, zolpidem and salts thereof and combinations thereof, etc., or the compounds of the present invention can be administered in combination with physical methods such as the use of light therapy or electrical stimulation.

[0419] The compounds of the invention can be used alone or in combination with an NMDA receptor antagonist such as memantine or in combination with an acetylcholinesterase inhibitor (AChEI) such as donepezil for the treatment of moderate to severe dementia of the Alzheimer's type.

[0420] The compounds of the present invention can be used alone or in combination with galantamine, rivastigmine or donepezil for the treatment of mild to moderate dementia of the Alzheimer's type.

[0421] The compounds of the present invention may be used alone or in combination with rivastigmine for the treatment of dementia associated with Parkinson's disease.

[0422] The compounds of the present invention can be used alone or in combination with carbidopa and levodopa for the treatment of symptom fluctuations in patients with advanced Parkinson's disease.

[0423] When the combination therapy of the present invention is administered to a patient, the therapeutic agent in the combination or one or more pharmaceutical compositions comprising the therapeutic agent can be administered in any order, such as, for example, sequentially, concurrently, together, simultaneously, etc. The amounts of the various actives in such a combination therapy can be different amounts (different dosage amounts) or the same amount (same dosage amount). The compound of the present invention and the additional therapeutic agent can be present in a single dosage unit (e.g., capsule, tablet, etc.) in a fixed amount (dosage amount).

[0424] The α7 nAChR positive allosteric modulator (PAM) activity of the compounds of the invention can be tested using assays known in the art. The α7 nAChR PAMs described herein are active in automated patch clamp electrophysiological functional assays as described in the Examples. The assays were performed using IonFlux HT in a whole cell population patch configuration. See Golden et al., Assay Drug Dev. Technol. (2011) 9:608-619. The ability of the compounds to modulate the function of human α7 nAChR stably expressed in a HEK cell line was assessed in the presence and absence of the natural α7 agonist acetylcholine. By performing a series of such measurements at different concentrations, the effective concentration (EC) of the α7 nAChR PAM was determined. 50 ). See Spencer et al., Assay Drug Dev. Technol. (2012) 10: 313-324.

[0425] The present invention also includes methods for preparing compounds of formula I or II. The compounds of the present invention can be easily prepared according to the following reaction schemes and examples or variations thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, variants that are known to those of ordinary skill in the art but not mentioned in more detail can also be used. In addition, in view of the following reaction schemes and examples, other methods for preparing the compounds of the present invention will be apparent to those of ordinary skill in the art. Unless otherwise indicated, all variables are as defined above. The following reaction schemes and examples are only used to illustrate the present invention and its practice.

[0426] Many compounds of the invention can be prepared according to Scheme 1, where the alkyne 1.1 participates in a [3+2] cycloaddition with a nitrile oxide (formed in situ by treatment of the oxime 1.2 with PIFA) to afford the isoxazole 1.3. Other nitrile oxide precursors such as nitroalkanes or chlorooximes can be employed to effect this transformation.

[0427] Solution 1

[0428]

[0429] In addition, other compounds of the invention can be prepared according to Scheme 2, wherein the acid 2.1 is reacted with CDI in dioxane and then treated with the amide oxime 2.2 in dioxane at elevated temperature to give the product 2.3. Other coupling reagents such as EDC and HOAt and solvents such as toluene, dichloroethane or DMSO can be used in this transformation. If 2.3 is a mixture of enantiomers or diastereomers, the mixture can be separated by chiral chromatography. Alternatively, 2.1 and 2.2 can be used in single enantiomer or diastereomer form to obtain 2.3 enriched in a single enantiomer or diastereomer. Other methods of forming oxadiazoles can also be used, such as reacting the corresponding ester of the acid 2.1 with the amide oxime 2.2 in the presence of potassium carbonate (or other base) in ethanol (or other solvent) at elevated temperature or by reacting the acid 2.1 with the amide oxime 2.2 in the presence of EDC and HOAt and then either adding T3P to the reaction mixture or treating the isolated intermediate with TBAF in THF.

[0430] Solution 2

[0431]

[0432] In a similar manner, some of the compounds of this invention can be prepared according to Scheme 3, wherein the cyclopropane intermediate 3.1 now bears an amide oxime. Reaction of the acid 3.2 with CDI in dioxane followed by treatment with the amide oxime 3.1 and warming to elevated temperature affords the product 3.3.

[0433] Solution 3

[0434]

[0435] Alternatively, compounds of the invention may be prepared according to Scheme 4, wherein a boronic acid ester (or boronic acid or boronic acid derivative) 4.1 is reacted with a heteroaryl bromide (or chloride, iodide, triflate or tosylate) 4.2 under palladium catalysis to give product 4.3. A variety of different catalysts (including other metals such as nickel), ligands, bases and solvents may be used in this reaction. Other six-membered and five-membered heteroaryl halides (such as 5-chloro-1,2,4-thiadiazole) may be used in place of 4.2. Carbamate 4.3 is then treated with HCl to remove the Boc protecting group and the resulting piperidine is reacted with sulfamide to give product 4.4. Other sulfamoylating agents (e.g., tert-butyl (chlorosulfonyl)carbamate) may be used in this transformation. If 4.4 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography. Alternatively, 4.1 and 4.2 may be used in single enantiomer or diastereomer form to obtain 4.4 enriched in a single enantiomer or diastereomer.

[0436] Solution 4

[0437]

[0438] Other compounds of the invention can be prepared according to Scheme 5, wherein the halo ketone 5.1 is reacted with the thioamide 5.2 in ethanol at elevated temperature to afford the thiazole 5.3. Soft Lewis acids and other halides and solvents can also be employed to effect this transformation. Additionally, a dehydrating agent can be employed after coupling of 5.1 and 5.2 to complete heterocyclic ring formation and an amine base can be introduced to chelate the acid formed during the reaction. A variation of 5.2 in which the thioamide is replaced with an amidine can be employed to provide the corresponding imidazole, which can then be N-alkylated by treatment with an alkyl halide in the presence of a base. The dimethylformamidine protecting group can then be removed by treatment with hydrazine to afford the product 5.4.

[0439] Solution 5

[0440]

[0441] Additionally, compounds of the invention can be prepared according to Scheme 6, wherein the iminium salt 6.1 is reacted with a hydrazine 6.2 in the presence of HCl in methanol at elevated temperature to provide the pyrazole 6.3. The pyrazole 6.3 is then treated with hydrogen in the presence of palladium hydroxide on carbon to remove the carboxybenzyl protecting group, and the resulting piperidine is then reacted with a sulfonamide to provide the product 6.4.

[0442] Solution 6

[0443]

[0444] Alternatively, compounds of the invention may be prepared according to Scheme 7, wherein the acid 7.1 is reacted with CDI in 1,4-dioxane, then treated with an acyl hydrazine 7.2 at elevated temperature, followed by dehydration of the resulting amide by treatment with phosphorus(V) oxychloride at elevated temperature to afford the product 7.3. Other coupling reagents and conditions may be employed to effect this transformation. Alternatively, other dehydrating agents such as Burgess reagent or trifluoromethanesulfonic anhydride may be used for this transformation.

[0445] Solution 7

[0446]

[0447] Alternatively, compounds of the invention may be prepared according to Scheme 8, wherein the acid 7.1 is reacted with the acyl hydrazine 7.2 in the presence of HATU and NMM. Other coupling reagents and conditions may be employed to achieve this transformation. The resulting amide is then treated with Lawesson's reagent and warmed to elevated temperature to afford the thiadiazole product 8.1. Other thiolation reagents such as P 4 S 10 Hexamethyldisiloxane or hexamethyldisilthioane and a solvent such as 1,4-dioxane can be used for this transformation. Alternatively, a dehydrating agent such as PTSA can be used after sulfidation to complete the heterocycle formation.

[0448] Solution 8

[0449]

[0450] Alternatively, compounds of the invention may be prepared according to Scheme 9, wherein amide 9.1 is reacted with haloketone 9.2 in the presence of silver triflate at elevated temperature to afford oxazole 9.3. Other soft Lewis acids such as boron trifluoride diethyl etherate and halides such as chloride or iodide may be employed to effect this transformation. Additionally, a dehydrating agent may be employed after coupling of 9.1 and 9.2 to complete the formation of the oxazole. As in Scheme 6, a two-step sequence may then be employed to afford sulfamide 9.4.

[0451] Solution 9

[0452]

[0453] Other regioisomeric oxazole compounds of the invention can be prepared similarly according to Scheme 10, wherein the haloketone 10.1 is reacted with the amide 10.2 in the presence of silver triflate at elevated temperature to afford the oxazole 10.3. Soft Lewis acids and other halides and solvents can also be employed to effect this transformation. Additionally, a dehydrating agent can be employed after the coupling of 10.1 and 10.2 to complete the formation of the heterocycle and an amine base can be introduced to chelate the acid formed during the reaction. The dimethylformamidine protecting group can then be removed by treatment with hydrazine to afford the product 10.4.

[0454] Solution 10

[0455]

[0456] Other compounds of the invention can be prepared according to Scheme 11 by reaction of the acid 7.1 with HATU in tetrahydrofuran, followed by treatment with the aminoketone 11.1, followed by cyclodehydration of the resulting amide by treatment with phosphorus oxychloride (V) to afford the product 11.2. Other coupling and dehydrating reagents and conditions can be employed to effect this transformation.

[0457] Solution 11

[0458]

[0459] Alternatively, compounds of the invention may be prepared according to Scheme 12, wherein isoxazole 1.3 is treated with Raney nickel to provide vinylogous amide 12.1. Vinylogous amide 12.1 may then be reacted with P 4 S 10 Reaction in the presence of choranil and sodium bicarbonate affords the isothiazole 12.1. Other coupling reagents such as Lawesson's reagent can be used in this transformation.

[0460] Solution 12

[0461]

[0462] Additionally, compounds of the invention can be prepared according to Scheme 13, wherein pyrazole 13.1 is reacted with arylboronic acid 13.2 under copper catalysis in the presence of oxygen to give product 13.3. Alternatively, aryl or heteroaryl halides can be used in place of 13.2 and reacted using palladium or copper catalysts in the presence of a base and a suitable ligand under an inert atmosphere to form products similar to 13.3. The carbamate 13.3 is then treated with HCl to remove the Boc protecting group and the resulting piperidine is reacted with a sulfamide to give product 13.4. Other sulfamoylating agents (e.g., tert-butyl (chlorosulfonyl)carbamate followed by removal of the Boc group with HCl) can be used in this transformation.

[0463] Solution 13

[0464]

[0465] Intermediates of the invention such as 14.6 can be prepared according to Scheme 14, which begins with the Wittig olefination of ketone 14.1 by reaction with phosphorane 14.2 at elevated temperature to give product 14.3. The α,β-unsaturated ester 14.3 is then reacted with the ylide formed by treating precursor 14.4 with sodium hydride to give cyclopropane 14.5. Other bases such as potassium tert-butoxide can be employed in this transformation. Alternatively, 14.1 can be converted to the corresponding terminal olefin by treatment with methylenetriphenylphosphorane and then reacted with ethyl diazoacetate in the presence of a rhodium, copper or palladium catalyst to form the ethyl ester analog of compound 14.5. Tri- and tetrasubstituted olefins can be employed in this latter transformation to provide cyclopropanes with a higher degree of substitution. Chiral ligands such as (R,R)-(-)-2,2'-isopropylidenebis(4-tert-butyl-2-oxazoline) in the presence of copper(I) trifluoromethanesulfonate can be employed in these carbene insertion reactions to give enantiomerically or diastereomerically enriched products. The cyclopropane 14.5 is then saponified by treatment with sodium hydroxide to give the acid 14.6.

[0466] Solution 14

[0467]

[0468] Intermediates of the invention such as 15.5 can be prepared according to Scheme 15, which begins with the reduction of the α,β-unsaturated ester 14.3 by treatment with DIBAL, followed by conversion of the resulting allyl alcohol to the corresponding acetate 15.1 by reaction with acetic anhydride in the presence of DMAP and triethylamine. Other reducing agents, acetylation agents, and bases can be used in this conversion. The allyl acetate 15.1 can then be difluorocyclopropanated by treatment with (trimethylsilyl)trifluoromethane in the presence of sodium iodide to give the difluorocyclopropane 15.2. Other difluorocarbene sources such as (bromodifluoromethyl)trimethylsilane or sodium chlorodifluoroacetate and initiators such as tetraalkylammonium salts can be employed in this conversion. Removal of the acetate group of 15.2 can be accomplished by treatment with potassium carbonate and oxidation of the resulting alcohol to the corresponding acid by reaction with TEMPO. The acid can then be converted to the benzyl ester 15.3 by treatment with benzyl bromide. The ester 15.3 is then treated with HCl to remove the Boc group and the resulting piperidine is reacted with a sulfamide to give the product 15.4. Removal of the benzyl ester can be accomplished by treatment with palladium on carbon in the presence of hydrogen to give the acid 15.5.

[0469] Solution 15

[0470]

[0471] Intermediates of the invention such as 3.1 can be prepared according to Scheme 16. The sequence begins with the acid 2.1, which is converted to the amide 16.1 by coupling with ammonium chloride in the presence of HATU and NMM (other coupling reagents and bases can also be used in this reaction). 3 Dehydration of the amide 16.1 (other dehydrating agents may also be used) followed by treatment of the resulting nitrile with hydroxylamine provides the amide oxime 3.1.

[0472] Scheme 16

[0473]

[0474] Intermediates of the invention such as 17.6 can be prepared according to Scheme 17, which begins with Wittig olefination of ketone 17.1 by reaction with phosphorane 17.2 at elevated temperature to give terminal olefin 17.3. Olefin 17.3 is then reacted with vinyl borate 17.4 over a second generation Grubbs catalyst. TM to give the vinyl borate ester 17.5. Other cross-metathesis catalysts such as Zhan's catalyst or Hoveyda-Grubbs' catalyst may be employed in this transformation. The vinyl borate ester 17.5 may then be difluorocyclopropanated by treatment with (trimethylsilyl)trifluoromethane in the presence of sodium iodide to give the difluorocyclopropane 17.6. Other difluorocarbene sources such as (bromodifluoromethyl)trimethylsilane or sodium chlorodifluoroacetate and initiators such as tetraalkylammonium salts may be employed in this transformation.

[0475] Solution 17

[0476]

[0477] Intermediates of the invention such as 5.1 can be prepared according to Scheme 18, wherein a solution of the acid 7.1 in dichloromethane and N,N-dimethylformamide is treated with oxalyl chloride to form the corresponding acid chloride. The acid chloride is then reacted with (trimethylsilyl)diazomethane followed by HCl to give the chloroketone 5.1. The chloroketone can be converted to the corresponding iodide by treatment with sodium iodide in acetone.

[0478] Scheme 18

[0479]

[0480] Intermediates of the invention such as 6.1 can be prepared according to Scheme 19. The sequence begins with treatment of (methoxymethyl)triphenylphosphonium chloride with LiHMDS, followed by reaction of the resulting ylide with aldehyde 19.1 to afford enol ether 19.2. The preformed Vilsmeier-Haack reagent (by reacting POCl 3 To the enol ether 19.2 (formed by treatment of DMF) is added the imine salt 6.1.

[0481] Solution 19

[0482]

[0483] Intermediates of the invention such as 20.4 can be prepared according to Scheme 20, which begins with the reduction of the α,β-unsaturated ester 14.3 by treatment with DIBAL, followed by conversion of the resulting allylic alcohol to the corresponding silyl ether 20.1 by reaction with TBSC1 in the presence of imidazole. Other reducing agents, silylating agents, and bases can be used in this conversion. The allylsilyl ether 20.1 can then be bromofluorocyclopropanated by treatment with dibromo(fluoro)methane in the presence of TBAI and sodium hydroxide to give the bromofluorocyclopropane 20.2. The bromofluorocyclopropane 20.2 is reduced by treatment with Zn in the presence of ammonium chloride, and then the silyl ether protection can be removed by reaction with TBAF to give the fluorocyclopropane alcohol 20.3. A two-step oxidation of the alcohol 20.3 to give the acid 20.4 can be achieved by first treating with DMP and then reacting the resulting aldehyde with sodium chlorite.

[0484] Solution 20

[0485]

[0486] Intermediates of the invention such as 13.1 can be prepared according to Scheme 21. The sequence begins by treating the acid 21.1 with CDI and reacting the resulting acyl imidazole with N,O-dimethylhydroxylamine hydrochloride to give the corresponding Weinreb amide. The Weinreb amide can then be treated with ethynylmagnesium bromide to give the alkynyl ketone 21.2. The alkynyl ketone 21.2 can then be treated with hydrazine to give the pyrazole 13.1.

[0487] Solution 21

[0488]

[0489] Intermediates of this invention such as 22.4 can be prepared according to Scheme 22, which begins with treating triphenylphosphonium bromide 22.1 with n-butyllithium and reacting the resulting ylide with piperidone 14.1 to give the olefin 22.2. The olefin 22.2 can then be reacted with ethyl diazoacetate in the presence of rhodium acetate to give the cyclopropane 22.3. Other metals such as copper or palladium can be used in this transformation. Chiral ligands such as (R,R)-(-)-2,2'-isopropylidenebis(4-tert-butyl-2-oxazoline), used in the presence of copper(I) trifluoromethanesulfonate, can be employed in these carbene insertion reactions to give enantiomerically or diastereomerically enriched products. The cyclopropane 22.3 is then saponified by treatment with sodium hydroxide to give the acid 22.4.

[0490] Solution 22

[0491]

[0492] Intermediates such as alkynes 1.1 can be prepared according to Scheme 23. The alcohol 23.1 can be oxidized by treatment with Dess-Martin periodinane to give the aldehyde 23.2. Other oxidizing agents such as Collin's reagent, PCC or PDC can be used in these transformations. The aldehyde 23.2 can then be reacted with dimethyl (1-diazo-2-oxopropyl)phosphonate in the presence of potassium carbonate to give the alkyne 9.1. Other bases can be employed in this transformation.

[0493] Solution 23

[0494]

[0495] It will be appreciated that the compounds and intermediates of the foregoing reaction schemes may be used as synthetic intermediates in other schemes involving similar intermediates to prepare alternative compounds of the invention.

[0496] In some cases, the order of performing the foregoing reaction schemes may be altered to facilitate the reaction or avoid undesirable reaction products. In addition, various protecting group strategies familiar to those skilled in the art of organic synthesis may be employed to facilitate the reaction or avoid undesirable reaction products.

[0497] In some cases, the final product can be further modified, for example, by manipulating substituents. These manipulations can include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions commonly known to those skilled in the art.

[0498] Provide the following examples so that the present invention can be more fully understood.These embodiments are only illustrative and should not be construed as limiting the present invention in any way.Wherein produce racemic mixture, can be after isolating final product or at suitable intermediate place use SFC reverse phase or normal phase chiral separation condition separation enantiomer, then handle single isomer separately.Should be understood that in the synthesis of these key intermediates and embodiments, alternative methods can also be adopted.Where possible and suitable, can use asymmetric method (for example, chiral catalysis, auxiliary agent).The exact selection of reagent, solvent, temperature and other reaction conditions depends on the property of expected product.

[0499] The following abbreviations are used throughout:

[0500]

[0501]

[0502]

[0503]

[0504]

[0505] Intermediate 1

[0506]

[0507] (1R)-6-Sulfonyl-6-azaspiro[2.5]octane-1-carboxylic acid

[0508] Step A: (1R)-6-Azaspiro[2.5]octane-1-carboxylic acid ethyl ester

[0509] To a solution of (1R)-6-azaspiro[2.5]octane-1,6-dicarboxylic acid 6-benzyl 1-ethyl ester (44.6 g, 141 mmol) (Brown et al., J. Med. Chem. (2014) 57:733-758) in methanol (400 mL) was added palladium hydroxide (20 w / w % on activated carbon, 4.94 g, 7.03 mmol). The reaction vessel was evacuated, backfilled with hydrogen (about 1 atm), and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was filtered through a Celite® pad, washed with methanol, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity for the next step. MS: m / z = 184.3 [M+H].

[0510] Step B: (1R)-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid ethyl ester

[0511] To a solution of (1R)-6-azaspiro[2.5]octane-1-carboxylic acid ethyl ester (25.6 g, 140 mmol) in 1,4-dioxane (400 mL) was added sulfamide (40.7 g, 423 mmol), and the reaction mixture was warmed to 95 ° C and stirred for 18 h. Sulfamide (9.00 g, 93.7 mmol) was added, and the reaction mixture was warmed to 100 ° C and stirred for 6 h. The reaction mixture was cooled to ambient temperature, poured into a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (2×). The combined organic extracts were washed with a saturated aqueous sodium chloride solution, dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography, eluting with a gradient of methanol: dichloromethane from 0:100 to 5:95 to give the title compound. MS: m / z=263.1[M+H].

[0512] Step C: (1R)-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid

[0513] To a solution of (1R)-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid ethyl ester (50.0 g, 191 mmol) in tetrahydrofuran (270 mL) and methanol (135 mL) was added aqueous sodium hydroxide solution (2 M, 286 mL, 572 mmol) and the reaction mixture was stirred at ambient temperature for 2 days. The reaction mixture was diluted with ice water (200 mL), the resulting mixture was slowly adjusted to pH = 5 with aqueous hydrochloric acid solution (12 M), and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity for the next step. MS: m / z = 235.1 [M+H].

[0514] Intermediate 2

[0515]

[0516] (1R)-N'-Hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (carboximidamide)

[0517] Step A: (1R)-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxamide

[0518] To a solution of (1R)-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 1) (1.20 g, 2.93 mmol) in dichloromethane (14 mL) was added HATU (1.15 g, 3.02 mmol), ammonium chloride (0.392 g, 7.32 mmol) and N-methylmorpholine (1.13 mL, 10.3 mmol) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was filtered, washed with dichloromethane, and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=234.0 [M+H].

[0519] Step B: (1R)-1-Cyano-6-azaspiro[2.5]octane-6-sulfonamide

[0520] To a solution of (1R)-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxamide (1.84 g, 7.89 mmol) in acetonitrile (39 mL) was added phosphorus oxychloride (1.47 mL, 15.8 mmol) and the reaction mixture was warmed to 80 °C and stirred for 2 h. The reaction mixture was cooled to ambient temperature, water was added, and the resulting mixture was extracted with ethyl acetate (2×). The combined organic extracts were concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=216.1[M+H].

[0521] Step C: (1R)-N'-Hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide

[0522] To a solution of (1R)-1-cyano-6-azaspiro[2.5]octane-6-sulfonamide (1.30 g, 6.04 mmol) in methanol (14 mL) was added aqueous hydroxylamine solution (50 w / w%, 3.50 mL, 57.1 mmol) and the reaction mixture was warmed to 60 °C and stirred for 1 h. The reaction mixture was cooled to ambient temperature, diluted with saturated aqueous sodium chloride solution and the resulting mixture was extracted with ethyl acetate (3×). The combined organic extracts were concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=249.1 [M+H].

[0523] Intermediate 3

[0524]

[0525] 6-(tert-Butoxycarbonyl)-2,2-difluoro-1-methyl-6-azaspiro[2.5]octane-1-carboxylic acid

[0526] Step A: 6-tert-Butyl 1-methyl 2,2-difluoro-6-azaspiro[2.5]octane-1,6-dicarboxylate

[0527] To a solution of 6-(tert-butoxycarbonyl)-2,2-difluoro-6-azaspiro[2.5]octane-1-carboxylic acid (described in Intermediate 10) (1.0 g, 3.43 mmol) in methanol (4 mL) and dichloromethane (20 mL) was added a solution of (trimethylsilyl)diazomethane in hexane (2M, 9.44 mL, 18.9 mmol) and the reaction mixture was stirred for 15 minutes. Methanol (15 mL) was added and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 95:5 petroleum ether:ethyl acetate to give the title compound. MS: m / z=250.0[M-tBu+H].

[0528] Step B: 6-tert-Butyl 1-methyl 2,2-difluoro-1-methyl-6-azaspiro[2.5]octane-1,6-dicarboxylate

[0529] To a -78°C solution of 6-tert-butyl 1-methyl 2,2-difluoro-6-azaspiro[2.5]octane-1,6-dicarboxylate (200 mg, 0.66 mmol) and iodomethane (0.85 mL, 13.6 mmol) in tetrahydrofuran (5 mL) was added a solution of lithium diisopropylamide in tetrahydrofuran and hexane (2M, 0.98 mL, 1.97 mmol) and the mixture was stirred at -78°C for 15 minutes, then warmed to ambient temperature and stirred for 30 minutes. Saturated aqueous ammonium chloride solution (3 mL) and water (5 mL) were added and the aqueous layer was extracted with ethyl acetate (3×5 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 95:5 petroleum ether:ethyl acetate to give the title compound.

[0530] MS: m / z=264.0 [M-tBu+H].

[0531] Step C: 6-(tert-Butoxycarbonyl)-2,2-difluoro-1-methyl-6-azaspiro[2.5]octane-1-carboxylic acid

[0532] To a solution of 6-tert-butyl 1-methyl 2,2-difluoro-1-methyl-6-azaspiro[2.5]octane-1,6-dicarboxylate (130 mg, 0.41 mmol) in methanol (3 mL), tetrahydrofuran (3 mL) and water (1.5 mL) was added sodium hydroxide (163 mg, 4.07 mmol) and the reaction mixture was stirred for 3 h. The reaction mixture was concentrated under reduced pressure, water (5 mL) was added and the resulting mixture was extracted with ethyl acetate (5 mL). The aqueous phase was adjusted to pH=3 with aqueous hydrogen chloride solution (2 M) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound of sufficient purity for the next step.

[0533] Intermediate 4

[0534]

[0535] 1-[3-(2,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl]-2,2-difluoro-1-methyl-6-azaspiro [2.5] Octane hydrochloride

[0536] Essentially following the procedure described in Intermediate 17, but substituting 6-(tert-butoxycarbonyl)-2,2-difluoro-1-methyl-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 3) for tert-butyl 2-{3-[2-(difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-carboxylate and substituting N-hydroxy-2,5-dimethylbenzanilideamide for 2-(difluoromethoxy)-N'-hydroxypyridine-4-carboximilideamide, the title compound was obtained. MS: m / z = 334.0 [M+H].

[0537] Intermediate 5

[0538]

[0539] 4,4-Difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid

[0540] Step A: tert-Butyl 4-[2-(Benzyloxy)-2-oxoethylidene]-3,3-difluoropiperidine-1-carboxylate

[0541] 2-(triphenylphosphoranylidene)benzyl acetate (2.62 g, 6.38 mmol) was added to a solution of tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (1.0 g, 4.3 mmol) in toluene (20 mL), and the reaction mixture was warmed to 110 ° C and stirred for 4 h. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride aqueous solution, dried (magnesium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with a gradient of hexane: ethyl acetate from 100: 0 to 75: 25 to give the title compound. MS: m / z = 312.1 [M-tBu + H].

[0542] Step B: 1-Benzyl 6-tert-butyl 4,4-difluoro-6-azaspiro[2.5]octane-1,6-dicarboxylate

[0543] To a 10°C mixture of sodium hydride (60% dispersion in mineral oil, 0.196 g, 4.90 mmol) and dimethyl sulfoxide (15 mL) was added a solution of trimethyl sulfoxide iodide in dimethyl sulfoxide (5.2 M, 10 mL) and the reaction mixture was stirred at 10°C for 2 h. A solution of tert-butyl 4-[2-(benzyloxy)-2-oxoethylidene]-3,3-difluoropiperidine-1-carboxylate in dimethyl sulfoxide (6.6 M, 5 mL) was added and the reaction mixture was warmed to ambient temperature and stirred for 18 h. The reaction mixture was diluted with water and the resulting mixture was extracted with ethyl acetate (2×). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexane:ethyl acetate from 100:0 to 80:20 to give the title compound. MS: m / z=326.2[M-tBu+H].

[0544] Step C: 4,4-difluoro-6-azaspiro[2.5]octane-1-carboxylic acid benzyl ester hydrochloride To a solution of 1-benzyl 6-tert-butyl 4,4-difluoro-6-azaspiro[2.5]octane-1,6-dicarboxylate (312 mg, 0.818 mmol) in ethyl acetate (2 mL) was added a solution of HCl in 1,4-dioxane (4 M, 1.0 mL, 4.0 mmol) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=282.2 [M+H].

[0545] Step D: Benzyl 4,4-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylate

[0546] To a solution of 4,4-difluoro-6-azaspiro[2.5]octane-1-carboxylic acid benzyl ester hydrochloride (255 mg, 0.802 mmol) in 1,4-dioxane (4 mL) was added sulfamide (231 mg, 2.41 mmol) and triethylamine (0.168 mL, 1.20 mmol), and the reaction mixture was warmed to 90°C and allowed to stir for 18 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexane:ethyl acetate:ethanol from 95:4:1 to 50:38:12 to give the title compound. MS: m / z=361.2 [M+H].

[0547] Step E: 4,4-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid

[0548] To a container containing benzyl 4,4-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylate (250 mg, 0.694 mmol) was added palladium on activated carbon (10 weight / weight%, 74 mg, 0.069 mmol) and methanol (3.5 mL) in sequence under an inert atmosphere. The reaction mixture was placed under a hydrogen atmosphere (about 1 atm) and allowed to stir at ambient temperature for 3 h. The reaction mixture was stirred at room temperature for 3 h. Filter through a Celite pad, wash with methanol, and concentrate the filtrate under reduced pressure. MS: m / z=271.1 [M+H].

[0549] Intermediate 6

[0550]

[0551] 6-(tert-Butoxycarbonyl)-4-fluoro-6-azaspiro[2.5]octane-1-carboxylic acid

[0552] Step A: tert-Butyl 3-fluoro-4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate

[0553] To a solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (10.0 g, 46.0 mmol) in toluene (115 mL) in a sealable container, 2-(triphenylphosphoranylidene)methyl acetate (26.2 g, 78 mmol) was added and the container was sealed. The reaction mixture was warmed to 140 ° C and stirred for 5 h. The reaction mixture was concentrated under reduced pressure and hexane was added to the residue. The resulting mixture was filtered, washed with hexane, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of hexane:ethyl acetate from 100:0 to 75:25 to give the title compound. MS: m / z=218.1[M-tBu+H].

[0554] Step B: 6-tert-Butyl 1-methyl 4-fluoro-6-azaspiro[2.5]octane-1,6-dicarboxylate

[0555] Trimethylsulfoxide iodide (14.26 g, 64.8 mmol) was added dropwise to a vessel containing sodium hydride (60% dispersion in mineral oil, 2.51 g, 62.7 mmol) and dimethylsulfoxide (200 mL) at 0°C over a period of 1.5 h. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. A solution of tert-butyl 3-fluoro-4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (6.03 g, 22.1 mmol) in dimethylsulfoxide (50 mL) was added dropwise and the reaction mixture was stirred for 18 h. The reaction mixture was slowly added to a mixture of ice and saturated aqueous ammonium chloride solution (225 mL) and the resulting mixture was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with saturated aqueous ammonium chloride solution (2×100 mL) and saturated aqueous sodium chloride solution (1×100 mL), dried (magnesium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate from 100:0 to 60:40 to afford the title compound. MS: m / z = 232.1 [M-tBu+H].

[0556] Step C: 6-(tert-Butyloxycarbonyl)-4-fluoro-6-azaspiro[2.5]octane-1-carboxylic acid

[0557] To a solution of 6-tert-butyl 1-methyl 4-fluoro-6-azaspiro[2.5]octane-1,6-dicarboxylate (4.86 g, 16.9 mmol) in tetrahydrofuran (64 mL) and methanol (20 mL) was added aqueous sodium hydroxide (1 M, 34 mL, 34 mmol) and the reaction mixture was warmed to 55 °C and allowed to stir for 15 minutes. The reaction mixture was cooled to ambient temperature and aqueous HCl (12.1 M, 2.79 mL, 34.0 mmol) was added. The mixture was concentrated under reduced pressure and the residue was coevaporated with acetonitrile (2×). The residue was dissolved in ethyl acetate (100 mL), washed with water (15 mL), dried (magnesium sulfate), filtered, and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=218.1 [M-tBu+H].

[0558] Intermediate 7

[0559]

[0560] 4-Fluoro-N'-hydroxy-2-(trifluoromethyl)benzamide

[0561] To a solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (15.0 g, 79.3 mmol) in methanol (190 mL) was added aqueous hydroxylamine (50 w / w%, 48 mL, 783 mmol) and the reaction mixture was warmed to 60°C and allowed to stir for 21 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexane:ethyl acetate from 100:0 to 70:30 to give the title compound. MS: m / z=223.3 [M+H].

[0562] Intermediate 8

[0563]

[0564] 4-Methyl-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid

[0565] Step A: tert-Butyl 3-methyl-4-methylenepiperidine-1-carboxylate

[0566] To a solution of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (2.95 g, 13.9 mmol) in dimethyl sulfoxide (45 mL) was added methyltriphenylphosphonium bromide (7.42 g, 20.8 mmol) and potassium tert-butoxide (2.33 g, 20.8 mmol) in sequence and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was poured into water (200 mL) and the resulting mixture was extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (150 mL), dried (sodium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of hexane:ethyl acetate from 100:0 to 70:30 to give the title compound. MS: m / z=212.2[M+H].

[0567] Step B: 6-tert-Butyl 1-ethyl 4-methyl-6-azaspiro[2.5]octane-1,6-dicarboxylate

[0568] Rhodium (II) acetate dimer (0.582 g, 1.32 mmol) was added to a solution of tert-butyl 3-methyl-4-methylenepiperidine-1-carboxylate (2.78 g, 13.2 mmol) in dichloromethane (42 mL). A solution of ethyl diazoacetate in dichloromethane (2.19 M, 18.0 mL, 39.4 mmol) was added dropwise at ambient temperature over a 75-minute period. The reaction mixture was poured into water (100 mL) and the resulting mixture was extracted with dichloromethane (2 × 100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (60 mL), 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 hexane: ethyl acetate from 100:0 to 60:40 to give the title compound. MS: m / z = 298.2 [M + H].

[0569] Step C: 4-Methyl-6-azaspiro[2.5]octane-1-carboxylic acid ethyl ester

[0570] To a solution of 6-tert-butyl 1-ethyl 4-methyl-6-azaspiro[2.5]octane-1,6-dicarboxylate in 1,4-dioxane (63 mL) was added a solution of HCl in 1,4-dioxane (4M, 31.5 mL, 126 mmol) and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was concentrated under reduced pressure to afford the title compound in sufficient purity for the next step.

[0571] Step D: 4-Methyl-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid ethyl ester

[0572] To a solution of ethyl 4-methyl-6-azaspiro[2.5]octane-1-carboxylate (3.07 g, 13.1 mmol) in 1,4-dioxane (50 mL) was added sulfamide (3.78 g, 39.3 mmol) and triethylamine (2.74 mL, 19.7 mmol), and the reaction mixture was warmed to 110°C and allowed to stir for 18 h. The reaction mixture was cooled to ambient temperature, poured into water (100 mL), and the resulting mixture was extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (100 mL), 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 dichloromethane:methanol from 100:0 to 95:5 to give the title compound. MS: m / z=277.2[M+H].

[0573] Step E: 4-Methyl-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid

[0574] To a solution of 4-methyl-6-sulfamoyl-6-azaspiro [2.5] octane-1-carboxylic acid ethyl ester (5.63 g, 21.5 mmol) in tetrahydrofuran (36 mL) and methanol (18 mL) was added aqueous sodium hydroxide solution (2 M, 37.0 mL, 74.0 mmol) and the reaction mixture was stirred for 12 h. The reaction mixture was poured into water (70 mL) and the resulting mixture was washed with diethyl ether (50 mL). The aqueous layer was adjusted to pH = 5 with aqueous hydrochloric acid solution (12 M) and extracted with ethyl acetate (2 × 200 mL). The combined organic extracts were washed with saturated sodium chloride aqueous solution (50 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure to obtain a sufficient purity of the title compound for the next step. MS: m / z = 249.1 [M + H].

[0575] Intermediate 9

[0576]

[0577] (1R)-1-(Chloroacetyl)-N-[(dimethylamino)methylene]-6-azaspiro[2.5]octane-6-sulfonamide

[0578] To a 0°C solution of (1R)-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 1) (500 mg, 2.13 mmol) in dichloromethane (5 mL) and N,N-dimethylformamide (0.1 mL) was added oxalyl chloride (0.558 mL, 6.51 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile (6 mL), cooled to 0°C, and (trimethylsilyl)diazomethane solution (2M, 3.90 mL, 7.80 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was cooled to 0°C and a solution of hydrogen chloride in 1,4-dioxane (4M, 2.92 mL, 11.7 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Saturated aqueous sodium bicarbonate solution was added and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to afford the title compound in sufficient purity for the next step. MS: m / z = 322.0 [M+H].

[0579] Intermediate 10

[0580]

[0581] (1R)-2,2-Difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid

[0582] Step A: tert-Butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate

[0583] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (8.40 g, 42.2 mmol) in toluene (100 mL) was added methyl 2-(triphenylphosphoranylidene)acetate (17.6 g, 52.7 mmol), and the reaction mixture was warmed to 110 ° C and stirred for 4 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. Hexane was added to the residue, the resulting mixture was filtered, washed with hexane, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of hexane:ethyl acetate from 100:0 to 50:50 to give the title compound. MS: m / z=200.1[M-tBu+H].

[0584] Step B: tert-Butyl 4-(2-hydroxyethylidene)piperidine-1-carboxylate

[0585] To a -78°C solution of tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (7.54 g, 29.5 mmol) in tetrahydrofuran (60 mL) was added a solution of diisobutylammonium hydride in tetrahydrofuran (1 M, 60.0 mL, 60.0 mmol) dropwise and the reaction mixture was stirred at -78°C for 1 h. The reaction mixture was allowed to warm to 0°C and stirred for 1 h. A solution of diisobutylammonium hydride in tetrahydrofuran (1 M, 40.0 mL, 40.0 mmol) was added dropwise and the reaction mixture was allowed to stand at 0°C for 18 h. An aqueous solution of Rochelle salt (0.5 M) was slowly added, the resulting mixture was diluted with water and extracted with ethyl acetate (2x). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (magnesium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z = 195.2 [M+Na-tBu].

[0586] Step C: tert-Butyl 4-(2-acetoxyethylidene)piperidine-1-carboxylate

[0587] To a solution of tert-butyl 4-(2-hydroxyethylidene)piperidine-1-carboxylate (5.80 g, 25.5 mmol) in dichloromethane (100 mL) was added pyridine (4.13 mL, 51.0 mmol), 4-dimethylaminopyridine (0.312 g, 2.55 mmol) and acetic anhydride (4.82 mL, 51.0 mmol) in sequence and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with a gradient of hexane:ethyl acetate from 100:0 to 25:75 to give the title compound. MS: m / z=292.2 [M+Na].

[0588] Step D: tert-Butyl 2-(acetoxymethyl)-1,1-difluoro-6-azaspiro[2.5]octane-6-carboxylate

[0589] Sodium iodide (0.899 g, 6.00 mmol) and trimethyl (trifluoromethyl) silane (4.43 mL, 30.0 mmol) were added sequentially to a solution of tert-butyl 4-(2-acetoxyethylidene) piperidine-1-carboxylate (3.23 g, 12.0 mmol) in tetrahydrofuran (30 mL) in a sealable container under a nitrogen atmosphere. The container was sealed and the reaction mixture was warmed to 90 ° C and stirred for 2 h. The reaction mixture was cooled to ambient temperature, sodium iodide (0.899 g, 6.00 mmol) and trimethyl (trifluoromethyl) silane (4.43 mL, 30.0 mmol) were added, and the reaction mixture was warmed to 90 ° C and stirred for 2 h. The reaction mixture was cooled to ambient temperature, diluted with water, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with a gradient of hexane: ethyl acetate from 100: 0 to 50: 50 to obtain the title compound. MS: m / z=264.1 [M-tBu+H].

[0590] Step E: tert-Butyl 1,1-difluoro-2-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate To a solution of tert-butyl 2-(acetoxymethyl)-1,1-difluoro-6-azaspiro[2.5]octane-6-carboxylate (5.68 g, 17.8 mmol) in methanol (50 mL) was added potassium carbonate (7.37 g, 53.4 mmol) and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was filtered, washed with methanol, and the filtrate was concentrated under reduced pressure. Ethyl acetate and water were added, the layers were separated, the aqueous layer was adjusted to pH=5 and extracted with ethyl acetate. The organic extract was dried (magnesium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity for the next step. MS: m / z=222.1[M-tBu+H].

[0591] Step F: 6-(tert-Butoxycarbonyl)-2,2-difluoro-6-azaspiro[2.5]octane-1-carboxylic acid

[0592] To a solution of tert-butyl 1,1-difluoro-2-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate (4.93 g, 17.9 mmol) in acetonitrile (100 mL) was added 4-methylmorpholine-4-oxide hydrate (24.0 g, 178 mmol) and tetrapropylammonium perruthenate (0.625 g, 1.78 mmol) in sequence and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with aqueous hydrochloric acid (1 M) and extracted with ethyl acetate. The aqueous layer was diluted with water and saturated aqueous sodium chloride solution, extracted with ethyl acetate, and the combined organic extracts were purified by centrifugation. Filtration through a pad of HPLC eluted with water and concentrated under reduced pressure afforded the title compound in sufficient purity for the next step. MS: m / z = 236.1 [M-tBu+H].

[0593] Step G: 1-Benzyl 6-tert-butyl 2,2-difluoro-6-azaspiro[2.5]octane-1,6-dicarboxylate

[0594] To a solution of 6-(tert-butoxycarbonyl)-2,2-difluoro-6-azaspiro[2.5]octane-1-carboxylic acid (5.18 g, 17.9 mmol) in N,N-dimethylformamide (100 mL) was added HATU (10.1 g, 26.7 mmol), benzyl alcohol (2.77 mL, 26.7 mmol) and diisopropylethylamine (9.32 mL, 53.3 mmol) in sequence and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic extracts were dried (magnesium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexane:ethyl acetate from 100:0 to 50:50 to give the title compound. MS: m / z=326.2 [M-tBu+H].

[0595] Step H: Benzyl 2,2-difluoro-6-azaspiro[2.5]octane-1-carboxylate hydrochloride To a solution of 1-benzyl 6-tert-butyl 2,2-difluoro-6-azaspiro[2.5]octane-1,6-dicarboxylate (4.70 g, 12.3 mmol) in ethyl acetate (25 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 12.3 mL, 49.3 mmol) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=282.2 [M+H].

[0596] Step I: (1R)-2,2-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid benzyl ester

[0597] To a solution of 2,2-difluoro-6-azaspiro[2.5]octane-1-carboxylic acid benzyl ester hydrochloride (3.92 g, 12.3 mmol) in 1,4-dioxane (60 mL) was added triethylamine (2.58 mL, 18.5 mmol) and sulfamide (3.56 g, 37.0 mmol), the reaction mixture was warmed to 90 ° C and allowed to stir for 4 h. The reaction mixture was cooled to ambient temperature and sulfamide (3.56 g, 37.0 mmol) was added. The reaction mixture was warmed to 90 ° C and allowed to stir for 4 h. The reaction mixture was concentrated under reduced pressure and ethyl acetate and water were added to the residue. The aqueous layer was extracted with ethyl acetate, the combined organic extracts were dried (magnesium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of hexane:ethyl acetate:ethanol from 100:0:0 to 52:36:12 to give the racemic title compound. The racemate was separated by SFC using a ChiralPak AD-H column and eluted with 40:60 methanol:carbon dioxide. The first major peak eluted was the title compound (1R)-2,2-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid benzyl ester, and the second major peak eluted was (1S)-2,2-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid benzyl ester. MS: m / z=361.2[M+H].

[0598] Step J: (1R)-2,2-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid

[0599] To a container containing (1R)-2,2-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid benzyl ester (1.20 g, 3.33 mmol) under an inert atmosphere was added palladium on activated carbon (10 weight / weight %, 0.354 g, 0.333 mmol). Methanol (17 mL) was added and the reaction mixture was placed under a hydrogen atmosphere (about 1 atm) and allowed to stir at ambient temperature for 3 h. The reaction mixture was filtered through a Celite® pad, washed with methanol, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity for the next step. MS: m / z = 271.1 [M+H].

[0600] Intermediate 11

[0601]

[0602] (1R)-2,2-Difluoro-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide

[0603] Step A: (1R)-2,2-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxamide

[0604] To a solution of (1R)-2,2-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 10) (10.8 g, 40.0 mmol) in dichloromethane (200 mL) and dimethyl sulfoxide (11 mL) were added ammonium chloride (6.5 g, 122 mmol), HATU (18.3 g, 48.0 mmol) and N-methylmorpholine (20 mL, 182 mmol) in sequence and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water, filtered, and the precipitate was dried under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=270.1 [M+H].

[0605] Step B: (2R)-2-Cyano-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide

[0606] Phosphorus oxychloride (4.26 mL, 45.8 mmol) was added dropwise to a solution of (1R)-2,2-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxamide (6.16 g, 22.9 mmol) in acetonitrile (100 mL) and the reaction mixture was warmed to 80 °C and allowed to stir for 3 h. The reaction mixture was cooled to ambient temperature and saturated aqueous sodium bicarbonate solution was slowly added. The resulting mixture was extracted with ethyl acetate (2×). The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=293.1 [M+CH 3 CN+H].

[0607] Step C: (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide

[0608] To a solution of (2R)-2-cyano-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide (320 mg, 1.27 mmol) in methanol (4 mL) was added aqueous hydroxylamine (50 w / w%, 1.00 mL, 16.3 mmol) and the reaction mixture was stirred at ambient temperature for 2 days. The reaction mixture was concentrated under reduced pressure to afford the title compound in sufficient purity for the next step. MS: m / z=285.2 [M+H].

[0609] Intermediate 12

[0610]

[0611] 3-Cyclopropyl-N'-hydroxyisoxazole-4-carboximidamide

[0612] Step A: 3-Cyclopropylisoxazole-4-carboxamide

[0613] To a solution of 3-cyclopropylisoxazole-4-carboxylic acid (0.758 g, 4.95 mmol) in dichloromethane (22 mL) and dimethyl sulfoxide (2.2 mL) was added HATU (2.06 g, 5.42 mmol), ammonium chloride (0.545 g, 10.2 mmol) and N-methylmorpholine (1.60 mL, 14.6 mmol) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was washed with saturated aqueous ammonium chloride (4×20 mL) and saturated aqueous sodium chloride (1×20 mL), dried (magnesium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexane:ethyl acetate:ethanol from 100:0:0 to 60:30:10 to give the title compound. MS: m / z=153.2 [M+H].

[0614] Step B: 3-Cyclopropylisoxazole-4-carbonitrile

[0615] To a solution of 3-cyclopropylisoxazole-4-carboxamide (330 mg, 2.17 mmol) in acetonitrile (11 mL) was added phosphorus oxychloride (0.404 mL, 4.34 mmol) and the reaction mixture was warmed to 80°C and allowed to stir for 1.3 h. The reaction mixture was cooled to ambient temperature, slowly added to cold saturated aqueous sodium bicarbonate solution (30 mL) and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (1 x 15 mL), dried (magnesium sulfate), filtered, and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. 1 H NMR (DMSO-d 6 )δ9.75(s,1H),2.13–2.06(m,1H),1.18–1.10(m,2H),1.03–0.97(m,2H).

[0616] Step C: 3-Cyclopropyl-N'-hydroxyisoxazole-4-carboximidamide

[0617] To a solution of 3-cyclopropylisoxazole-4-carbonitrile (230 mg, 1.72 mmol) in ethanol (5.80 mL) was added hydroxylamine (0.841 mL, 13.7 mmol) and the reaction mixture was warmed to 80°C and allowed to stir for 3 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was co-evaporated with ethanol (3×) and acetonitrile (2×) to give the title compound in sufficient purity for the next step. MS: m / z=168.1 [M+H].

[0618] Intermediate 13

[0619]

[0620] N'-Hydroxy-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboximidamide

[0621] Step A: 1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxamide

[0622] To a solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylic acid (388 mg, 2.00 mmol) in dichloromethane (9.5 mL) and dimethyl sulfoxide (0.50 mL) was added ammonium chloride (267 mg, 5.00 mmol), HATU (837 mg, 2.20 mmol) and N-methylmorpholine (0.660 mL, 6.00 mmol) in sequence and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water and the layers were separated. The aqueous layer was extracted with dichloromethane and the combined organic extracts were concentrated under reduced pressure. The residue was purified by silica gel chromatography with a gradient elution of hexane: ethyl acetate: ethanol from 96:3:1 to 52:36:12 to give the title compound. MS: m / z=194.1[M+H].

[0623] Step B: 5-cyano-1-(2,2,2-trifluoroethyl)-1H-pyrazole

[0624] To a solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxamide (365 mg, 1.89 mmol) in acetonitrile (10 mL) was added phosphorus oxychloride (0.352 mL, 3.78 mmol) dropwise and the reaction mixture was warmed to 80 °C and allowed to stir for 2 h. The reaction mixture was cooled to ambient temperature, phosphorus oxychloride (0.352 mL, 3.78 mmol) was added, the reaction mixture was warmed to 85 °C and allowed to stir for 1 h. The reaction mixture was cooled to ambient temperature and saturated aqueous sodium bicarbonate solution was slowly added. The mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure to give the title compound in sufficient purity for the next step.

[0625] Step C: (R)-N'-Hydroxy-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboximidamide

[0626] To a solution of 5-cyano-1-(2,2,2-trifluoroethyl)-1H-pyrazole (135 mg, 0.771 mmol) in methanol (1.6 mL) was added aqueous hydroxylamine (50 w / w%, 0.400 mL, 6.53 mmol) and the reaction mixture was warmed to 65°C and allowed to stir for 2 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to afford the title compound in sufficient purity for the next step. MS: m / z=209.1 [M+H].

[0627] Intermediate 14

[0628] 2-(Difluoromethoxy)-5-methylisonicotinic acid

[0629]

[0630] Step A: 5-bromo-2-(difluoromethoxy)isonicotinic acid methyl ester

[0631] To a solution of methyl 5-bromo-2-hydroxyisonicotinate (2.00 g, 8.62 mmol) in acetonitrile (100 mL) was added sodium chlorodifluoroacetate (4.00 g, 26.2 mmol) and the reaction mixture was warmed to 90 ° C and allowed to stir for 16 h. The reaction mixture was cooled to ambient temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate:hexane from 0:100 to 50:50 to give the title compound. MS: m / z=284.0 [M+H].

[0632] Step B: Methyl 2-(difluoromethoxy)-5-methylisonicotinate

[0633] To a solution of 5-bromo-2-(difluoromethoxy)isonicotinate (282 mg, 1.00 mmol) and potassium phosphate (424 mg, 2.00 mmol) in 1,4-dioxane (4.50 mL) and water (0.50 mL) was added 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (65.2 mg, 0.100 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborin (251 mg, 2.00 mmol). The reaction mixture was warmed to 100°C and allowed to stir for 16 h. The reaction mixture was cooled to ambient temperature and stirred by The residue was purified by silica gel chromatography using a gradient of ethyl acetate:hexanes from 0:100 to 50:50 to afford the title compound. MS: m / z=218.1 [M+H].

[0634] Step C: 2-(Difluoromethoxy)-5-methylisonicotinic acid

[0635] To a solution of methyl 2-(difluoromethoxy)-5-methylisonicotinate (110 mg, 0.507 mmol) in tetrahydrofuran (1.5 mL) was added aqueous sodium hydroxide (1 M, 1.52 mL, 1.52 mmol) and the reaction mixture was warmed to 40°C and allowed to stir for 1 h. The reaction mixture was cooled to ambient temperature, adjusted to pH=1 with aqueous hydrochloric acid (1 M) and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=204.1 [M+H].

[0636] Intermediate 15

[0637]

[0638] (1R)-1-{1-[3-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-6-azaspiro[2.5]octane

[0639] Step A: (1R)-6-[(Benzyloxy)carbonyl]-6-azaspiro[2.5]octane-1-carboxylic acid

[0640] To a stirred solution of 6-benzyl 1-ethyl (1R)-6-azaspiro[2.5]octane-1,6-dicarboxylate (Brown et al., J. Med. Chem. (2014) 57:733-758) (2.0 g, 6.3 mmol) in ethanol (30 mL) was added aqueous sodium hydroxide solution (1 M, 19 mL, 19 mmol) and the reaction mixture was warmed to 50 °C and allowed to stir for 2 h. The reaction mixture was cooled and concentrated under reduced pressure. Water (20 mL) was added and the resulting mixture was adjusted to pH = 4 by adding aqueous hydrochloric acid solution (2 M). The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z = 290.0 [M+H].

[0641] Step B: (1R)-1-(Hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylic acid benzyl ester

[0642] To a 0°C solution of (1R)-6-((benzyloxy)carbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (100 mg, 0.35 mmol) in tetrahydrofuran (2 mL) was added borane dimethyl sulfide complex / tetrahydrofuran (10 M, 0.07 mL, 0.7 mmol) and the reaction mixture was stirred at 0°C for 0.5 h. The reaction mixture was warmed to ambient temperature and allowed to stir for 1 h. Methanol was slowly added until gas evolution ceased and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:50 petroleum ether:ethyl acetate to give the title compound. MS: m / z=276.1 [M+H].

[0643] Step C: (1R)-1-Formyl-6-azaspiro[2.5]octane-6-carboxylic acid benzyl ester

[0644] To a solution of (1R)-1-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylic acid benzyl ester (70 mg, 0.25 mmol) in dichloromethane (3 mL) was added Dess-Martin periodinane (162 mg, 0.382 mmol) and the reaction mixture was stirred at ambient temperature for 1 h. Water (5 mL) was added and the aqueous layer was extracted with dichloromethane (2×5 mL). The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 75:25 petroleum ether:ethyl acetate to give the title compound. MS: m / z=274.1[M+H].

[0645] Step D: (1S)-1-(2-methoxyvinyl)-6-azaspiro[2.5]octane-6-carboxylic acid benzyl esterTo a -78°C solution of (methoxymethyl)triphenylphosphonium chloride (188 mg, 0.55 mmol) in tetrahydrofuran (5 mL) was added a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 0.531 mL, 0.531 mmol) and the reaction mixture was stirred at -78°C for 0.5 h. (1R)-1-formyl-6-azaspiro[2.5]octane-6-carboxylic acid benzyl ester (50 mg, 0.18 mmol) was added and the reaction mixture was stirred for 15 minutes. The reaction mixture was warmed to ambient temperature and stirred for 1 h. Water (5 mL) was added and the resulting mixture was extracted with ethyl acetate (2×5 mL). The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 75:25 petroleum ether:ethyl acetate to give the title compound. MS: m / z=302.1[M+H].

[0646] Step E: N-[2-{(1R)-6-[(benzyloxy)carbonyl]-6-azaspiro[2.5]octan-1-yl}-3-methoxypropane-2-yl [1-ene]-N-methylammonium carbonate

[0647] To a 0°C solution of N,N-dimethylformamide (0.032 mL, 0.42 mmol) in chloroform (1 mL) was added phosphorus oxychloride (0.039 mL, 0.42 mmol) and the reaction mixture was warmed to 40°C and allowed to stir for 0.5 h. The reaction mixture was cooled to 0°C and (1S)-1-(2-methoxyvinyl)-6-azaspiro[2.5]octane-6-carboxylic acid benzyl ester (25 mg, 0.08 mmol) was added. The reaction mixture was warmed to 70°C and allowed to stir for 1 h. The reaction mixture was cooled to 0°C and an aqueous solution of potassium carbonate (0.83 M, 1 mL, 0.83 mmol) was added. The reaction mixture was diluted with water (3 mL) and the aqueous layer was extracted with dichloromethane (2×5 mL). The combined organic extracts were dried (sodium sulfate) and filtered and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=357.1 [M+H].

[0648] Step F: (1R)-1-{1-[3-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-6-azaspiro[2.5]octane- Benzyl 6-carboxylate

[0649] To a solution of (R)-N-(2-(6-((benzyloxy)carbonyl)-6-azaspiro[2.5]octan-1-yl)-3-methoxyallylidene)-N-methylammonium carbonate (150 mg, 0.42 mmol) in methanol (4 mL) was added (3-(trifluoromethoxy)phenyl)hydrazine (806 mg, 4.20 mmol) and aqueous hydrochloric acid (2 M, 2.10 mL, 4.20 mmol) and the reaction mixture was warmed to 60 °C and allowed to stir for 1 h. The reaction mixture was adjusted to pH = 10 with saturated aqueous sodium bicarbonate and the aqueous layer was extracted with ethyl acetate (2 x 5 mL). The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 75:25 petroleum ether:ethyl acetate to give the title compound. MS: m / z = 472.1 [M+H].

[0650] Step G: (1R)-1-{1-[3-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-6-azaspiro[2.5]octane

[0651] To a solution of (1R)-benzyl 1-{1-[3-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-6-azaspiro[2.5]octane-6-carboxylate (150 mg, 0.32 mmol) in methanol (5 mL) and ethyl acetate (5 mL) was added palladium on activated carbon (10 w / w%, 22.3 mg, 0.032 mmol) and the reaction mixture was stirred under a hydrogen atmosphere (25 psi) at ambient temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound. MS: m / z = 338.1 [M+H].

[0652] Intermediate 16

[0653]

[0654] 1-Cyclopropyl-1H-pyrazole-5-carbohydrazide

[0655] To a solution of 1-cyclopropyl-1H-pyrazole-5-carboxylic acid (300 mg, 1.97 mmol) in dichloromethane (4.0 mL) was added a solution of oxalyl chloride in dichloromethane (2M, 2.96 mL, 5.92 mmol), and the reaction mixture was stirred at ambient temperature for 0.5 h. The reaction mixture was concentrated under reduced pressure. Dichloromethane (4.0 mL) and methanol (0.16 mL, 3.94 mmol) were added sequentially and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethanol (2.0 mL), hydrazine (0.60 mL, 19 mmol) was added and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of dichloromethane:methanol from 100:0 to 95:5 to give the title compound. MS: m / z=167.0[M+H].

[0656] Intermediate 17

[0657]

[0658] 2-{3-[2-(difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6-azaspiro [2.5] Octane hydrochloride

[0659] Step A: 6-(tert-Butoxycarbonyl)-2,2-difluoro-6-azaspiro[2.5]octane-1-carboxylic acid

[0660] To a solution of 1-benzyl 6-tert-butyl 2,2-difluoro-6-azaspiro[2.5]octane-1,6-dicarboxylate (described in Intermediate 10) (500 mg, 1.31 mmol) in methanol (26 mL) was added palladium on carbon (10 w / w%, 42 mg, 0.039 mmol) and the reaction mixture was stirred under a hydrogen atmosphere at ambient temperature for 1.5 h. The reaction mixture was filtered, washed with methanol, and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z = 236.1 [M-tBu+H].

[0661] Step B: 2-{3-[2-(difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6-nitrogen Heterospiro[2.5]octane-6-carboxylic acid tert-butyl ester

[0662] To a solution of 6-(tert-butoxycarbonyl)-2,2-difluoro-6-azaspiro[2.5]octane-1-carboxylic acid (386 mg, 1.325 mmol) in 1,2-dichloroethane (12 mL) and dimethyl sulfoxide (1.2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (330 mg, 1.72 mmol), 1-hydroxy-7-azabenzotriazole (126 mg, 0.928 mmol) and 2-(difluoromethoxy)-N'-hydroxypyridine-4-carboximidamide (Intermediate A7) (350 mg, 1.72 mmol) and the reaction mixture was stirred at ambient temperature for 0.5 h. The reaction mixture was warmed to 100° C. and stirred for 4.5 h. The reaction mixture was cooled to ambient temperature, poured into saturated aqueous ammonium chloride solution (20 mL) and the resulting mixture was extracted with dichloromethane (3×25 mL). The combined organic extracts were washed with saturated aqueous ammonium chloride (2×20 mL) and saturated aqueous sodium chloride (1×20 mL), dried (magnesium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of hexane:ethyl acetate from 100:0 to 61:39, to give the title compound. MS: m / z=403.2 [M-tBu+H].

[0663] Step C: 2-{3-[2-(difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6-nitrogen Spiro[2.5]octane hydrochloride

[0664] To a solution of tert-butyl 2-{3-[2-(difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-carboxylate (393 mg, 0.858 mmol) in 1,4-dioxane (4.3 mL) was added a solution of HCl in 1,4-dioxane (4M, 4.30 mL, 17.2 mmol) and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated under a stream of nitrogen to give the title compound in sufficient purity for the next step. MS: m / z=359.2 [M+H].

[0665] Intermediate 18

[0666]

[0667] (1R)-1-[4-(3-Cyclopropylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro[2.5]octane

[0668] Step A: (1R)-1-Carbamoyl-6-azaspiro[2.5]octane-6-carboxylic acid benzyl ester

[0669] To a solution of (1R)-6-[(benzyloxy)carbonyl]-6-azaspiro[2.5]octane-1-carboxylic acid (described in Intermediate 15) (1.95 g, 6.74 mmol) in dichloromethane (60 mL) and dimethyl sulfoxide (3.0 mL) were added HATU (2.69 g, 7.07 mmol), N-methylmorpholine (2.97 mL, 27.0 mmol) and ammonium chloride (1.44 g, 26.9 mmol) in sequence and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was poured into saturated aqueous ammonium chloride (70 mL) and the resulting mixture was extracted with dichloromethane (3 x 75 mL). The combined organic extracts were washed with saturated aqueous ammonium chloride (3 x 75 mL) and saturated aqueous sodium chloride (1 x 75 mL), dried (magnesium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 100:0:0 to 40:45:15 to give the title compound. MS: m / z = 289.2 [M+H].

[0670] Step B: (1R)-1-[4-(3-cyclopropylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro[2.5]oxane Benzyl 6-alkanecarboxylate

[0671] To a solution of (1R)-1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylic acid benzyl ester (106 mg, 0.369 mmol) in ethyl acetate (2.0 mL) was added 2-bromo-1-(3-cyclopropylisoxazol-4-yl)ethanone (Intermediate E1) (76.2 mg, 0.330 mmol) and silver trifluoromethanesulfonate (100 mg, 0.390 mmol) in sequence, and the reaction mixture was warmed to 75 ° C and stirred for 3.5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of hexane:ethyl acetate from 100:0 to 70:30 to give the title compound. MS: m / z=389.3[M+H].

[0672] Step C: (1R)-1-[4-(3-cyclopropylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro[2.5]oxane alkyl

[0673] To a solution of (1R)-1-[4-(3-cyclopropylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro[2.5]octane-6-carboxylic acid benzyl ester (22 mg, 0.057 mmol) in ethyl acetate (1.5 mL) and methanol (2 mL) was added palladium hydroxide on carbon (20 w / w%, 4.0 mg, 5.7 μmol). The reaction mixture was placed under a hydrogen atmosphere and allowed to stir at ambient temperature for 5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=255.1 [M+H].

[0674] Intermediate 19

[0675]

[0676] 2-Cyclopropylisonicotinic acid

[0677] To a mixture of sodium hydride (60% dispersion in mineral oil, 64.5 mg, 1.61 mmol) in tetrahydrofuran (8 mL) at ambient temperature was added cyclopropanol (94.0 mg, 1.61 mmol) and the reaction mixture was stirred for 15 minutes after gas evolution ceased. Methyl 2-fluoroisonicotinate (250 mg, 1.61 mmol) was added dropwise and the reaction mixture was stirred for 16 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and water and the aqueous layer was adjusted to pH = 1 with aqueous hydrochloric acid (1 M). The layers were separated and the organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC, eluting with acetonitrile: water from 0: 100 to 95: 5 to give the title compound. MS: m / z = 180.0 [M + H].

[0678] Intermediate 20

[0679]

[0680] 1-Cyclopropyl-4-methyl-1H-pyrazole-3-carboxylic acid

[0681] Step A: 1-Cyclopropyl-4-methyl-1H-pyrazole-5-carboxylic acid ethyl ester

[0682] Cyclopropylboronic acid (1.11 g, 13.0 mmol) and sodium carbonate (1.38 g, 13.0 mmol) were added to a solution of ethyl 4-methyl-1H-pyrazole-5-carboxylate (1.00 g, 6.49 mmol) in 1,2-dichloroethane (50 mL) under an air atmosphere. The reaction mixture was warmed to 70 ° C and 2,2'-bipyridine (1.01 g, 6.49 mmol) and copper (II) acetate (1.18 g, 6.49 mmol) were added. The reaction mixture was stirred for 18 h. The reaction mixture was cooled to ambient temperature, diluted with saturated aqueous sodium bicarbonate solution and the resulting mixture was extracted with ethyl acetate (2×). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of hexane:ethyl acetate from 100:0 to 50:50 to give the title compound. MS: m / z=195.0[M+H].

[0683] Step B: 1-Cyclopropyl-4-methyl-1H-pyrazole-5-carboxylic acid

[0684] To a solution of ethyl 1-cyclopropyl-4-methyl-1H-pyrazole-5-carboxylate (425 mg, 2.19 mmol) in tetrahydrofuran (12 mL) was added aqueous sodium hydroxide solution (1 M, 9.00 mL, 9.00 mmol) and the reaction mixture was stirred at ambient temperature for 1.5 days. The reaction mixture was adjusted to pH = 1 with aqueous hydrochloric acid solution (1 M) and the mixture was extracted with ethyl acetate (2×). The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z = 189.1 [M+Na].

[0685] Intermediate 21

[0686]

[0687] N'-Hydroxy-6-methylsulfonyl-6-azaspiro[2.5]octane-1-carboximidamide

[0688] Step A: tert-Butyl 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylate

[0689] To a solution of 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (1.50 g, 5.88 mmol) in dichloromethane (28 mL) and dimethyl sulfoxide (1.4 mL) were added HATU (2.30 g, 6.05 mmol), ammonium chloride (1.35 g, 25.2 mmol) and N-methylmorpholine (2.60 mL, 23.7 mmol) in sequence, and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was filtered, and the precipitate was washed with dichloromethane and water and dried under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=255.2 [M+H].

[0690] Step B: 6-Azaspiro[2.5]octane-1-carboxamide

[0691] To a solution of tert-butyl 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylate (703 mg, 2.76 mmol) in 1,4-dioxane (6.0 mL) and methanol (3.0 mL) was added HCl / dioxane (6.91 mL, 27.6 mmol) and the reaction mixture was stirred at ambient temperature for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=155.1 [M+H].

[0692] Step C: 6-(Methylsulfonyl)-6-azaspiro[2.5]octane-1-carboxamide

[0693] To a solution of 6-azaspiro[2.5]octane-1carboxamide hydrochloride (625 mg, 2.76 mmol) in dichloromethane (20 mL) was added triethylamine (2.30 mL, 16.5 mmol) and methanesulfonyl chloride (0.344 mL, 4.41 mmol) in sequence and the reaction mixture was stirred at ambient temperature for 2.5 h. The reaction mixture was concentrated under reduced pressure and ethyl acetate (75 mL) was added to the resulting residue. The mixture was filtered, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity for the next step. MS: m / z=233.2[M+H].

[0694] Step D: 6-(Methylsulfonyl)-6-azaspiro[2.5]octane-1-carbonitrile

[0695] Phosphorus oxychloride (0.940 mL, 10.1 mmol) was added to a solution of 6-(methylsulfonyl)-6-azaspiro[2.5]octane-1-carboxamide (702 mg, 2.75 mmol) in acetonitrile (25 mL), and the reaction mixture was warmed to 60 ° C and stirred for 2 h. The reaction mixture was cooled to ambient temperature and slowly poured into a mixture of ice and saturated aqueous sodium bicarbonate solution (25 mL). The resulting mixture was extracted with ethyl acetate (3×35 mL). The combined organic phases were washed with saturated aqueous sodium chloride solution (1×15 mL), dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of hexane:ethyl acetate:ethanol from 100:0:0 to 35:49:16 to give the title compound. MS: m / z=215.3[M+H].

[0696] Step E: N'-Hydroxy-6-methylsulfonyl-6-azaspiro[2.5]octane-1-carboximidamide

[0697] To a solution of 6-(methylsulfonyl)-6-azaspiro[2.5]octane-1-carbonitrile (370 mg, 1.73 mmol) in ethanol (8.60 mL) was added aqueous hydroxylamine (50 w / w%, 0.969 mL, 17.2 mmol). The reaction mixture was warmed to 80°C and allowed to stir for 3 h. The reaction mixture was cooled to ambient temperature and concentrated under a stream of nitrogen to afford the title compound in sufficient purity for the next step. MS: m / z=248.2 [M+H].

[0698] Intermediate 22

[0699]

[0700] 2-Azido-1-(3-cyclopropyl-5-methylisoxazol-4-yl)ethanone

[0701] Step A: 3-Cyclopropyl-N-methoxy-N,5-dimethylisoxazole-4-carboxamide

[0702] To a solution of 3-cyclopropyl-5-methylisoxazole-4-carboxylic acid (995 mg, 5.95 mmol) in dichloromethane (20 mL) and dimethyl sulfoxide (2.0 mL) was added HATU (2.49 g, 6.55 mmol), 4-methylmorpholine (1.96 mL, 17.8 mmol) and N,O-dimethylhydroxylamine hydrochloride (639 mg, 6.55 mmol) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was poured into water (40 mL) and the resulting mixture was extracted with dichloromethane (150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (50 mL), dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of dichloromethane:methanol from 100:0 to 95:5 to give the title compound. MS: m / z=211.1 [M+H].

[0703] Step B: 1-(3-cyclopropyl-5-methylisoxazol-4-yl)ethanone

[0704] To a 0°C solution of 3-cyclopropyl-N-methoxy-N,5-dimethylisoxazole-4-carboxamide (1.04 g, 4.95 mmol) in tetrahydrofuran (15 mL) was added a solution of methylmagnesium bromide in toluene and tetrahydrofuran (1.4 M, 7.70 mL, 9.89 mmol) and the reaction mixture was stirred at 0°C for 1.5 h. The reaction mixture was warmed to ambient temperature, poured into saturated aqueous ammonium chloride solution (30 mL) and the resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (50 mL), dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexane:ethyl acetate from 100:0 to 60:40 to give the title compound. MS: m / z=166.0 [M+H].

[0705] Step C: 2-Bromo-1-(3-cyclopropyl-5-methylisoxazol-4-yl)ethanone

[0706] Bromine (0.25 mL, 4.85 mmol) was added dropwise to a 0°C solution of 1-(3-cyclopropyl-5-methylisoxazol-4-yl)ethanone (682 mg, 4.13 mmol) in methanol (14 mL), and the reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was poured into water (40 mL) and the resulting mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of hexane:ethyl acetate from 100:0 to 50:50 to give the title compound. MS: m / z=244.0[M+H].

[0707] Step D: 2-Azido-1-(3-cyclopropyl-5-methylisoxazol-4-yl)ethanone

[0708] To a solution of 2-bromo-1-(3-cyclopropyl-5-methylisoxazol-4-yl)ethanone (856 mg, 3.51 mmol) in acetonitrile (11 mL) was added sodium azide (342 mg, 5.26 mmol) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was poured into water (40 mL) and the resulting mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=207.1 [M+H].

[0709] Intermediate 23

[0710]

[0711] 1-Cyclopropyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid

[0712] Step A: Ethyl 1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate

[0713] To a solution of ethyl 3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (1.00 g, 4.80 mmol) in 1,2-dichloroethane (40 mL) was added cyclopropylboronic acid (0.825 g, 9.61 mmol) and sodium carbonate (1.02 g, 9.61 mmol). The reaction mixture was warmed to 70°C, 2,2'-bipyridine (0.750 g, 4.80 mmol) and copper (II) acetate (0.873 g, 4.80 mmol) were added and the reaction mixture was stirred at 70°C for 18 h. The reaction mixture was cooled to ambient temperature, diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×). The combined organic extracts were washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexane:ethyl acetate from 95:5 to 50:50 to give the title compound. MS: m / z=249.1 [M+H].

[0714] Step B: 1-Cyclopropyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid

[0715] To a solution of ethyl 1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (368 mg, 1.48 mmol) in tetrahydrofuran (9 mL) was added aqueous sodium hydroxide solution (1 M, 4.5 mL, 4.50 mmol) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was acidified to pH = 1 by the addition of aqueous hydrochloric acid (1 M) and the resulting mixture was extracted with ethyl acetate (2×). The combined organic extracts were dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z = 221.0 [M+H].

[0716] Intermediate 24

[0717]

[0718] (2R)-N-[(dimethylamino)methylene]-1,1-difluoro-2-(iodoacetyl)-6-azaspiro[2.5]octane-6- Sulfonamide

[0719] Step A: (1R)-6-{[(dimethylamino)methylene]sulfamoyl}-2,2-difluoro-N-methoxy-N-methyl-6- Azaspiro[2.5]octane-1-carboxamide

[0720] To a solution of (1R)-2,2-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 10) (700 mg, 2.59 mmol) in N,N-dimethylformamide (13 mL) were added HATU (1083 mg, 2.85 mmol), 4-methylmorpholine (0.997 mL, 9.07 mmol) and N,O-dimethylhydroxylamine hydrochloride (303 mg, 3.11 mmol) in sequence and the reaction mixture was stirred at ambient temperature for 1 h. Oxalyl chloride (3.11 mL, 6.22 mmol) was added and the reaction mixture was stirred at ambient temperature for 18 h. Water was added and the resulting mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution (3×). The organic layer was dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 100:0:0 to 40:45:15 to give the title compound. MS: m / z=369.2 [M+H].

[0721] Step B: (2R)-2-(Chloroacetyl)-N-[(dimethylamino)methylene]-1,1-difluoro-6-azaspiro[2.5]octane Alkane-6-sulfonamide

[0722] To a -78°C solution of (1R)-6-{[(dimethylamino)methylene]sulfamoyl}-2,2-difluoro-N-methoxy-N-methyl-6-azaspiro[2.5]octane-1-carboxamide (200 mg, 0.543 mmol) in tetrahydrofuran (5.4 mL) was added dropwise and sequentially chloroiodomethane (0.162 mL, 2.17 mmol) and a solution of methyllithium lithium bromide complex in tetrahydrofuran (1.5 M, 1.09 mL, 1.63 mmol) and the reaction mixture was stirred at -78°C for 2 h. Saturated aqueous ammonium chloride was added and the resulting mixture was warmed to ambient temperature and allowed to stir for 20 minutes. The mixture was diluted with ethyl acetate and the organic layer was washed with saturated aqueous ammonium chloride (2x) and saturated aqueous sodium chloride, dried (magnesium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 100:0:0 to 40:45:15 to afford the title compound. MS: m / z = 358.1 [M+H].

[0723] Step C: (2R)-N-[(dimethylamino)methylene]-1,1-difluoro-2-(iodoacetyl)-6-azaspiro[2.5]octane Alkane-6-sulfonamide

[0724] To a solution of (2R)-2-(chloroacetyl)-N-[(dimethylamino)methylene]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide (65 mg, 0.18 mmol) in acetone (0.60 mL) was added sodium iodide (27.2 mg, 0.182 mmol) and the reaction mixture was stirred at ambient temperature for 0.5 h. The reaction mixture was filtered, washed with acetone, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic layer was washed with saturated aqueous sodium bicarbonate solution, dried (magnesium sulfate), filtered, and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=450.1 [M+H].

[0725] Intermediate 25

[0726]

[0727] 5-Chloro-3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazole

[0728] Step A: 3-[4-Fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5(4H)-one

[0729] To a solution of 4-fluoro-N'-hydroxy-2-(trifluoromethyl)benzenecarboximidamide (500 mg, 2.25 mmol) in tetrahydrofuran (50 mL) at ambient temperature was added 1,1'-thiocarbonyldiimidazole (501 mg, 2.81 mmol) and the reaction mixture was stirred for 30 minutes. Water (50 mL) was added and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (100 mL), dried (sodium sulfate), and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 mL), cooled to 0°C, and boron trifluoride diethyl etherate (1.43 mL, 11.3 mmol) was added and the reaction mixture was stirred for 10 minutes. Water (30 mL) was added and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (100 mL), 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 petroleum ether:ethyl acetate from 100:0 to 72:28 to give the title compound. 1 H NMR (400 MHz, CDCl 3 ): δ10.83(m,1H),7.70(m,1H),7.54(m,1H),7.41(m,1H).

[0730] Step B: 5-Chloro-3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazole

[0731] Phosphorus oxychloride (3.0 mL, 32 mmol) was added to a flask containing 3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5(4H)-one (180 mg, 0.68 mmol), and the reaction mixture was warmed to 120°C and allowed to stir for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was redissolved in dichloromethane (50 mL). Water (cold water, 50 mL) was added and the resulting mixture was extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (50 mL), dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of petroleum ether:ethyl acetate from 100:0 to 90:10 to give the title compound. 1 H NMR (400 MHz, CDCl 3 ): δ7.90(m,1H),7.54(m,1H),7.36(m,1H).

[0732] Intermediate 26

[0733]

[0734] tert-Butyl 1,1-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-azaspiro[2.5]octane-6-carboxylate

[0735] Step A: tert-4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]piperidine-1-carboxylic acid Butyl Ester

[0736] To a solution of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.03 g, 45.6 mmol) in toluene (60 mL) was added tert-butyl 4-methylenepiperidine-1-carboxylate (3.0 g, 15.2 mmol) and dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II) (0.56 g, 0.76 mmol) and the reaction mixture was warmed to 90°C and allowed to stir for 3 h. The reaction mixture was cooled to ambient temperature, water (20 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of petroleum ether:ethyl acetate from 95:5 to 90:10 to give the title compound. MS: m / z = 224.1 [M-100+H].

[0737] Step B: 1,1-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-azaspiro [2.5] Octane-6-carboxylic acid tert-butyl ester

[0738] To a solution of tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (1.00 g, 3.09 mmol) in tetrahydrofuran (10 mL) was added trimethyl(trifluoromethyl)silane (4.40 g, 30.9 mmol) and sodium iodide (0.23 g, 1.6 mmol), the reaction mixture was warmed to 120 ° C and stirred for 12 h. The reaction mixture was cooled to ambient temperature, water (15 mL) was added, and the resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of petroleum ether:ethyl acetate from 100:0 to 80:20 to give the title compound. MS: m / z=359.2 [M-tBu+CH 3 CN+H].

[0739] Intermediate 27

[0740]

[0741] 1,1-Difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl}-6-azaspiro [2.5] Octane

[0742] Essentially following the procedure described in Intermediate 35, but substituting 5-chloro-3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazole (Intermediate 25) for 3-bromo-5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazole, the title compound was obtained. MS: m / z = 394.1 [M+H].

[0743] Intermediate 28

[0744]

[0745] 2,2-Difluoro-6-(methylsulfonyl)-6-azaspiro[2.5]octane-1-carboxylic acid

[0746] Step A: Benzyl 2,2-difluoro-6-(methylsulfonyl)-6-azaspiro[2.5]octane-1-carboxylate To a solution of 2,2-difluoro-6-azaspiro[2.5]octane-1-carboxylic acid benzyl ester (described in Intermediate 10) (2.58 g, 9.17 mmol) in dichloromethane (30 mL) was added triethylamine (3.84 mL, 27.5 mmol) and methanesulfonyl chloride (1.07 mL, 13.8 mmol) in sequence and the reaction mixture was stirred at ambient temperature for 1 h. Water (30 mL) was added and the resulting mixture was extracted with dichloromethane (3×30 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 dichloromethane:ethyl acetate from 100:0 to 90:10 to give the title compound. MS: m / z=382.1[M+Na].

[0747] Step B: 2,2-Difluoro-6-(methylsulfonyl)-6-azaspiro[2.5]octane-1-carboxylic acid

[0748] To a solution of benzyl 2,2-difluoro-6-(methylsulfonyl)-6-azaspiro[2.5]octane-1-carboxylate (2.9 g, 8.1 mmol) in methanol (50 mL) and dichloromethane (20 mL) was added palladium on activated carbon (wet, 10 w / w%, 0.86 g, 0.81 mmol). The reaction mixture was placed under a hydrogen atmosphere (30 psi) and allowed to stir at ambient temperature for 3 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=270.0 [M+H].

[0749] Intermediate 29

[0750]

[0751] 2-(Difluoromethoxy)pyridine-4-carboxamide

[0752] HATU (10.1 g, 50.4 mmol), ammonium chloride (5.66 g, 105 mmol) and N-methylmorpholine (12.2 mL, 58.2 mmol) were added to a solution of 2-(difluoromethoxy)isonicotinic acid (5.0 g, 26 mmol) in dichloromethane (48 mL) and dimethyl sulfoxide (4.80 mL). The reaction mixture was stirred for 18 h. Saturated aqueous ammonium chloride solution (75 mL) was added and the resulting mixture was extracted with dichloromethane (3×100 mL). The combined organic phases were washed with saturated aqueous ammonium chloride solution (2×30 mL) and saturated aqueous sodium chloride solution (1×30 mL), dried (magnesium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of hexane:ethyl acetate from 80:20 to 15:85 to give the title compound. MS: m / z=189.1[M+H].

[0753] Intermediate 30

[0754]

[0755] 1,1-Difluoro-2-(1H-pyrazol-3-yl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester

[0756] Step A: 1,1-difluoro-2-[methoxy(methyl)carbamoyl]-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester

[0757] To a solution of 6-(tert-butoxycarbonyl)-2,2-difluoro-6-azaspiro[2.5]octane-1-carboxylic acid (described in Intermediate 10) (4.0 g, 13.7 mmol) in dichloromethane (50 mL) was added triethylamine (5.74 mL, 41.2 mmol), 1,1'-carbonyldiimidazole (4.45 g, 27.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.01 g, 20.6 mmol) and the reaction mixture was stirred at ambient temperature for 1 h. Water (50 mL) was added and the resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers 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 petroleum ether:ethyl acetate from 90:10 to 75:25 to give the title compound. MS: m / z=335.1[M+H].

[0758] Step B: tert-Butyl 1,1-difluoro-2-propioloyl-6-azaspiro[2.5]octane-6-carboxylate

[0759] To a 0°C solution of 1,1-difluoro-2-[methoxy(methyl)carbamoyl]-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (2.0 g, 5.98 mmol) in tetrahydrofuran (5 mL) was added a solution of ethynylmagnesium bromide in tetrahydrofuran (0.5 M, 120 mL, 59.8 mmol) and the reaction mixture was stirred at 0°C for 1 h. Water (150 mL) was added and the resulting mixture was extracted with ethyl acetate (2×100 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 petroleum ether:ethyl acetate from 95:5 to 75:25 to give the title compound. 1 HNMR (400MHz, CDCl 3 ): δ3.48–3.58(m,4H),3.37(s,1H),2.55–2.65(m,1H),1.51–1.89(m,4H),1.44(s,9H).

[0760] Step C: tert-Butyl 1,1-difluoro-2-(1H-pyrazol-3-yl)-6-azaspiro[2.5]octane-6-carboxylate

[0761] To a solution of tert-butyl 1,1-difluoro-2-propioloyl-6-azaspiro[2.5]octane-6-carboxylate (700 mg, 2.34 mmol) in ethanol (10 mL) was added hydrazine (85 weight / weight%, 353 mg, 9.35 mmol) and the reaction mixture was stirred at ambient temperature for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with a gradient of petroleum ether:ethyl acetate from 90:10 to 75:25 to give the title compound. MS: m / z=314.0 [M+H].

[0762] Intermediate 31

[0763]

[0764] 1,1-Difluoro-2-{1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}-6-azaspiro[2.5]octane Hydrochloride

[0765] Step A: 1,1-difluoro-2-{1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}-6-azaspiro [2.5] Octane-6-carboxylic acid tert-butyl ester

[0766] To a solution of tert-butyl 1,1-difluoro-2-(1H-pyrazol-3-yl)-6-azaspiro[2.5]octane-6-carboxylate (Intermediate 30) (200 mg, 0.64 mmol) in 1,4-dioxane (1 mL) was added [4-fluoro-2-(trifluoromethyl)phenyl]boronic acid (265 mg, 1.28 mmol), cesium carbonate (416 mg, 1.28 mmol), 4-(dimethylamino)pyridine (312 mg, 2.55 mmol) and copper(II) acetate (116 mg, 0.64 mmol) and the resulting mixture was placed under an oxygen atmosphere (15 psi). The reaction mixture was warmed to 50 °C and allowed to stir for 15 h. The reaction mixture was cooled and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 75:25 petroleum ether:ethyl acetate to give the title compound. MS: m / z=476.0[M+H].

[0767] Step B: 1,1-difluoro-2-{1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}-6-azaspiro [2.5] Octane hydrochloride

[0768] To a flask containing tert-butyl 1,1-difluoro-2-{1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}-6-azaspiro[2.5]octane-6-carboxylate (30 mg, 0.06 mmol) was added hydrogen chloride / 1,4-dioxane (4M, 2.0 mL, 8.0 mmol) and the reaction mixture was stirred at ambient temperature for 30 min. The reaction mixture was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=376.0 [M+H].

[0769] Intermediate 32

[0770]

[0771] 6-(tert-Butoxycarbonyl)-2-fluoro-6-azaspiro[2.5]octane-1-carboxylic acid

[0772] Step A: tert-Butyl 4-{2-[(tert-butyldimethylsilyl)oxy]ethylidene}piperidine-1-carboxylate

[0773] To an ambient temperature solution of tert-butyl 4-(2-hydroxyethylidene)piperidine-1-carboxylate (750mg, 3.30mmol) in dichloromethane (10mL), imidazole (337mg, 4.95mmol) and tert-butylchlorodimethylsilane (547mg, 3.63mmol) were added and the reaction mixture was stirred for 2h. The reaction mixture was diluted with water (10mL) and the resulting mixture was extracted with dichloromethane (3×10mL). 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, eluted with a gradient of petroleum ether:ethyl acetate from 95:5 to 90:10 to obtain the title compound. MS: m / z=342.1[M+H].

[0774] Step B: 1-bromo-2-{[(tert-butyldimethylsilyl)oxy]methyl}-1-fluoro-6-azaspiro[2.5]octane- 6-Carboxylic acid tert-butyl ester

[0775] To a solution of tert-butyl 4-{2-[(tert-butyldimethylsilyl)oxy]ethylidene}piperidine-1-carboxylate (100 mg, 0.29 mmol) in dichloromethane (1 mL) at ambient temperature was added bromodifluoromethane (192 mg, 1.46 mmol), tetrabutylammonium iodide (10.8 mg, 0.0292 mmol) and aqueous sodium hydroxide solution (50%, 1.0 mL, 0.29 mmol), and the reaction mixture was warmed to 40°C and allowed to stir for 12 h. Water (5 mL) was added and the resulting mixture was extracted with ethyl acetate (3×5 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 95:5 petroleum ether:ethyl acetate to give the title compound. MS: m / z=351.9 [M-100+H].

[0776] Step C: 1-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluoro-6-azaspiro[2.5]octane-6-carboxylic acid Tert-butyl ester

[0777] To a solution of tert-butyl 1-bromo-2-{[(tert-butyldimethylsilyl)oxy]methyl}-1-fluoro-6-azaspiro[2.5]octane-6-carboxylate (50 mg, 0.11 mmol) in ethanol (1 mL) was added zinc (29 mg, 0.44 mmol) and ammonium chloride (36 mg, 0.66 mmol), and the reaction mixture was warmed to 70 ° C and stirred for 5 h. The reaction mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography eluting with 95:5 petroleum ether:ethyl acetate to give the title compound. MS: m / z=318.0[M-tBu+H].

[0778] Step D: tert-Butyl 1-fluoro-2-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate

[0779] To a solution of 1-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluoro-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (400mg, 1.07mmol) in tetrahydrofuran (5mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 5.35mL, 5.35mmol) at ambient temperature and the reaction mixture was stirred for 3h. The reaction mixture was diluted with water (10mL) and the resulting mixture was extracted with ethyl acetate (3×10mL). 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, eluted with a gradient of petroleum ether:ethyl acetate from 90:10 to 80:20 to give the title compound. MS:m / z=204.0[M-tBu+H].

[0780] Step E: tert-Butyl 1-fluoro-2-formyl-6-azaspiro[2.5]octane-6-carboxylate To a solution of 1-fluoro-2-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (50 mg, 0.19 mmol) in dichloromethane (2 mL) was added Dess-Martin periodinane (164 mg, 0.39 mmol) at ambient temperature and the reaction mixture was stirred for 2 h. Water (5 mL) was added and the resulting mixture was extracted with dichloromethane (3 × 5 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, eluted with 75:25 petroleum ether:ethyl acetate to give the title compound. 1 HNMR (400MHz, CDCl 3 ): δ9.75–9.81(m,1H); 3.37–3.58(m,3H); 3.22–3.34(m,1H); 2.31(brd,J=18.0 Hz,1H);1.64–1.84(m,3H);1.53–1.59(m,1H);1.45(s,9H);1.20–1.33(m,1H).

[0781] Step F: 6-(tert-Butyloxycarbonyl)-2-fluoro-6-azaspiro[2.5]octane-1-carboxylic acid

[0782] To an ambient temperature solution of 1-fluoro-2-formyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (15 mg, 0.06 mmol) in t-BuOH (0.5 mL) was added 2-methylbut-2-ene (20 mg, 0.29 mmol) and a solution of sodium chlorite (16 mg, 0.17 mmol) and sodium dihydrogen phosphate (28 mg, 0.23 mmol) in water (0.5 mL) and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with water (5 mL) and the resulting mixture was extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. 1 H NMR (400MHz, CD 3 OD): δ3.39–3.57(m,3H); 1.96(dd,J 1 =18.4Hz,J 2 =2.6Hz,1H);1.55–1.80(m,5H);1.46(s,10H).

[0783] Intermediate 33

[0784]

[0785] 3-[4-Fluoro-2-(trifluoromethyl)phenyl]-5-(2-fluoro-6-azaspiro[2.5]octan-1-yl)-1,2,4-oxadiazole Azole hydrochloride

[0786] Following essentially the procedure described in Intermediate 17, but substituting 6-(tert-butoxycarbonyl)-2-fluoro-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 32) for tert-butyl 2-{3-[2-(difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-carboxylate and substituting 4-fluoro-N-hydroxy-2-(trifluoromethyl)benzenecarboximidamide for 2-(difluoromethoxy)-N'-hydroxypyridine-4-carboximidamide, the title compound was obtained. MS: m / z = 360.0 [M+H].

[0787] Intermediate 34

[0788]

[0789] 3-Bromo-5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazole

[0790] To a solution of 3-bromo-5-chloro-1,2,4-thiadiazole (60 mg, 0.30 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added [4-fluoro-2-(trifluoromethyl)phenyl]boronic acid (62.5 mg, 0.30 mmol), potassium carbonate (125 mg, 0.90 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22.01 mg, 0.03 mmol). The reaction mixture was warmed to 100°C and allowed to stir for 30 minutes. The mixture was cooled to ambient temperature and diluted with water (5 mL). The resulting mixture was extracted with ethyl acetate (3×5 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether to give the title compound. MS: m / z=326.7, 328.7 [M+H].

[0791] Intermediate 35

[0792]

[0793] 1,1-Difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}-6-azaspiro [2.5] Octane hydrochloride

[0794] Step A: 1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}-6-azepine Spiro[2.5]octane-6-carboxylic acid tert-butyl ester

[0795] To a solution of 3-bromo-5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazole (Intermediate 34) (65 mg, 0.20 mmol) in tert-amyl alcohol (2 mL) were added cesium carbonate (0.40 mL, 0.60 mmol), tert-butyl 1,1-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-azaspiro[2.5]octane-6-carboxylate (Intermediate 26) (89 mg, 0.24 mmol) and chloro{[di(1-adamantyl)-n-butylphosphine]-2-(2-aminobiphenyl)}palladium(II) (13.3 mg, 0.0199 mmol). The reaction mixture was warmed to 100°C and allowed to stir for 12 h. The reaction mixture was cooled to ambient temperature and diluted with water (5 mL). The resulting mixture was extracted with ethyl acetate (3×5 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 90:10 petroleum ether:ethyl acetate to give the title compound. MS: m / z = 438.1 [M-tBu+H].

[0796] Step B: 1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}-6-azepine Spiro[2.5]octane hydrochloride

[0797] To a flask containing tert-butyl 1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}-6-azaspiro[2.5]octane-6-carboxylate (70 mg, 0.14 mmol) was added a solution of HCl in 1,4-dioxane (4M, 10 mL, 40 mmol) and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=394.1 [M+H].

[0798] Intermediate 36

[0799]

[0800] 1-Ethynyl-4-fluoro-2-(trifluoromethyl)benzene

[0801] To a solution of 4-fluoro-2-(trifluoromethyl)benzaldehyde (1.0 g, 5.2 mmol) in methanol (15 mL) was added dimethyl (1-diazo-2-oxopropyl)phosphonate (1.20 g, 6.25 mmol) and potassium carbonate (2.16 g, 15.6 mmol) and the reaction mixture was warmed to 50° C. and allowed to stir for 16 h. The reaction mixture was cooled to ambient temperature, water (15 mL) was added, and the resulting mixture was extracted with dichloromethane (3×15 mL). The combined organic extracts were dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. 1 H NMR (400 MHz, CDCl 3 ): δ7.63–7.65(m,1H); 7.47–7.40(m,1H); 7.22–7.27(m,1H); 3.35(s,1H).

[0802] Intermediate 37

[0803]

[0804] 1,1-Difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isoxazol-3-yl}-6-azaspiro[2.5]octane tris(II) Fluoroacetate

[0805] Step A: tert-Butyl 1,1-difluoro-2-formyl-6-azaspiro[2.5]octane-6-carboxylate

[0806] To an ambient temperature solution of 1,1-difluoro-2-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (described in Intermediate 10) (760 mg, 2.74 mmol) in dichloromethane (10 mL) was added Dess-Martin periodinane (2.33 g, 5.48 mmol) and the reaction mixture was stirred for 2 h. Saturated aqueous sodium bicarbonate solution (20 mL) was slowly added and the resulting mixture was extracted with dichloromethane (3×10 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 petroleum ether:ethyl acetate from 95:5 to 90:10 to give the title compound. MS: m / z=220.1[M-tBu+H].

[0807] Step B: tert-Butyl 1,1-difluoro-2-[(hydroxyimino)methyl]-6-azaspiro[2.5]octane-6-carboxylate

[0808] Hydroxylamine hydrochloride (0.51 g, 7.3 mmol) was added to an ambient temperature solution of 1,1-difluoro-2-formyl-6-azaspiro [2.5] octane-6-carboxylic acid tert-butyl ester (1.0 g, 3.6 mmol) and sodium carbonate (0.78 g, 7.3 mmol) in ethanol (20 mL) and the reaction mixture was stirred for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with petroleum ether from 100:0 to 90:10: ethyl acetate gradient to give the title compound.

[0809] Step C: 1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isoxazol-3-yl}-6-azaspiro[2.5] Octane-6-carboxylic acid tert-butyl ester

[0810] To a solution of tert-butyl 1,1-difluoro-2-[(hydroxyimino)methyl]-6-azaspiro[2.5]octane-6-carboxylate (772 mg, 2.66 mmol) and 1-ethynyl-4-fluoro-2-(trifluoromethyl)benzene (Intermediate 36) (500 mg, 1.33 mmol) in methanol (10 mL) was added [bis(trifluoroacetoxy)iodo]benzene (1.71 g, 3.98 mmol) and the reaction mixture was warmed to 50 °C and allowed to stir for 7 h. Water (15 mL) was added and the resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (15 mL), 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 petroleum ether:ethyl acetate from 100:0 to 92:8 to give the title compound. MS: m / z=421.1 [M-tBu+H].

[0811] 1,1-Difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isoxazol-3-yl}-6-azaspiro[2.5]octane tris(II) Fluoroacetate

[0812] To a solution of tert-butyl 1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isoxazol-3-yl}-6-azaspiro[2.5]octane-6-carboxylate (50 mg, 0.11 mmol) in dichloromethane (5 mL) at ambient temperature was added trifluoroacetic acid (2.0 mL, 26 mmol) and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure to afford the title compound in sufficient purity for the next step. MS: m / z=377.1 [M+H].

[0813] Intermediate 38

[0814]

[0815] 1,1-Difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-5-yl}-6-azaspiro[2.5]octane tris(III) Fluoroacetate

[0816] Step A: tert-Butyl 2-ethynyl-1,1-difluoro-6-azaspiro[2.5]octane-6-carboxylate

[0817] Potassium carbonate (210 mg, 1.53 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (293 mg, 1.53 mmol) were added to a solution of tert-butyl 1,1-difluoro-2-formyl-6-azaspiro[2.5]octane-6-carboxylate (described in Intermediate 37) (210 mg, 0.76 mmol) in methanol (10 mL) and the reaction mixture was stirred for 16 h. Water (20 mL) was added and the resulting mixture was extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (50 mL), 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 petroleum ether:ethyl acetate from 100:0 to 85:15 to give the title compound. MS: m / z=257.1[M-tBu+CH 3 CN+H].

[0818] Step B: 1,1-difluoro-2-{3-[3-fluoro-5-(trifluoromethyl)phenyl]isoxazol-5-yl}-6-azaspiro[2.5] Octane-6-carboxylic acid tert-butyl ester

[0819] To an ambient temperature solution of tert-butyl 2-ethynyl-1,1-difluoro-6-azaspiro[2.5]octane-6-carboxylate (500 mg, 1.84 mmol) and 3-fluoro-5-(trifluoromethyl)benzaldehyde oxime (916 mg, 4.42 mmol) in methanol (12 mL) was added [bis(trifluoroacetoxy)iodo]benzene (2.38 g, 5.52 mmol) and the reaction mixture was warmed to 60 °C and allowed to stir for 7 h. Water (15 mL) was added and the resulting mixture was extracted with ethyl acetate (3×15 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 petroleum ether:ethyl acetate from 100:0 to 95:5 to give the title compound. MS: m / z=421.2 [M-tBu+H].

[0820] Step C: 2-{3-amino-3-[4-fluoro-2-(trifluoromethyl)phenyl]acryloyl}-1,1-difluoro-6-azaspiro [2.5] Octane-6-carboxylic acid tert-butyl ester

[0821] To a solution of tert-butyl 1,1-difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]isoxazol-5-yl}-6-azaspiro[2.5]octane-6-carboxylate (400 mg, 0.84 mmol) in ethanol (25 mL) was added Raney nickel (4.93 mg, 0.08 mmol) under Ar and ambient temperature. The reaction mixture was placed under a hydrogen atmosphere (about 40 psi), warmed to 40 °C and allowed to stir for 8 h. The reaction mixture was cooled, purged with inert gas, and heated to 40 °C by evaporation. The filtrate was concentrated under reduced pressure to afford the title compound of sufficient purity for the next step. MS: m / z = 479.1 [M+H].

[0822] Step D: 1,1-difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-5-yl}-6-azaspiro[2.5] Octane-6-carboxylic acid tert-butyl ester

[0823] To an ambient temperature solution of tert-butyl 2-{3-amino-3-[4-fluoro-2-(trifluoromethyl)phenyl]acryloyl}-1,1-difluoro-6-azaspiro[2.5]octane-6-carboxylate (380 mg, 0.79 mmol) in toluene (10 mL) were added phosphorus pentasulfide (530 mg, 2.38 mmol) and chlorobenzoquinone (586 mg, 2.38 mmol) in sequence and the reaction mixture was warmed to 115°C and allowed to stir for 2 h. The reaction mixture was cooled to ambient temperature and water (5 mL), ethyl acetate (5 mL), sodium carbonate (421 mg, 3.97 mmol) and di-tert-butyl dicarbonate (1.84 mL, 7.94 mmol) were added. The reaction mixture was stirred at ambient temperature for 1 h. Water (15 mL) was added and the resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (15 mL), 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 petroleum ether:ethyl acetate from 100:0 to 90:10 to give the title compound. MS: m / z=493.1 [M+H].

[0824] Step E: 1,1-difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-5-yl}-6-azaspiro[2.5] Octane trifluoroacetate

[0825] To a solution of tert-butyl 1,1-difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-5-yl}-6-azaspiro[2.5]octane-6-carboxylate (880 mg, 0.50 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL) and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=393.1 [M+H].

[0826] Intermediate 39

[0827]

[0828] 1,1-Difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-3-yl}-6-azaspiro[2.5]octane tris(II) Fluoroacetate

[0829] Step A: 1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isoxazol-3-yl}-6-azaspiro[2.5] Octane-6-carboxylic acid tert-butyl ester

[0830] To a solution of tert-butyl 1,1-difluoro-2-[(hydroxyimino)methyl]-6-azaspiro[2.5]octane-6-carboxylate (described in Intermediate 37) (772 mg, 2.66 mmol) and 1-ethynyl-4-fluoro-2-(trifluoromethyl)benzene (Intermediate 36) (500 mg, 1.33 mmol) in methanol (10 mL) was added [bis(trifluoroacetyloxy)iodo]benzene (1.71 g, 3.98 mmol) and the mixture was stirred at 50 °C for 7 h. Water (15 mL) was added and the resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (15 mL), 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 petroleum ether:ethyl acetate from 100:0 to 92:8 to give the title compound. MS: m / z=421.1 [M-tBu+H].

[0831] Step B: 2-{1-amino-3-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxoprop-1-en-1-yl}-1,1-difluorophenyl Fluoro-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester

[0832] To a solution of tert-butyl 1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isoxazol-3-yl}-6-azaspiro[2.5]octane-6-carboxylate (100 mg, 0.21 mmol) in ethanol (10 mL) was added Raney nickel (1.2 mg, 0.021 mmol) under Ar. The reaction mixture was placed under a hydrogen atmosphere (about 40 psi), warmed to 35 ° C and allowed to stir for 3 h. The reaction mixture was cooled, purged with inert gas, and heated to 40 ° C. by evaporation. The pad was filtered and washed with ethanol (100 mL). The filtrate was concentrated under reduced pressure to give the title compound of sufficient purity for the next step. MS: m / z = 479.3 [M+H].

[0833] Step C: 1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-3-yl}-6-azaspiro[2.5] Octane-6-carboxylic acid tert-butyl ester

[0834] To a solution of tert-butyl 2-{1-amino-3-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxoprop-1-en-1-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-carboxylate (160 mg, 0.33 mmol) in toluene (8 mL) at ambient temperature were added phosphorus pentasulfide (223 mg, 1.00 mmol) and chlorobenzoquinone (247 mg, 1.00 mmol) in sequence and the reaction mixture was warmed to 115°C and allowed to stir for 1 h. The reaction mixture was cooled to ambient temperature and water (5 mL), ethyl acetate (5 mL), sodium carbonate (177 mg, 1.67 mmol) and di-tert-butyl dicarbonate (0.39 mL, 1.67 mmol) were added and the reaction mixture was allowed to stir at ambient temperature for 1 h. Water (15 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (15 mL), 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 petroleum ether:ethyl acetate from 100:0 to 92:8 to give the title compound. MS: m / z = 437.2 [M-tBu+H].

[0835] Step D: 1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-3-yl}-6-azaspiro[2.5] Octane trifluoroacetate

[0836] To a solution of tert-butyl 1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-3-yl}-6-azaspiro[2.5]octane-6-carboxylate (70 mg, 0.11 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL, 38.9 mmol) and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound in sufficient purity for the next step. MS: m / z=393.1 [M+H].

[0837] The intermediates appearing in the following table are prepared by similar conversions as described in the above intermediates or using modifications known to those skilled in the art. Necessary starting materials are described herein, commercially available, known in the literature, or easily synthesized by those skilled in the art. Straightforward protecting group strategies are used in some routes.

[0838] Table INT-A

[0839]

[0840]

[0841]

[0842] Table INT-B

[0843]

[0844]

[0845]

[0846] Table INT-C

[0847]

[0848]

[0849]

[0850] Table INT-D

[0851]

[0852]

[0853] Table INT-E

[0854]

[0855]

[0856]

[0857] Example 1

[0858]

[0859] (1R)-1-{5-[2-methyl-5-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5] Octane-6-sulfonamide

[0860] To a solution of 2-methyl-5-(trifluoromethyl)benzoic acid (40.4 mg, 0.198 mmol) in 1,4-dioxane (1 mL) was added 1,1'-carbonyldiimidazole (32.1 mg, 0.198 mmol) and the reaction mixture was warmed to 50°C and allowed to stir for 2 h. (1R)-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 2) (44.7 mg, 0.18 mmol) was added and the reaction mixture was warmed to 110°C and allowed to stir for 16 h. The reaction mixture was cooled to ambient temperature and purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 96:3:1 to 24:57:19 to give the title compound. MS: m / z = 417.1 [M+H]. 1 H NMR (DMSO-d 6)δ8.26(s,1H),7.94(d,J=8.0Hz,1H),7.73(d,J=8.1Hz,1H),6.71(s,2H),3.17–3.09(m,1H),3.08–2 .95(m,2H),2.85–2.75(m,1H),2.70(s,3H),2.28–2.17(m,1H),1.81–1.59(m,4H),1.28–1.17(m,2H).

[0861] Example 2

[0862]

[0863] (1R)-1-[5-(2,5-dimethylphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonate Amide

[0864] To a solution of 2,5-dimethylbenzoic acid (30.0 mg, 0.200 mmol) in 1,4-dioxane (1 mL) was added 1,1'-carbonyldiimidazole (32.4 mg, 0.200 mmol) and the reaction mixture was warmed to 50°C and allowed to stir for 2 h. (1R)-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 2) (49.7 mg, 0.200 mmol) was added and the reaction mixture was warmed to 100°C and allowed to stir for 16 h. The reaction mixture was cooled to ambient temperature and purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 96:3:1 to 52:36:12 to give the title compound. MS: m / z=363.2 [M+H]. 1 H NMR (DMSO-d 6 )δ7.82(s,1H),7.37(d,J=7.7Hz,1H),7.34(d,J=7.9Hz,1H),6.72(s,2H),3.12(d,J=6.7Hz,1H),3.02(dt,J=15.1,7.5Hz,2H) ,2.78(t,J=8.2Hz,1H),2.56(s,3H),2.36(s,3H),2.18(dd,J=7.8,6.2Hz,1H),1.83–1.56(m,4H),1.19(dd,J=7.5,5.2Hz,2H).

[0865] Example 3

[0866]

[0867] 4,4-Difluoro-1-{3-[3-(2,2,2-trifluoroethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro [2.5] Octane-6-sulfonamide, diastereomer C

[0868] To a solution of 4,4-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 5) (93.0 mg, 0.344 mmol) in 1,4-dioxane (2 mL) was added 1,1'-carbonyldiimidazole (61.4 mg, 0.379 mmol) and the reaction mixture was warmed to 50 °C and allowed to stir for 2 h. N'-hydroxy-3-(2,2,2-trifluoroethoxy)benzimidamide (81.0 mg, 0.344 mmol) was added and the reaction mixture was warmed to 90 °C and allowed to stir for 18 h. Sulfamide (50.0 mg, 0.52 mmol) was added and the reaction mixture was stirred at 90 °C for 4 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 96:3:1 to 52:36:12 to give a mixture of diastereomers. The mixture was resolved by SFC using a ChiralPak AD-H column and eluting with 20:80 ethanol:carbon dioxide. The first major peak to elute was 4,4-difluoro-1-{3-[3-(2,2,2-trifluoroethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer A; the second major peak to elute was 4,4-difluoro-1-{3-[3-(2,2,2-trifluoroethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer B; The third main peak is 4,4-difluoro-1-{3-[3-(2,2,2-trifluoroethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer C, the title compound; the fourth main peak eluted is 4,4-difluoro-1-{3-[3-(2,2,2-trifluoroethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer D. Diastereomer C: MS: m / z=469.2[M+H]. 1 H NMR (DMSO-d 6 )δ7.69(d,J=7.9Hz,1H),7.60(s,1H),7.55(t,J=8.0Hz,1H),7.31(dd,J=8.3,1.9Hz,1H),7.08(s,2H),4.89(q,J=8.7Hz,2H),3.53–3.41(m ,1H),3.38–3.23(m,1H),3.14–2.98(m,2H),2.92(dd,J=9.1,6.2Hz,1H),1.99–1.83(m,2H),1.75(dd,J=8.9,5.5Hz,1H),1.63–1.54(m,1H).

[0869] Example 4

[0870]

[0871] 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane- 6-Sulfonamide, diastereomer E

[0872] Step A: 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5] Octane-6-carboxylic acid tert-butyl ester

[0873] To a solution of 6-(tert-butoxycarbonyl)-4-fluoro-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 6) (955.6 mg, 3.50 mmol) in 1,4-dioxane (18 mL) in a sealable container was added 1,1'-carbonyldiimidazole (854 mg, 5.27 mmol) and the container was sealed. The reaction mixture was warmed to 80°C and allowed to stir for 1 h. The reaction mixture was cooled to ambient temperature and a solution of 3-(difluoromethoxy)-N'-hydroxybenzenecarboximidamide (843 mg, 4.17 mmol) in 1,4-dioxane (6 mL) was added. The reaction mixture was warmed to 120°C and allowed to stir for 1.5 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexane:ethyl acetate from 100:0 to 70:30 to give the title compound. MS: m / z=384.2 [M-tBu+H].

[0874] Step B: 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5] Octane hydrochloride

[0875] To a vessel containing tert-butyl 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6-carboxylate (1.04 g, 2.32 mmol) was added a solution of HCl in 1,4-dioxane (4 M, 12 mL, 48.0 mmol) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was concentrated under reduced pressure to afford the title compound in sufficient purity for the next step. MS: m / z=340.2 [M+H].

[0876] Step C: 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5] Octane-6-sulfonamide, diastereomer E

[0877] To a solution of 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazole-5-yl}-4-fluoro-6-azaspiro[2.5]octane hydrochloride (913 mg, 2.31 mmol) in 1,4-dioxane (12 mL) was added sulfamide (571 mg, 5.94 mmol) and triethylamine (0.644 mL, 4.62 mmol) and the reaction mixture was warmed to 100 °C and allowed to stir for 2 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexane:ethyl acetate from 75:25 to 0:100 to give a mixture of diastereomers. The mixture was split by SFC using a ChiralPak AD-H column and eluted with 30:70:0.2 ethanol:carbon dioxide:ammonium hydroxide. The first main peak eluted was 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer A; the second main peak eluted was 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer B; the third main peak eluted was 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer C; The fourth main peak was 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer D; the fifth main peak eluted was 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer E, the title compound; the sixth main peak eluted was 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer F. Diastereomer E: MS: m / z=419.2[M+H]. 1 H NMR (CD 3OD)δ7.91(d,J=7.8Hz,1H),7.78(s,1H),7.55(t,J=8.0Hz,1H),7.33(d,J=8.1Hz,1H),6.91(t,J=73.6Hz,1H),4.39(d,J=47.3Hz,1H),3.64–3.55 (m,1H),3.30–3.24(m,1H),2.75–2.66(m,1H),2.63–2.56(m,1H),2.32–2 .24(m,1H),1.78–1.71(m,1H),1.71–1.65(m,1H),1.55(t,J=5.5Hz,1H).

[0878] Example 5

[0879]

[0880] (1R)-1-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane Alkane-6-sulfonamide

[0881] To a solution of (1R)-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 1) (5.00 g, 21.3 mmol) in 1,4-dioxane (80 mL) was added 1,1'-carbonyldiimidazole (5.19 g, 32.0 mmol) and the reaction mixture was warmed to 50°C and allowed to stir for 3.5 h. The reaction mixture was cooled to ambient temperature and 4-fluoro-N'-hydroxy-2-(trifluoromethyl)benzenecarboximidamide (Intermediate 7) (4.98 g, 22.4 mmol) was added. The reaction mixture was warmed to 100°C and allowed to stir for 2 days. The reaction mixture was cooled to ambient temperature and sulfamide (1.03 g, 10.7 mmol) was added. The reaction mixture was warmed to 100°C and allowed to stir for 2 h. The reaction mixture was cooled to ambient temperature, saturated aqueous sodium bicarbonate solution (300 mL) was added and the resulting mixture was extracted with ethyl acetate (2 x 700 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (300 mL), dried (sodium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of dichloromethane:methanol from 100:0 to 96:4. The resulting solid was crystallized from hexane:dichloromethane to give the title compound. MS: m / z=421.1 [M+H]. 1 H NMR (DMSO-d 6)δ7.97–7.86(m,2H),7.75(td,J=8.3,2.3Hz,1H),6.77(s,2H),3.22–3.12(m,1H),3.10–3.01(m,1H),3.02–2.92(m,1H),2.69–2.58(m,1H),2.53–2.45(m,1H),1.84–1.78(m,1H),1.78–1.72(m,1H),1.72–1.66(m,1H),1.65–1.59(m,1H),1.43(dd,J=8.3,4.7Hz,1H),1.34(t,J=5.0Hz,1H)。

[0882] Example 6

[0883]

[0884] 1-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-4-methyl-6-azaspiro[2.5] Octane-6-sulfonamide, diastereomer D

[0885] To a solution of 4-methyl-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 8) (300 mg, 1.21 mmol) in 1,4-dioxane (5.0 mL) was added 1,1'-carbonyldiimidazole (206 mg, 1.27 mmol) and the reaction mixture was warmed to 50°C and allowed to stir for 0.5 h. The reaction mixture was cooled to ambient temperature and 4-fluoro-N'-hydroxy-2-(trifluoromethyl)benzenecarboximidamide (Intermediate 7) (341 mg, 1.27 mmol) was added. The reaction mixture was warmed to 100°C and allowed to stir for 2 days. The reaction mixture was cooled to ambient temperature and sulfamide (116 mg, 1.21 mmol) was added. The reaction mixture was warmed to 100°C and allowed to stir for 18 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of hexane: ethyl acetate from 100:0 to 60:40 to give three main elution peaks, each of which was a mixture of diastereomers of the title compound. The first main peak contained four isomers, the second main peak contained two isomers, and the third main peak contained two isomers. The first main peak eluted from silica gel chromatography was resolved by SFC, using a ChiralPak AD-H column and eluting with 12:88 methanol: carbon dioxide. The first main peak eluted was 1-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-4-methyl-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer A; the second main peak eluted was 1-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-4-methyl-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer B; The third main peak is 1-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-4-methyl-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer C; the fourth main peak eluted is 1-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-4-methyl-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer D, the title compound. Diastereomer D: MS: m / z=435.2[M+H]. 1 H NMR (DMSO-d 6)δ7.96–7.87(m,2H),7.75(dt,J=8.4,4.2Hz,1H),6.72(s,2H),3.21–3.13(m,1 H),3.13–3.05(m,1H),2.92(d,J=9.0Hz,1H),2.55(dd,J=8.3,5.7Hz,1H),2.35( t,J=10.6Hz,1H),1.97(t,J=10.7Hz,1H),1.64–1.58(m,1H),1.55(d,J=14.1Hz ,1H),1.43(dd,J=8.3,5.0Hz,1H),1.26(t,J=5.2Hz,1H),1.04(d,J=6.9Hz,3H).

[0886] Example 7

[0887]

[0888] (1R)-1-{2-[3-(trifluoromethoxy)phenyl]-1,3-thiazol-4-yl}-6-azaspiro[2.5]octane-6-sulfonate Amide

[0889] Step A: (1R)-N,N-dimethyl-N'-{[1-(2-(3-(trifluoromethoxy)phenyl]thiazol-4-yl}-6-azepine Spiro[2.5]octan-6-yl)sulfonyl)formimide amide

[0890] To a solution of (1R)-N'-{[1-(2-chloroacetyl)-6-azaspiro[2.5]octan-6-yl]sulfonyl}-N,N-dimethylformimideamide (Intermediate 9) (100 mg, 0.31 mmol) in ethanol (1 mL) was added 3-(trifluoromethoxy)benzothioamide (68.7 mg, 0.31 mmol). The reaction mixture was warmed to 70°C and allowed to stir for 2 h. The reaction mixture was cooled and concentrated under reduced pressure to afford the title compound in sufficient purity for the next step. MS: m / z=489.1 [M+H].

[0891] Step B: (1R)-1-{2-[3-(trifluoromethoxy)phenyl]-1,3-thiazol-4-yl}-6-azaspiro[2.5]octane Alkane-6-sulfonamide

[0892] To a solution of (1R)-N,N-dimethyl-N'-{[1-(2-(3-(trifluoromethoxy)phenyl]thiazol-4-yl}-6-azaspiro[2.5]octan-6-yl)sulfonyl)carboximidamide (152 mg, 0.31 mmol) in ethanol (2 mL) was added hydrazine (0.5 mL, 0.31 mmol) and the reaction mixture was cooled to 10 °C and allowed to stir for 2 h. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC eluting with a gradient of acetonitrile:water:ammonium hydroxide from 48:52:0.05 to 78:22:0.05 to give the title compound. MS: m / z=433.9 [M+H]. 1 H NMR (400MHz, CD3 OD): δ7.90(d,J=7.9Hz,1H),7.83(s,1H),7.57(t,J=8.1Hz,1H),7.36(d,J =8.4Hz,1H),7.23(s,1H),3.25–3.27(m,1H),3.02–3.08(m,1H),2.95(dd,J 1 =7.9Hz,J 2 =3.5Hz,1H),2.17(dd,J 1 =8.3Hz,J 2 =5.7Hz,1H),1.66–1.75(m,2H),1.52–1.66(m,3H),1.21(t,J=5.3Hz,1H),1.03(dd,J 1 =8.6Hz,J 2 =5.0Hz,1H).

[0893] Example 8

[0894]

[0895] (1R)-1-{5-[4-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazole-3- 6-Azaspiro[2.5]octane-6-sulfonamide

[0896] To a solution of 4-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylic acid (30 mg, 0.14 mmol) in 1,4-dioxane (2.4 mL) was added 1,1'-carbonyldiimidazole (30.4 mg, 0.19 mmol). The reaction mixture was warmed to 80 °C and allowed to stir for 1 h. The reaction mixture was cooled to 10 °C and ( R )-N-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 2) (53.7 mg, 0.22 mmol). The reaction mixture was warmed to 100°C and allowed to stir for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of acetonitrile:water:ammonium hydroxide from 27:73:0.05 to 57:43:0.05 to give the title compound. MS: m / z=421.0 [M+H]. 1 H NMR (400MHz, CD 3OD): δ7.62(s,1H),5.48–5.65(m,1H),5.29–5.44(m,1H),3.24–3.30(m,1H),3.08–3.23(m,2H),2.87–2. 95(m,1H),2.40(s,3H),2.15–2.22(m,1H),1.62–1.89(m,4H),1.33(t,J=5.3Hz,1H),1.20–1.27(m,1H).

[0897] Example 9

[0898]

[0899] (2R)-2-[5-(1,4-dimethyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-nitropropene Heterospiro[2.5]octane-6-sulfonamide

[0900] To a solution of 1,4-dimethyl-1H-pyrazole-5-carboxylic acid (28.1 mg, 0.201 mmol) in 1,4-dioxane (1 mL) was added 1,1'-carbonyldiimidazole (35.8 mg, 0.221 mmol) and the reaction mixture was warmed to 50°C and allowed to stir for 2 h. The reaction mixture was cooled to ambient temperature, (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 11) (57.0 mg, 0.201 mmol) was added and the reaction mixture was warmed to 85°C and allowed to stir for 16 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 96:3:1 to 24:57:19 to give the title compound. MS: m / z=389.3 [M+H]. 1 HNMR (DMSO-d 6 )δ7.54(s,1H),6.79(s,2H),4.15(s,3H),3.41–3.25(m,1H),3.24–3.13m, 1H),3.13–2.98(m,2H),2.94–2.81(m,1H),2.31(s,3H),2.02–1.83(m,4H).

[0901] Example 10

[0902]

[0903] (2R)-2-{5-[2-(difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-nitropropene Heterospiro[2.5]octane-6-sulfonamide

[0904] To a solution of 2-difluoromethoxyisonicotinic acid (37.9 mg, 0.201 mmol) in 1,4-dioxane (1 mL) was added 1,1'-carbonyldiimidazole (35.8 mg, 0.221 mmol) and the reaction mixture was warmed to 50°C and allowed to stir for 2 h. The reaction mixture was cooled to ambient temperature, (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 11) (57.0 mg, 0.201 mmol) was added and the reaction mixture was warmed to 85°C and allowed to stir for 16 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 96:3:1 to 24:57:19 to give the title compound. MS: m / z=438.2 [M+H]. 1 H NMR (DMSO-d 6 )δ8.57(d,J=5.2Hz,1H),7.91(d,J=5.1Hz,1H),7.80(t,J=72Hz,1H),7.69(s,1H),6.81(s,2H),3. 39(d,J=12.0Hz,1H),3.22–3.12(m,1H),3.12–3.00(m,2H),2.98–2.88(m,1H),2.03–1.83(m,4H).

[0905] Embodiment 11

[0906]

[0907] (2R)-2-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-azaspiro [2.5] Octane-6-sulfonamide

[0908] To an ambient temperature solution of (2R)-2,2-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 10) (54.1 mg, 0.200 mmol) in 1,2-dichloroethane (0.90 mL) and dimethyl sulfoxide (0.10 mL) were added 1-hydroxy-7-azabenzotriazole (13.6 mg, 0.100 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg, 0.300 mmol) in sequence and the reaction mixture was stirred for 15 minutes. 3-Cyclopropyl-N'-hydroxyisoxazole-4-carboximidamide (Intermediate 12) (36.8 mg, 0.220 mmol) was added and the reaction mixture was stirred for 2 h. The reaction mixture was warmed to 90 °C and allowed to stir for 16 h. The reaction mixture was cooled to ambient temperature, diluted with water, the layers separated, and the organic layer purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 96:3:1 to 24:57:19 to afford the title compound. MS: m / z = 402.2 [M+H]. 1 H NMR (DMSO-d 6 )δ9.59(s,1H),6.80(s,2H),3.72(d,J=11.1Hz,1H),3.22–2.95(m,3H),2.90–2.73(m,1H),2 .37(ddd,J=13.3,8.4,5.1Hz,1H),2.09–1.85(m,4H),1.15–1.04(m,2H),1.01–0.89(m,2H).

[0909] Example 12

[0910]

[0911] (2R)-1,1-difluoro-2-{3-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazole-5- 6-Azaspiro[2.5]octane-6-sulfonamide

[0912] To an ambient temperature solution of (2R)-2,2-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 10) (54.1 mg, 0.200 mmol) in 1,2-dichloroethane (0.90 mL) and dimethyl sulfoxide (0.10 mL) were added 1-hydroxy-7-azabenzotriazole (13.6 mg, 0.100 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg, 0.300 mmol) in sequence and the reaction mixture was stirred for 15 minutes. N'-Hydroxy-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboximidamide (Intermediate 13) (45.8 mg, 0.220 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was warmed to 90°C and stirred for 2 h. The reaction mixture was cooled to ambient temperature, diluted with water, the layers separated, and the organic layer purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 96:3:1 to 24:57:19 to afford the title compound. MS: m / z = 443.2 [M+H]. 1 H NMR (DMSO-d 6 )δ7.85(d,J=1.9Hz,1H),7.11(d,J=1.9Hz,1H),6.81(s,2H),5.57–5.39(m,2H),3.79(d,J =11.5Hz,1H),3.22–3.12(m,1H),3.12–2.99(m,2H),2.86–2.72(m,1H),2.12–1.88(m,4H).

[0913] Embodiment 13

[0914]

[0915] (2R)-2-{5-[2-(difluoromethoxy)-5-methylpyridin-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoromethoxy Fluoro-6-azaspiro[2.5]octane-6-sulfonamide

[0916] To a solution of 2-(difluoromethoxy)-5-methylisonicotinic acid (Intermediate 14) (50.0 mg, 0.246 mmol) in 1,2-dichloroethane (1.10 mL) and dimethyl sulfoxide (0.12 mL) was added 1-hydroxy-7-azabenzotriazole (33.5 mg, 0.246 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70.8 mg, 0.369 mmol) at ambient temperature and the reaction mixture was stirred for 15 minutes. (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 11) (98.0 mg, 0.345 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was warmed to 90°C and stirred for 2 h. The reaction mixture was cooled to ambient temperature, diluted with water, the layers separated, and the organic layer purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 96:3:1 to 24:57:19 to afford the title compound. MS: m / z = 452.1 [M+H]. 1 H NMR (DMSO-d 6 )δ8.44(s,1H),7.81(t,J=72.7Hz,1H),7.63(s,1H),6.80(s,2H),3.40(d,J=12.0Hz,1H), 3.22–3.13(m,1H),3.11–3.00(m,2H),2.96–2.85(m,1H),2.57(s,3H),2.04–1.84(m,4H).

[0917] Embodiment 14

[0918]

[0919] (2R)-1,1-difluoro-2-{5-[1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazole-3- 6-Azaspiro[2.5]octane-6-sulfonamide

[0920] To an ambient temperature solution of 1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (39.0 mg, 0.201 mmol) in 1,2-dichloroethane (0.90 mL) and dimethyl sulfoxide (0.10 mL) was added 1-hydroxy-7-azabenzotriazole (27.3 mg, 0.201 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.8 mg, 0.301 mmol) and the reaction mixture was stirred for 15 minutes. (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 11) (80.0 mg, 0.281 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was warmed to 90°C and stirred for 2 h. The reaction mixture was cooled to ambient temperature, diluted with water, the layers separated, and the organic layer purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate from 95:5 to 25:75 to afford the title compound. MS: m / z = 443.2 [M+H]. 1 H NMR (DMSO-d 6 )δ8.21(s,1H),6.80(s,2H),4.24(s,3H),3.44(d,J=12.0Hz,1H),3.25–3.12(m,1H),3.12–2.99(m,2H),2.96–2.83(m,1H),2.04–1.86(m,4H).

[0921] Embodiment 15

[0922]

[0923] (1R)-1-{1-[3-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-6-azaspiro[2.5]octane-6-sulfonyl amine

[0924] To a solution of (1R)-1-{1-[3-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-6-azaspiro[2.5]octane (Intermediate 15) (100 mg, 0.30 mmol) in 1,4-dioxane (3 mL) was added triethylamine (0.062 mL, 0.45 mmol) and sulfamide (85 mg, 0.89 mmol) and the reaction mixture was warmed to 90°C and allowed to stir for 10 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC eluting with a gradient of acetonitrile:water:ammonium hydroxide from 43:57:0.05 to 73:27:0.05 to give the title compound. MS: m / z=417.1 [M+H]. 1 H NMR (400 MHz, CDCl 3): δ7.67(s,1H),7.52–7.60(m,2H),7.44–7.47(m,1H),7.25(s,1H),7.15–7.18(s,1H),4.29–4.30(m,2H),3.34–3.26(m ,2H),3.10–3.15(m,2H),1.79–1.81(m,1H),1.60–1.70(m,2H),1.40–1.52(m,2H),0.94–0.96(m,1H),0.72–0.75(m,1H).

[0925] Example 16

[0926]

[0927] (2R)-2-[5-(1-cyclopropyl-1H-pyrazol-5-yl)-1,3,4-oxadiazol-2-yl]-1,1-difluoro-6-azepine Spiro[2.5]octane-6-sulfonamide

[0928] Step A: (2R)-2-({2-[(1-cyclopropyl-1H-pyrazol-5-yl)carbonyl]hydrazine}carbonyl)-1,1-difluoro-6- Azaspiro[2.5]octane-6-sulfonamide

[0929] To an ambient temperature solution of (1R)-2,2-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 10) (80 mg, 0.30 mmol) in dichloromethane (1.5 mL) and dimethyl sulfoxide (0.20 mL) were added 1-hydroxy-7-azabenzotriazole (24 mg, 0.18 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (91 mg, 0.48 mmol) and the reaction mixture was stirred for 10 minutes. 1-Cyclopropyl-1H-pyrazole-5-carbohydrazide (Intermediate 16) (54 mg, 0.325 mmol) was added and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was poured into water (30 mL) and the resulting mixture was extracted with ethyl acetate (2×80 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (30 mL), 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 dichloromethane:methanol from 100:0 to 95:5 to give the title compound. MS: m / z = 419.2 [M+H].

[0930] Step B: (2R)-2-[5-(1-cyclopropyl-1H-pyrazol-5-yl)-1,3,4-oxadiazol-2-yl]-1,1-difluoro- 6-Azaspiro[2.5]octane-6-sulfonamide

[0931] To a solution of (2R)-2-({2-[(1-cyclopropyl-1Hpyrazol-5-yl)carbonyl]hydrazine}carbonyl)-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide (50 mg, 0.12 mmol) in acetonitrile (1.5 mL) was added phosphorus oxychloride (0.022 mL, 0.23 mmol) and the reaction mixture was warmed to 85 °C and allowed to stir for 10 h. The reaction mixture was cooled to ambient temperature, slowly poured into saturated aqueous sodium bicarbonate solution (30 mL) and the resulting mixture was extracted with ethyl acetate (2×70 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 hexanes:ethyl acetate from 100:0 to 50:50 to give the title compound. MS: m / z=401.4 [M+H]. 1 H NMR (DMSO-d 6 )δ7.62(d,J=2.0Hz,1H),6.99(d,J=2.0Hz,1H),6.82(s,2H),4.25(tt,J=7.4,3.9Hz,1H),3.58(d,J=11. 8Hz,1H),3.20–3.12(m,1H),3.12–3.03(m,2H),2.98–2.86(m,1H),2.03–1.87(m,4H),1.22–1.04(m,4H).

[0932] Embodiment 17

[0933]

[0934] (2S)-2-[5-(1-cyclopropyl-1H-pyrazol-5-yl)-1,3,4-thiadiazol-2-yl]-1,1-difluoro-6-azepine Spiro[2.5]octane-6-sulfonamide

[0935] To a solution of (2R)-2-({2-[(1-cyclopropyl-1Hpyrazol-5-yl)carbonyl]hydrazine}carbonyl)-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide (described in Example 16) (50 mg, 0.115 mmol) in tetrahydrofuran (1.50 mL) was added Lawesson's reagent (97 mg, 0.24 mmol) and the reaction mixture was warmed to 65° C. and allowed to stir for 3.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate from 100:0 to 50:50 to give the title compound. MS: m / z=417.4[M+H]. 1 H NMR (DMSO-d 6)δ7.57(d,J=1.9Hz,1H),6.98(d,J=1.9Hz,1H),6.81(s,2H),4.18(tt,J=7.4,3.9Hz,1H),3.77(d,J=12. 5Hz,1H),3.20–3.07(m,2H),3.07–2.96(m,1H),2.96–2.85(m,1H),2.03–1.80(m,4H),1.22–1.06(m,4H).

[0936] Embodiment 18

[0937]

[0938] (2R)-2-[5-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-3-yl)-1,2,4-oxadiazole-3- [2.5]octane-6-sulfonamide

[0939] To an ambient temperature solution of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazine-3-carboxylic acid (36.8 mg, 0.200 mmol) in 1,2-dichloroethane (0.90 mL) and dimethyl sulfoxide (0.10 mL) were added 1-hydroxy-7-azabenzotriazole (27.2 mg, 0.200 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg, 0.300 mmol) in sequence and the reaction mixture was stirred for 15 minutes. (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 11) (59.7 mg, 0.210 mmol) was added and the reaction mixture was stirred for 2 h. The reaction mixture was warmed to 90°C and stirred for 4 h. The reaction mixture was cooled to ambient temperature, diluted with water, the layers separated, and the organic layer purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 96:3:1 to 24:57:19 to afford the title compound. MS: m / z = 433.2 [M+H]. 1 H NMR (DMSO-d 6 )δ8.17(s,1H),6.78(s,2H),4.43–4.32(m,2H),4.23(s,2H),3.28–3.10(m,4H),3.10–2.97(m,2H),2.93–2.82(m,1H),2.00–1.82(m,4H).

[0940] Embodiment 19

[0941]

[0942] (2R)-1,1-difluoro-2-{5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3- 6-Azaspiro[2.5]octane-6-sulfonamide

[0943] To an ambient temperature solution of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (38.8 mg, 0.200 mmol) in 1,2-dichloroethane (0.90 mL) and dimethyl sulfoxide (0.10 mL) were added 1-hydroxy-7-azabenzotriazole (27.2 mg, 0.200 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg, 0.300 mmol) in sequence and the reaction mixture was stirred for 15 minutes. (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 11) (59.7 mg, 0.210 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was warmed to 90°C and stirred for 4 h. The reaction mixture was cooled to ambient temperature, diluted with water, the layers separated, and the organic layer purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate from 95:5 to 25:75 to afford the title compound. MS: m / z = 443.2 [M+H]. 1 H NMR (DMSO-d 6 )δ8.91(s,1H),6.78(s,2H),4.03(s,3H),3.37–3.24(m,1H),3.22–3.09(m,1H),3.10–2.97(m,2H),2.95–2.79(m,1H),2.04–1.83(m,4H).

[0944] Embodiment 20

[0945]

[0946] (2R)-1,1-difluoro-2-[5-(2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-1,2,4- Oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide

[0947] To an ambient temperature solution of 2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylic acid (33.2 mg, 0.200 mmol) in 1,2-dichloroethane (0.90 mL) and dimethyl sulfoxide (0.10 mL) were added 1-hydroxy-7-azabenzotriazole (27.2 mg, 0.200 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg, 0.300 mmol) in sequence and the reaction mixture was stirred for 15 minutes. (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 11) (68.2 mg, 0.240 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was warmed to 95°C and stirred for 3 h. The reaction mixture was cooled to ambient temperature, diluted with water, the layers separated, and the organic layer purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate from 90:10 to 0:100 to afford the title compound. MS: m / z = 415.2 [M+H]. 1 H NMR (DMSO-d 6 )δ6.79(s,2H),4.13(s,3H),3.39–3.26(m,1H),3.24–3.12(m,1H),3.11–2.97(m,2H) ,2.91–2.81(m,3H),2.69(t,J=7.3Hz,2H),2.43(p,J=7.4Hz,2H),2.02–1.82(m,4H).

[0948] Embodiment 21

[0949]

[0950] 1,1-Difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-(methylsulfonyl 6-azaspiro[2.5]octane

[0951] To an ambient temperature solution of 2,2-difluoro-6-(methylsulfonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 28) (135 mg, 0.501 mmol) in 1,2-dichloroethane (2.25 mL) and dimethyl sulfoxide (0.25 mL) was added 1-hydroxy-7-azabenzotriazole (77 mg, 0.50 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115 mg, 0.600 mmol) and the reaction mixture was stirred for 20 minutes. 4-Fluoro-N'-hydroxy-2-(trifluoromethyl)benzimidamide (122 mg, 0.550 mmol) was added and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was warmed to 95 °C and stirred for 6 h. The reaction mixture was warmed to 105 °C and stirred for 4 h. The reaction mixture was cooled to ambient temperature and diluted with water. The layers were separated and the organic layer was purified by silica gel chromatography, eluting with a gradient of hexane:ethyl acetate:ethanol from 95:4:1 to 50:38:12. The product fractions were combined and concentrated under reduced pressure. The residue was purified by preparative HPLC, eluting with a gradient of acetonitrile:water:trifluoroacetic acid from 10:90:0.1 to 95:5:0.1, to give the title compound. MS: m / z=456.2 [M+H]. 1 H NMR (DMSO-d 6 )δ8.00–7.91(m,2H),7.77(t,J=8.1Hz,1H),3.77(d,J=11.2Hz,1H),3.37–3.29(m,1H ),3.28–3.18(m,2H),3.03–2.94(m,1H),2.90(s,3H),2.06(s,2H),2.02–1.90(m,2H).

[0952] Embodiment 22

[0953]

[0954] (2R)-1,1-difluoro-2-[5-(1,3,4-trimethyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6- Azaspiro[2.5]octane-6-sulfonamide

[0955] To an ambient temperature solution of 1,3,4-trimethyl-1H-pyrazole-5-carboxylic acid (46.2 mg, 0.300 mmol) in 1,2-dichloroethane (1.4 mL) and dimethyl sulfoxide (0.15 mL) was added 1-hydroxy-7-azabenzotriazole (40.8 mg, 0.300 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86.0 mg, 0.450 mmol) and the reaction mixture was stirred for 15 minutes. (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 11) (102 mg, 0.360 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was warmed to 90°C and stirred for 2 h. The reaction mixture was cooled to ambient temperature, diluted with water, the layers separated, and the organic layer purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 96:3:1 to 52:36:12 to afford the title compound. MS: m / z = 403.2 [M+H]. 1 H NMR (DMSO-d 6 )δ6.79(s,2H),4.07(s,3H),3.34(d,J=12.6Hz,1H),3.23–3.13(m,1H),3.12– 2.98(m,2H),2.95–2.81(m,1H),2.24(s,3H),2.17(s,3H),2.02–1.85(m,4H).

[0956] Embodiment 23

[0957]

[0958] (1R)-1-[4-(3-cyclopropylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonyl Amide

[0959] To a solution of (1R)-1-[4-(3-cyclopropylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro[2.5]octane (Intermediate 18) (13.7 mg, 0.047 mmol) in 1,4-dioxane (0.50 mL) was added sulfamide (24 mg, 0.25 mmol) and the reaction mixture was warmed to 100°C and allowed to stir for 2 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate from 100:0 to 70:30 to give the title compound. MS: m / z=365.1 [M+H]. 1 H NMR (DMSO-d 6)δ9.07(s,1H),8.33(s,1H),6.72(s,2H),3.16–3.06(m,1H),3.06–2.91(m,2H),2.80–2.67(m,1H),2.18(dd,J=8.5,5.7 Hz,1H),2.10(ddd,J=13.4,8.3,5.0Hz,1H),1.73–1.50(m,5H),1.21–1.13(m,2H),1.07–0.98(m,2H),0.90–0.81(m,2H).

[0960] Embodiment 24

[0961]

[0962] (2R)-1,1-Difluoro-2-{2-[4-fluoro-2-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-6-azaspiro [2.5] Octane-6-sulfonamide

[0963] Step A: (2R)-N-[(dimethylamino)methylene]-1,1-difluoro-2-{2-[4-fluoro-2-(trifluoromethyl)benzene 1,3-oxazol-4-yl}-6-azaspiro[2.5]octane-6-sulfonamide

[0964] To a solution of (2R)-N-[(dimethylamino)methylene]-1,1-difluoro-2-(iodoacetyl)-6-azaspiro[2.5]octane-6-sulfonamide (Intermediate 24) (133 mg, 0.296 mmol) in ethyl acetate (1.48 mL) was added 4-fluoro-2-(trifluoromethyl)benzamide (77 mg, 0.37 mmol) and silver trifluoromethanesulfonate (95 mg, 0.37 mmol) and the reaction mixture was warmed to 60°C and allowed to stir for 3 h. The reaction mixture was cooled to ambient temperature, diluted with saturated aqueous sodium chloride solution (10 mL) and ethyl acetate (10 mL) and the resulting mixture was stirred for 3.5 h. The mixture was stirred by Filter and wash with ethyl acetate. Separate the layers and extract the aqueous layer with ethyl acetate (2×). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, aqueous HCl solution (1M), and saturated aqueous sodium chloride solution, 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 hexane: ethyl acetate: ethanol from 100:0:0 to 40:45:15 to give the title compound. MS: m / z=511.2[M+H].

[0965] Step B: (2R)-1,1-difluoro-2-{2-[4-fluoro-2-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-6-nitrogen Heterospiro[2.5]octane-6-sulfonamide

[0966] To a solution of (2R)-N-[(dimethylamino)methylene]-1,1-difluoro-2-{2-[4-fluoro-2-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-6-azaspiro[2.5]octane-6-sulfonamide (72 mg, 0.14 mmol) in methanol (1.41 mL) was added hydrazine (0.0443 mL, 1.41 mmol) and the reaction mixture was warmed to 60°C and allowed to stir for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 100:0:0 to 40:45:15 to give the title compound. MS: m / z=456.2 [M+H]. 1 H NMR (500 MHz, CDCl 3 )δ7.95(dd,J=8.6,5.4Hz,1H),7.66(s,1H),7.53(dd,J=8.9,2.5Hz,1H),7.46–7.32(m,1H),4.35(s,2H),3 .49–3.28(m,2H),3.19(m,2H),2.49(d,J=13.7Hz,1H),2.03(m,1H),1.89(m,1H),1.78(m,1H),1.65(m,1H).

[0967] Embodiment 25

[0968]

[0969] (2R)-2-[5-(1-cyclopropyl-4-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro- 6-Azaspiro[2.5]octane-6-sulfonamide

[0970] To an ambient temperature solution of 1-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 20) (33.2 mg, 0.200 mmol) in 1,2-dichloroethane (0.90 mL) and dimethyl sulfoxide (0.10 mL) was added 1-hydroxy-7-azabenzotriazole (30.8 mg, 0.200 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (49.8 mg, 0.260 mmol) and the reaction mixture was stirred for 15 minutes. (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 11) (62.5 mg, 0.220 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was warmed to 90°C and stirred for 3 h. The reaction mixture was cooled to ambient temperature, diluted with water, the layers separated, and the organic layer purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 96:3:1 to 52:36:12 to afford the title compound. MS: m / z = 415.3 [M+H].1 H NMR (DMSO-d 6 )δ7.91(s,1H),6.80(s,2H),3.91–3.81(m,1H),3.39–3.25(m,1H),3.21–3.10(m,1H),3 .10–2.99(m,2H),2.91–2.80(m,1H),2.27(s,3H),2.02–1.84(m,4H),1.15–0.98(m,4H).

[0971] Embodiment 26

[0972]

[0973] 1-[5-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]-6-(methylsulfonyl)-6-azaspiro [2.5] Octane, enantiomer A

[0974] To a solution of 5-chloro-5-methoxybenzoic acid (93.0 mg, 0.501 mmol) in 1,4-dioxane (2 mL) was added 1,1'-carbonyldiimidazole (89.0 mg, 0.550 mmol) and the reaction mixture was warmed to 50 °C and stirred for 2 h. N'-hydroxy-6-methylsulfonyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 21) (124 mg, 0.498 mmol) was added and the reaction mixture was warmed to 120 °C and stirred for 16 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexane:ethyl acetate:ethanol from 96:3:1 to 52:36:12 to give the racemic title compound. The mixture was resolved by SFC using a ChiralPak AS-H column and eluting with 25:75 methanol:carbon dioxide. The first main peak eluted was 1-[5-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]-6-(methylsulfonyl)-6-azaspiro[2.5]octane, enantiomer A, the title compound; the second main peak eluted was 1-[5-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]-6-(methylsulfonyl)-6-azaspiro[2.5]octane, enantiomer B. MS: m / z=398.2[M+H]. 1 H NMR (DMSO-d 6)δ7.94(d,J=2.7Hz,1H),7.71(dd,J=9.0,2.7Hz,1H),7.33(d,J=9.1Hz,1H),3.93(s,3H),3.36–3.27(m,1H),3.21(t,J=5.4Hz,2H),3.11(ddd ,J=11.1,7.3,3.5Hz,1H),2.98(ddd,J=11.1,7.0,3.3Hz,1H),2.87(s,3H),2.19(dd,J=7.9,6.2Hz,1H),1.77–1.56(m,3H),1.26–1.13(m,2H).

[0975] Embodiment 27

[0976]

[0977] (1R)-1-[5-(1-ethyl-5-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro [2.5] Octane-6-sulfonamide

[0978] To a solution of 1-ethyl-5-methyl-1H-pyrazole-3-carboxylic acid (31.0 mg, 0.201 mmol) in 1,4-dioxane (1 mL) was added 1,1'-carbonyldiimidazole (32.7 mg, 0.201 mmol) and the reaction mixture was warmed to 50°C and allowed to stir for 2 h. (1R)-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 2) (50.0 mg, 0.201 mmol) was added and the reaction mixture was warmed to 90°C and allowed to stir for 16 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by HPLC eluting with a gradient of acetonitrile:water:trifluoroacetic acid from 5:95:0.1 to 95:5:0.1 to give the title compound. MS: m / z=367.3 [M+H]. 1 H NMR (DMSO-d 6 )δ6.74(s,1H),6.72(s,2H),4.18(q,J=7.4Hz,2H),3.13–3.07(m,1H),3.06–2.93(m,2H),2.79–2.72 (m,1H),2.35(s,3H),2.17–2.10(m,1H),1.73–1.55(m,4H),1.35(t,J=7.2Hz,3H),1.21–1.12(m,2H).

[0979] Embodiment 28

[0980]

[0981] (1R)-1-[5-(3-cyclopropyl-5-methylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro[2.5]oxane Alkane-6-sulfonamide

[0982] Step A: (1R)-N-[2-(3-cyclopropyl-5-methylisoxazol-4-yl)-2-oxoethyl]-6-sulfamoyl-6- Azaspiro[2.5]octane-1-carboxamide

[0983] To a solution of 2-azido-1-(3-cyclopropyl-5-methylisoxazol-4-yl)ethanone (Intermediate 22) (157 mg, 0.761 mmol) in tetrahydrofuran (3.0 mL) was added triphenylphosphine (200 mg, 0.761 mmol) and the reaction mixture was stirred at ambient temperature for 2 h. Water (0.05 mL) was added and the reaction mixture was stirred at ambient temperature for 1 h. Molecular sieves and the reaction mixture was stirred at ambient temperature for 15 minutes. (1R)-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 1) (0.196 g, 0.837 mmol), HATU (0.347 mg, 0.913 mmol) and 4-methylmorpholine (0.25 mL, 2.274 mmol) were added sequentially and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was poured into water (50 mL) and the resulting mixture was extracted with ethyl acetate (2×80 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (50 mL), 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 dichloromethane:methanol from 100:0 to 95:5 to give the title compound. MS: m / z=397.2[M+H].

[0984] Step B: (1R)-1-[5-(3-cyclopropyl-5-methylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro [2.5] Octane-6-sulfonamide

[0985] To a solution of (1R)-N-[2-(3-cyclopropyl-5-methylisoxazol-4-yl)-2-oxoethyl]-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxamide (45 mg, 0.11 mmol) in acetonitrile (1 mL) was added phosphorus oxychloride (0.013 mL, 0.136 mmol) and the reaction mixture was warmed to 85 °C and allowed to stir for 2 h. The reaction mixture was cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate solution (20 mL) and the resulting mixture was extracted with ethyl acetate (2×40 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (20 mL), 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 hexanes:ethyl acetate from 100:0 to 50:50 to give the title compound. MS: m / z=379.1 [M+H]. 1 H NMR (DMSO-d 6)δ7.33(s,1H),6.73(s,2H),3.19–3.08(m,1H),3.07–2.91(m,2H),2.76–2.67(m,1H),2.53(s,3H),2.19(dd,J=8.4,5.6Hz,1H),1.99( ddd,J=13.3,8.2,5.0Hz,1H),1.74–1.62(m,2H),1.61–1.47(m,2H),1.22–1.12(m,2H),1.01(dd,J=8.3,2.5Hz,2H),0.88–0.79(m,2H).

[0986] Embodiment 29

[0987]

[0988] (2R)-2-{5-[1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-1, 1-Difluoro-6-azaspiro[2.5]octane-6-sulfonamide

[0989] To an ambient temperature solution of 1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (Intermediate 23) (66.0 mg, 0.300 mmol) in 1,2-dichloroethane (1.4 mL) and dimethyl sulfoxide (0.15 mL) was added 1-hydroxy-7-azabenzotriazole (40.8 mg, 0.300 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86.0 mg, 0.450 mmol) and the reaction mixture was stirred for 15 minutes. (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 11) (102 mg, 0.360 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was warmed to 95°C and stirred for 2 h. The reaction mixture was cooled to ambient temperature, diluted with water, the layers separated, and the organic layer purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 96:3:1 to 52:36:12 to afford the title compound. MS: m / z = 469.2 [M+H]. 1 H NMR (DMSO-d 6 )δ7.74(s,1H),6.80(s,2H),4.31(dt,J=7.1,3.6Hz,1H),3.39(d,J=11.7Hz,1H),3.23–3.13(m,1H ),3.11–3.00(m,2H),2.95–2.85(m,1H),2.02–1.87(m,4H),1.30–1.22(m,2H),1.22–1.13(m,2H).

[0990] Embodiment 30

[0991]

[0992] (2R)-2-[5-(2-Cyclopropyl-5-methylphenyl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro [2.5] Octane 6-sulfonamide

[0993] To a solution of 2-cyclopropyl-5-methylbenzoic acid (37.2 mg, 0.211 mmol) in 1,2-dichloroethane (1.6 mL) and dimethyl sulfoxide (0.16 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (43.8 mg, 0.229 mmol), 1-hydroxy-7-azabenzotriazole (19.2 mg, 0.141 mmol) and (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (Intermediate 11) (50 mg, 0.18 mmol) in sequence and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was warmed to 110° C. and stirred for 2.5 h. The reaction mixture was cooled to ambient temperature, filtered and the filtrate concentrated under a stream of nitrogen. The residue was purified by HPLC eluting with a gradient of acetonitrile:water from 20:80 to 95:5 to give the title compound. MS: m / z = 425.2 [M+H]. 1 H NMR (DMSO-d 6 )δ7.76(s,1H),7.39(d,J=8.0Hz,1H),7.11(d,J=8.0Hz,1H),6.81(s,2H),3.33(s,1H),3.16(s,1H),3.11–3.01(m,2H),2.89(d,J= 6.6Hz,1H),2.61–2.53(m,1H),2.35(s,3H),1.97(d,J=6.9Hz,3H),1.95–1.88(m,1H),0.97(d,J=8.5Hz,2H),0.70(q,J=5.8Hz,2H).

[0994] Embodiment 31

[0995]

[0996] (2R)-2-[2-(3-cyclopropylisoxazol-4-yl)-1,3-oxazol-4-yl]-1,1-difluoro-6-azaspiro[2.5] Octane-6-sulfonamide

[0997] Step A: (2R)-2-[2-(3-cyclopropylisoxazol-4-yl)-1,3-oxazol-4-yl]-N-[(dimethylamino) [Methylene]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide

[0998] To a solution of (2R)-N-[(dimethylamino)methylene]-1,1-difluoro-2-(iodoacetyl)-6-azaspiro[2.5]octane-6-sulfonamide (Intermediate 24) (74.5 mg, 0.166 mmol) in ethyl acetate (0.83 mL) was added 3-cyclopropylisoxazole-4-carboxamide (31.5 mg, 0.207 mmol) and silver trifluoromethanesulfonate (53.3 mg, 0.207 mmol) and the reaction mixture was warmed to 60 °C and allowed to stir for 2 h. The mixture was diluted with saturated aqueous sodium chloride solution (10 mL) and ethyl acetate (10 mL) and allowed to stir for 4 h. The resulting mixture was filtered, washed with ethyl acetate, the layers of the filtrate were separated, and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (2×), aqueous HCl solution (1 M), and saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 100:0:0 to 60:30:10 to give the title compound. MS: m / z = 456.3 [M+H].

[0999] Step B: (2R)-2-[2-(3-cyclopropylisoxazol-4-yl)-1,3-oxazol-4-yl]-1,1-difluoro-6-azepine Spiro[2.5]octane-6-sulfonamide

[1000] To a solution of (2R)-2-[2-(3-cyclopropylisoxazol-4-yl)-1,3-oxazol-4-yl]-N-[(dimethylamino)methylene]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide (42 mg, 0.092 mmol) in methanol (0.92 mL) was added hydrazine (0.0289 mL, 0.922 mmol) and the reaction mixture was warmed to 50° C. and allowed to stir for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate:ethanol from 100:0:0 to 70:23:7 to give the title compound. MS: m / z=401.2 [M+H]. 1 H NMR (500 MHz, CDCl 3 )δ8.82(s,1H),7.54(s,1H),4.34(s,2H),3.45(m,1H),3.33–3.24(m,2H),3.11(m,1H),2.55–2.52(m ,1H),2.49(d,J=13.8Hz,1H),1.97(m,2H),1.79–1.70(m,1H),1.71–1.63(m,1H),1.17–1.07(m,4H).

[1001] Embodiment 32

[1002]

[1003] 2-[3-(2,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-(methylsulfonyl)-6-nitropropene Spiro[2.5]octane

[1004] Essentially following the procedure described in Example 21, but substituting N'-hydroxy-2,5-dimethylbenzenecarboximidamide for 4-fluoro-N'-hydroxy-2-(trifluoromethyl)benzenecarboximidamide, the title compound was obtained. MS: m / z = 398.3 [M+H].

[1005] 1 H NMR (DMSO-d 6 )δ7.70(s,1H),7.29(s,2H),3.69(d,J=11.4Hz,1H),3.31–3.20(m,3H),3.10–3.03( m,1H),2.90(s,3H),2.48(s,3H),2.35(s,3H),2.14–2.03(m,2H),2.02–1.91(m,2H).

[1006] Embodiment 33

[1007]

[1008] (1R)-1-[5-(2-methylphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide

[1009] Following essentially the procedure described in Example 1, but substituting 2-methylbenzoic acid for 2-methyl-5-(trifluoromethyl)benzoic acid, the title compound was obtained. MS: m / z = 349.1 [M+H]. 1 H NMR (DMSO-d 6 )δ8.00(d,J=7.8Hz,1H),7.56(t,J=7.4Hz,1H),7.46(d,J=7.6Hz,1H),7.42(t,J=7.5Hz,1H),6.71(s,2H),3.17–3.10(m, 1H), 3.07–2.98 (m, 2H), 2.62 (s, 3H), 2.19 (t, J = 6.9Hz, 1H), 1.80–1.73 (m, 1H), 1.72–1.59 (m, 3H), 1.20 (d, J = 7.0Hz, 2H).

[1010] Embodiment 34

[1011]

[1012] (2R)-2-[5-(2,5-dimethylphenyl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5] Octane-6-sulfonamide

[1013] Essentially following the procedure described in Example 30, but substituting 2,5-dimethylbenzoic acid for 2-cyclopropyl-5-methylbenzoic acid, provided the title compound. MS: m / z = 399.2 [M+H]. 1 H NMR (DMSO-d 6 )δ7.85(s,1H),7.42–7.35(m,2H),6.79(s,2H),3.32(s,1H),3.20–3.14(m,1H),3 .10–3.01(m,2H),2.92–2.85(m,1H),2.58(s,3H),2.37(s,3H),2.03–1.88(m,4H).

[1014] Embodiment 35

[1015]

[1016] (2R)-2-{2-[2-(difluoromethoxy)pyridin-4-yl]-1,3-oxazol-4-yl}-1,1-difluoro-6-azaspiro [2.5] Octane-6-sulfonamide

[1017] Essentially following the procedure described in Example 24, but substituting 2-(difluoromethoxy)pyridine-4-carboxamide (Intermediate 29) for 4-fluoro-2-(trifluoromethyl)benzamide, the title compound was obtained. MS: m / z = 437.2 [M+H]. 1 H NMR (500 MHz, CDCl 3 )δ8.31(d,J=5.2Hz,1H),7.67(d,J=5.3Hz,1H),7.65(s,1H),7.64–7.36(t,J=74.5Hz,1H),7.46(s,1H),4.36(s,2H),3.48–3.4 4(m,1H),3.41–3.18(m,2H),3.14–3.09(m,1H),2.50(d,J=13.6Hz,1H),2.04–1.92(m,2H),1.78–1.73(m,1H)1.67–1.60(m,1H).

[1018] Embodiment 36

[1019]

[1020] 1,1-Difluoro-2-{1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}-6-azaspiro[2.5]octane Alkane-6-sulfonamide

[1021] To a solution of 1,1-difluoro-2-{1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}-6-azaspiro[2.5]octane hydrochloride (Intermediate 31) (23.7 mg, 0.0576 mmol) in 1,4-dioxane (2 mL) was added sulfamide (24.3 mg, 0.253 mmol) and triethylamine (0.04 mL, 0.25 mmol) and the reaction mixture was warmed to 100 °C and allowed to stir for 12 h. The reaction mixture was cooled to ambient temperature and water (5 mL) was added. The resulting mixture was extracted with ethyl acetate (2×5 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of acetonitrile:water:ammonium hydroxide from 36:64:0.1 to 66:34:0.1 to give the title compound. MS: m / z=454.9 [M+H]. 1 H NMR (400MHz, CD 3 OD)δ7.80(s,1H),7.67–7.70(m,1H),7.59–7.60(m,2H),6.43(s,1H),3.34–3.35(m ,1H),3.00–3.31(m,3H),2.63–2.66(m,1H),1.93–1.96(m,2H),1.75–1.79(m,2H).

[1022] Embodiment 37

[1023]

[1024] 1,1-Difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}-6-azaspiro [2.5] Octane-6-sulfonamide

[1025] To a solution of 1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}-6-azaspiro[2.5]octane hydrochloride (Intermediate 35) (61 mg, 0.14 mmol) in 1,4-dioxane (2 mL) were added triethylamine (43.1 mg, 0.43 mmol) and sulfamide (68.2 mg, 0.71 mmol) and the reaction mixture was warmed to 95 °C and allowed to stir for 12 h. The reaction mixture was cooled to ambient temperature and diluted with water (5 mL). The resulting mixture was extracted with ethyl acetate (3×5 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 50:50 petroleum ether:ethyl acetate to give the title compound. MS: m / z=472.8[M+H]. 1 H NMR (400 MHz, CDCl 3 ):δ7.71(dd,J 1=8.4Hz,J 2 =5.6Hz,1H),7.58(dd,J 1 =8.8Hz,J 2 =2.0Hz,1H),7.40–7.57(m,1H),4.43(br,2H),3.39–3.42(m,1H),3.29–3.31(m,1H ),3.15–3.18(m,2H),2.99(d,J=12.8Hz,1H),2.13–2.19(m,2H),1.99–2.01(m,2H).

[1026] The examples appearing in the following table are prepared by being similar to the above-mentioned examples as described or by using modifications known to those skilled in the art with similar transformations. Necessary starting materials are described herein, commercially available, known in the literature or easily synthesized by those skilled in the art. Straightforward protecting group strategies have been applied in some routes.

[1027] Table EX-A

[1028]

[1029]

[1030]

[1031] Table EX-B

[1032]

[1033]

[1034]

[1035] Table EX-C

[1036]

[1037]

[1038]

[1039] Table EX-D

[1040]

[1041]

[1042]

[1043] Table EX-E

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052]

[1053]

[1054] Table EX-F

[1055]

[1056]

[1057]

[1058] Table EX-G

[1059]

[1060]

[1061]

[1062] Table EX-H

[1063]

[1064]

[1065]

[1066] Table EX-I

[1067]

[1068]

[1069]

[1070]

[1071] Table EX-J

[1072]

[1073]

[1074] Table EX-K

[1075]

[1076]

[1077] The utility of the compounds according to the invention as positive allosteric modulators of α7 nicotinic acetylcholine receptor activity can be demonstrated by methods known in the art. Direct activation (agonism) of α7 and enhancement of acetylcholine-induced α7 currents were determined as follows:

[1078] Automated patch clamp electrophysiology

[1079] Functional assay (Assay A)

[1080] Automated patch clamp electrophysiology studies were performed using the IonFlux HT (Fluxion Biosciences Inc., San Francisco, CA) in a whole-cell population patch configuration. The ability of test compounds to modulate the function of α7 nicotinic acetylcholine receptors was assessed in the presence and absence of the natural α7 agonist acetylcholine. 2HEK cell lines (PrecisionION hnAChRα7 / RIC-3, Eurofins Pharma, St. Charles, MO) that stably express human RIC-3 and human α7 were cultured in DMEM / F-12 growth medium supplemented with 10% heat-inactivated fetal bovine serum, 1% non-essential amino acids, 0.625 μg / mL puromycin and 400 μg / mL geneticin in three-layer tissue culture flasks to a confluence of no more than 90%. Immediately before the assay, the cells were detached by first aspirating the growth medium, rinsing with Dulbecco's phosphate-buffered saline, then adding 10 mL Accutase (Innovative Cell Technologies, San Diego, CA) to the flask and then incubating at 37°C for 5 minutes. The detached cells were then recovered by adding 40 mL of CHO serum-free medium supplemented with 25 mM HEPES and gently shaken for 20 minutes in a 50 mL conical tube before the patch clamp assay. After recovery, cells were pelleted by centrifugation at 1,000 RPM for 1 min in a compact tabletop centrifuge; the recovery medium was aspirated and cells were resuspended in external recording solution (150 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES, 12 mM dextrose) to 5.0 × 10 6 The density of cells / mL was 1.5 cells / mL. 2 The cell suspension was added to the cell inlet well of the IonFlux HT swarm patch plate that had been flushed and pre-stimulated. Test compounds were serially diluted in DMSO and 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 swarm patch plate. Internal recording solution (110 mM TrisPO 40 μM) was added to the internal recording solution inlet well of the IonFlux HT patch plate that had been previously loaded with cells and test compounds. 4 、28mM TrisBase、0.1mM CaCl 2 , 2 mM MgCl 2, 11mM EGTA, 4mM MgATP), and then load the plate into the IonFlux HT instrument. The protocol was executed on the IonFlux HT to capture the cell, break into the cell, and establish the whole-cell recording configuration; the cell voltage was clamped at a holding potential of -60mV for the duration of the experiment, all experiments were performed at room temperature, and the IonFlux HT injection pressure was 8psi for solution application. After the whole-cell configuration was established, the recording chamber was perfused with external recording solution for 120 seconds, and then 40μM acetylcholine was applied for 1 second and immediately rinsed with external recording solution for 60 seconds. The 40μM acetylcholine-induced α7 current served as the current response to which the current response produced by subsequent test compounds in the presence or absence of 40μM acetylcholine will be quantified. Next, the ability of the test compound to induce or modulate the α7 current response was evaluated at multiple concentrations; three concentrations of the test compound were evaluated in an increasing dose manner for each recording. To evaluate the agonist activity of the test compound, the test compound diluted in the external recording solution was applied for 58 seconds, starting with the lowest concentration of the test compound tested in the concentration series; the first 20 seconds of the 58-second compound application period coincided with a data acquisition scan lasting 20 seconds and collected at a rate of 5,000 samples / second. To evaluate the positive allosteric modulator activity of the test compound, the same concentration of the test compound diluted in the external recording solution containing 40 μM acetylcholine was applied for 1 second immediately after the 58-second test compound-only application period; thus, the test compound and the natural receptor agonist acetylcholine were co-applied, and potentiation by the test compound was observed. The 1-second application of the test compound diluted in the external solution containing 40 μM acetylcholine coincided with a data acquisition scan lasting 20 seconds and collected at a rate of 5,000 samples / second, followed by the application of the external recording solution alone for 42 seconds. After this 42-second wash with the external recording solution alone, the next highest concentration of the test compound in the concentration series was applied in the absence and then presence of acetylcholine as before, and data was collected as before. After assessing the test compound agonist and positive allosteric modulator activity at three increasing concentrations, the experiment was terminated and leak current subtraction was performed using IonFlux HT data analysis software. Both peak current amplitude and area under the curve (AUC) were quantified for each current scan using proprietary software and the test compound effect, with quantification being performed as follows.

[1081] The agonist activity of the test compound was calculated as follows:

[1082] % agonism = (Y / X) × 100

[1083] The enhancer activity of the test compound was calculated as follows:

[1084] % Enhancement = [(Z / X) × 100] – 100

[1085] X = peak current amplitude (or AUC) evoked by 40 μM acetylcholine

[1086] Y = peak current amplitude (or AUC) evoked by test compound diluted in external recording solution

[1087] Z = peak current amplitude (or AUC) evoked by test compound diluted in external recording solution containing 40 μM acetylcholine

[1088] Thus, a test compound that induces a current amplitude identical to that induced by 40 μM acetylcholine alone would have a calculated % agonism of 100%. A test compound co-applied with 40 μM acetylcholine that induces a current amplitude twice that induced by 40 μM acetylcholine alone would have a calculated % potentiation of 100%, while a test compound co-applied with 40 μM acetylcholine that induces a current amplitude identical to that induced by 40 μM acetylcholine alone would be characterized as having no potentiation.

[1089] Agonist and potentiation data derived from peak current amplitude or area under the curve (AUC) were plotted and fit using a 4-parameter logistic fit based on the Levenberg-Marquardt algorithm, where y = A + ((BA) / (1 + ((C / x)^D))), where:

[1090] A=minimum

[1091] B = maximum value

[1092] C=EC 50

[1093] D = slope

[1094] x = test compound concentration

[1095] y = % agonism or % potentiation

[1096] The following table presents the performance of selected compounds of the invention in an automated patch clamp electrophysiological functional assay (Assay A). Efficacy data in:

[1097]

[1098]

[1099]

[1100]

[1101]

[1102]

[1103]

[1104]

[1105]

[1106]

[1107] *Potency is defined as: A(EC 50 ≤0.1μM); B(0.1μM <EC 50 ≤0.5μM); C(0.5μM <EC 50 ≤5μM); D(5μM <EC 50 ≤50μM)

[1108] The following table provides the electrophysiological EC values ​​of selected compounds of the invention in an automated patch clamp electrophysiological functional assay (Assay A): 50 value:

[1109]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116]

[1117]

[1118] It should be understood that the above-mentioned various and other features and functions or their alternatives may be desirably combined into many other different systems or applications. Likewise, those skilled in the art may subsequently make various currently unforeseen or unanticipated substitutions, modifications, changes or improvements, which are also intended to be covered by the appended claims.

Claims

1. A compound having formula (II) or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2 or 3; Z is independently selected from F, Cl, Br, methyl, methoxy, ethyl, ethoxy, propyl, -CH2OH, -CH2CH2OH, -CF3, -CH2CF3, -OCF3, -OCHF2, -OCH2CF3 and cyclopropyl; Ring A is oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, isothiazolyl, thiazolyl, pyrazolyl or imidazolyl; Ring B is cyclohexyl, phenyl, pyrazolyl, pyridinyl or isoxazolyl; R 3 is H, F or (C1-C4)alkyl, wherein the alkyl is optionally substituted with one or more halogens; and R 4 is H, F or (C1-C4)alkyl, wherein the alkyl is optionally substituted by one or more halogens.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which has the formula (II) or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1 or 2; Z is independently selected from F, Cl, Br, methyl, methoxy, ethyl, ethoxy, propyl, -CH2OH, -CH2CH2OH, -CF3, -CH2CF3, -OCF3, -OCHF2, -OCH2CF3 and cyclopropyl; Ring A is oxadiazolyl, oxazolyl, isoxazolyl or thiazolyl; Ring B is phenyl, pyrazolyl, pyridyl or isoxazolyl; R 3 and R 4 All are H or R 3 and R 4 All are F.

3. The compound according to claim 1, selected from (1R)-1-{5-[2-methyl-5-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(2,5-dimethylphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; 4,4-difluoro-1-{3-[3-(2,2,2-trifluoroethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer C; 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide; diastereomer E; (1R)-1-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; 1-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-4-methyl-6-azaspiro[2.5]octane-6-sulfonamide, diastereomer D; (1R)-1-{2-[3-(trifluoromethoxy)phenyl]-1,3-thiazol-4-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[4-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[5-(1,4-dimethyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{5-[2-(difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-{3-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{5-[2-(difluoromethoxy)-5-methylpyridin-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-{5-[1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{1-[3-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[5-(1-cyclopropyl-1H-pyrazol-5-yl)-1,3,4-oxadiazol-2-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2S)-2-[5-(1-cyclopropyl-1H-pyrazol-5-yl)-1,3,4-thiadiazol-2-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[5-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-3-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-{5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[5-(2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[5-(1,3,4-trimethyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[4-(3-cyclopropylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-{2-[4-fluoro-2-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[5-(1-cyclopropyl-4-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(1-ethyl-5-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(3-cyclopropyl-5-methylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{5-[1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[5-(2-cyclopropyl-5-methylphenyl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane 6-sulfonamide; (2R)-2-[2-(3-cyclopropylisoxazol-4-yl)-1,3-oxazol-4-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(2-methylphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[5-(2,5-dimethylphenyl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro [2.5] Octane-6-sulfonamide; (2R)-2-{2-[2-(difluoromethoxy)pyridin-4-yl]-1,3-oxazol-4-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; 1,1-Difluoro-2-{1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; 1,1-Difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{3-[5-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-{3-[4-(2-hydroxypropan-2-yl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; 1-{3-[2-(methylamino)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; 1-{3-[2-(Pyrrolidin-1-yl)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; 2-[3-(3,5-dimethylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[3-(3-cyclopropyl-5-methylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-(3-cyclohexyl-1,2,4-oxadiazol-5-yl)-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[3-(2-methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-{3-[2-(trifluoromethyl)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{3-[2-(difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[3-(1-cyclopropyl-4-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[3-(imidazo[1,2-a]pyridin-7-yl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{3-[5-cyclopropyl-3-(trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; 1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[3-(1-cyclopropyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{3-[3-cyclopropyl-5-(trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{3-[5-cyclopropyl-3-(trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; 1,1-Dichloro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(2-cyanophenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[5-bromo-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-(5-phenyl-1,2,4-oxadiazol-3-yl)-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[4-chloro-2-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-fluoro-6-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[4-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(2,4-difluorophenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(2,4-dimethylphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[5-fluoro-2-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[5-chloro-2-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[4-(2-hydroxypropan-2-yl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(difluoromethoxy)-4-fluorophenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(2,4,5-trimethylphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[5-(2-Cyclopropylphenyl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(5-fluoro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(1-cyclopropyl-3-methyl-1H-indol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(2-methylpyridin-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[3-(propan-2-yl)cyclobutyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-fluoro-6-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-fluoro-5-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(2,6-dimethylbenzyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(3-methylcyclohexyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[1-(2-chlorophenyl)ethyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[5-fluoro-2-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[1-(2,5-difluorophenyl)cyclobutyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(Spiro[2.5]octane-4-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[4-fluoro-2-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-(5-{1-[3-(trifluoromethyl)phenyl]cyclopropyl}-1,2,4-oxadiazol-3-yl)-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(3-phenylcyclobutyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(3,6-dimethylpyridin-2-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[6-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(2,2,2-trifluoroethoxy)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[3-methyl-6-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(Spiro[3.3]hept-2-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[4-(trifluoromethyl)-1,3-oxazol-5-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(4-ethyl-1,3-oxazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(4,5-dimethylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[(3,5-dimethylisoxazol-4-yl)methyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[3-(trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(1-cyclopropyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(1H-imidazol-1-yl)-5-(trifluoromethyl)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{5-[2-(cyclopropyloxy)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[5-(1-cyclopropyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[5-(1-tert-butyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[5-(3-methylimidazo[1,2-a]pyridin-7-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[5-(3-cyclopropyl-1-ethyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-{5-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{5-[1-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[5-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[5-(1-cyclopropyl-4-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[5-(1-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[5-(1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-{5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{5-[1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[5-(2-cyclopropyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{5-[1-cyclopropyl-4-(trifluoromethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[5-(3-cyclopropylpyridazin-4-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(3-cyclopropylpyridazin-4-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-{5-[2-(propane-2-oxy)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(1,4-dimethyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[5-(4H-pyrazolo[1,5-c][1,3]thiazol-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{5-[1-cyclopropyl-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{5-[3-cyclopropyl-5-(trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[4-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[5-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-methyl-5-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(1-cyclopropyl-4-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[5-(2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-{5-[3-(trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-(5-{3-[5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1,2,4-oxadiazol-3-yl)-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(2-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(1H-pyrrol-1-yl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(4'-fluorobiphenyl-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(1-cyanocyclopropyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(pyrimidin-2-yl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(1H-pyrazol-1-yl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[3-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[3-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[3-(trifluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(2,5-difluorophenyl)-1,3,4-thiadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(5-fluoro-2-methylphenyl)-1,3,4-oxadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(2,2,2-trifluoroethoxy)phenyl]-1,3,4-oxadiazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[2-(2,2,2-trifluoroethoxy)phenyl]-1,3,4-thiadiazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(2-methylphenyl)-1,3,4-thiadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[3-(difluoromethoxy)phenyl]-1,3,4-thiadiazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(3-cyclopropyl-5-methylisoxazol-4-yl)-1,3,4-oxadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[5-(3-cyclopropyl-5-methylisoxazol-4-yl)-1,3,4-thiadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[5-(2-methylphenyl)-1,3,4-oxadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[5-(2-methylphenyl)-1,3,4-thiadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-(4-phenyl-1,3-oxazol-2-yl)-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[2-(3-cyclopropylisoxazol-4-yl)-1,3-thiazol-4-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (1R)-1-[1-(3,5-dimethylisoxazol-4-yl)-1H-pyrazol-4-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[2-(3-cyclopropylisoxazol-4-yl)-1,3-thiazol-4-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{3-[2-(difluoromethoxy)pyridin-4-yl]isoxazol-5-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[4-(3-cyclopropylisoxazol-4-yl)-1-methyl-1H-imidazol-2-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-(3'-cyclopropyl-3,4'-bisisoxazol-5-yl)-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-{4-[4-fluoro-2-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (1S)-1-[3-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2S)-1,1-difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (2S)-2-(3-cyclohexyl-1,2,4-oxadiazol-5-yl)-1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; (2S)-1,1-difluoro-2-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2S)-1,1-difluoro-2-[5-(2-methylphenyl)-1,3,4-oxadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-difluoro-2-[5-(2-methylphenyl)-1,3,4-thiadiazol-2-yl]-6-azaspiro[2.5]octane-6-sulfonamide; 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide; 4,4-difluoro-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[2.5]octane-6-sulfonamide; 1-[3-(2,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl]-4,4-difluoro-6-azaspiro[2.5]octane-6-sulfonamide; 4-methyl-1-{3-[2-(2,2,2-trifluoroethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; 1-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide; 2-[3-(3-cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1,4-trifluoro-6-azaspiro[2.5]octane-6-sulfonamide; 1,1,4-Trifluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; 1,1-Difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; 1-Fluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6-sulfonamide; 1-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-2-methyl-6-azaspiro[2.5]octane-6-sulfonamide; 2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-1,1-dimethyl-6-azaspiro[2.5]octane-6-sulfonamide; 1,1-Difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; 1,1-Difluoro-2-[5-(piperidin-1-yl)-1,2,4-thiadiazol-3-yl]-6-azaspiro[2.5]octane-6-sulfonamide; 3'-[5-(2,5-dimethylphenyl)-1,2,4-oxadiazol-3-yl]-2',2'-difluoro-3-azaspiro[bicyclo[3.2.1]octane-8,1'-cyclopropane]-3-sulfonamide; and 2-[5-(2,5-dimethylphenyl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-5-methyl-6-azaspiro[2.5]octane-6-sulfonamide; or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition of claim 4, further comprising a second therapeutic agent selected from the group consisting of an acetylcholinesterase inhibitor; an NMDA receptor antagonist; an antipsychotic; a MAO-B inhibitor and levodopa.

6. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in therapy.

7. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for modulating α7 nAChR activity or treating cognitive impairment associated with Alzheimer's disease, Parkinson's disease and schizophrenia in a patient in need thereof.

8. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in treating patients suffering from cognitive impairment associated with Alzheimer's disease, Parkinson's disease and schizophrenia.

9. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in a method of treating a patient suffering from cognitive impairment associated with Alzheimer's disease, Parkinson's disease and schizophrenia, the method comprising administering to the patient a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the patient.

10. A compound which is or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10, which is 12. The compound according to claim 10, which is A pharmaceutically acceptable salt of .

13. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound of claim 11.

14. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the pharmaceutically acceptable salt of claim 12.

15. A compound according to any one of claims 10 to 12, or a pharmaceutically acceptable salt thereof, for use in a method of treating a patient suffering from mild to moderate Alzheimer's type dementia, the method comprising administering to the patient the compound according to claim 11 in an amount effective to treat the patient.

16. A compound which is or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 16, which is 18. A compound according to claim 16, which is A pharmaceutically acceptable salt of .

19. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound of claim 17.

20. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound of claim 18.

21. A compound according to any one of claims 16 to 18, or a pharmaceutically acceptable salt thereof, for use in a method of treating a patient suffering from mild to moderate Alzheimer's type dementia, the method comprising administering to the patient a compound according to claim 17 in an amount effective to treat the patient.

22. A compound which is or a pharmaceutically acceptable salt thereof.

23. A compound according to claim 22, which is 24. A compound according to claim 22, which is A pharmaceutically acceptable salt of .

25. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound of claim 23.

26. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound of claim 24.

27. A compound according to any one of claims 22 to 24, or a pharmaceutically acceptable salt thereof, for use in a method of treating a patient suffering from mild to moderate Alzheimer's type dementia, the method comprising administering to the patient a compound according to claim 23 in an amount effective to treat the patient.

28. A compound which is or a pharmaceutically acceptable salt thereof.

29. A compound according to claim 28, which is 30. The compound according to claim 28, which is A pharmaceutically acceptable salt of .

31. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound of claim 29.

32. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound of claim 30.

33. A compound according to any one of claims 28 to 30, or a pharmaceutically acceptable salt thereof, for use in a method of treating a patient suffering from mild to moderate Alzheimer's type dementia, the method comprising administering to the patient a compound according to claim 29 in an amount effective to treat the patient.

34. A compound which is or a pharmaceutically acceptable salt thereof.

35. A compound according to claim 34, which is 36. A compound according to claim 34, which is A pharmaceutically acceptable salt of .

37. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound of claim 35.

38. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound of claim 36.

39. A compound as claimed in any one of claims 34 to 36, or a pharmaceutically acceptable salt thereof, for use in a method of treating a patient suffering from mild to moderate Alzheimer's type dementia, the method comprising administering to the patient a compound as claimed in claim 35 in an amount effective to treat the patient.

40. A compound which is or a pharmaceutically acceptable salt thereof.

41. A compound according to claim 40, which is 42. A compound according to claim 40, which is A pharmaceutically acceptable salt of .

43. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound of claim 41.

44. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound of claim 42.

45. A compound as claimed in any one of claims 40 to 42, or a pharmaceutically acceptable salt thereof, for use in a method of treating a patient suffering from mild to moderate Alzheimer's type dementia, the method comprising administering to the patient the compound of claim 42 in an amount effective to treat the patient.

46. ​​A compound which is or a pharmaceutically acceptable salt thereof.

47. A compound according to claim 46, which is 48. A compound according to claim 46, which is A pharmaceutically acceptable salt of .

49. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound of claim 47.

50. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound of claim 48.

51. A compound as claimed in any one of claims 46 to 48, or a pharmaceutically acceptable salt thereof, for use in a method of treating a patient suffering from mild to moderate Alzheimer's type dementia, the method comprising administering to the patient the compound as claimed in claim 47 in an amount effective to treat the patient.

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