EA042108B1 - SPIROPIPERIDINE ALLOSTERIC MODULATORS OF NICOTINE ACETYLCHOLIN RECEPTORS - Google Patents

Description

The field of technology to which the invention belongs

The present invention relates to compounds useful as α7 nAChR modulators, to compositions containing such compounds, and to the use of such compounds for the prevention, treatment or amelioration of a disease, in particular disorders of the central nervous system such as cognitive impairment in Alzheimer's disease. , Parkinson's disease and schizophrenia.

BACKGROUND OF THE INVENTION α7 nAChR is a fast desensitizing ligand-gated ion channel that has high Ca ²⁺ permeability. In the human brain, α7 nAChRs are highly expressed in the cerebral cortex and hippocampus, in areas associated with cognition, see, for example, Breese et al. J. Comp. Neurol. (1997) 387: 385-398. In neurons, α7 nAChRs are localized to presynaptic and postsynaptic structures, where receptor activation can modulate neurotransmitter production, neuronal excitability, and intracellular signaling, see, for example, Frazier et al. J. Neurosci. (1998) 18:1187-1195.

Cognitive impairment predominates in many neurological and psychiatric diseases, including Alzheimer's disease (AD), schizophrenia, and Parkinson's disease, and dysfunction in cholinergic signaling contributes to cognitive impairment in these diseases, see, for example, Francis et al. J. Neurol. neurosurgery. 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 enhancement of cholinergic transmission by acetylcholinesterase inhibition is the standard of care for the cognitive symptoms of AD. It is with reference to the α7 nAChR that encenicline, a partial α7 nAChR agonist, has recently been shown to improve cognition in Alzheimer's disease, see, for example, Moebius H et al., 67 Annual Meeting. Am. Acad. Neurol. (AAN) 2015, Abst P7.100. Evidence for the involvement of α7 nAChRs in the etiology of schizophrenia comes from studies that have found reduced expression of neuronal α7 nAChRs in the brains of patients with schizophrenia and found that schizophrenics smoke frequently, which appears to be a form of self-medication. In addition, variants in the promoter region of the gene encoding α7 nAChR, CHRNA7, which affects the expression of the α7 nAChR protein, are associated with symptoms of schizophrenia, see, for example, Sinkus et al. Neuropharmacology (2015) 96: 274-288. In addition, a growing body of clinical research evidence has shown that activation of α7 nAChR agonists may benefit cognition, see, for example, Keefe et al. Neuropsychopharmacology (2015) 40: 3053-3060 and Bertrand et al. Pharmacology Reviews (2015) 67:1025-1073. Therefore, targeting the α7 nAChR represents a therapeutic strategy for the treatment of cognitive decline associated with various cognitive impairments.

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive deficiencies in motor function such as tremor, bradykinesia, rigidity, and impaired postural reflex. The main pathological manifestation associated with the disease is the degeneration of dopaminergic neurons in the substantia nigra, leading to loss of dopaminergic tone in the striatum. L-DOPA is currently the standard treatment for motor symptoms in PD. However, long-term treatment of PD patients with L-DOPA also causes dyskinesia, a side effect of treatment with L-DOPA. New sets of data show that activation of α7 nAChRs drastically reduces dyskinesias in some animal models, see, for example, Zhang et al. J Pharmacol. Exp. Ther. (2014) 351:25-32. In addition, a growing body of evidence indicates that pre-treatment with α7 nAChR agonists may protect against neurodegeneration in nigrostriatal neurons, suggesting that α7 activation may alter disease characteristics, see, for example, Suzuki et al. J. Neurosci. Res. (2013) 91:462-471. Overall, α7 nAChR is an attractive target for attenuating disease progression and treating dyskinesia.

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

In recent years, α7-selective positive allosteric modulators (PAMs) have been proposed as a therapeutic approach for the treatment of cognitive impairment in AD, PD, and schizophrenia, as well as L-DOPA-induced dyskinesia and inflammation. Unlike α7 agonists, which activate the channel independently of the endogenous agonist, PAMs increase endogenous agonist activity without altering the temporal and spatial integrity of neurotransmission. There are two classes of α7 PAMs, type I and type II, which differ in modulation performance. PAMs

- 1 042108 type I (e.g. NS1738, see e.g. Timmermann et al. J. Pharmacol. Exp. Ther. (2007) 323: 294-307) predominantly affect peak current and have little or no effect on receptor desensitization , a Type II PAMs (eg PNU120596, see eg Hurst et al. J. Neurosci. (2005) 25: 4396-4405) markedly delay receptor desensitization. In addition, α7 nAChR PAMs may have improved selectivity over related channel targets, presumably by binding to non-conserved regions of the receptor.

The present invention relates to a new class of compounds that provide positive allosteric modulation of a7 nAChR.

The essence of the invention

The present invention relates to new compounds of formulas I and II and their pharmaceutically acceptable salts. These compounds may be useful, in the form of compounds or their pharmaceutically acceptable salts (if appropriate), to modulate α7 nAChR, prevent, treat or improve the course of a disease, especially disorders of the central nervous system, such as cognitive impairment in Alzheimer's disease, Parkinson's disease and schizophrenia and/or as ingredients of a pharmaceutical composition. As ingredients of a pharmaceutical composition, these compounds and their salts can be the primary active therapeutic agent and, if appropriate, they can be combined with other therapeutic agents including, but not limited to, acetylcholinesterase inhibitors, NMDA receptor antagonists, betasecretase inhibitors, M4 agonists. mAChR or PAMs, mGluR2 or NAMs or PAMs antagonists, 5HT6 antagonists, H3 histamine receptor antagonists, PDE4 inhibitors, PDE9 inhibitors, HDAC6 inhibitors, antipsychotics, MAO-B inhibitors and levodopa.

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

or its pharmaceutically acceptable salt, where n is 0, 1 or 2;

X is S(O) ₂ or C(O);

R ¹ is selected from NR ^a R ^b and R ^c ;

R ^a is selected from H, (C ₁ -C 4 )alkyl, (C ₃ -C ₆ ) cycloalkyl, aryl, heteroaryl and heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from R ⁸ ;

R ^b is H or (C ₁ -C 4 )alkyl;

Rc means (C ₁ -C4)alkyl, where the specified alkyl is optionally substituted with R ⁹ ; or

Rc is heteroaryl, wherein said heteroaryl is optionally substituted with one or more R ¹⁰ ;

A is a 5-membered heteroaryl ring which is substituted with 1 to 3 R groups, each independently selected from OH, oxo, NR ⁶ R ⁷ , CN, alkoxy, halogen, aminoalkyl, hydroxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said R groups are selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, optionally substituted with one or more substituents independently selected from R11;

R ² is independently halogen, (C1-C ₄ )alkyl or O(C1-C ₄ )alkyl, wherein said alkyl is optionally substituted with one or more halogens; or two R ² if both are (C1-C4) alkyl and are attached to the same carbon atom, may optionally together form a cyclopropyl, cyclobutyl or cyclopentyl ring or two R ² if both are (C1-C4) alkyl and are not attached to the same carbon atom, may optionally together form a bridging ring, wherein said cyclopropyl, cyclobutyl, cyclopentyl or bridging ring may optionally be substituted with one or more substituents independently selected from OH, halogen or (C1-C ₄ )alkyl;

R ³ means H, halogen or (C1-C ₄ )alkyl, where the specified alkyl is optionally substituted with one or more halogens;

R ⁴ means H, halogen or (C1-C ₄ )alkyl, where the specified alkyl is optionally substituted with one or more halogens;

or, R ³ and R ⁴ may optionally together form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring, wherein said ring may optionally be substituted with one or more substituents independently selected from OH, halo, or (C1- _C4 ) alkyl;

R ⁵ means H or (C1-C ₄ )alkyl;

- 2 042108

R ⁶ means H or (C ₁ -C ₄ )alkyl;

R ⁷ means H or (C1-C ₄ )alkyl;

R ⁸ means OH, (C1-C ₄ )alkyl, aryl, heteroaryl or heterocyclyl;

R ⁹ means aryl, heteroaryl or heterocyclyl;

R ¹⁰ means methyl or hydroxyl;

R ¹¹ is halo, OH, oxo, CF3, OCF3, CN, (C1-C6)alkyl, O(C1-C6)alkyl, S(C1-C4)alkyl, C=O(C1-C4)alkyl, NR ¹² R ¹³ , (C=O)NR ⁶ R ⁷ , (C=O)OR ⁶ , (C2-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 said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more halogens, (C ₁ -C ₄ )alkyls, (C ₃ -C ₆ )cycloalkyls, CF ₃ , OCF ₃ , OCH ₃ , CN, OH and oxo;

R ¹² is (C1-C4)alkyl, heterocyclyl, cycloalkyl, heteroaryl, aryl, or (C=O)R ⁶ each optionally substituted with one or more substituents independently selected from halo, (C1-C4)alkyl and OH; And

R ¹³ is (C1-C4)alkyl, heterocyclyl, cycloalkyl, heteroaryl, aryl, or (C=O)R ⁶ , each optionally substituted with one or more substituents independently selected from halo, (C1-C4)alkyl and OH.

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

Other embodiments, objects and features of the present invention are further described or apparent from the description, examples and appended claims.

Detailed description of the invention

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

In the first embodiment of the present invention, -XR ¹ means about

and other groups are as defined in the above general formula.

In the second embodiment of the present invention, R ² is independently methyl, ethyl or F, and the other groups are as defined in the above general formula or as in the first embodiment.

In a third embodiment of the present invention, A is a 5-membered heteroaryl ring which is substituted with 1 R group independently selected from OH, oxo, NR ⁶ R ⁷ , CN, alkoxy, halogen, aminoalkyl, hydroxyalkyl, alkyl, alkenyl, alkynyl , cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said R group selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is further optionally substituted with one or more substituents independently selected from R ¹¹ , and the other groups are as follows, as indicated in the above general formula, or as in the first and second embodiments.

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

In a fifth embodiment of the present invention, R is cyclohexyl, phenyl, pyrazolyl, pyridinyl, or isoxazolyl, each optionally substituted with one or more substituents independently selected from R ¹¹ , and other groups are as defined in the above general formula, or as in first to fourth embodiments.

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

In the seventh embodiment of the present invention, the compound of the present invention is represented by the formula (II)

- 3 042108

or its pharmaceutically acceptable salt, where m is 0, 1, 2 or 3;

Z is independently selected from F, Cl, Br, methyl, methoxy, ethyl, ethoxy, propyl, -CH2OH, -CH2CH2OH, -CF ₃ , -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 means H, F or (C ₁ -C ₄ )alkyl, where the specified alkyl is optionally substituted with one or more halogens; And

R ⁴ means H, F or (C ₁ -C ₄ )alkyl, where the specified alkyl is optionally substituted with one or more halogens.

In the eighth embodiment of the present invention, the compound of the present invention is described by formula (II) or a pharmaceutically acceptable salt thereof, where m is 0, 1 or 2;

Z is independently selected from F, Cl, Br, methyl, methoxy, ethyl, ethoxy, propyl, -CH2OH, -CH2CH2OH, -CF ₃ , -CH2CF3, -OCF3, -OCHF2, -OCH2CF3 and cyclopropyl;

ring A is oxadiazolyl, oxazolyl, isoxazolyl or thiazolyl;

ring B is phenyl, pyrazolyl, pyridinyl or isoxazolyl; And

R ³ and R ⁴ are both H, or R ³ and R ⁴ are both F.

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

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

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

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

1-{3-[3-(Difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-4 042108 azaspiro[2.5]octane-6-sulfonamide, diastereoisomer E;

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

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

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

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

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

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

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

(2R)-2- {5 - [2-(Difluoromethoxy)-5-methylpyride in-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]-1,2,4oxadiazol-3-yl}-6-azaspiro [2.5]octane-6-sulfonamide;

(lR)-l-{1-[3-(Trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-6-azaspiro[2.5]octane-6sulfonamide;

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

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

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

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

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

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

(2R)-l,l-Diφτop-2-[5-(l,3,4-τpimethyl-lH-pyrazol-5-yl)-l,2,4-oκcadiazol-3-yl]-6azaspiro[2.5] octane-6-sulfonamide;

(1E)-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- 5 042108 azaspiro[2.5]octane-6 -sulfonamide;

(2R)-2-[5-(l-Cyclopropyl-4-methyl-lH-pyrazol-3-yl)-l,2,4-oκcadiazol-3-yl]-l,ldifluoro-6-azaspiro[2.5] octane-6-sulfonamide;

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

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

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

(2R)-2-{5-[l-Cyclopropyl-3-(τpiφtormethyl)-lH-pyrazol-5-yl]-l,2,4-oκcadiazol-3yl}-1,1-difluoro-6-azaspiro[ 2.5]octane-6-sulfonamide;

(2R)-2-[5-(2-Cyclopropyl-5-methylφenyl)-l,2,4-ocadiazol-3-yl]-l,l-diφτop-6azaspiro[2.5]octane-6-sulfonamide;

(2R)-2-[2-(3-Cyclopro-pylisocazol-4-yl)-l,3-ocazol-4-yl]-l,l-diφτop-6azaspiro[2.5]octane-6-sulfonamide;

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

(G)-1-[5-(2-Methylphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6sulfonamide;

(2R)-2-[5-(2,5-Dimethylφenyl)-l,2,4-oκcadiazol-3-yl]-l,l-diφτop-6azaspiro[2.5]octane-6-sulfonamide;

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

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

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

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

(2R)-l,l-Diφτop-2-(3-φenyl-l,2,4-oκcadiazol-5-yl)-6-azacpipo[2.5]oκtaan-6sulfonamide;

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

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

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

(2R)-l,l-Diφτop-2-[3-(3-φτopφenyl)-l,2,4-oκcadiazol-5-yl]-6-azacpipo[2.5]oκtan-6 sulfonamide;

(2R)-2-[3-(2,4-Difluorophenyl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-6 042108 azaspiro[2.5]octane-6-sulfonamide;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

- {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}-6azaspiro[2.5]octane-6-sulfonamide;

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

(1C)-1-[3-(3-Cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-6azaspiro[2.5]octane-6-sulfonamide;

(2C)-2-[3-(3-Cyclopropyl-5-methylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1- 7 042108 difluoro-6-azaspiro[2.5] octane-6-sulfonamide;

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

(2R)-l,l-Diφτop-2-[3-(2-methylpyridin-3-yl)-l,2,4-ocadiazol-5-yl]-6azaspiro[2.5]octane-6-sulfonamide;

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

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

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

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

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

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

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

(2R)-2-{3-[3-Cyclopropyl-5-(τpiφtormethyl)isoκcazol-4-yl]-l,2,4-oκcadiazol-5yl}-1,1-difluoro-6-azaspiro[2.5]octane -6-sulfonamide;

(2R)-2-{3-[5-Cyclopropyl-3-(τpiφtormethyl)isoκcazol-4-yl]-l,2,4-oκcadiazol-5yl}-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}-6azaspiro[2.5]octane-6-sulfonamide;

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

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

(G)-1-[5-(2-Cyanophenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6sulfonamide;

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

(1 R)-l-{5-[4-(Triφτopmethyl)φenyl]-l,2,4-oκcadiazol-3-yl }-6-azaspiro[2.5]octane-6sulfonamide;

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

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

(III)-1-(5-Phenyl-1,2,4-oxadiazol-3-yl)-6-azaspiro[2.5]octane-6-sulfonamide;

- 8 042108 (1C)-1-{5-[2-(Difluoromethoxy)-4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6azaspiro[2.5]octane-6-sulfonamide;

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

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

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

(1K)-1-[5-(4-Methoxyphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6sulfonamide;

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

(1C)-1-[5-(2,4-Difluorophenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6sulfonamide;

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

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

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

(1K)-1-[5-(2,4-Dimethylphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6sulfonamide;

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

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

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

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

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

(lR)-l-[5-(2,4,5-Trimethylphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6sulfonamide;

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

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

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

- 9 042108 (1B)-1-[5-(2-Methylpyridin-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6sulfonamide;

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

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

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

(1K)-1-[5-(2,6-Dimethylbenzyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6sulfonamide;

(1B)-1-[5-(3-Methylcyclohexyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6sulfonamide;

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

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

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

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

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

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

(lR)-l-(5-{1-[3-(Trifluoromethyl)phenyl]cyclopropyl}-1,2,4-oxadiazol-3-yl)-6azaspiro[2.5]octane-6-sulfonamide;

(III)-1-[5-(3-Phenylcyclobutyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6sulfonamide;

(III)-1-[5-(3,6-Dimethylpyridin-2-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane 6-sulfonamide;

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

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

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

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

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

- 10 042108 (Sh)-1-{5-[1-(2,2,2-Trifluoroethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}-6azaspiro[2.5 ]octane-6-sulfonamide;

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

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

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

(III)-1-[5-(3-Cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-3-yl]-6azaspiro[2.5]octane-6-sulfonamide;

(III)-1-[5-(4,5-Dimethylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl]-6azaspiro[2.5]octane-6-sulfonamide;

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

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

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

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

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

(2R)-2-{5-[2-(Cyclopropyloxy)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro6-azaspiro[2.5]octane-6-sulfonamide ;

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

(2R)-2-[5-(l-τpet-Butyl-lH-pyrazol-5-yl)-l,2,4-oκcadiazol-3-yl]-l,l-diφtorop-6azaspiro[2.5]octane- 6-sulfonamide;

(2R)-1,1 - Difluoro-2-[5-(3-methylimidazo[1,2-a]pyride in-7-yl)-1,2,4-oxadiazol-3-yl] 6-azaspiro [2.5]octane-6-sulfonamide;

(2R)-2-[5-(3-Cyclopropyl-l-ethyl-lH-pyrazol-4-yl)-l,2,4-oxadiazol-3-yl]-l,ldifluoro-6-azaspiro[2.5] octane-6-sulfonamide;

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

(2R)-2-{5-[l-τpet-Butyl-5-(τpiφtormethyl)-lH-pyrazol-4-yl]-l,2,4-oκcadiazol-3yl}-1,1-difluoro-6- azaspiro[2.5]octane-6-sulfonamide;

(2R)-l,l-Diφτop-2-[5-(4,5,6,7-teτpahydropyrazolo[l,5-a]pyridin-3-yl)-l,2,4oxadiazol-3-yl] - 6-azaspiro[2.5]octane-6-sulfonamide;

(2R)-2-[5-(l-Cyclopropyl-4-methyl-lH-pyrazol-5-yl)-l,2,4-oκcadiazol-3-yl]-l,ldifluoro-6-azaspiro[2.5] octane-6-sulfonamide;

- 11 042108 (2R)-2-[5-(5,6-Dihydro-4H-pyrpolo[l,2-b]pyrazol-3-yl)-l,2,4-oκcadiazol-3-yl]-l ,ldifluoro-6-azaspiro[2.5]octane-6-sulfonamide;

(2R)-l,l-Diφτop-2-[5-(l-methyl-lH-pyrazol-5-yl)-l,2,4-oκcadiazol-3-yl]-6azaspiro[2.5]octane-6- sulfonamide;

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

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

(2R)-2-{5-[l-Cyclopropyl-5-(τpiφtormethyl)-lH-pyrazol-3-yl]-l,2,4-oκcadiazol-3yl}-1,1-difluoro-6-azaspiro[ 2.5]octane-6-sulfonamide;

(2R)-2-[5-(2-Cyclopropyl-4,5,6,7-teτpahydro-2H-indazol-3-yl)-l,2,4-oκcadiazol-3yl] -1,1 - difluoro- 6-azaspiro[2.5]octane-6-sulfonamide;

(2R)-2-{5-[l-Cyclopropyl-4-(τpiφtormethyl)-lH-pyrazol-5-yl]-l,2,4-oκcadiazol-3yl}-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-6azaspiro[2.5]octane-6-sulfonamide;

(III)-1-[5-(3-Cyclopropylpyridazin-4-yl)-1,2,4-oxadiazol-3-yl]-6azaspiro[2.5]octane-6-sulfonamide;

(2R)-l,l-Diφτop-2-{5-[2-(propan-2-yloκci)pyridin-4-yl]-l,2,4-oκcadiazol-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]-6azaspiro[2.5]octane-6-sulfonamide;

(2R)-l,l-Diφτop-2-[5-(4H-pyrazolo[l,5-c][l,3]thiazol-3-yl)-l,2,4-oκcadiazol-3-yl] 6-azaspiro[2.5]octane-6-sulfonamide;

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

(2R)-2-{5-[3-Cyclopropyl-5-(τpiφtormethyl)isoκcazol-4-yl]-l,2,4-oκcadiazol-3yl}-1,1-difluoro-6-azaspiro[2.5]octane -6-sulfonamide;

(2R)-l,l-Diφτop-2-[5-(pyridin-3-yl)-l,2,4-oκcadiazol-3-yl]-6-azacpipo[2.5]oκtaan6-sulfonamide;

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

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

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

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

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

- 12 042108 (Sh)-1-{5-[1-(Propan-2-yl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-6azaspiro[2.5]octane -6-sulfonamide;

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

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

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

(2R)-l,l-DiφΊΌp-2-[5-(2-methyl-4,5,6,7-teτpahydro-2H-indazol-3-yl)-l,2,4oxadiazol-3-yl] - 6-azaspiro[2.5]octane-6-sulfonamide;

(2R)-l,l-Diφτop-2-[5-(pyridin-2-yl)-l,2,4-oκcadiazol-3-yl]-6-azacpipo[2.5]oκtaan6-sulfonamide;

(2R)-l,l-Diφτop-2-{5-[3-(τpiφtormethyl)isoκcazol-4-yl]-l,2,4-oκcadiazol-3-yl}-6azaspiro[2.5]octane-6-sulfonamide ;

(lR)-l-[5-(2,3-Dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-3-yl]-6azaspiro[2.5]octane-6-sulfonamide;

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

(III)-1-[5-(2-Phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6sulfonamide;

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

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

(III)-1-[5-(4'-Fluoro-biphenyl-3-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6sulfonamide;

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

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

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

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

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

(III)-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}-6azaspiro[2.5]octane-6-sulfonamide;

- 13 042108 (IRj-1-(5-(2,5-Difluorophenyl)-1,3,4-thiadiazol-2-yl]-6-azaspiro[2.5]octane-6sulfonamide;

(1C)-1-[5-(5-Fluoro-2-methylphenyl)-1D4-oxadiazol-2-yl]-6-azaspiro[2.5]octane-6sulfonamide;

(lR)-l-{5-(2-(2,2,2-Trifluoroethoxy)phenyl]-1,3,4-oxadiazol-2-yl(-6azaspiro[2.5]octane-6-sulfonamide;

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

(III)-1-[5-(2-Methylphenyl)-1,3,4-thiadiazol-2-yl]-6-azaspiro[2.5]octane-6sulfonamide;

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

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

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

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

(2R)-l,l-Diφτop-2-[5-(2-methylφenyl)-l,3,4-oκcadiazol-2-yl]-6-azacpipo[2.5]oκtaan6-sulfonamide;

(2R)-l,l-Diφτop-2-[5-(2-methylφenyl)-l,3,4-thiadiazol-2-yl]-6-azacpipo[2.5]oktaan-6 sulfonamide;

(III)-1-(4-Phenyl-1,3-oxazol-2-yl)-6-azaspiro[2.5]octane-6-sulfonamide;

(III)-1-[2-(3-Cyclopropylisoxazol-4-yl)-1,3-thiazol-4-yl]-6-azaspiro[2.5]octane-6sulfonamide;

(lR)-l-[1-(3,5-Dimethylisoxazol-4-yl)-1H-pyrazol-4-yl]-6-azaspiro[2.5]octane-6sulfonamide;

(2R)-2-[2-(3-Cyclopropylizocazol-4-yl)-l,3-thiazol-4-yl]-l,l-diφτop-6azaspiro[2.5]octane-6-sulfonamide;

(2R)-2-{3-[2-(Diφτopmetoκci)pyridin-4-yl]isoκcazol-5-yl}-l,l-diφτop-6azaspiro[2.5]octane-6-sulfonamide;

(2R)-2-[4-(3-Cyclopropylisoxazol-4-yl)-1-methyl-1H-imidazol-2-yl]-1,1-difluoro6-azaspiro[2.5]octane-6-sulfonamide;

(2R)-2-(3 ^, -Cyclopropyl-3,4 ^, -biisoκcazol-5-yl)-l,l-diφtorop-6-azacpipo[2.5]oκtaan-6sulfonamide;

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

(18)-1-[3-(5-Chloro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6sulfonamide;

(28)-1,1-Difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6- 14 042108 azaspiro[2.5]octane -6-sulfonamide;

(28)-2-(3-Cyclohexyl-1,2,4-oxadiazol-5-yl)-1,1-difluoro-6-azaspiro[2.5]octane-6sulfonamide;

(28)-1,1-Difluoro-2-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6sulfonamide;

(28)-1,1-Difluoro-2-[5-(2-methylphenyl)-1,3,4-oxadiazol-2-yl]-6-azaspiro[2.5]octane 6-sulfonamide;

(2K)-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-6azaspiro[2.5]octane-6-sulfonamide;

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

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

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 } -6azaspiro[2.5]octane-6-sulfonamide ;

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

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

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

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

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

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

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

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

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

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

1,1,4-Trifluoro-2- {3-[4-fluoro-2-(trifluoromethyl)phenyl] -1,2,4-oxadiazol-5-yl } -6- 15 042108 azaspiro[2.5]octane-6 -sulfonamide;

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

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

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

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

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

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

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

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

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

3'-[5-(2,5-Dimethylphenyl)-1,2,4-oxadiazol-3-yl]-2',2'-difluoro-3azaspiro[bicyclo[3.2.1]octane-8,G-cyclopropane ]-3-sulfonamide; And

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

Other embodiments of the present invention include the following.

(a) A pharmaceutical composition containing a compound of formula I or II and a pharmaceutically acceptable carrier.

(b) The pharmaceutical composition of paragraph (a), further comprising a second therapeutic agent selected from the group consisting of acetylcholinesterase inhibitors such as donepezil, rivastigmine and galantamine; NMDA receptor antagonists such as memantine; beta-secretase inhibitors such as verubecestat and AZD3293; M4 mAChR or PAMs agonists; 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.

(c) The pharmaceutical composition of paragraph (b), wherein the second therapeutic agent is an antipsychotic agent selected from the group consisting of clozapine, olanzapine, risperidone, aripiprazole, quetiapine, haloperidol, loxapine, thioridazine, molindone, thiothixene, fluphenazine, mesoridazine, trifluoperazine, chlorpromazine and perphenazine.

(d) A pharmaceutical combination which is (i) a compound of formula I or II and (ii) a second therapeutic agent selected from the group consisting of acetylcholinesterase inhibitors such as donepezil, rivastigmine and galantamine; NMDA receptor antagonists such as memantine; beta-secretase inhibitors such as verubecestat and AZD3293; M4 mAChR or PAMs agonists; 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, where the compound of formula I or II and the second therapeutic agent are used in an amount that makes the combination effective for the treatment of cognitive impairment associated with Alzheimer's disease, Parkinson's disease or schizophrenia.

(e) The combination of paragraph (d), wherein the second therapeutic agent is an antipsychotic agent selected from the group consisting of clozapine, olanzapine, risperidone, aripiprazole, quetiapine, haloperidol, loxapine, thioridazine, molindone, thiothixene, fluphenazine, mesoridazine, trifluoperazine , chlorpromazine and perphenazine.

(f) The use of a compound of formula I or II for the preparation of a medicament for modulating α7 nAChR activity in a subject in need thereof.

(g) The use of a compound of formula I or II for the preparation of a medicament for the treatment of cognitive impairment associated with Alzheimer's disease, Parkinson's disease and schizophrenia in a subject in need thereof.

- 16 042108 (h) A method for 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, which comprises administering to the subject an effective amount of a compound of formula I or II.

(i) The method of paragraph (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 the group consisting of acetylcholinesterase inhibitors such as donepezil, rivastigmine and galantamine; NMDA receptor antagonists such as memantine; beta-secretase inhibitors such as verubecestat and AZD3293; M4 mAChR or PAMs agonists; mGluR2 antagonists or NAMs or PAMs; 5-HT6 antagonists such as idalopirdine, RVT-101, AVN-101, AVN322, SUVN-502 and SYN-120; histamine H3 receptor antagonists such as S38093; PDE4 inhibitors such as HT0712; PDE9 inhibitors such as BI40936; HDAC6 inhibitors; antipsychotics; LRRK2 inhibitors; MAO-B inhibitors; and levodopa.

(j) The method of paragraph (i), wherein the second therapeutic agent is an antipsychotic agent selected from the group consisting of clozapine, olanzapine, risperidone, aripiprazole, quetiapine, haloperidol, loxapine, thioridazine, molindone, thiothixene, fluphenazine, mesoridazine, trifluoperazine , chlorpromazine and perphenazine.

(k) A method for modulating α7 nAChR activity in a subject in need thereof, which comprises administering to the subject a pharmaceutical composition of paragraph (a), (b) or (c), or a combination of paragraph (d) or (e).

(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, which comprises administering to the subject a pharmaceutical composition under paragraph (a), (b) or (c), or a combination under paragraph (d) or (e).

For the compound and salt embodiments above, it is to be understood that each embodiment can be combined with one or more other embodiments to the extent that such combination produces a stable compound or salt and is consistent with the description of the embodiments. It is also to be understood that the embodiments of the compositions and methods set forth in paragraphs (a) to (l) above include all embodiments of the compounds and/or salts, including such embodiments that result from combinations of embodiments.

Additional embodiments of the present invention include the pharmaceutical compositions, combinations, uses and methods described in paragraphs (a) to (l) above, where the compound of the present invention used therein is a compound of one of the embodiments, objects, classes , subclasses or features of the compounds described above. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate, if appropriate.

The present invention also includes a compound of the present invention for use in (i), in (ii) as a medicament for, or (iii) for the preparation of a medicament for: (a) preventing or treating cognitive impairment associated with the disease Alzheimer's disease, Parkinson's disease, schizophrenia, and L-DOPA-induced dyskinesia, or (b) treating cognitive impairment associated with Alzheimer's disease, Parkinson's disease, schizophrenia, and L-DOPA-induced dyskinesia, and/or reducing the likelihood or severity of symptoms of cognitive impairment associated with Alzheimer's disease, Parkinson's disease, schizophrenia and L-DOPA induced dyskinesia, or (c) medical applications. In these uses, the compounds of the present invention may optionally be used in combination with one or more second therapeutic agents selected from the group consisting of acetylcholinesterase inhibitors such as donepezil, rivastigmine and galantamine; NMDA receptor antagonists such as memantine; beta-secretase inhibitors such as verubecestat and AZD3293; M4 mAChR or PAMs agonists; mGluR2 antagonists or NAMs or PAMs; 5-HT6 antagonists such as idalopirdin, RVT-101, AVN101, 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.

Chemical names, common names, and chemical structures can be used interchangeably to describe the same structure. If a chemical compound is indicated by both the chemical structure and the chemical name, and there is a conflict between the structure and the name, the structure is dominant. As used in the present invention, the term 5-membered heteroaryl ring means a stable, unsaturated 5-membered ring that contains 1 to 4 heteroatoms selected from O, N, and S. A 5-membered heteroaryl ring within the scope of this definition includes, but is not limited to: furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl and triazolyl.

- 17 042108

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

When used in the present invention, the term introduction and its variants (for example, the introduction of the connection) when referring to the connection proposed in the present invention, means the provision of compounds to an individual in need of treatment. When a compound of the present 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 include simultaneous and sequential administration of the compound or salt and other agents.

The term alkenyl means a linear or branched hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Up to 4 carbon-carbon double bonds may be present. Thus, C ₂ -C 6 -alkenyl means alkenyl radical containing from 2 to 6 carbon atoms. Thus, C ₂ -C ₄ -alkenyl means alkenyl radical containing from 2 to 4 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl, 3-methylbutynyl, and the like. In one embodiment, the alkenyl group is linear. In another embodiment, the alkenyl group is branched.

The term alkyl means an aliphatic hydrocarbon group in which one of its hydrogen atoms has been replaced by a bond. The alkyl group may be linear or branched. The alkyl group contains 1 to 8 carbon atoms [(C1-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 t-butyl. In one embodiment, the alkyl group is linear. In another embodiment, the alkyl group is branched.

When alkyl is substituted, said alkyl includes alkyl, O-alkyl, S-alkyl and (C=O)-alkyl.

The term alkynyl means a linear or branched hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Up to 3 carbon-carbon triple bonds may be contained. Thus, C ₂ -C ₆ alkynyl means an alkynyl radical containing from 2 to 6 carbon atoms. Thus, C ₂ -C ₄ alkynyl means an alkynyl radical containing from 2 to 4 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like. In one embodiment, the alkynyl group is linear. In another embodiment, the alkynyl group is branched.

The term aryl means any mono- and polycarbocyclic ring systems in which the individual carbocyclic rings in the polycyclic systems are fused or attached to each other via a single bond and in which at least one ring is aromatic. Suitable aryl groups include phenyl, indanyl, naphthyl, tetrahydronaphthyl and biphenyl. Aryl ring systems may include, if appropriate, an indication of the variable to which the particular ring atom is attached. Unless otherwise indicated, substituents on aryl ring systems may be attached to any ring atom, provided that such attachment results in the formation of a stable ring system.

In one embodiment, aryl is phenyl.

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

The term composition includes a product containing the specified ingredients, as well as any product that is formed by combining the specified ingredients.

The term compound includes the chemical reagents described by the generic formula I or II, in all forms. Such chemicals may be in various forms such as hydrates, solvates and polymorphs.

The term cycloalkyl as used in the present invention means any non-aromatic mono- and polycarbocyclic ring systems containing from 3 to 10 ring carbon atoms [(C ₃ -C ₁₀ )cycloalkyl] or from 3 to 6 ring carbon atoms [(C ₃ -C ₆ )cycloalkyl], where individual carbocyclic rings in polycyclic systems are fused, including spiro-rings, or attached 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 atom of a cycloalkyl group may be functionalized to form a carbonyl group. An illustrative example of such a cycloalkyl group (also referred to herein as a cycloalkanoyl group) includes, but is not limited to, cyclobutanoyl

- 18 042108

When cycloalkyl is substituted, said cycloalkyl includes cycloalkyl, Ocycloalkyl, and (C=O)-cycloalkyl.

In one embodiment, cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term effective amount as used in the present invention means that amount of active compound or pharmaceutical agent that provides a biological or medical response in a tissue, system, animal or human, which is expected by the researcher, veterinarian, physician or other clinician. In one embodiment, the effective amount is a therapeutically effective amount for alleviating one or more symptoms of the disease or condition being treated. In another embodiment, the effective amount is a prophylactically effective amount to reduce the severity or likelihood of one or more symptoms of a disease or condition. In the present invention, the term also includes an amount of active compound sufficient to modulate α7 nAChR activity and thereby provide the desired response (ie, a therapeutically effective amount). When the active compound (ie the active ingredient) is administered as a salt, an indication of the amount of the active ingredient is an indication of the free acid or free base form of the compound.

The term halogen refers to the atoms of fluorine, chlorine, bromine, and iodine (alternatively referred to as fluorine (F), chlorine (Cl), bromine (Br), and iodine (I)).

The term heteroaryl as used in the present invention means any monocyclic or polycyclic ring system containing from 5 to 14 ring atoms, where from 1 to 4 ring atoms are independently O, N or S and the remaining ring atoms are carbon atoms, and where at least one ring is aromatic. In one embodiment, the heteroaryl group contains 5 to 10 ring atoms. In another embodiment, the heteroaryl group is monocyclic and contains 5 or 6 ring atoms. In another embodiment, the heteroaryl group is bicyclic and contains 9 or 10 ring atoms. The heteroaryl group is usually attached via a ring carbon atom, but may be attached via a non-carbon atom, provided that this gives a stable connection, and any heteroaryl nitrogen atom may optionally be oxidized to the corresponding Noxide. The term heteroaryl also includes a heteroaryl group as defined above which is fused to a benzene ring. The term heteroaryl also includes 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 9-10 membered bicyclic heteroaryl includes a non-aromatic 5-membered heterocyclic ring that is fused to a benzene or pyridyl ring. Non-limiting examples of heteroaryls include benzimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolzazinyl, indazolyl, isobenzofuranyl, isoindolyl, iso-pyrazolyl, iso-pyrazolyl, оксадиазолил, оксазолил, пиразинил, пиразолил, пиридазинил, пиридопиридинил, пиридазинил, пиридил, пиримидил, пирролил, хиназолинил, хинолил, хиноксалинил, тетразолил, тетразолопиридил, тиадиазолил, тиазолил, тиенил, триазолил, дигидробензимидазолил, дигидробензофуранил, дигидробензотиофенил, дигидробензоксазолил, дигидроиндолил, дигидрохинолинил, methylenedioxybenzoyl and the like, and all isomeric forms thereof. The term heteroaryl also means partially saturated heteroaryl moieties such as, for example, tetrahydrisoquinolyl, tetrahydroquinolyl and the like, provided that 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 includes a 5-6 membered heteroaryl group fused to a benzene ring.

In one embodiment, heteroaryl is benzimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoxathiazolyl, isoxathiazolyl , naphthpyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl or triazolyl.

In another embodiment, heteroaryl is carbazolyl, carbolinyl, cin

- 19 042108 nolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolzazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyridyl, pyridyl , quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl or triazolyl.

In another embodiment, heteroaryl is furanyl, imidazolyl, indolinyl, indolyl, indolzazinyl, indazolyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl.

The term heterocycle or heterocyclyl as used in the present invention means a 310-membered non-aromatic heterocycle containing from 1 to 4 heteroatoms selected from O, N and S and includes monocyclic or bicyclic groups (fused, bridged or spirocyclic). 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, dihydroisooxazolyl, dihydroisothiazolyl, dihydroisothiazolyl , dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, tetrahydrofuranyl and tetrahydrothienyl, and their N-oxides. The attachment of the heterocyclyl substituent may be at the carbon atom or at the heteroatom.

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

In one embodiment, the heterocycle or heterocyclyl is dihydrofuranyl, dihydroimidazolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, or tetrathiofuranyl.

Pharmaceutically acceptable means that the ingredients of the pharmaceutical composition must be compatible with each other and not harmful to its recipient.

The term prevention when used in the present invention for Alzheimer's disease or other neurological diseases means to reduce the likelihood of progression of the disease.

The term subject (alternatively referred to in the present invention as a patient) as used in the present invention means an animal, preferably a mammal, most preferably a human.

The term "substituted" means that one or more hydrogen atoms of the specified atom is replaced with a choice from the specified group, provided that, under existing circumstances, the normal valence of the specified atom is not exceeded and that the substitution gives a stable connection. Unless explicitly stated otherwise, substitution with the indicated substituent is permitted only if the substitution for any atom is chemically possible and results in a stable compound. Combinations of substituents and/or variables are only allowed if such combinations give stable compounds. A stable compound is a compound that can be prepared and isolated and whose structure and characteristics remain or can be made substantially unchanged for a period of time sufficient for the compound to be used for the purpose of the present invention (e.g., therapeutic or prophylactic administration to a subject).

In another embodiment of formula IX is S(O) ₂ .

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

In another embodiment of the formula, IR ¹ means NR ^a R ^b .

In another embodiment of the formula, IR ¹ means R ^c .

In another embodiment of formula IR ^a is H, (C1-C4) alkyl or (C ₃ -C ₆ ) cycloalkyl, wherein said alkyl is optionally substituted with phenyl, pyridinyl or isothiazolyl.

In another embodiment of formula IR ^a is H or (C ₁ -C 4 )alkyl.

In another embodiment of formula IR, ^a is H or methyl.

In another embodiment of formula IR, ^a is H.

In another embodiment of formula IR, ^b is H or methyl.

In another embodiment of formula IR, ^b is H.

In another embodiment of formula IR, ^c is (C ₁ -C 4 )alkyl wherein said thienyl, pyrazolyl, benzoxadiazolyl and oxadiazolyl are optionally substituted with one or more methyl or hydroxyls and wherein said alkyl is optionally substituted with pyridinyl, tetrahydropyranyl, isothiazolyl or phenyl.

In another embodiment of formula IR, ^c is methyl.

In another embodiment of the formula IXR ¹ means -(C=O)-R ¹ .

- 20 042108

In another embodiment of formula IXR ¹ means

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.

In another embodiment of formula I or II, A (or ring A) is oxadiazolyl, thiazolyl, pyrazolyl, thiadiazolyl, oxazolyl, isoxazolyl, or imidazolyl.

In another embodiment of formula I or II, A (or ring A) is oxadiazolyl, thiazolyl, oxazolyl, pyrazolyl, isoxazolyl, or thiadiazolyl.

In another embodiment of formula I or II, A (or ring A) is oxadiazolyl, oxazolyl, isoxazolyl, or thiazolyl.

In another embodiment of Formula I, the R groups are selected from OH, oxo, NR ⁶ R ⁷ , CN, alkoxy, halogen, aminoalkyl, hydroxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein said R groups are selected from alkyl , alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl further optionally substituted with one or more substituents independently selected from R ¹¹ .

In another embodiment, the formula I groups R are independently selected from NR ⁶ R ⁷ , CN, (CiC4)alkoxy, halogen, (C ₁ -C4)alkyl, (C ₃ -C8)cycloalkylα, phenyl, indanyl, tetrahydronaphthalenyl, pyrazolyl, pyridinyl , оксазолила, изоксазолила, тетрагидроциклопентапиразолила, имидазопиридинила, индолила, тетрагидропиразолопиридинила, дигидропирролопиразолила, пиридазинила, пиразолотиазолила и пиперидинила, где указанная алкоксигруппа, алкил, циклоалкил, инданил, тетрагидронафталинил, пиразолил, пиридинил, оксазолил, изоксазолил, тетрагидроциклопентапиразолил, имидазопиридинил, индолил, тетрагидропиразолопиридинил, дигидропирролопиразолил , pyridazinyl, pyrazolothiazolyl and piperidinyl are optionally substituted with one or more substituents independently selected from R ¹¹ .

In another embodiment of formula IR is selected from (C ₃ -C ₈ )cycloalkyl, phenyl, indanyl, tetrahydronaphthalenyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, tetrahydrocyclopentapyrazolyl, imidazopyridinyl, indolyl, tetrahydropyrazolopyridinyl, dihydropyrrolopyrazolyl, pyridazinyl, pyrazolothiazolyl and piperidinyl, each optionally substituted with one or more substituents independently selected from R ¹¹ .

In another embodiment of the formula, IR is cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazolyl, pyridinyl, or isoxazolyl, each optionally substituted with one or more substituents independently selected from F, Cl, Br, methyl, methoxy, ethyl, ethoxy, propyl, CF3, CH2CF3, OCH ₃ , OCHF2, OCH2CF3, cyclopropyl, NR ⁶ R ⁷ and CN.

In another embodiment of formula IR is selected from phenyl, pyrazolyl, pyridinyl and isoxazolyl, wherein said phenyl, pyrazolyl, pyridinyl and isoxazolyl are optionally substituted with one or more substituents 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.

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

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

In another embodiment of Formula I, n is 0.

In another embodiment of formula IR ² is independently halogen or (C ₁ -C 4 )alkyl, wherein said alkyl is optionally substituted with one or more halogens; or two R ² if both are (C ₁ -C 4 )alkyl and are attached to the same carbon atom, may optionally together form a cyclopropyl, cyclobutyl or cyclopentyl ring or if both are (C ₁ -C ₄ )alkyl and are not attached to the same carbon atom, may optionally together form a bridged ring, wherein said cyclopropyl, cyclobutyl, cyclopentyl or bridged ring may optionally be substituted with one or more substituents independently selected from OH, halogen or (C ₁ -C ₄ )alkyl.

In another embodiment of formula IR ² is independently halogen, methyl or ethyl, wherein said methyl or ethyl is optionally substituted with one or more halogens; or two R ² , if both are methyl or ethyl and are attached to the same carbon atom, optionally may together form a cyclopropyl, cyclobutyl or cyclopentyl ring or, if both are methyl or ethyl and are not attached to the same carbon atom, optionally may together form a bridged ring .

In another embodiment of formula IR ² is F or methyl.

In another embodiment of formula I or II, R ³ means H, F or methyl.

In another embodiment of formula I or II, R ⁴ is H, F or methyl.

- 21 042108

In another embodiment of Formula I or II, R ³ and R ⁴ may optionally together form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring, wherein said ring may optionally be substituted with one or more substituents independently selected from OH, halo, or (C ₁ - C ₄ )alkyl.

In another embodiment of formula I or II, R ³ and R ⁴ may optionally together form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

In another embodiment of formula IR ⁵ is H or methyl.

In another embodiment of the formula, IR ⁵ is H.

In another embodiment of formula IR ⁶ is H or Me.

In another embodiment of the formula, IR ⁷ is H or Me.

In another embodiment of formula IR ⁸ is OH, (C ₁ -C ₄ )alkyl, phenyl, pyridinyl or isothiazolyl.

In another embodiment of formula IR ⁸ is phenyl, pyridinyl or isothiazolyl.

In another embodiment of formula IR ⁹ is pyridinyl, tetrahydropyranyl or phenyl.

In another embodiment of formula IR ¹⁰ is methyl or hydroxyl.

In another embodiment of formula IR ¹¹ is halo, OH, oxo, CF3, OCF3, CN, (C1-C4)alkyl, O(C1-C4)alkyl, S(C1-C4)alkyl, C=O(CrC4)alkyl , NR ¹² R ¹³ , (C=O)NR ⁶ R ⁷ , (C=O)OR ⁶ , (C2-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 said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally independently substituted with one or more halogens, (C1-C ₄ )alkyls, (C ₃ -C ₆ )cycloalkyls, CF ₃ , OCF3, OCH3, CN, OH and oxo.

In another embodiment of formula IR ¹¹ is F, Cl, Br, OH, NR ¹² R ¹³ , CF ₃ , OCF ₃ , CN, (C1-C ₄ )alkyl, O(C1-C ₄ )alkyl, (C ₃ - C ₆ )cycloalkyl, O(C ₃ -C ₆ )cycloalkyl, phenoxy, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl or imidazolyl, wherein said alkyl, cycloalkyl, phenoxy, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl and imidazolyl are optionally substituted with one or more substituents independently selected from halogen, (C1-C ₄ )alkyl, CN and OH, wherein said alkyl is optionally substituted with one or more fluorine atoms.

In another embodiment of formula IR ¹¹ is F, Cl, Br, OH, NR ¹² R ¹³ , CF ₃ , OCF ₃ , CN, (C1-C ₄ )alkyl, O(C1-C ₄ )alkyl, (C ₃ - C ₆ )cycloalkyl, O(C ₃ -C ₆ )cycloalkyl, phenoxy, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl or imidazolyl, wherein said alkyl, cycloalkyl, phenoxy, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl and imidazolyl are optionally substituted with one or more substituents independently selected from halogen, (C1-C ₄ )alkyl, CN and OH, wherein said alkyl is optionally substituted with one or more fluorine atoms.

In another embodiment of formula IR ¹¹ is F, Cl, Br, methyl, methoxy, ethyl, ethoxy, propyl, Cf ₃ , CH ₂ Cf ₃ , OCH ₃ , OCHF2, OCH2CF3, cyclopropyl, NR ¹² R ¹³ or CN.

In another embodiment of formula IR ¹¹ is 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 or cyclopropyl.

In another embodiment of formula IR ¹² is H or (C1-C ₄ )alkyl.

In another embodiment of formula IR ¹³ is H or (C1-C ₄ )alkyl.

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

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

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

In compounds of formula I or II, the atoms may be characterized by their natural abundance of isotopes, 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 occurring in nature. . The present invention includes all suitable isotopically substituted variants of the compounds of formula I or II. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium ( ^2H or D). Protium is the predominant isotope of hydrogen found in nature. Enrichment with deuterium may provide some therapeutic benefits, such as increased in vivo half-life or the ability to use lower doses, or may provide a compound useful as a standard for the characterization of biological samples. Isotopically enriched compounds of formula I or II can be prepared without extensive experimentation by conventional procedures well known to those skilled in the art, or by procedures analogous to those described in the Schemes and Examples of the present invention, using suitable isotopically enriched reagents and/or intermediates. products.

Unless explicitly stated otherwise, all ranges referred to in the present invention are inclusive. For example, a heteroaryl ring described as having 1 to 3 heteroatoms means that the ring may contain 1, 2, or 3 heteroatoms. It should also be understood that any range specified in the present invention includes within its scope all subranges of this range. Oxidized forms of the N and S heteroatoms are also included within the scope of the present invention.

- 22 042108

One skilled in the art will understand that carbon atoms in organic molecules can often be replaced by silicon atoms to form similar stable compounds. For example, carbon atoms in alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl groups can often be replaced by silicon atoms to form stable compounds. All such compounds are included within the scope of the present invention.

If any variable (e.g. R) occurs more than once in any component or formula I or any other formula depicting and describing the compounds of the present invention, its definition in each instance is independent of its definition in each other instance. . In addition, combinations of substituents and/or variables are allowed only if such combinations give stable compounds.

Some of the compounds of the present invention may contain asymmetric centers and may exist as mixtures of stereoisomers, or as single diastereoisomers or enantiomers. All isomeric forms of these compounds, whether isolated or in mixtures, are within the scope of the present invention.

Some of the compounds of the present invention may exist as tautomers. For purposes of the present invention, a reference to a compound of formula I or II is a reference to the compound itself, or to any of its tautomers, or to a mixture of two or more tautomers.

The compounds of the present invention can be used to prevent, treat or improve the course of Alzheimer's disease. The compounds can also be used to prevent, treat or ameliorate other α7 nAChR mediated diseases such as schizophrenia, sleep disorders, Parkinson's disease, autism, microdeletion syndrome, inflammatory diseases, pain disorders (including acute pain, inflammatory pain and neuropathic pain) and cognitive impairment (including mild cognitive impairment). Other pathological conditions that can be prevented, treated or ameliorated by the compounds of the present invention include pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, trisomy 21 (Down's syndrome), amyloid angiopathy of the brain , degenerative dementia, hereditary cerebral hemorrhage with dutch-type amyloidosis (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, myositis with included bodies, other peripheral amyloidoses, diabetes , kidney disease, cancer and atherosclerosis.

In preferred embodiments, the compounds of the present invention can be used to prevent, treat or improve Alzheimer's disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders. For example, the compounds can be used to prevent dementia of the Alzheimer's disease type, as well as to treat early, intermediate, or advanced dementia of the Alzheimer's disease type.

Potential schizophrenic pathological conditions or disorders for which the compounds of the present invention may be used include one or more of the following pathological conditions or diseases: schizophrenia or psychosis, including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophrenia-like disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, induced psychotic disorder, psychotic disorder due to a general health condition and substance-related or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and cocaine) psychotic disorder, psychosis associated with affective disorders , brief reactive psychosis, schizoaffective psychosis, schizophrenia spectrum disorders such as schizoid or schizotypal personality disorders, or illnesses associated with 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 impairment, including dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular or stroke problems, HIV, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, perinatal hypoxia, other general medical conditions, or alcohol abuse or drugs) delirium, amnestic disturbances, or age-related cognitive decline.

Thus, in another preferred embodiment, the present invention relates to a method of preventing, treating or improving the course of schizophrenia or psychosis, comprising administering to a patient in need thereof an effective amount of a compound of the present invention. The current revised text of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) includes a diagnostic tool that includes paranoid, disorganized

- 23 042108 new, catatonic or undifferentiated schizophrenia and substance abuse-induced psychotic disorder. When used in the present invention, the term schizophrenia or psychosis includes the treatment of such mental disorders as described in the DSM-IV-TR. One skilled in the art should understand that there are alternative nomenclatures, nosologies, and classification systems for mental disorders, and that these systems change as medicine and science advance. Thus, the term schizophrenia or psychosis includes similar disorders that are described in other diagnostic sources.

Potential sleep conditions or disorders for which the compounds of the present invention may be used include improved sleep quality; improving the quality of sleep; increased sleep maintenance; increasing the ratio of the amount of time the subject sleeps to the amount of time the subject tries to sleep; reducing the duration of falling asleep or the time before falling asleep (the time when he falls asleep); reduction of difficulty in falling asleep; increasing the duration of uninterrupted sleep; reducing the number of awakenings during sleep; reduction in the number of night awakenings; reduction of time from initial falling asleep to awakening; increase in total sleep duration; reduced fragmentation of sleep; changing the timing, frequency, or duration of the number of REM (REM) episodes; change in timing, frequency, or duration of the number of non-REM sleep episodes (i.e., stages 3 or 4); increasing the duration and relative duration of stage 2 sleep; stimulation of slow sleep; increased EEGdelta activity during sleep; increase in daily activity; reduction of daytime sleepiness; treatment or reduction of excessive daytime sleepiness; insomnia; hypersomnia; narcolepsy; sleep interruption; sleep apnea; insomnia; nocturnal myoclonus; interruption of REM episodes; violation of the daily rhythm of the body; displacement of sleep disorders in workers; dyssomnias; night fears; insomnia associated with depression; emotional/mood disorders; as well as somnambulism and bedwetting; and age-related sleep disorders; evening exacerbation of Alzheimer's disease; pathological conditions associated with the circadian rhythm, as well as mental and physical disorders associated with the intersection of time zones and with a sliding work schedule; pathological conditions due to drugs that reduce REM as a side effect; syndromes that are accompanied by non-restoration of sleep and muscle pain or sleep apnea, which is associated with respiratory disorders during sleep; and pathological conditions that lead to poor sleep quality.

Pain disorders for which the compounds of the present invention can be used include neuropathic pain (such as postherpetic neuralgia, nerve damage, dynia, e.g., vulvodynia, phantom pain in amputees, tooth avulsion, painful diabetic neuropathy, painful traumatic mononeuropathy , painful polyneuropathy); central pain syndromes (potentially caused by almost any lesion at any level of the nervous system); postoperative pain syndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stump pain); pain in bones and joints (osteoarthritis); recurring pain on movement toothache; cancer pain; myofascial pain (muscle damage, fibromyalgia); perioperative pain (general surgery, gynecological); chronic pain; dysmenorrhea as well as pain associated with angina pectoris and inflammatory pain of various etiologies (eg osteoarthritis, rheumatoid arthritis, rheumatic disease, tenosynovitis and gout); headache; migraine and severe paroxysmal headache with periodic relapses; primary hyperalgesia; secondary hyperalgesia; primary allodynia; secondary allodynia; or other pain caused by central sensitization.

Potential conditions or disorders that include a strong inflammatory component for which the compounds of the present invention can be used include one or more of the following conditions or diseases: diabetes (systemic inflammation in diabetes, manifested by an increase in blood levels of cytokines, for example, IL-6 and TNFa, which can lead to insulin resistance); asthma; arthritis; cystic fibrosis; sepsis; ulcerative colitis; inflammatory bowel disease; atherosclerosis; neuroinflammation associated with neurodegenerative diseases (eg, 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).

The compounds of the present invention can also be used to prevent or treat or improve the course of dyskinesia and protect against neurodegeneration in nigrostriatal neurons in Parkinson's disease. In addition, the compounds of the present invention can be used to reduce tolerance to and/or dependence on opioid pain and withdrawal treatments such as alcohol, opioids and cocaine.

The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term pharmaceutically acceptable salt means a salt which has the efficacy of the parent compound and which is not biologically or otherwise undesirable.

- 24 042108 non-toxic (for example, non-toxic and otherwise harmful to its recipient). Suitable salts include acid addition salts, which can, for example, be prepared by mixing a solution of a compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Many of the compounds of the present invention contain an acid moiety, in which case suitable pharmaceutically acceptable salts thereof may include alkali metal salts (eg sodium or potassium salts), alkaline earth metal salts (eg calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of the presence of a carboxyl (-COOH) or hydroxy group, pharmaceutically acceptable esters can be used to modify the solubility or hydrolysis characteristics of the compound.

Typical acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates (mesylates), naphthalenesulfonates, nitrates, oxalates, phosphates , propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as tosylates), and the like. In addition, acids are generally considered suitable for the formation of pharmaceutically acceptable salts from basic pharmaceutical compounds, for example, see P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1):1-19; 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, D.C. on their website).

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

In order to prevent, treat or improve the course of cognitive impairment in Alzheimer's disease, Parkinson's disease, schizophrenia, L-DOPA-induced dyskinesia and inflammation, the compounds of the present invention, optionally in the form of a salt, can be administered by any means that provide interaction of the active agent with the position of exposure facilities. They can be administered by one or more conventional agents available for use with drugs, as single therapeutic agents, or in combination of therapeutic agents. They can be administered alone, but are usually administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice. The compounds of the present invention, for example, can be administered by one or more of the following routes: orally, parenterally (including subcutaneous injection, intravenous, intramuscular, epigastric injection or infusion techniques), by inhalation (for example, as a spray), or rectally, in the form of a single dose pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically acceptable carriers, excipients and diluents. Liquid preparations suitable for oral administration (e.g., suspensions, syrups, elixirs, and the like) can be prepared according to methods known in the art, and any of the usual means can be used, such as water, glycols, oils, alcohols, and etc. Solid preparations suitable for oral administration (e.g., powders, pills, capsules, and tablets) can be prepared by methods known in the art and solid excipients such as starches, sugars, kaolin, lubricants, binders, disintegrants can be used. agents, etc. Enteral compositions can be prepared according to methods known in the art and typically use sterile water as a carrier and optionally other ingredients such as solubility enhancers. Solutions for injection can be obtained by methods known in the art, where the carrier includes saline solution, glucose solution or a solution containing a mixture of saline and glucose. Additional descriptions of methods suitable for use in preparing the pharmaceutical compositions of the present invention and ingredients suitable for use in said compositions are provided in Remington's Pharmaceutical Sciences, ^18th edition (ed. AR Gennaro, Mack Publishing Co., 1990).

The compounds of the present invention may be administered orally at a dose in the range of 0.001 to 1000 mg/kg body weight per day to a mammal (eg, human) in a single dose or in divided doses. The single dose range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses. Another range of the value of one dose is from 0.1 to 100

- 25 042108 mg/kg of body weight per day orally in a single dose or in divided doses. For oral administration, the compositions may be provided in the form of a tablet or capsule containing 1.0 to 500 mg of the active ingredient, preferably 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400 and 500 mg of the active ingredient for symptomatic titration for the patient to be treated. The specific dosage and frequency of administration for any particular patient may vary and depend on various factors, including the activity of the particular compound used, the metabolic stability and duration of action of that compound, age, body weight, general health, sex, diet, route and time of administration, rate excretion, combination of drugs and the severity of a particular pathological condition.

As noted above, the present invention also relates to a method for preventing, treating or improving the course of cognitive impairment in Alzheimer's disease, Parkinson's disease, schizophrenia, caused by L-DOPA dyskinesia and inflammation with a compound of the present invention, in combination with one or more therapeutic agents and a pharmaceutical composition containing a compound of the present invention and one or more therapeutic agents selected from the group consisting of for the treatment of Alzheimer's disease, for example beta-secretase inhibitors; M1 mAChR or PAMs agonist; M4 mAChR or PAMs agonists; mGluR2 antagonists or NAMs or PAMs; ligands or activators ADAM 10; gammasecretase inhibitors such as LY450139 and TAK 070; gamma-secretase modulators inhibitors; tau phosphorylation; glycine transport inhibitors; LXR β agonists; conformational modulators ApoE4; NR2B antagonists; androgen receptor modulators; blockers of the formation of Av oligomer; 5-HT4 agonists such as PRX-03M0; 5-HT6 antagonists such as GSK 742467, SGS-518, FK-962, SL-65.0155, SRA-333 and xaliproden; 5-HT1a antagonists such as lecozotan; p25/CDK5 inhibitors; NK1/NK3 receptor antagonists; COX-2 inhibitors; inhibitors; LRRK2 inhibitors; HMG-CoA reductase inhibitors; NSAIDs including ibuprofen; vitamin E; antibodies to amyloids (including humanized monoclonal antibodies to amyloids) such as bapineuzumab, ACC001, CAD106, AZD3102, H12A11V1; anti-inflammatory compounds such as (R)-flurbiprofen, nitroflurbiprofen, ND1251, VP-025, HT-0712 and UNT-202; PPAR gamma agonists such as pioglitazone and rosiglitazone; CB-1 receptor antagonists or CB-1 receptor inverse agonists such as AVE1625; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptor antagonists such as memantine, neramexane and EVT101; cholinesterase inhibitors such as galantamine, rivastigmine donepezil, tacrine, fenserin, ladostigil and ABT-089; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate and capromorelin; histamine H3 receptor antagonists such as ABT-834, ABT 829, GSK 189254 and CEP16795; AMPA agonists or AMPA modulators such as CX717, LY 451395, LY404187 and S-18986; PDE IV inhibitors including MEM1414, HT0712 and AVE8112; GABA inverse agonists; GSK3P inhibitors including AZD1080, SAR502250 and CEP16805; neuronal nicotinic agonists; selective M1 agonists; HDAC inhibitors; and ligands of kinase (MARK), which regulates the affinity of microtubules; or other drugs that affect receptors or enzymes that improve the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention.

Examples of combinations of compounds of the present invention include combinations with agents for the treatment of schizophrenia, for example, in combination with sedatives, hypnotics, anxiolytics, antipsychotics, anti-anxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, agonists and antagonists. melatonin, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, etc., such as: adinazolam, allobarbital, alonimide, aiprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, cloretate, chlorpromazine, clozapine, ciprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, ethazolvinol, estazolam, etomidate, phenobam, flunitraz epam, flupenthixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fozazepam, glutethimide, galazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, meprobamate, methaqualone, midazolam, neozobmidaflu, nitrazepam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapin, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproelone, temazepam, thiothixene, tracasolate, tranylcypromine, trazodone, triazolam, trepipam, tricetamide, triclophos, trifluoperazine, trimetosine, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem and their salts and combinations thereof, etc., or the compound in question can be used in conjunction with the use of physical methods such as light therapy or electrical stimulation.

In another embodiment, the compounds of the present invention can be used

- 26 042108 use in combination with levodopa (with or without the use of or a selective excerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally in the form of its hydrochloride or lactate) and trihexyphenidyl (benzexol) hydrochloride; COMT inhibitors such as entacapone, MAO-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide and pramipexole. It should be understood that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopammesylate, naxagolide hydrochloride and pergolide mesylate.

In another embodiment, a compound of the present invention may be used in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophene, diphenylbutylpiperidine, and indolone antipsychotic classes. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine, and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of butyrophenone is haloperidol. An example of diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptics include loxapine, sulpiride, and risperidone. It should be understood that antipsychotics when used in combination with the compounds of the present invention may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, fluphenazine enatate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide, and risperidone are commonly used in non-salt form. Thus, the compounds of the present invention can be used in combination with the following: acetophenazine, alentemol, aripiprazole, amisuipride, benzexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide , levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, frihexyphenidyl, thioridazine, thiothixene, trifluoperazine, or ziprasidone.

Examples of compound combinations of the present invention include combinations with pain management agents such as non-steroidal anti-inflammatory agents such as aspirin, diclofenac, duflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2 inhibitors such as celecoxib, rofecoxib, valdecoxib, 406381 and 644784; CB-2 agonists such as 842166 and SAB378; VR-1 antagonists such as AMG517, 705498, 782443, PAC20030, V114380 and A425619; bradykinin receptor Bl antagonists such as SSR240612 and NVPSAA164; sodium channel blockers and antagonists such as VX409 and SPI860; nitric oxide synthase (NOS) inhibitors (including iNOS and nNOS inhibitors) such as SD6010 and 274150; glycine site antagonists, including lacosamide; neuronal nicotinic agonists such as ABT 894; NMDA antagonists such as AZD4282; potassium channel activators; AMPA/kainate receptor antagonists; calcium channel blockers such as ziconotide and NMED160; GABA-A IO receptor modulators (eg, a GABA-A receptor agonist); matrix metalloprotease (MMP) inhibitors; thrombolytic agents; opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene; neutrophil inhibitory factor (NIF); pramipexole, ropinirole; anticholinergics; amantadine; inhibitors of monoamine oxidase Bl5 (MAO-B); 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.

The compounds of the present invention may be administered in combination with compounds useful in improving sleep quality and preventing and treating sleep disorders and sleep disorders, including, for example, sedatives, hypnotics, anxiolytics, antipsychotics, anti-anxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, orexin antagonists, alpha-1 antagonists, GABA agonists, 5HT-2 antagonists, including 5HT-2A antagonists and 5HT-2A/2C antagonists, histamine antagonists, including H3 histamine antagonists, H3 histamine inverse agonists, imidazopyridines, small tranquilizers, melatonin agonists and antagonists, melatonergics, other orexin antagonists, orexin agonists, prokinetecin agonists and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, three

- 27 042108 azolopyridines and the like, such as: adinazolam, allobarbital, alonimide, alprazolam, amitriptyline, amobarbital, amoxapine, armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion, buprion, butabarbital, butalbital, capromorelin , carbochloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate, cloretate, clozapine, conazepam, ciprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014, episoclone, estazolam, ethchlorinol, etomidate, phenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fozazepam, gaboxadol, glutethimide, galazepam, hydroxyzine, ibutamoren, imipramine, indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline, MDL100907, mecfolocine, mecfolocine, mecfolocine meprobamate, methaqualone, metiprilon, midaflur, midazolam, modafinil, nefazodone, NGD-2-73, nizobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarb ital, perlapin, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide, secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracasolate, tranylcypromine, trazodone, triazolam, trepipam, tricetamide, triclophos, trifluoperazine, trimetosine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone, zolpidem and their salts, and combinations thereof, etc., or the compound of the present invention can be used in conjunction with the use of physical way, such as light therapy or electrical stimulation.

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

The compounds of the present invention are useful in the treatment of mild to moderate dementia of the Alzheimer's disease type alone or in combination with galantamine, rivastigmine or donepezil.

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

The compounds of the present invention are useful in the treatment of motor fluctuations in patients with advanced Parkinson's disease alone or in combination with carbidopa and levodopa.

When using the combination therapy of the present invention, the therapeutic agents in combination or the pharmaceutical composition or compositions containing the therapeutic agents may be administered to a patient in any order, for example, sequentially, simultaneously, together, jointly, and the like. The amounts of different active agents in such combination therapy may be different (different doses) or the same (same doses). The compound of the present invention and the additional therapeutic agent may be in fixed amounts (doses) in a single unit dosage form (eg, capsule, tablet, etc.).

The α7 nAChR positive allosteric modulator (PAM) activity of the compounds of the present invention was tested using assays known in the art. The α7 nAChR PAMs described in the present invention have activities when assayed by the local clamp technique as described in the examples. The study was performed using IonFlux HT using whole cells with a population clamp configuration. See Golden et al. Assay Drug Dev. Technol. (2011) 9:608-619. Compounds were determined for their ability to modulate the function of human α7 nAChRs stably expressed in the HEK cell line in the presence and absence of a suitable α7 acetylcholine agonist. By conducting a series of such studies at different concentrations, the effective concentrations of α7 nAChR PAMs (EC ₅₀ ) were determined. See Spencer et al. Assay Drug Dev. Technol. (2012) 10:313-324.

The present invention also includes processes for the preparation of compounds of formula I or II. The compounds of the present invention can be readily prepared according to the reaction schemes and examples below, or modifications thereof, using readily available starting materials, reagents, and conventional synthetic procedures. These reactions can also use options that are known to a person with general training in the art, but are not specified in more detail. In addition, other ways to obtain the compounds proposed in the present invention, obvious to a person with a general training in the art in view of the following reaction schemes and examples. Unless otherwise noted, all variables are as defined above. The following reaction schemes and examples are intended only to illustrate the present invention and its practical implementation.

Many of the compounds of the present invention can be prepared according to Scheme 1, where alkyne 1.1 is involved in [3+2]-cycloaddition with nitrile oxide (formed in situ by treatment of oxime 1.2 with PIFA) to give isoxazole 1.3. Other nitrile oxide precursors such as nitroalkanes or chlorooximes can be used to carry out this conversion.

- 28 042108

Scheme 1.

In addition, other compounds of the present invention can be prepared according to Scheme 2 where acid 2.1 is reacted with CDI in dioxane and then treated with amidoxime 2.2 in dioxane at elevated temperature to give product 2.3. Other coupling reagents such as EDC and HOAt and solvents such as toluene, dichloroethane or DMSO can be used in this conversion. If 2.3 is a mixture of enantiomers or diastereoisomers, the mixture can be separated using chiral chromatography. Alternatively, 2.1 and 2.2 can be used as separate enantiomers or diastereoisomers to give 2.3 enriched in one enantiomer or diastereoisomer. Other procedures for preparing oxadiazole can also be used, such as the reaction of the corresponding acid ester 2.1 with amidoxime 2.2 in the presence of potassium carbonate (or other bases) in ethanol (or other solvents) at elevated temperature, or the reaction of acid 2.1 with amidoxime 2.2 in the presence of EDC and HOAt followed by the addition of T3P to the reaction mixture, or by treating the isolated intermediate with TBAF in THF.

Scheme 2.

Similarly, some of the compounds of the present invention can be prepared according to scheme 3, where the intermediate cyclopropane 3.1 now contains amidoxime. Acid 3.2 is reacted with CDI in dioxane and then treated with amidoxime 3.1 and heated at elevated temperature to give product 3.3.

Scheme 3.

In addition, the compounds of the present invention can be prepared according to Scheme 4 wherein a boronic acid ester (or an acid boronate or a boronic acid derivative) 4.1 is reacted with a heteroaryl bromide (or chloride, iodide, triflate or tosylate) 4.2 under catalysis palladium and get the product 4.3. Many different catalysts (including other metals such as nickel), ligands, bases, and solvents can be used in this reaction. Other 6- and 5-membered heteroaryl halides (such as 5-chloro-1,2,4-thiadiazole) can be used instead 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 sulfamylating reagents can be used in this conversion (eg tert-butyl-(chlorosulfonyl)carbamate). If 4.4 is a mixture of enantiomers or diastereoisomers, the mixture can be separated by chiral chromatography. Alternatively, 4.1 and 4.2 can be used as separate enantiomers or diastereoisomers to give 4.4 enriched in one enantiomer or diastereoisomer.

- 29 042108

Scheme 4.

1.HCI

2. _SO2NH2

4.4

If a mixture of enantiomers or diastererisomers, then:

Chiral separation I _w mixture one isomer

Other compounds proposed in the present invention can be obtained in accordance with scheme 5, where the haloketone 5.1 is introduced into the reaction with thioamide 5.2 in ethanol at elevated temperature and receive thiazole 5.3. Weak Lewis acids and other halides and solvents can also be used to carry out this transformation. In addition, dehydrating reagents can be used to complete the formation of the heterocycle after the coupling of 5.1 and 5.2, and an amine base can be included to scavenge the acid formed during the reaction. Option 5.2, in which the thioamide is replaced by an amidine, can be used to give the corresponding imidazole, which can then be N-alkylated by treatment with an alkyl halide in the presence of a base. The din protecting group can then be removed with dimethylforms by treatment with hydrazine to give product 5.4.

Scheme 5.

In addition, the compounds of the present invention can be obtained in accordance with scheme 6, where the iminium salt 6.1 is introduced into the reaction with hydrazine 6.2 in the presence of HCl in methanol at elevated temperature and pyrazole 6.3 is obtained. Pyrazole 6.3 is then treated with hydrogen in the presence of palladium hydroxide on charcoal to remove the carboxybenzyl protecting group, then product 6.4 is obtained by reacting the resulting piperidine with sulfamide.

Scheme 6.

In addition, the compounds of the present invention can be obtained in accordance with scheme 7, where the acid 7.1 is introduced into the reaction with CDI in 1,4-dioxane and then treated with acylhydrazide 7.2 at elevated temperature, then the resulting amide is dehydrated by treatment with phosphorus oxychloride ( Y) at elevated temperature and get the product 7.3. Other coupling reagents and conditions can be used to carry out this transformation. In addition, other dehydrating reagents such as Burgess reagent or trifluoroacetic anhydride can be used for this conversion.

- 30 042108

Scheme 7.

1. CDI, dioxane

2. 7.2, heating

3. growing up | ₃ ,heating

R ³ R ⁴

In addition, the compounds of the present invention can be obtained in accordance with scheme 8, where the acid 7.1 is introduced into the reaction with acylhydrazide 7.2 in the presence of HATU and NMM. Other coupling reagents and conditions can be used to carry out this conversion. The resulting amide is then treated with Lawesson's reagent and heated at elevated temperature to give thiadiazole 8.1. Other thionizing reagents such as P ₄ S ₁₀ and hexamethyldisiloxane or hexamethyldisilathiane and solvents such as 1,4-dioxane can be used for this conversion. In addition, dehydrating reagents such as PTSA can be used to complete heterocycle formation after thionization.

Scheme 8.

In addition, the compounds proposed in the present invention can be obtained in accordance with scheme 9, where the amide 9.1 is introduced into the reaction with haloketone 9.2 in the presence of silver trifluoromethanesulfonate at an elevated temperature and oxazole 9.3 is obtained. Other weak Lewis acids such as boron trifluoride diethyl etherate and halides such as chloride or iodide can be used to carry out this conversion. In addition, dehydrating reagents can be used to complete the formation of the oxazole after coupling 9.1 and 9.2. As shown in Scheme 6, a two-step sequence can then be used to give sulfamide 9.4.

Scheme 9.

Other regioisomeric oxazoles of the present invention can be similarly prepared according to Scheme 10, where haloketone 10.1 is reacted with amide 10.2 in the presence of silver trifluoromethanesulfonate at elevated temperature to give oxazole 10.3. Weak Lewis acids and other halides and solvents can also be used to carry out this transformation. In addition, dehydrating reagents can be used to complete the formation of the heterocycle after the coupling of 10.1 and 10.2, and an amine base can be included to scavenge the acid formed during the reaction. The dimethylformamidine protecting group can then be removed by treatment with hydrazine to give product 10.4.

Scheme 10.

Other compounds proposed in the present invention can be obtained in accordance with scheme 11, where acid 7.1 is introduced into the reaction with HATU in tetrahydrofuran and then treated with aminoketone 11.1, then the resulting amide is cyclodehydrated by treatment with phosphorus (V) oxychloride and product 11.2 is obtained. Other coupling and dehydrating reagents and conditions may be used to effect this conversion. Scheme 11.

In addition, the compounds of the present invention can be obtained in accordance with scheme 12, where the isoxazole 1.3 is treated with Raney nickel and vinylogous amide 12.1 is obtained. Then

- 31 042108 Vinyl amide 12.1 can be reacted with P ₄ S ₁₀ in the presence of chloranil and sodium bicarbonate to give isothiazole 12.1. Other thionylating reagents such as Lawesson's reagent can be used in this conversion.

Scheme 12.

In addition, the compounds of the present invention can be prepared according to Scheme 13, where pyrazole 13.1 is reacted with arylboronic acid 13.2 by copper catalysis in the presence of oxygen to give product 13.3. Alternatively, an aryl or heteroaryl halide can be used in place of 13.2 with a palladium or copper catalyst in the presence of a base and a suitable ligand under an inert atmosphere to give products similar to 13.3. Carbamate 13.3 is then treated with HCl to remove the Boc protecting group and the resulting piperidine is reacted with sulfamide to give product 13.4. Other sulfamylating reagents can be used in this conversion (eg, tert-butyl-(chlorosulfonyl)carbamate followed by removal of the Boc group with HCl).

Scheme 13.

Intermediates such as 14.6 of the present invention can be prepared according to Scheme 14, which begins with Wittig olefination of ketone 14.1 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 the precursor 14.4 with sodium hydride to give cyclopropane 14.5. Other bases such as potassium tert-butoxide can be used in this conversion. Alternatively, 14.1 can be converted to the corresponding terminal olefin by treatment with methyltriphenylphosphorane and subsequent reaction 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 tetra-substituted olefins can be used in this last transformation to produce highly substituted cyclopropanes. Chiral ligands can be used in these carbene inclusion reactions (such as (R,R)-(-)-2,2'isopropylidenebis(4-tert-butyl-2-oxazoline) used in the presence of copper(I) triflate) to give enantio- or diastereo-enriched foods. Then cyclopropane 14.5 is saponified by treatment with sodium hydroxide and acid 14.6 is obtained.

Scheme 14.

X

14.4. NaH then 14.3

X'

CO ₂ Me

If a mixture of enantiomers or diastererisomers, then:

Chiral separation I mixture one isomer

CO ₂ H

14.6

Intermediates such as 15.5 of the present invention can be prepared according to Scheme 15, which begins with the reduction of the α,β-unsaturated complex

- 32 042108 ester 14.3 by treatment with DIBAL, then carry out the transformation of the resulting allyl alcohol into the corresponding acetate 15.1 by reaction with acetic anhydride in the presence of DMAP and triethylamine. Other reducing reagents, acetylating reagents and bases can be used in this conversion. Allyl acetate 15.1 can then be difluorocyclopropane by treatment with (trimethylsilyl)trifluoromethane in the presence of sodium iodide to give difluorocyclopropane 15.2. Other difluorocarbene sources (such as (bromodifluoromethyl)trimethylsilane or sodium chlorodifluoroacetate) and initiators (such as tetraalkylammonium salts) can be used in this conversion. Removal of the acetate group from 15.2 can be carried out by treatment with potassium carbonate and oxidation of the resulting alcohol to the corresponding acid by reaction with TEMPO. This acid can then be converted to benzyl ester 15.3 by treatment with benzyl bromide. The ester 15.3 can then be treated with HCl to remove the Boc group and the resulting piperidine reacted with sulfamide to give the product 15.4. Removal of the benzyl ester group can be carried out by treatment with palladium on carbon in the presence of hydrogen to give acid 15.5.

Scheme 15.

1.K ₂ CO ₃

2. TEMPO; VpVg

If a mixture of enantiomers or diastererisomers, then:

Chiral separation I mixture one isomer

Intermediates such as 3.1 of the present invention can be prepared according to Scheme 16. This sequence begins with acid 2.1 which is converted to amide 16.1 by coupling with ammonium chloride in the presence of HATU and NMM (other coupling reagents and bases can also be use for this reaction). Amide 16.1 is then dehydrated with POCl ₃ (other dehydrating reagents can also be used), then amidoxime 3.1 is obtained by treating the resulting nitrile with hydroxylamine.

Scheme 16.

2.1

_NH4CI , NMM, HATU

1. POCI ₃₎ MeCN

2. ΝΗ ₂ ΟΗ

EtOH heating

Intermediates such as 17.6 of the present invention can be prepared according to Scheme 17, which begins with Wittig olefination of ketone 17.1 with phosphorane 17.2 at elevated temperature to give terminal olefin 17.3. Alkene 17.3 is then reacted with vinyl boronate 17.4 in the presence of a 2nd generation Grubbs™ Catalyst to give vinyl boronate 17.5. Other cross-metathesis catalysts (such as Jean's catalyst or Hoveyd-Grubbs' catalyst) can be used in this conversion. The vinylboronate 17.5 can then be difluorocyclopropane by treatment with (trimethylsilyl)trifluoromethane in the presence of sodium iodide to give difluorocyclopropane 17.6. Other difluorocarbene sources (such as (bromodifluoromethyl)trimethylsilane or sodium chlorodifluoroacetate) and initiators (such as tetraalkylammonium salts) can be used in this conversion.

- 33 042108

Scheme 17.

Intermediates such as 5.1, proposed in the present invention, can be obtained in accordance with scheme 18, where a solution of acid 7.1 in dichloromethane and N,N-dimethylformamide is treated with oxalyl chloride to obtain the corresponding acyl chloride. This acyl chloride is then reacted with (trimethylsilyl)diazomethane and then with HCl to give chloroketone 5.1. This chloroketone can be converted to the corresponding iodide by treatment with sodium iodide in acetone.

Scheme 18.

Intermediates such as 6.1 of the present invention can be prepared according to Scheme 19. This sequence begins with treatment of (methoxymethyl)triphenylphosphonium chloride with LiHMDS followed by reaction of the resulting ylide with aldehyde 19.1 to give the enol ether 19.2. The enol ether 19.2 can then be added to the previously prepared Wismeier-Haack reagent (obtained by treating DMF with POCl ₃ ) to give the iminium salt 6.1.

Scheme 19.

R ³ R ⁴ .. _ ShchRp R ³ R ^{4 R} t/ ^R4 CO _{3 v} y _ vYs γ _Λ X r5 ³

V^/VR ⁵ ! jg ^P \ POCI ₃ , DMF; 19.2; K _g CO ₃ Me

CbzN^^J D LiHMDS; 19.1 CbzN^ ^X ' ^z oMe CbzN^JJ ⁰ MeO

19.1 19.26.1

Intermediates such as 20.4 of the present invention can be prepared according to Scheme 20, which starts by reducing the α,β-unsaturated ester 14.3 by treatment with DIBAL, then converting the resulting allyl alcohol to the corresponding silyl ether 20.1 by reaction with TBSCl in the presence of imidazole. Other reducing reagents, silylating reagents and bases can be used in this transformation. The allylsilyl ether 20.1 can then be bromofluorocyclopropane by treatment with dibromo(fluoro)methane in the presence of TBAI and sodium hydroxide to give bromofluorocyclopropane 20.2. After reduction of bromofluorocyclopropane 20.2 by treatment with Zn in the presence of ammonium chloride, the silyl ether protecting group can be removed by reaction with TBAF to give fluorocyclopropyl alcohol 20.3. The two-step oxidation of the alcohol 20.3 can be carried out by first treating with DMP followed by the reaction of the resulting aldehyde with sodium chlorite to give the acid 20.4.

- 34 042108

Scheme 20.

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

Scheme 21.

Intermediates such as 22.4 of the present invention can be prepared according to Scheme 22, which begins by treating triphenylphosphonium bromide 22.1 with nbutyllithium and reacting the resulting ylide with piperidinone 14.1 to give alkene 22.2. Alkene 22.2 can then be reacted with ethyl diazoacetate in the presence of rhodium acetate to give cyclopropane 22.3. Other metals such as copper or palladium can be used in this transformation. Chiral ligands can be used in these carbene inclusion reactions (such as (R,R)-(-)-2,2'isopropylidenebis(4-tert-butyl-2-oxazoline) carried out in the presence of copper(X) triflate) to give enantio- or diastereo-enriched foods. Then cyclopropane 22.3 is saponified by treatment with sodium hydroxide and acid 22.4 is obtained.

Scheme 22.

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

- 35 042108

Scheme 23.

23.1 23.2 9.1

It should be understood that the compounds and intermediates indicated in the above reaction schemes can be used as synthetic intermediates in other schemes that include similar intermediates to obtain alternative compounds proposed in the present invention.

In some cases, the order of the above reaction schemes can be changed to facilitate the reactions or avoid the formation of unwanted reaction products. In addition, various protecting group strategies known to those skilled in the organic synthesis can be used to facilitate reactions or avoid the formation of undesired reaction products.

In some cases, the final product can be further modified, for example, by operations with substituents. These operations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis, which are generally known to those skilled in the art.

The following examples are presented for a more complete understanding of the present invention. These examples are illustrative only and should not be considered as limiting the present invention in any way. If a racemic mixture is obtained, the enantiomers can be separated by chiral reverse or normal phase SFC separation after isolation of the final product or a suitable intermediate, followed by individual processing of the individual isomers. It should be understood that alternative methodologies can also be used in the synthesis of these key intermediates and compounds of the examples. Asymmetric methodologies (eg, chiral catalysis, excipients) may be used if possible or appropriate. The exact choice of reagents, solvents, temperatures, and other reaction conditions depends on the nature of the target product.

The following abbreviations are used in the text.________________________________

ace Acetyl AIBN 2,2'-azobisisobutyronitrile Ag Aryl B ₂ (Pin) ₂ bis(pinacolato)dibor BIN AP 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene bn Benzyl Vos tert-butoxycarbonyl THIEF (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate ush broadened BSA bovine serum albumin In and Butyl CAN ammonium-cerium nitrate(1U) cbz Carboxybenzyl

- 36 042108

CDI 1,1'-carbonyldiimidazole d doublet DABCO d-iazabicyclo[2.2.2]octane DAST (diethylamino)sulfur trifluoride dba Dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene EDC 1,2-dichloroethane DXM dichloromethane DD doublet of doublets DIBAL diisobutylaluminum hydride DIEA Ν,Ν-diisopropylethylamine DMA Ν,Ν-dimethylacetamide DMAP 4-(dimethylamino)pyridine DMEM Dulbecco's Modified Eagle's Medium (High Glucose) DMF Ν,Ν-dimethylformamide DMF-DMA Ν,Ν-dimethylformamide dimethyl acetal DMP periodinan Dess-Martin DMPU N,N-dimethylpropyleneurea DMSO Dimethyl sulfoxide DPBF 1,3-diphenylisobenzofuran Dppf 1,1'-bis(diphenylphosphino)ferrocene EDC N-(3-d and methylam and nopropyl)-N'-ethylcarbodiimide hydrochloride EDTA ethylenediaminetetraacetic acid EKV. equivalents ESI electrospray ionization Et Ethyl FBS fetal bovine serum HATU O-(7-azabsnzotriazol-1-yl)-M,M,M'M'-tstramstyluronium hexafluorophosphate HEPES N-(2-hydroxyethyl)piperazine-^-(2-ethansylphonic acid) HMDS Hexamethyldisilazane HMTA Hexamethylenetetramine HOAt 1-hydroxy-7-azabenzotriazole HOBt 1-hydroxybenzotriazole

-37 042108

HPLC high performance liquid chromatography Hz hertz Imid Imidazole i-Pr Isopropyl J interaction constant LAH lithium aluminum hydride LCMS liquid chromatography-mass spectrometry LDA lithium diisopropylamide m/z mass-to-charge ratio M multiplet mCPBA 3-chloroperbenzoic acid Me Methyl MP macroporous polystyrene Ms Methansulfonyl MTBE methyl tert-butyl ether MW molecular mass NBS N-bromosuccinimide NHS N-hydroxysuccinimide n-BuLi n-butyllithium n-HexLi n-hexyllithium NMM N-methylmorpholine NMP 1-methyl-2-pyrrolidinone NMR nuclear magnetic resonance oac Acetate P pentet PBPB pyridinium bromide perbromide PBS phosphate buffered saline PCC pyridinium chlorochromate PDC pyridinium dichromate Pd/C palladium on coal Ph Phenyl PIFA [bis(trifluoroacetoxy)iodine]benzene PMBC1 4-methoxybenzyl chloride p-Ts 4-toluenesulfonyl

-38042108

PTSA para-toluenesulfonic acid RU Pyridyl sq. quartet Rt room temperature With singlet SEM 2-trimethylsilylethoxymethyl SEMC1 2-trimethylsilylethoxymethyl chloride SFC supercritical liquid chromatography SM starting material T triplet TZR 2,4,6-tripropyl-1,3,5,2,4,6-trioxatrifphosphorinan-2,4,6-trioxide TBAF n-tetrabutylammonium fluoride TBAI n-tetrabutylammonium iodide TBS tert-butyldimethylsilyl TBSC1 tert-butyldimethylsilyl chloride TBDPS tert-butyldiphenylsilyl TBDPSC1 tert-butyldiphenylsilyl chloride t-Bu tert-butyl TSSA trichloroisocyanuric acid TEA Trimethylamine TFA trifluoroacetic acid Tf Trifluoro methanesulfonyl TCFH tetramethylchloroformamidinium hexafluorophosphate THF T tetrahydrofuran TMG T tetramethylguanidine TMSD Trimethylsilyldiazomethane Trisyl 2,4,6-triisopropylbenzenesulfonyl about. /about. volume to volume X-Phos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

intermediate product 1.

o* o (1R)-6-Sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid.

Step A. Ethyl-(1R)-6-azaspiro[2.5]octane-1-carboxylate.

To a solution of 6-benzyl-1-ethyl-(1R)-6-azaspiro[2.5]octane-1,6-dicarboxylate (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, activated carbon, 4.94 g, 7.03 mmol). The reaction vessel was evacuated and refilled with hydrogen (about 1 atm) and the reaction mixture was stirred at ambient temperature for 18 h. for use in the next step. MS: m/z=184.3 [M+H].

Step B Ethyl (1R)-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylate.

To a solution of ethyl (1R)-6-azaspiro[2.5]octane-1-carboxylate (25.6 g, 140 mmol) in 1,4-dioxane (400 ml) was added sulfamide (40.7 g, 423 mmol) and the reaction mixture was heated at 95° C. and stirred for 18 h. Sulfamide (9.00 g, 93.7 mmol) was added and the reaction mixture was heated at 100° C. and stirred for 6 h. The reaction mixture was allowed to cool to ambient temperature , poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2x). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure. Crude

- 39 042108 the 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].

Step C. (1R)-6-Sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid.

An aqueous solution of sodium hydroxide ( 2 M, 286 ml, 572 mmol) and the reaction mixture was stirred for 2 days at ambient temperature. The reaction mixture was diluted with ice water (200 ml) and the resulting mixture was slowly adjusted to pH 5 with aqueous hydrochloric acid (12 M) and extracted with ethyl acetate (3x). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity for use in the next step. MS: m/z=235.1 [M+H].

intermediate product 2.

(1 R)-N'-H hydroxy-6-sulfamoyl-6-azaspiro[2.5] octane-1-carboximidamide.

Step A. (1R)-6-Sulfamoyl-6-azaspiro[2.5]octane-1-carboxamide.

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 for 18 h at ambient temperature. The reaction mixture was filtered, washed with dichloromethane, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=234.0 [M+H].

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

Phosphorus oxychloride (1.47 ml, 15.8 mmol) and the reaction mixture was heated at 80°C and stirred for 2 hours. The reaction mixture was cooled to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate (2x). The combined organic extracts were concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=216.1 [M+H].

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

An aqueous solution of hydroxylamine (50% w/w, 3.50 ml, 57.1 mmol) and the reaction mixture was heated at 60°C and stirred for 1 h. The reaction mixture was cooled to ambient temperature and diluted with saturated aqueous sodium chloride solution and the resulting mixture was extracted with ethyl acetate (3x). The combined organic extracts were concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=249.1 [M+H].

intermediate product 3.

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

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

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 (2 M, 9.44 ml, 18.9 mmol) and the reaction mixture was stirred for 15 min. Methanol (15 ml) was added and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether:ethyl acetate 95:5 to give the title compound. MS: m/z=250.0 [M-tBu+H].

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

To a 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) at -78°C was added a solution of lithium diisopropylamide in tetrahydrofuran and hexanes (2 M 0.98 ml, 1.97 mmol) and the mixture was stirred at -78°C for 15 min, then heated to ambient temperature and stirred for 30 minutes. Saturated ammonium chloride aqueous solution (3 ml) and water (5 ml) were added and the aqueous layer was extracted with ethyl acetate (3x5 ml). The combined organic extracts were dried (sulfate

- 40 042108 sodium) and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether:ethyl acetate 95:5 to give the title compound. MS: m/z=264.0 [M-tBu+H].

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

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) were added sodium hydroxide (163 mg, 4.07 mmol) and the reaction mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure and water (5 ml) was added and the resulting the mixture was extracted with ethyl acetate (5 ml). The pH of the aqueous phase was adjusted to 3 with an aqueous solution of hydrogen chloride (2 M) and extracted with ethyl acetate (3x10 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (10 ml), dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity for use in the next step.

Intermediate 4.

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

Basically following the procedures described in Intermediate 17, but using 6(tert-butoxycarbonyl)-2,2-difluoro-1-methyl-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 3) instead of tert -butyl-2-{3-[2-(difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-1,1difluoro-6-azaspiro[2.5]octane-6-carboxylate and N-hydroxy-2,5-dimethylbenzimidamide instead of 2(difluoromethoxy)-N'-hydroxypyridine-4-carboximidamide gave the title compound. MS: m/z=334.0 [M+H].

Intermediate 5.

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

Step A. tert-Butyl 4-[2-(benzyloxy)-2-oxoethylidene]-3,3-difluoropiperidine-1-carboxylate.

To a solution of tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (1.0 g, 4.3 mmol) in toluene (20 ml) was added benzyl 2-(triphenylphosphoranylidene) acetate (2.62 g , 6.38 mmol) and the reaction mixture was heated at 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 aqueous sodium chloride, 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 100:0 to 75:25 hexanes:ethyl acetate to give the title compound. MS: m/z=312.1 [M-tBu+H].

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

To a mixture of sodium hydride (60% dispersion in mineral oil, 0.196 g, 4.90 mmol) and dimethyl sulfoxide (15 ml) at 10°C was added a solution of trimethylsulfoxonium iodide in dimethyl sulfoxide (5.2 M, 10 ml) and the reaction mixture was stirred at 10 °C over 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 given warm to ambient temperature and stirred for 18 h. The reaction mixture was diluted with water and the resulting mixture was 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. The residue was purified by silica gel chromatography eluting with a gradient of 100:0 to 80:20 hexanes:ethyl acetate to give the title compound. MS: m/z=326.2 [M-tBu+H].

Step C. Benzyl 4,4-difluoro-6-azaspiro[2.5]octane-1-carboxylate 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 for 18 h at ambient temperature. The reaction mixture was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=282.2 [M+H].

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

To a solution of benzyl-4,4-difluoro-6-azaspiro[2.5]octane-1-carboxylate hydrochloride (255 mg, 0.802

- 41 042108 mmol) in 1,4-dioxane (4 ml) were added sulfamide (231 mg, 2.41 mmol) and triethylamine (0.168 ml, 1.20 mmol) and the reaction mixture was heated at 90°C and stirred 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 95:4:1 to 50:38:12 hexanes:ethyl acetate:ethanol to give the title compound. MS: m/z=361.2 [M+H].

Step E. 4,4-Difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid.

To a vessel containing benzyl 4,4-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylate (250 mg, 0.694 mmol) under an inert atmosphere was added palladium on activated carbon (10% w/w). , 74 mg, 0.069 mmol) and methanol (3.5 ml) in succession. The reaction mixture was placed under a hydrogen atmosphere (about 1 atm) and stirred for 3 hours at ambient temperature. The reaction mixture was filtered through a pad of Celite®, washed with methanol, and the filtrate was concentrated under reduced pressure. MS: m/z=271.1 [M+H].

intermediate product 6.

F

q' b

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

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

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

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

To a vessel containing sodium hydride (60% dispersion in mineral oil, 2.51 g, 62.7 mmol) and dimethyl sulfoxide (200 ml) was added trimethylsulfoxonium iodide (14.26 g, 64.8 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. dimethyl sulfoxide (50 ml) was added dropwise and the reaction mixture was stirred for 18 hours. The reaction mixture was slowly added to a mixture of ice and saturated aqueous ammonium chloride (225 ml) and the resulting mixture was extracted with ethyl acetate (3x200 ml). The combined organic extracts were washed with saturated aqueous ammonium chloride (2x100 ml) and saturated aqueous sodium chloride (1x100 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 100:0 to 60:40 hexanes:ethyl acetate to give the title compound. MS: m/z=232.1 [M-tBu+H].

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

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 an aqueous solution of sodium hydroxide (1 M, 34 ml, 34 mmol) and the reaction mixture was heated at 55°C and stirred for 15 min. The reaction mixture was cooled to ambient temperature and an aqueous solution of HCl (12.1 M, 2.79 ml, 34.0 mmol) was added. The mixture was concentrated under reduced pressure and the residue was evaporated with acetonitrile (2x). The residue was dissolved in ethyl acetate (100 ml), washed with water (15 ml), dried (magnesium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity for use in the next step. MS: m/z=218.1 [M-tBu+H].

Intermediate 7.

4-Fluoro-N'-hydroxy-2-(trifluoromethyl)benzenecarboxyimidamide.

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

Intermediate 8.

- 42 042108

Me h ₂ n^n O* o

CO ₂ H

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

Step A. tert-Butyl-3-methyl-4-methylidenpiperidine-1-carboxylate.

To a solution of tert-butyl-3-methyl-4-oxo-piperidine-1-carboxylate (2.95 g, 13.9 mmol) in dimethyl sulfoxide (45 ml) was added successively methyltriphenylphosphonium bromide (7.42 g, 20.8 mmol) and tert -potassium butoxide (2.33 g, 20.8 mmol) and the reaction mixture was stirred for 16 h at ambient temperature. The reaction mixture was poured into water (200 ml) and the resulting mixture was extracted with ethyl acetate (2x300 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (150 ml), dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 100:0 to 70:30 hexanes:ethyl acetate to give the title compound. MS: m/z=212.2 [M+H].

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

To a solution of tert-butyl-3-methyl-4-methylidenpiperidine-1-carboxylate (2.78 g, 13.2 mmol) in dichloromethane (42 ml) was added rhodium(II) acetate dimer (0.582 g, 1.32 mmol) . A solution of ethyl diazoacetate in dichloromethane (2.19 M, 18.0 mL, 39.4 mmol) was added dropwise over 75 minutes at ambient temperature. The reaction mixture was poured into water (100 ml) and the resulting mixture was extracted with dichloromethane (2x100 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (60 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 100:0 to 60:40 hexanes:ethyl acetate to give the title compound. MS: m/z=298.2 [M+H].

Step C Ethyl 4-methyl-6-azaspiro[2.5]octane-1-carboxylate.

A solution of HCl in 1,4-dioxane (4 M, 31.5 ml, 126 mmol) and the reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step.

Step D Ethyl 4-methyl-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylate.

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 heated at 110°C and stirred for 18 hours.

The reaction mixture was cooled to ambient temperature and poured into water (100 ml) and the resulting mixture was extracted with ethyl acetate (3x150 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (100 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=277.2 [M+H].

Step E: 4-Methyl-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid To a solution of ethyl 4methyl-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylate (5.63 g, 21.5 mmol) in tetrahydrofuran (36 ml) and methanol (18 ml) was added an aqueous solution of sodium hydroxide (2 M, 37.0 ml, 74.0 mmol) and the reaction mixture was stirred for 12 hours. The reaction mixture was poured into water (70 ml) and the resulting mixture was washed with diethyl ether (50 ml). The pH of the aqueous layer was adjusted to 5 with an aqueous solution of hydrochloric acid (12 M) and was extracted with ethyl acetate (2x200 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (50 ml), dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity for use in the next step. MS: m/z=249.1 [M+H].

Intermediate 9.

(1R)-1-(Chloroacetyl)-N-[(dimethylamino)methylidene]-6-azaspiro[2.5]octane-6-sulfonamide.

To a 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-dimethylformamidine (0 .1 ml) oxalyl chloride (0.558 ml, 6.51 mmol) was added at 0°C. The reaction mixture was allowed to warm to approx.

- 43 042108 chewing medium 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 a solution of (trimethylsilyl)diazomethane (2 M, 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 (4 M, 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 was added and the aqueous layer was extracted with ethyl acetate (3x10 ml). The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=322.0 [M+H].

Intermediate 10.

F, h ₂ n„ „n

J o ^r CO ₂ H (1R)-2,2-Difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid.

Step A: tert-Butyl-4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate.

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 heated at 110° C. and stirred for 4 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. Hexanes were added to the residue, and the resulting mixture was filtered, washed with hexanes, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 100:0 to 50:50 hexanes:ethyl acetate to give the title compound. MS: m/z=200.1 [M-tBu+H].

Step B: tert-Butyl 4-(2-hydroxyethylidene)piperidine-1-carboxylate.

A solution of diisobutylammonium hydride in tetrahydrofuran (1 M, 60.0 ml, 60.0 mmol) and the reaction mixture was stirred for 1 h at -78°C. 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 kept at 0°C for 18 h. an aqueous solution of Rochelle's salt (0.5 M) was added and 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 of sufficient purity for use in the next step. MS: m/z=195.2 [M+Na-tBu].

Step C: tert-Butyl 4-(2-acetoxyethylidene)piperidine-1-carboxylate.

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

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

Sodium iodide (0.899 g, 6 .00 mmol) and trimethyl(trifluoromethyl)silane (4.43 ml, 30.0 mmol). The vessel was sealed and the reaction mixture was heated at 90° C. and stirred for 2 h. .0 mmol) and the reaction mixture was heated at 90°C and stirred for 2 hours. The reaction mixture was allowed to cool 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 100:0 to 50:50 hexanes:ethyl acetate to give the title compound. MS: m/z=264.1 [M-tBu+H].

Step E. tert-Butyl-1,1-difluoro-2-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate.

Potassium carbonate ( 7.37 g, 53.4 mmol) and the reaction mixture was stirred for 2 hours at ambient temperature. 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 and the pH of the aqueous layer was adjusted to 5 and extracted with ethyl acetate

- 44 042108 vol. 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 to be used in the next step. MS: m/z=222.1 [M-tBu+H].

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

4- methylmorpholine 4-oxide hydrate (24.0 g, 178 mmol) and tetrapropylammonium perruthenate (0.625 g, 1.78 mmol) and the reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was diluted with aqueous hydrochloric acid (1M) and extracted with ethyl acetate. The aqueous layer was diluted with water and saturated aqueous sodium chloride, extracted with ethyl acetate, and the combined organic extracts were filtered through a pad of Celite® and concentrated under reduced pressure to give the title compound of sufficient purity for use in the next step. MS: m/z=236.1 [M-tBu+H].

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

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) successively HATU (10.1 g, 26.7 mmol), benzyl alcohol (2.77 ml, 26.7 mmol), and diisopropylethylamine (9.32 ml, 53.3 mmol) were added and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (2x). 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 100:0 to 50:50 hexanes:ethyl acetate to give the title compound. MS: m/z=326.2 [M-tBu+H].

Step H. Benzyl-2,2-difluoro-6-azaspiro[2.5]octane-1-carboxylate hydrochloride.

A solution of hydrogen chloride in 1,4-dioxane (4 M, 12.3 ml, 49.3 mmol) and the reaction mixture was stirred for 18 h at ambient temperature. The reaction mixture was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=282.2 [M+H].

Step I. (1R)-Benzyl-2,2-difluoro-6-sulfamoyl-6-azacniro[2.5]octane-1-carboxylate.

Triethylamine (2.58 ml, 18.5 mmol) and sulfamide (3.56 g, 37.0 mmol) and the reaction mixture was heated at 90°C and stirred for 4 hours. The reaction mixture was cooled to ambient temperature and sulfamide (3.56 g, 37 .0 mmol). The reaction mixture was heated at 90° C. and stirred for 4 hours. 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 and 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 100:0:0 to 52:36:12 hexanes:ethyl acetate:ethanol to give the racemic title compound. The racemate was separated by SFC using a ChiralPak AD-H column and eluting with methanol:carbon dioxide 40:60. The first major eluting peak was (1R)-benzyl-2,2-difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylate, the title compound, and the second major eluting peak was (1S)-benzyl-2, 2-difluoro-6sulfamoyl-6-azaspiro[2.5]octane-1-carboxylate. MS: m/z=361.2 [M+H].

Step J. (1R)-2,2-Difluoro-6-sulfamoyl-6-azacniro[2.5]octane-1-carboxylic acid.

Palladium on activated charcoal (10 % w/w, 0.354 g, 0.333 mmol) in an inert atmosphere. Methanol (17 ml) was added and the reaction mixture was placed under a hydrogen atmosphere (about 1 atm) and stirred for 3 h at ambient temperature. The reaction mixture was filtered through a pad of Celite®, washed with methanol, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=271.1 [M+H].

Intermediate 11.

gK ^h ! ⁿ _s ; ⁿ X K o''o ^he (1R)-2,2-Difluoro-N'-hydroxy-6-sulfamoyl-6-azacniro[2.5]octane-1-carboximidamide.

Step A. (1R)-2,2-Difluoro-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxamide.

To a solution of (1R)-2,2-difluoro-6-sulfamoyl-6-azacniro[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 successively ammonium chloride (6.5 g, 122 mmol), HATU (18.3 g, 48.0 mmol) and N-methylmorpholine

- 45 042108 (20 ml, 182 mmol) and the reaction mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with water and filtered, and the precipitate was dried under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=270.1 [M+H].

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

Phosphorus oxychloride ( 4.26 ml, 45.8 mmol) and the reaction mixture was heated at 80° C. and stirred for 3 hours. The reaction mixture was cooled to ambient temperature and saturated aqueous sodium bicarbonate was added slowly. The resulting mixture was extracted with ethyl acetate (2x). The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=293.1 [M+CH3CN+H].

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

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 solution (50% ./wt., 1.00 ml, 16.3 mmol) and the reaction mixture was stirred for 2 days at ambient temperature. The reaction mixture was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=285.2 [M+H].

Intermediate 12.

3-Cyclopropyl-N'-hydroxyisoxazole-4-carboximidamide.

Step A. 3-Cyclopropylisoxazole-4-carboxamide.

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 for 18 h at ambient temperature. The reaction mixture was washed with saturated aqueous ammonium chloride (4x20 ml) and saturated aqueous sodium chloride (1x20 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 100:0:0 to 60:30:10 hexanes:ethyl acetate:ethanol to give the title compound. MS: m/z=153.2 [M+H].

Step B. 3-Cyclopropylisoxazole-4-carbonitrile.

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 heated at 80°C and stirred for 1, 3 hours The reaction mixture was cooled to ambient temperature and slowly added to cold saturated aqueous sodium bicarbonate (30 ml) and the resulting mixture was extracted with ethyl acetate (3x30 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (1 x 15 ml), dried (magnesium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity for use in the next step. ¹ H NMR (DMSO-d ₆ ) δ 9.75 (s, 1H), 2.13-2.06 (m, 1H), 1.18-1.10 (m, 2H), 1.03-0 .97 (m, 2H).

Step C. 3-Cyclopropyl-N'-hydroxyisoxazole-4-carboximidamide.

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 heated at 80°C and stirred for 3 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was co-evaporated with ethanol (3x) and acetonitrile (2x) to give the title compound of sufficient purity to be used in the next step. MS: m/z=168.1 [M+H].

Intermediate 13.

HCV, GR

N'-Hydroxy-1-(2,2,2-trifluoroethyl)-1 H-pyrαzol-5-carboximidamide.

Step A. 1-(2,2,2-Trifluoroethyl)-1H-pyrazole-5-carboxamide.

Chloride ammonium (267 mg, 5.00 mmol), HATU (837 mg, 2.20 mmol) and N-methylmorpholine (0.660 ml, 6.00 mmol) and reaction

- 46 042108 the mixture was stirred for 16 hours at ambient temperature. 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 eluting with a gradient of 96:3:1 to 52:36:12 hexanes:ethyl acetate:ethanol to give the title compound. MS: m/z=194.1 [M+H].

Step B. 5-Cyano-1-(2,2,2-trifluoroethyl)-1H-pyrazole.

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

Step C. (R)-N'-Hydroxy-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboximidamide.

An aqueous solution of hydroxylamine (50% w/w, 0.400 ml, 6.53 mmol) and the reaction mixture was heated at 65°C and stirred for 2 hours. The reaction mixture was cooled to ambient temperature and the reaction mixture was concentrated under reduced pressure to obtain the title compound of sufficient purity for use in the next step. MS: m/z=209.1 [M+H].

Intermediate 14.

ABOUT

2-(Difluoromethoxy)-5-methylisonicotinic acid.

Step A. Methyl 5-bromo-2-(difluoromethoxy)isonicotinate.

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 heated at 90°C and stirred for 16 hours. 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 0:100 to 50:50 ethyl acetate:hexanes to give the title compound. MS: m/z=284.0 [M+H].

Step B. Methyl 2-(difluoromethoxy)-5-methylisonicotinate.

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 trioxatriborinan (251 mg, 2 .00 mmol). The reaction mixture was heated at 100° C. and stirred for 16 hours. The reaction mixture was cooled to ambient temperature, filtered through a pad of Celite®, washed with 1,4-dioxane, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0:100 to 50:50 ethyl acetate:hexanes to give the title compound. MS: m/z=218.1 [M+H].

Step C. 2-(Difluoromethoxy)-5-methylisonicotinic acid.

To a solution of methyl 2-(difluoromethoxy)-5-methylisonicotinate (110 mg, 0.507 mmol) in tetrahydrofuran (1.5 ml) was added an aqueous solution of sodium hydroxide (1 M, 1.52 ml, 1.52 mmol) and the reaction mixture heated at 40° C. and stirred for 1 h. The reaction mixture was cooled to ambient temperature and the pH was adjusted to 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 of sufficient purity to be used in the next step. MS: m/z=204.1 [M+H].

Intermediate 15.

OCF ₃ (1R)-1-{1-[3-(Trifluoromethoxy)phenyl]-1 H-pyrazol-4-yl}-6-azaspiro[2.5] octane.

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

With stirring, to a solution of 6-benzyl-1-ethyl-(1R)-6-αzaspiro[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 ras

- 47 042108 solution of sodium hydroxide (1 M, 19 ml, 19 mmol) and the reaction mixture was heated at 50°C and stirred for 2 hours, 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 (2 M). The aqueous layer was extracted with ethyl acetate (2x20 ml). The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=290.0 [M+H].

Step B. Benzyl-(1R)-1-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate.

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

Step C. Benzyl-(1R)-1-formyl-6-azaspiro[2.5]octane-6-carboxylate.

Dess-Martin periodinan (162 mg, 0.382 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. Water (5 ml) was added and the aqueous layer was extracted with dichloromethane (2x5 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 petroleum ether:ethyl acetate-75:25 to give the title compound. MS: m/z=274.1 [M+H].

Step D. Benzyl (1S)-1-(2-methoxyvinyl)-6-azaspiro[2.5]octane-6-carboxylate.

To a solution of (methoxymethyl)triphenylphosphonium chloride (188 mg, 0.55 mmol) in tetrahydrofuran (5 ml) at -78°C 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 for 0.5 h at -78°C. Benzyl-(1R)-1formyl-6-azaspiro[2.5]octane-6-carboxylate (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 (2x5 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 petroleum ether:ethyl acetate-75:25 to give the title compound. MS: m/z=302.1 [M+H].

Step E. K-[2-{(^)-6-[(Benzyloxy)carbonyl]-6-azaspiro[2.5]oct-1-yl}-3-methoxyprop-2-en-1ylidene]-N-methylmethaneammonium carbonate.

Phosphorus oxychloride (0.039 ml, 0.42 mmol) was added to a solution of K,K-dimethylformamide (0.032 ml, 0.42 mmol) in chloroform (1 ml) at 0°C and the reaction mixture was heated at 40°C and stirred for 0.5 h. The reaction mixture was cooled to 0° C. and (1S)-benzyl-1-(2-methoxyvinyl)-6azaspiro[2.5]octane-6-carboxylate (25 mg, 0.08 mmol) was added. The reaction mixture was heated at 70° C. and stirred 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 (2x5 ml). The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=357.1 [M+H].

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

To a solution of (R)-N-(2-(6-((benzyloxy)carbonyl)-6-azaspiro[2.5]octan-1-yl)-3-methoxyallylidene)-N-methylmethaneamminium 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 heated at 60°C and stirred for 1 hour. The pH of the reaction mixture was adjusted to 10 with saturated aqueous sodium bicarbonate and the aqueous layer was extracted with ethyl acetate (2x5 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 petroleum ether:ethyl acetate 75:25 to give the title compound. MS: m/z=472.1 [M+H].

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

To a solution of benzyl-(1R)-1-{1-[3-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-6-azaspiro[2.5]octane-6carboxylate (150 mg, 0.32 mmol) in methanol (5 ml) and ethyl acetate (5 ml) were added palladium hydroxide on activated carbon (10% w/w, 22.3 mg, 0.032 mmol) and the reaction mixture was stirred under a hydrogen atmosphere (25 lbf/in ² ) for 1 hour at ambient temperature. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give

- 48 042108 whether the desired connection. MS: m/z=338.1 [M+H].

Intermediate 16.

-Cyclopropyl-1 H-pyrazole-5-carbohydrazide.

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 (2 M, 2.96 ml, 5.92 mmol) and the reaction mixture was stirred for 0.5 h at ambient temperature. The reaction mixture was concentrated under reduced pressure. Dichloromethane (4.0 ml) and methanol (0.16 ml, 3.94 mmol) were added successively and the reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethanol (2.0 ml) and hydrazine (0.60 ml, 19 mmol) was added and the reaction mixture was stirred for 18 h at ambient temperature. 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].

Intermediate 17.

2-{3-[2-(Difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6azaspiro[2.5]octane hydrochloride.

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

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 hydrogen atmosphere for 1.5 h at ambient temperature. The reaction mixture was filtered through Celite®, washed with methanol, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity for use in the next step. MS: m/z=236.1 [M-tBu+H].

Step B. tert-Butyl-2-{3-[2-(difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6azaspiro[2.5]octane- 6-carboxylate.

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-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (330 mg, 1.72 mmol), 1-hydroxy-7azabenzotriazole (126 mg, 0.928 mmol), and 2-(difluoromethoxy)-N'-hydroxypyridine-4- carboxymidamide (intermediate A7) (350 mg, 1.72 mmol) and the reaction mixture was stirred for 0.5 h at ambient temperature. The reaction mixture was heated at 100° C. and stirred for 4.5 hours. The reaction mixture was cooled to ambient temperature and poured into a saturated aqueous ammonium chloride solution (20 ml) and the resulting mixture was extracted with dichloromethane (3x25 ml). The combined organic extracts were washed with saturated aqueous ammonium chloride (2x20 ml) and saturated aqueous sodium chloride (1x20 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 100:0 to 61:39 hexanes:ethyl acetate to give the title compound. MS: m/z=403.2 [M-tBu+H].

Step C. 2-{3-[2-(Difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6azaspiro[2.5]octane hydrochloride.

To a solution of tert-butyl-2-{3-[2-(difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6azaspiro[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 (4 M, 4.30 ml, 17.2 mmol) and the reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was concentrated under a stream of nitrogen to give the title compound of sufficient purity to be used in the next step. MS: m/z=359.2 [M+H].

Intermediate 18.

- 49 042108 (1R)-1-[4-(3-Cyclopropylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro[2.5]octane.

Step A. Benzyl-(1R)-1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylate.

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 successively HATU (2.69 g, 7.07 mmol), N-methylmorpholine (2.97 ml, 27.0 mmol) and ammonium chloride (1.44 g, 26.9 mmol) and the reaction mixture was stirred for 18 h at ambient temperature. The reaction mixture was poured into a saturated aqueous ammonium chloride solution (70 ml) and the resulting mixture was extracted with dichloromethane (3x75 ml). The combined organic extracts were washed with saturated aqueous ammonium chloride (3x75 ml) and saturated aqueous sodium chloride (1x75 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 100:0:0 to 40:45:15 hexanes:ethyl acetate:ethanol to give the title compound. MS: m/z=289.2 [M+H].

Step B. Benzyl-(1R)-1-[4-(3-cyclopropylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro[2.5]octane 6-carboxylate.

2-bromo-1-(3-cyclopropylisoxazole) -4-yl)ethanone (intermediate E1) (76.2 mg, 0.330 mmol) and silver trifluoromethanesulfonate (100 mg, 0.390 mmol) and the reaction mixture was heated at 75°C and stirred for 3.5 hours. 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 100:0 to 70:30 hexanes:ethyl acetate to give the title compound. MS: m/z=389.3 [M+H].

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

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

Intermediate 19.

2-Cyclopropoxyisonicotinic acid.

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) dropwise and the reaction mixture stirred for 15 min 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 layers were separated 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 0:100 to 95:5 acetonitrile:water to give the title compound. MS: m/z=180.0 [M+H].

Intermediate 20.

1-Cyclopropyl-4-methyl-1H-pyrazole-3-carboxylic acid.

Step A Ethyl 1-cyclopropyl-4-methyl-1H-pyrazole-5-carboxylate.

To a solution of ethyl 4-methyl-1H-pyrazole-5-carboxylate (1.00 g, 6.49 mmol) in 1,2-dichloroethane (50 ml) under air was added cyclopropylboronic acid (1.11 g, 13 0 mmol) and sodium carbonate (1.38 g, 13.0 mmol). The reaction mixture was heated at 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 hours. The reaction mixture was cooled to ambient temperature and diluted with saturated aqueous sodium bicarbonate and the resulting mixture was extracted with ethyl acetate (2x). The combined organic extracts were washed with saturated aqueous sodium chloride, 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 100:0 to 50:50 hexanes:ethyl acetate to give the title compound. MS: m/z=195.0 [M+H].

- 50 042108

Step B. 1-Cyclopropyl-4-methyl-1H-pyrazole-5-carboxylic acid.

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 for 1.5 days at ambient temperature. The pH of the reaction mixture was adjusted to 1 aqueous hydrochloric acid (1 M) and the mixture was extracted with ethyl acetate (2x). The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=189.1 [M+Na].

Intermediate 21.

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

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

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) was added successively HATU (2.30 g, 6.05 mmol), ammonium chloride (1.35 g, 25.2 mmol) and N-methylmorpholine (2.60 ml, 23.7 mmol) and the reaction mixture was stirred for 18 h at a temperature environment. The reaction mixture was filtered and the precipitate was washed with dichloromethane and water and dried under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=255.2 [M+H].

Step B. 6-Azaspiro[2.5]octane-1-carboxamide.

HCl in dioxane (6.91 ml, 27.6 mmol) and the reaction mixture was stirred for 0.5 h at ambient temperature. The reaction mixture was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=155.1 [M+H].

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

To a solution of 6-azaspiro[2.5]octane-1-carboxamide hydrochloride (625 mg, 2.76 mmol) in dichloromethane (20 ml) were added successively triethylamine (2.30 ml, 16.5 mmol) and 41 mmol) and the reaction mixture was stirred for 2.5 h at ambient temperature. 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 to be used in the next step. MS: m/z=233.2 [M+H].

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

To a solution of 6-(methylsulfonyl)-6-azaspiro[2.5]octane-1-carboxamide (702 mg, 2.75 mmol) in acetonitrile (25 ml) was added phosphorus oxychloride (0.940 ml, 10.1 mmol) and the reaction mixture was heated at 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 (25 ml). The resulting mixture was extracted with ethyl acetate (3x35 ml). The combined organic phases were washed with saturated aqueous sodium chloride (1x15 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 100:0:0 to 35:49:16 hexanes:ethyl acetate:ethanol to give the title compound. MS: m/z=215.3 [M+H].

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

An aqueous solution of hydroxylamine (50% w/w, 0.969 ml, 17.2 mmol). The reaction mixture was heated at 80° C. and stirred for 3 hours. The reaction mixture was cooled to ambient temperature and concentrated in a stream of nitrogen to give the title compound of sufficient purity for use in the next step. MS: m/z=248.2 [M+H].

Intermediate 22.

2-Azido-1-(3-cyclopropyl-5-methylisoxazol-4-yl)ethanone.

Step A. 3-Cyclopropyl-N-methoxy-H,5-dimethylisoxazole-4-carboxamide.

To a solution of 3-cyclopropyl-5-methylisoxazole-4-carboxylic acid (995 mg, 5.95 mmol) in dichloro

- 51 042108 methane (20 ml) and dimethyl sulfoxide (2.0 ml) were 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 for 18 h at ambient temperature. 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 (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].

Step B. 1-(3-Cyclopropyl-5-methylisoxazol-4-yl)ethanone.

To a solution of 3-cyclopropyl-N-methoxy-K,5-dimethylisoxazole-4-carboxamide (1.04 g, 4.95 mmol) in tetrahydrofuran (15 ml) at 0°C was added a solution of methyl magnesium bromide in toluene and 4 M, 7.70 ml, 9.89 mmol) and the reaction mixture was stirred for 1.5 h at 0°C. The reaction mixture was warmed to ambient temperature and poured into a saturated aqueous ammonium chloride solution (30 ml) and the resulting mixture was extracted with ethyl acetate (2x50 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (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 100:0 to 60:40 hexanes:ethyl acetate to give the title compound. MS: m/z=166.0 [M+H].

Step C. 2-Bromo-1-(3-cyclopropyl-5-methylisoxazol-4-yl)ethanone.

Bromine (0.25 ml, 4.85 mmol) 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 (2x100 ml). The combined organic extracts were washed with saturated aqueous sodium chloride, 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 100:0 to 50:50 hexanes:ethyl acetate to give the title compound. MS: m/z=244.0 [M+H].

Step D 2-Azido-1-(3-cyclopropyl-5-methylisoxazol-4-yl)ethanone.

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 for 18 hours at ambient temperature. The reaction mixture was poured into water (40 ml) and the resulting mixture was extracted with ethyl acetate (2x100 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (30 ml), dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity for use in the next step. MS: m/z=207.1 [M+H].

Intermediate 23.

_CF3

1-Cyclopropyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid.

Step A. Ethyl-1-cyclopropyl-3-(trifluoromethyl)-1 H-pyrazole-5-carboxylate.

Cyclopropylboronic acid (0.825 g, 9.61 mmol) and carbonate sodium (1.02 g, 9.61 mmol). The reaction mixture was heated at 70°C and 2,2'-bipyridine (0.750 g, 4.80 mmol) and copper(II) acetate (0.873 g, 4.80 mmol) was added and the reaction mixture was stirred for 18 h at 70° C. The reaction mixture was cooled to ambient temperature and diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2x). The combined organic extracts were washed with saturated aqueous sodium chloride and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 95:5 to 50:50 hexanes:ethyl acetate to give the title compound. MS: m/z=249.1 [M+H].

Step B. 1-Cyclopropyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid.

Aqueous sodium hydroxide solution (1 M, 4.5 ml, 4.50 mmol) and the reaction mixture was stirred for 18 h at ambient temperature. The reaction mixture was acidified to pH 1 by adding an aqueous solution of hydrochloric acid (1 M) and the resulting mixture was extracted with ethyl acetate (2x). The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=221.0 [M+H].

- 52 042108

Intermediate 24.

(2R)-N-[(Dimethylamino)methylidene]-1,1-difluoro-2-(iodoacetyl)-6-azaspiro[2.5]octane-6sulfonamide.

Step A. (1R)-6-{[(Dimethylamino)methylidene]sulfamoyl}-2,2-difluoro-N-methoxy-N-methyl-6azaspiro[2.5]octane-1-carboxamide.

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 Ν,N-dimethylformamide (13 mL) HATU (1083 mg, 2.85 mmol), 4-methylmorpholine (0.997 mL, 9.07 mmol), and Ν,Θdimethylhydroxylamine hydrochloride (303 mg, 3.11 mmol) were added successively and the reaction mixture was stirred for 1 h at ambient temperature. Oxalyl chloride (3.11 ml, 6.22 mmol) was added and the reaction mixture was stirred for 18 h at ambient temperature. 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 (3x). 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 100:0:0 to 40:45:15 hexanes:ethyl acetate:ethanol to give the title compound. MS: m/z=369.2 [M+H].

Step B. (2R)-2-(Chloroacetyl)-N-[(dimethylamino)methylidene]-1,1-difluoro-6-azaspiro[2.5]octane-6sulfonamide.

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

Step C. (2R)-N-[(dimethylamino)methylidene]-1,1-difluoro-2-(iodoacetyl)-6-azaspiro[2.5]octane-6sulfonamide.

To a solution of (2R)-2-(chloroacetyl)-N-[(dimethylamino)methylidene]-1,1-difluoro-6-azaspiro[2.5]octane-6sulfonamide (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 for 0.5 h at ambient temperature. 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, dried (magnesium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=450.1 [M+H].

Intermediate 25.

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

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

To a solution of 4-fluoro-N'-hydroxy-2-(trifluoromethyl)benzenecarboxyimidamide (500 mg, 2.25 mmol) in tetrahydrofuran (50 ml) at ambient temperature was added 1,1'-thiocarbonyldiimidazole (501 mg, mmol) and the reaction mixture was stirred for 30 min. Water (50 ml) was added and the resulting mixture was extracted with ethyl acetate (3x50 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (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 min. Water (30 ml) was added and the resulting mixture was extracted with ethyl acetate (3x30 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (100 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

- 53 042108 IU with a mixture of petroleum ether: ethyl acetate - from 100:0 to 72:28, and the desired compound was obtained. 1H NMR (400 MHz, CDCl3): δ 10.83 (m, 1H), 7.70 (m, 1H), 7.54 (m, 1H), 7.41 (m, 1H).

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

Phosphorus oxychloride (3.0 ml, 32 mmol) and the reaction mixture was heated at 120°C and stirred for 16 hours, the Reaction mixture was concentrated under reduced pressure and the residue was redissolved in dichloromethane (50 ml). Water (cold, 50 ml) was added and the resulting mixture was extracted with dichloromethane (2x50 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (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. 1H NMR (400 MHz, CDCl ₃ ): δ 7.90 (m, 1H), 7.54 (m, 1H), 7.36 (m, 1H).

Intermediate 26.

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

Step A. tert-Butyl-4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylidene]piperidine-1carboxylate.

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(2,4,6trimethylphenyl)-2-imidazolidinylidene][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxyO )phenyl]methylene-C]ruthenium(II) (0.56 g, 0.76 mmol) and the reaction mixture was heated at 90°C and stirred for 3 hours. The reaction mixture was cooled to ambient temperature and water (20 ml ) and the resulting mixture was extracted with ethyl acetate (3x30 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (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 95:5 to 90:10 to give the title compound. MS: m/z=224.1 [M-100+H].

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

To a solution of tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1carboxylate (1.00 g, 3.09 mmol) in tetrahydrofuran (10 ml) trimethyl(trifluoromethyl)silane (4.40 g, 30.9 mmol) and sodium iodide (0.23 g, 1.6 mmol) were added and the reaction mixture was heated at 120°C and stirred for 12 h. The reaction mixture was allowed to cool to ambient temperature, was added water (15 ml) and the resulting mixture was extracted with ethyl acetate (3x15 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (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 [MtBu+CH ₃ CN+H].

Intermediate 27.

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

Basically following the procedures described in Intermediate 35, but using 5chloro-3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazole (Intermediate 25) instead of 3-bromo-5[ 4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazole gave the title compound. MS: m/z=394.1 [M+H].

Intermediate 28.

kJ

Oh oh

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

- 54 042108

Step A: Benzyl 2,2-difluoro-6-(methylsulfonyl)-6-azaspiro[2.5]octane-1-carboxylate.

Triethylamine (3 .84 ml, 27.5 mmol) and methanesulfonyl chloride (1.07 ml, 13.8 mmol) and the reaction mixture was stirred for 1 hour at ambient temperature. Water (30 ml) was added and the resulting mixture was extracted with dichloromethane (3x30 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 a gradient of dichloromethane:ethyl acetate from 100:0 to 90:10 to give the title compound. MS: m/z=382.1 [M+Na].

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

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) palladium on activated charcoal (wet, 10% w/w, 0.86 g, 0.81 mmol) was added. The reaction mixture was placed under a hydrogen atmosphere (30 lbf/in ² ) and stirred for 3 h at ambient temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=270.0 [M+H].

Intermediate 29.

2-(Difluoromethoxy)pyridine-4-carboxamide.

To a solution of 2-(difluoromethoxy)isonicotinic acid (5.0 g, 26 mmol) in dichloromethane (48 ml) and dimethyl sulfoxide (4.80 ml) was added HATU (10.1 g, 50.4 mmol), ammonium chloride (5 .66 g, 105 mmol) and N-methylmorpholine (12.2 ml, 58.2 mmol). The reaction mixture was stirred for 18 hours. Saturated aqueous ammonium chloride solution (75 ml) was added and the resulting mixture was extracted with dichloromethane (3x100 ml). The combined organic phases were washed with saturated aqueous ammonium chloride (2x30 ml) and saturated aqueous sodium chloride (1x30 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 80:20 to 15:85 hexanes:ethyl acetate to give the title compound. MS: m/z=189.1 [M+H].

Intermediate 30.

R F

Y/N

MeI T

Me O tert-Butyl-1,1-difluoro-2-(1H-pyrazol-3-yl)-6-azaspiro[2.5]octane-6-carboxylate.

Step A. tert-Butyl-1,1-difluoro-2-[methoxy(methyl)carbamoyl]-6-azaspiro[2.5]octane-6-carboxylate.

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) were added triethylamine (5.74 ml, 41.2 mmol), 1,1'-carbonyldiimidazole (4.45 g, 27.5 mmol) and N,Odimethylhydroxylamine hydrochloride (2.01 g, 20.6 mmol) and reaction the mixture was stirred for 1 hour at ambient temperature. Water (50 ml) was added and the resulting mixture was extracted with ethyl acetate (2x50 ml). The combined organic layers were 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 90:10 to 75:25 to give the title compound. MS: m/z=335.1 [M+H].

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

To a solution of tert-butyl-1,1-difluoro-2-[methoxy(methyl)carbamoyl]-6-azaspiro[2.5]octane-6carboxylate (2.0 g, 5.98 mmol) in tetrahydrofuran (5 ml) at 0 °C was added a solution of ethynyl magnesium bromide in tetrahydrofuran (0.5 M, 120 ml, 59.8 mmol) and the reaction mixture was stirred for 1 h at 0°C. Water (150 ml) was added and the resulting mixture was extracted with ethyl acetate (2x100 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 a gradient of petroleum ether:ethyl acetate 95:5 to 75:25 to give the title compound. ¹ H NMR (400 MHz, CDCls): δ 3.48-3.58 (m, 4H), 3.37 (s, 1H), 2.55-2.65 (m, 1H), 1.51- 1.89 (m, 4H), 1.44 (s, 9H).

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

To a solution of tert-butyl-1,1-difluoro-2-propioloyl-6-azaspiro[2.5]octane-6-carboxylate (700 mg, 2.34

- 55042108 mmol) in ethanol (10 ml) was added hydrazine (85% w/w, 353 mg, 9.35 mmol) and the reaction mixture was stirred for 6 h at ambient temperature. 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 90:10 to 75:25 to give the title compound. MS: m/z=314.0 [M+H].

Intermediate 31.

F F

X

HCI

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

Step A. tert-Butyl-1,1-difluoro-2-{1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}-6azaspiro[2.5]octane-6-carboxylate.

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 lbf/in). The reaction mixture was heated at 50° C. and stirred for 15 hours. 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 petroleum ether:ethyl acetate-75:25 to give the title compound. MS: m/z=476.0 [M+H].

Step B. 1,1 - Difluoro-2-{1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}-6azaspiro[2.5]octane hydrochloride.

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

Intermediate 32.

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

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

Imidazole (337 mg, 4.95 mmol) and tert -butylchlorodimethylsilane (547 mg, 3.63 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with water (10 ml) and the resulting mixture was extracted with dichloromethane (3x10 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 a gradient of petroleum ether:ethyl acetate 95:5 to 90:10 to give the title compound. MS: m/z=342.1 [M+H].

Step C. tert-Butyl-1-bromo-2-{[(tert-butyldimethylsilyl)oxy]methyl}-1-fluoro-6azaspiro[2.5]octane-6-carboxylate.

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 heated at 40°C and stirred for 12 hours Water (5 ml) was added and the resulting mixture was extracted with ethyl acetate (3x5 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 petroleum ether:ethyl acetate -95:5 to give the title compound. MS: m/z=351.9 [M100+H].

Step C. tert-Butyl-1-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluoro-6-azaspiro[2.5]octane-6carboxylate.

To a solution of tert-butyl-1-bromo-2- {[(tert-butyldimethylsilyl)oxy]methyl} -1 -fluoro-6azaspiro[2.5]octane-6-carboxylate (50 mg, 0.11 mmol) in ethanol (1 ml) added zinc (29 mg, 0.44 mm

- 56 042108 la) and ammonium chloride (36 mg, 0.66 mmol) and the reaction mixture was heated at 70°C and stirred for 5 hours, the Reaction mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether:ethyl acetate 95:5 to give the title compound. MS: m/z=318.0 [M-tBu+H].

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

A solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 5.35 ml, 5.35 mmol) at ambient temperature and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with water (10 ml) and the resulting mixture was extracted with ethyl acetate (3x10 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 a gradient of petroleum ether:ethyl acetate 90:10 to 80:20 to give the title compound. MS: m/z=204.0 [M-tBu+H].

Step E. tert-Butyl-1-fluoro-2-formyl-6-azaspiro[2.5]octane-6-carboxylate.

DessaMartin periodinan ( 164 mg, 0.39 mmol) and the reaction mixture was stirred for 2 hours. Water (5 ml) was added and the resulting mixture was extracted with dichloromethane (3x5 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 petroleum ether:ethyl acetate 75:25 to give the title compound. 1 H NMR (400 MHz, CDCl ₃ ): δ 9.75-9.81 (m, 1H); 3.37-3.58 (m, 3H); 3.22-3.34 (m, 1H); 2.31 (br, 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).

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

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 reaction the mixture was stirred for 12 hours. The reaction mixture was diluted with water (5 ml) and the resulting mixture was extracted with ethyl acetate (3x5 ml). The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. 1H NMR (400 MHz, CD3OD): δ 3.39-3.57 (m, 3H); 1.96 (dd, J1=18.4 Hz, J2=2.6 Hz, 1H); 1.55-1.80 (m, 5H); 1.46 (s, 10H).

Intermediate 33.

•HCI

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

Basically following the procedures described in Intermediate 17, but using 6(t-butoxycarbonyl)-2-fluoro-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 32) instead of t-butyl-2-{ 3-[2-(difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6azaspiro[2.5] octane-6-carboxylate and 4-Φτορ-Ν- hydroxy-2-(trifluoromethyl)benzenecarboxyimidamide instead of 2-(difluoromethoxy)-N'-hydroxypyridine-4-carboximidamide gave the title compound. MS: m/z=360.0 [M+H].

Intermediate 34.

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

[4-Fluoro- 2-(trifluoromethyl)phenyl]boronic acid (62.5mg, 0.30mmol), potassium carbonate (125mg, 0.90mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(P)dichloride (22.01 mg, 0.03 mmol). The reaction mixture was heated at 100°C and stirred for 30 min. The mixture was cooled to ambient temperature and diluted with water (5 ml). The resulting mixture was extracted with ethyl acetate (3x5 ml), dried (sodium sulfate) and 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].

Intermediate 35.

- 57 042108

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

Step A. tert-Butyl-1,1-difluoro-2 -{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3 -yl}-6azaspiro[2.5]octane- 6-carboxylate.

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 successively added cesium carbonate (0.40 ml, 0.60 mmol), tert-butyl-1,1-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)-6azaspiro[2.5]octane-6-carboxylate (intermediate 26) (89 mg, 0.24 mmol) and chloro{[di(1adamantyl)-n-butylphosphine]-2-(2-aminobiphenyl)}palladium( II) (13.3 mg, 0.0199 mmol). The reaction mixture was heated at 100° C. and stirred for 12 hours. The reaction mixture was cooled to ambient temperature and diluted with water (5 ml). The resulting mixture was extracted with ethyl acetate (3x5 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 petroleum ether:ethyl acetate 90:10 to give the title compound. MS: m/z=438.l [M-tBu+H].

Step B 1,1-Difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}-6azaspiro[2.5]octane hydrochloride.

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

Intermediate 36.

1-Ethynyl-4-fluoro-2-(trifluoromethyl)benzene.

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 group (1.20 g, 6 .25 mmol) and potassium carbonate (2.16 g, 15.6 mmol) and the reaction mixture was heated at 50°C and stirred for 16 hours. The reaction mixture was cooled to ambient temperature, water (15 ml) was added and the resulting mixture was extracted with dichloromethane (3x15 ml). The combined organic extracts were dried (sodium sulfate) and filtered, and the filtrate was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.63-7.65 (m, 1H); 7.47-7.40 (m, 1H); 7.22-7.27 (m, 1H); 3.35 (s, 1H).

Intermediate 37.

1,1-Difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isoxazol-3-yl}-6-azaspiro[2.5]octane trifluoroacetate.

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

To a solution of tert-butyl 1,1-difluoro-2-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate (described in Intermediate 10) (760 mg, 2.74 mmol) in dichloromethane (10 ml ) at ambient temperature, Dess-Martin periodinan (2.33 g, 5.48 mmol) was added and the reaction mixture was stirred for 2 h. Saturated aqueous sodium bicarbonate solution (20 ml) was added slowly and the resulting mixture was extracted with dichloromethane (3x10 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 a gradient of petroleum ether:ethyl acetate 95:5 to 90:10 to give the title compound. MS: m/z=220.1 [M-tBu+H].

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

To a solution of tert-butyl 1,1-difluoro-2-formyl-6-azaspiro[2.5]octane-6-carboxylate (1.0 g, 3.6 mmol) and sodium carbonate (0.78 g, 7.3 mmol) in ethanol (20 ml) at ambient temperature was added hydroxylamine hydrochloride (0.51 g, 7.3 mmol) and the reaction mixture was stirred for 1 h.

- 58 042108 the mixture was 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.

Step C. tert-Butyl-1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isoxazol-3-yl}-6azaspiro[2.5]octane-6-carboxylate.

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) [bis(trifluoroacetoxy)iodine]benzene (1.71 g, 3.98 mmol) was added and the reaction mixture was heated at 50° C. and stirred for 7 hours. Water (15 ml) was added and the resulting mixture was extracted with ethyl acetate (3x10 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (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 petroleum ether:ethyl acetate from 100:0 to 92:8 to give the title compound. MS: m/z=421.1 [M-tBu+H].

1,1-Difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isoxazol-3-yl}-6-azaspiro[2.5]octane trifluoroacetate.

To a solution of tert-butyl-1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isoxazol-3-yl}-6azaspiro[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 hour. The reaction mixture was concentrated under reduced pressure to give the title compound of sufficient purity for use in next stage. MS: m/z=377.1 [M+H].

Intermediate 38.

•TFA

1,1-Difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-5-yl}-6azaspiro[2.5]octanetrifluoroacetate.

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

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) was added potassium carbonate (210 mg, 1.53 mmol) and dimethyl-(1-diazo-2-oxopropyl)phosphonate (293 mg, 1.53 mmol) and the reaction mixture was stirred for 16 hours. Water (20 ml) was added and the resulting the mixture was extracted with ethyl acetate (2x30 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (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 85:15 to give the title compound. MS: m/z=257.1 [M-tBu+CH ₃ CN+H].

Step B. tert-Butyl-1,1-difluoro-2-{3-[3-fluoro-5-(trifluoromethyl)phenyl]isoxazol-5-yl}-6azaspiro[2.5]octane-6-carboxylate.

To a 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) at ambient temperature was added [bis(trifluoroacetoxy)iodine]benzene (2.38 g, 5.52 mmol) and the reaction mixture was heated at 60°C and stirred for 7 hours Was added water (15 ml) and the resulting mixture was extracted with ethyl acetate (3x15 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 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].

Step C. tert-Butyl 2-{3-amino-3-[4-fluoro-2-(trifluoromethyl)phenyl]acryloyl}-1,1-difluoro-6azaspiro[2.5]octane-6-carboxylate.

To a solution of tert-butyl-1,1-difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]isoxazol-5-yl}-6azaspiro[2.5]octane-6-carboxylate (400 mg, 0 .84 mmol) in ethanol (25 mL) Raney nickel (4.93 mg, 0.08 mmol) was added under argon at ambient temperature. The reaction mixture was placed under a hydrogen atmosphere (about 40 lbf/in ² ), heated at 40°C and stirred for 8 hours. The reaction mixture was cooled, purged with an inert gas and filtered through a pad of Celite®, washed with ethanol (100 ml). The filtrate was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=479.1 [M+H].

Step D. tert-Butyl-1,1-difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-5-yl}-6azaspiro[2.5]octane-6-carboxylate.

To a solution of tert-butyl-2-{3-amino-3-[4-fluoro-2-(trifluoromethyl)phenyl]acryloyl}-1,1-difluoro-6

Phosphorus pentasulfide (530 mg, 2.38 mmol) and chloranil (586 mg, 2.38 mmol) and the reaction mixture was heated at 115°C and stirred for 2 hours. 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). The reaction mixture was stirred at ambient temperature for 1 hour. Water (15 ml) was added and the resulting mixture was extracted with ethyl acetate (3x10 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (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 petroleum ether:ethyl acetate from 100:0 to 90:10 to give the title compound. MS: m/z=493.1 [M+H].

Step E. 1,1-Difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-5-yl}-6-azaspiro[2.5]octane trifluoroacetate.

To a solution of tert-butyl-1,1-difluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-5-yl}-6azaspiro[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 hour. The reaction mixture was concentrated under reduced pressure to give the desired compound of sufficient purity for use in the next step. MS: m/z=393.1 [M+H].

Intermediate 39.

TFA

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

Step A. tert-Butyl-1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isoxazol-3-yl}-6azaspiro[2.5]octane-6-carboxylate.

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(trifluoroacetoxy)iodine]benzene (1.71 g, 3.98 mmol) and the mixture was stirred at 50°C for 7 hours. Water (15 ml) was added and the resulting mixture was extracted with ethyl acetate (3x10 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (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 petroleum ether:ethyl acetate from 100:0 to 92:8 to give the title compound. MS: m/z=421.1 [M-tBu+H].

Step B. tert-Butyl-2-{1-amino-3-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxoprop-1-en-1-yl}-1,1difluoro-6-azaspiro[ 2.5]octane-6-carboxylate.

To a solution of tert-butyl-1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isoxazol-3-yl}-6azaspiro[2.5]octane-6-carboxylate (100 mg, 0 .21 mmol) in ethanol (10 ml) Raney nickel (1.2 mg, 0.021 mmol) was added under argon. The reaction mixture was placed under a hydrogen atmosphere (about 40 lbf/in ² ), heated at 35°C and stirred for 3 hours. The reaction mixture was cooled, purged with an inert gas and filtered through a pad of Celite®, washed with ethanol (100 ml). The filtrate was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=479.3 [M+H].

Step C. tert-Butyl-1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-3-yl}-6azaspiro[2.5]octane-6-carboxylate.

To a solution of tert-butyl-2-{1-amino-3-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxoprop-1-en-1-yl}-1,1difluoro-6-azaspiro[2.5 ]octane-6-carboxylate (160 mg, 0.33 mmol) in toluene (8 mL) phosphorus pentasulfide (223 mg, 1.00 mmol) and chloranil (247 mg, 1.00 mmol) were added successively at ambient temperature and the reaction mixture was heated at 115° C. and stirred 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) and 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 (3x10 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (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 petroleum ether:ethyl acetate from 100:0 to 92:8 to give the title compound. MS: m/z=437.2 [M-tBu+H].

Step D. 1,1-Difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-3-yl}-6-azaspiro[2.5]octane

- 60 042108 trifluoroacetate.

To a solution of tert-butyl-1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-3-yl}-6azaspiro[2.5]octane-6-carboxylate (70 mg, 0 ,11 mmol) in dichloromethane (10 ml) at ambient temperature was added trifluoroacetic acid (3 ml, 38.9 mmol) and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give the desired compound of sufficient purity for use in next stage. MS: m/z=393.1 [M+H].

The intermediates indicated in the following tables were prepared by analogy with the above intermediates, as described, or obtained by analogous transformations with modifications known to those skilled in the art. The necessary starting materials are described in the present invention, commercially available, known in the literature or easily synthesized by a person skilled in the art. In some cases, obvious strategies for the use of protecting groups have been used.

Table INT-A ^N %

_H2NR

Intermediate R MS [M+H] A1 CF ₃ % F 223.0 A2 I ⁵ 203.1 AZ Ϊ ^ΟΗ Me 195.1 A4 μΛ° 182.1 A5 Me % 386.2 Ab ηLLO :- 206.1 A7 llO / 204.1 A8 _m JOn f Me 218.1 A9 4" 177.0

- 61 042108

AYu _CF3 236.1 AP 4 G ₃ S 236.1 A12 F ₃ C^ u 236.3

Table INT-B x ¹ x ²

Intermediate ^{x1 x2} R w MS [M+H] Bl n Η MeO Cl H 320.2 AT 2 F F F p-4 T 44/ON ^v ' H 359.2 VZ H Η V'NH: 0 -SO2NH2 249.1 AT 4 C1 Cl F^cx /vf H 409.8 AT 5 Me Η V ^H 0 -SO2NH2 249.0 wb Me Me V ^H 0 -SO2NH2 263.1

INT-C table

A

Intermediate R MS [M+H]

- 62 042108

Cl F ₃ C^ 222.1 C2 A B A_.n 1? Me 167.0 C3 AN /, Τ'n-<4 CF ₃ 221.1 C4 Y in 207.1 C5 F ₃ C' Me 235.1 C6 li Yr°y o τι ω 222.1 C7 Me ^x F ₃ C^ V 236.1 C8 Me' °4 “Π 204.1 C9 F I _3C ^{^} u 236.1 CIO A 204.1 joint venture s N about τι ω 222.1

- 63 042108

INT-D table

Intermediate Z R MS [M+H] D1 Mei D Me Oh A^nh ₂ II %n 332.2 D2 Me^^A Me^O^N^J Me Oh A^nh ₂ 1 %n 264.1 [M- tBu+H] D3 Me 1GCH Me 346.2 D4 Me^^x^A Me /А-N / \ S-Am Me 334.2

Example 1

(1R)-1-{5-[2-Methyl-5-(Ίrifluoromethyl)phenyl]-1,2,4-oxαdiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide.

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 the mixture was heated at 50° C. and stirred for 2 h. mmol) and the reaction mixture was heated at 110°C and stirred for 16 hours. 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 and obtained the desired compound. MS: m/z=417.1 [M+H]. 1H NMR (DMSO-d6) δ 8.26 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.1 Hz, 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).

Example 2

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

- 64 042108

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 heated at 50° C and stirred 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 heated at 100° C. and stirred for 16 h. The reaction mixture was cooled to ambient temperature and purified by silica gel chromatography eluting with a gradient of 96:3:1 to 52:36:12 hexanes:ethyl acetate:ethanol and obtained the desired compound. MS: m/z=363.2 [M+H]. ¹ H NMR (DMSOCH) δ 7.82 (s, 1H), 7.37 (d, J=7.7 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 6, 72 (s, 2H), 3.12 (d, J=6.7 Hz, 1H), 3.02 (dt, J=15.1, 7.5 Hz, 2H), 2.78 (t, J = 8.2 Hz, 1H), 2.56 (s, 3H), 2.36 (s, 3H), 2.18 (dd, J=7.8, 6.2 Hz, 1H), 1.83 -1.56 (m, 4H), 1.19 (dd, J=7.5, 5.2 Hz, 2H).

Example 3

E ^F o - \

HACF

Η ₂ Ν^Ν. J ΤΗ

XX ^Ν ο ο

4,4-Difluoro-1-{3-[3-(2,2,2-trifluoroethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6sulfonamide, diastereoisomer WITH.

1,4-dioxane (2 ml) was added ,1'-carbonyldiimidazole (61.4 mg, 0.379 mmol) and the reaction mixture was heated at 50°C and stirred for 2 h. N'hydroxy-3-(2,2,2-trifluoroethoxy)benzimidamide (81.0 mg, 0.344 mmol) and the reaction mixture was heated at 90°C and stirred for 18 hours. Sulfamide (50.0 mg, 0.52 mmol) was added and the reaction mixture was stirred at 90°C for 4 hours. 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 96:3:1 to 52:36:12 hexanes:ethyl acetate:ethanol to give a mixture of diastereoisomers. The mixture was separated by SFC using a ChiralPak AD-H column eluting with 20:80 ethanol:carbon dioxide. The first main eluting peak was 4,4-difluoro-1-{3-[3-(2,2,2-trifluoroethoxy)phenyl]-1,2,4-oxadiazol5-yl}-6-azaspiro[2.5]octane- 6-sulfonamide, diastereoisomer A, the second main eluting peak was 4,4-difluoro-1-{3-[3-(2,2,2-trifluoroethoxy)phenyl]-1,2,4-oxadiazol-5-yl} -6azaspiro[2.5]octane-6-sulfonamide, diastereoisomer B, the third main eluting peak was 4,4-difluoro-1-{3-[3-(2,2,2-trifluoroethoxy)phenyl]-1,2,4 -oxadiazol-5-yl}-6-azaspiro[2.5]octane6-sulfonamide, diastereoisomer C, desired compound, and the fourth main eluting peak was 4,4-difluoro-1-{3-[3-(2,2,2 -trifluoroethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-6azaspiro[2.5]octane-6-sulfonamide, diastereoisomer D. Diastereoisomer C: MS: m/z=469.2 [M+H]. 1H NMR (DMSOO δ 7.69 (d, J=7.9 Hz, 1H), 7.60 (s, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.31 ( dd, J=8.3, 1.9 Hz, 1H), 7.08 (s, 2H), 4.89 (kv, J=8.7 Hz, 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, 6.2 Hz, 1H), 1.99-1.83 (m, 2H), 1.75 (dd, J=8.9, 5.5 Hz, 1H), 1.63-1.54 (m, 1H).

Example 4

1-{3-[3-(Difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6sulfonamide, diastereoisomer E.

Step A. tert-Butyl-1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6azaspiro[2.5]octane-6-carboxylate.

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) 1,1'-carbonyldiimidazole (854 mg, 5.27 mmol) was added in a sealable vial and the vial was sealed. The reaction mixture was heated at 80°C and stirred 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). The reaction mixture was heated at 120° C. and stirred for 1.5 hours. 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 100:0 to 70:30 hexanes:ethyl acetate to give the title compound. MS: m/z=384.2 [M-tBu+H].

Step B. 1-{3-[3-(Difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6azaspiro[2.5]octane hydrochloride.

- 65 042108

In a vessel containing tert-butyl-1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6azaspiro[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 for 18 h at ambient temperature. The reaction mixture was concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=340.2 [M+H].

Step C. 1-{3-[3-(Difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6sulfonamide, diastereoisomer E.

To a solution of 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6azaspiro[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 heated at 100°C and stirred for 2 hours. The reaction mixture was cooled to ambient temperature medium and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 75:25 to 0:100 hexanes:ethyl acetate to give a mixture of diastereoisomers. The mixture was separated by SFC using a ChiralPak AD-H column eluting with 30:70:0.2 ethanol:carbon dioxide:ammonium hydroxide. The first main eluting peak corresponded to 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6azaspiro[2.5]octane-6-sulfonamide, diastereoisomer A, the second the main eluting peak corresponded to 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6sulfonamide, diastereoisomer B, the third main the eluting peak corresponded to 1-{3-[3(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide, diastereoisomer C, the fourth main the eluting peak corresponded to 1-{3-[3-(difluoromethoxy)phenyl]1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6-sulfonamide, diastereoisomer D, fifth major the eluting peak corresponded to 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4fluoro-6-azaspiro[2.5]octane-6-sulfonamide, diastereoisomer E, desired compound, and the sixth main eluting peak corresponded to 1-{3-[3-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4fluoro-6-azaspiro[2.5]octane-6-sulfonamide , diastereoisomer F. Diastereoisomer E: MS: m/z=419.2 [M+H]. Ή NMR (CD ₃ OD) δ 7.91 (d, J=7.8 Hz, 1H), 7.78 (s, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 6.91 (t, J=73.6 Hz, 1H), 4.39 (d, J=47.3 Hz, 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=5.5 Hz, 1H).

Example 5

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

1 ,1'-carbonyldiimidazole (5.19 g, 32.0 mmol) and the reaction mixture was heated at 50°C and stirred for 3.5 hours. The reaction mixture was cooled to ambient temperature and 4-fluoro-N'-hydroxy was added -2(trifluoromethyl)benzenecarboxyimidamide (intermediate 7) (4.98 g, 22.4 mmol). The reaction mixture was heated at 100°C and stirred 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 heated at 100° C. and stirred for 2 hours. 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 (2x700 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (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 hexanes:dichloromethane to give the title compound. MS: m/z=421.1 [M+H]. 1H NMR (DMSOd6) δ 7.97-7.86 (m, 2H), 7.75 (td, J=8.3, 2.3 Hz, 1H), 6.77 (s, 2H), 3, 22-3.12 (m, 1H), 3.10-3.01 (m, 1H), 3.022.92 (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, 4.7 Hz, 1H), 1.34 (t, J=5.0 Hz, 1H).

Example 6

1-{3-[4-Fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-4-methyl-6-azaspiro[2.5]octane-6sulfonamide, diastereoisomer D.

To a solution of 4-methyl-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboxylic acid (intermediate

- 66 042108 product 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 heated at 50° C and stirred for 0.5 h. The reaction mixture was cooled to ambient temperature and 4-fluoro-N'-hydroxy-2(trifluoromethyl)benzenecarboxyimidamide (intermediate 7) (341 mg, 1.27 mmol) was added. The reaction mixture was heated at 100°C and stirred for 2 days. The reaction mixture was cooled to ambient temperature and sulfamide (116 mg, 1.21 mmol) was added. The reaction mixture was heated at 100° C. and stirred for 18 hours. 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 100:0 to 60:40 hexanes:ethyl acetate to give three major eluting peaks, each corresponding to a mixture of diastereoisomers of the title compound. The first main peak corresponds to four isomers, the second main peak corresponds to two isomers and the third main peak corresponds to two isomers. The first major peak from silica gel chromatography was separated by SFC using a ChiralPak AD-H column eluting with 12:88 methanol:carbon dioxide. The first major eluting peak was 1-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-4-methyl6-azaspiro[2.5]octane-6-sulfonamide, diastereoisomer A, the second main eluting peak corresponded to 1-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-4-methyl-6azaspiro[2.5]octane-6 -sulfonamide, diastereoisomer B, the third main eluting peak was 1-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-4-methyl-6-azaspiro[ 2.5] octane-6-sulfonamide, diastereoisomer C, and the fourth main eluting peak corresponded to 1-{3[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-4-methyl-6 -azaspiro[2.5]octane-6-sulfonamide, diastereoisomer D, desired compound. Diastereoisomer D: MS: m/z=435.2 [M+H]. 1H NMR (DMSO-d ₆ ) δ 7.96-7.87 (m, 2H), 7.75 (dt, J=8.4, 4.2 Hz, 1H), 6.72 (s, 2H) , 3.21-3.13 (m, 1H), 3.13-3.05 (m, 1H), 2.92 (d, J=9.0 Hz, 1H), 2.55 (dd, J = 8.3, 5.7 Hz, 1H), 2.35 (t, J=10.6 Hz, 1H), 1.97 (t, J=10.7 Hz, 1H), 1.64-1 .58 (m, 1H), 1.55 (d, J=14.1 Hz, 1H), 1.43 (dd, J=8.3, 5.0 Hz, 1H), 1.26 (t, J=5.2 Hz, 1H), 1.04 (d, J=6.9 Hz, 3H).

Example 7

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

Step A. (1 R)-N,N-Dimethyl-N'- {[ 1 -(2-(3 -(trifluoromethoxy)phenyl]thiazol-4-yl}-6azaspiro[2.5]octan-6-yl)sulfonyl ) formimidamide.

To a solution of (1R)-N'-{[1-(2-chloroαcetyl)-6-azaspiro[2.5]octan-6-yl]sulfonyl}-N,Ndimethylformimidamide (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 heated at 70° C. and stirred for 2 hours. The reaction mixture was cooled and concentrated under reduced pressure to give the title compound of sufficient purity to be used in the next step. MS: m/z=489.1 [M+H].

Step B. (1R)-1-{2-[3-(T Rifluoromethoxy)phenyl]-1,3-thiazol-4-yl}-6-azaspiro[2.5]octane-6sulfonamide.

To a solution of (1 R)-N,N-dimethyl-N'- {[ 1 -(2-(3-(trifluoromethoxy)phenyl]thiazol-4-yl} -6azaspiro[2.5]octan-6-yl)sulfonyl) formimidamide (152 mg, 0.31 mmol) in ethanol (2 mL) hydrazine (0.5 mL, 0.31 mmol) was added and the reaction mixture was cooled to 10° C. and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC eluting with a gradient of 48:52:0.05 to 78:22:0.05 acetonitrile:water:ammonium hydroxide to give the title compound. MS: m/z=433.9 [M+H]. 1H NMR (400 MHz, CD3OD): δ 7.90 (d, J=7.9 Hz, 1H), 7.83 (s, 1H), 7.57 (t, J=8.1 Hz, 1H) , 7.36 (d, J=8.4 Hz, 1H), 7.23 (s, 1H), 3.25-3.27 (m, 1H), 3.02-3.08 (m, 1H ), 2.95 (dd, J1=7.9 Hz, J2=3.5 Hz, 1H), 2.17 (dd, J1=8.3 Hz, J2=5.7 Hz, 1H), 1, 66-1.75 (m, 2H), 1.52-1.66 (m, 3H), 1.21 (t, J=5.3 Hz, 1H), 1.03 (dd, J1=8, 6Hz, J2=5.0Hz, 1H).

Example 8

(1R)-1 - {5-[4-Methyl-1 -(2,2,2-trifluoroethyl)-1 N-pyrazol-5-yl] -1,2,4-oxadiazol-3 -yl} -6azaspiro [2.5] octane-6-sulfonamide.

To a solution of 4-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylic acid (30 mg, 0.14 mmol) in

- 67 042108

1,4-dioxane (2.4 ml) was added 1,1'-carbonyldiimidazole (30.4 mg, 0.19 mmol). The reaction mixture was heated at 80°C and stirred for 1 h. The reaction mixture was cooled to 10°C and (R)-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide (intermediate 2) was added ( 53.7 mg, 0.22 mmol). The reaction mixture was heated at 100° C. and stirred for 12 hours. 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 27:73:0.05 to 57:43:0.05 acetonitrile:water:ammonium hydroxide to give the title compound. MS: m/z=421.0 [M+H]. 1H NMR (400 MHz, CD3OD): δ 7.62 (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=5.3 Hz, 1H), 1.20-1.27 (m, 1H).

Example 9

(2R)-2-[5-(1,4-Dimethyl-1 N-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6-azaspiro[2.5 ]octane-6-sulfonamide.

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 heated at 50°C and stirred for 2 h. octane-1-carboximidamide (intermediate 11) (57.0 mg, 0.201 mmol) and the reaction mixture was heated at 85° C. and stirred for 16 hours. 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 96:3:1 to 24:57:19 hexanes:ethyl acetate:ethanol to give the title compound. MS: m/z=389.3 [M+H]. ¹ H NMR (DMSO^) δ 7.54 (s, 1H), 6.79 (s, 2H), 4.15 (s, 3H), 3.41-3.25 (m, 1H), 3, 24-3.13 t, 1H), 3.13-2.98 (m, 2H), 2.94-2.81 (m, 1H), 2.31 (s, 3H), 2.02-1 .83 (m, 4H).

Example 10

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

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 heated at 50°C and stirred for 2 h. The reaction mixture was cooled to ambient temperature, (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6-αzaspiro[2.5]octane-1-carboximidamide was added (intermediate 11) (57.0 mg, 0.201 mmol) and the reaction mixture was heated at 85° C. and stirred for 16 hours. 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 96:3:1 to 24:57:19 hexanes:ethyl acetate:ethanol to give the title compound. MS: m/z=438.2 [M+H]. ¹ H NMR (DMSS-N) δ 8.57 (d, J=5.2 Hz, 1H), 7.91 (d, J=5.1 Hz, 1H), 7.80 (t, J=72 Hz, 1H), 7.69 (s, 1H), 6.81 (s, 2H), 3.39 (d, J=12.0 Hz, 1H), 3.22-3.12 (m, 1H ), 3.12-3.00 (m, 2H), 2.982.88 (m, 1H), 2.03-1.83 (m, 4H).

Example 11.

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

To a 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) at ambient temperature were added successively 1-hydroxy-7-azabenzotriazole (13.6 mg, 0.100 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg, 0.300 mmol) and the reaction mixture was stirred for 15 min. 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 heated at 90° C. and stirred for 16 h.

- 68 042108 the mixture was cooled to ambient temperature, diluted with water, the layers were separated and the organic layer was purified by silica gel chromatography eluting with a gradient of 96:3:1 to 24:57:19 hexanes:ethyl acetate:ethanol to give desired connection. MS: m/z=402.2 [M+H]. ¹ H NMR (DMSO-d ₆ ) δ 9.59 (s, 1H), 6.80 (s, 2H), 3.72 (d, J=11.1 Hz, 1H), 3.22-2, 95 (m, 3H), 2.90-2.73 (m, 1H), 2.37 (ddd, J=13.3, 8.4, 5.1 Hz, 1H), 2.09-1, 85 (m, 4H), 1.15-1.04 (m, 2H), 1.01-0.89 (m, 2H).

Example 12.

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

To a 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) at ambient temperature were added successively 1-hydroxy-7-azabenzotriazole (13.6 mg, 0.100 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg, 0.300 mmol) and the reaction mixture was stirred for 15 min. N'-hydroxy-1-(2,2,2-trifluoroethyl)-1Hpyrazole-5-carboximidamide (intermediate 13) (45.8 mg, 0.220 mmol) was added and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was heated at 90° C. and stirred for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with water, the layers were separated and the organic layer was purified using 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=443.2 [M+H]. ¹ H NMR (DMSO-d ₆ ) δ 7.85 (d, J=1.9 Hz, 1H), 7.11 (d, J=1.9 Hz, 1H), 6.81 (s, 2H) , 5.57-5.39 (m, 2H), 3.79 (d, J=11.5 Hz, 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).

Example 13

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

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) at ambient temperature 1-hydroxy-7-azabenzotriazole (33.5 mg, 0.246 mmol) and 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70.8 mg, 0.369 mmol) were added and the reaction mixture was stirred for 15 minutes. (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6azaspiro[2.5]octane-1-carboximidamide (intermediate 11) (98.0 mg, 0.345 mmol) was added and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was heated at 90° C. and stirred for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with water, the layers were separated and the organic layer was purified using 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=452.1 [M+H]. ¹ H NMR (DMSO-d ₆ ) δ 8.44 (s, 1H), 7.81 (t, J=72.7 Hz, 1H), 7.63 (s, 1H), 6.80 (s, 2H), 3.40 (d, J=12.0 Hz, 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).

Example 14

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

To a 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) at ambient temperature, 1-hydroxy-7-azabenzotriazole (27.3 mg, 0.201 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.8 mg, 0.301 mmol) were added and the reaction mixture was stirred for 15 minutes. (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6-azaspiro[2.5]octane-1-carboximidamide was added

- 69 042108 (intermediate 11) (80.0 mg, 0.281 mmol) and the reaction mixture was stirred for 1 hour at ambient temperature. The reaction mixture was heated at 90°C and stirred for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with water, the layers were separated and the organic layer was purified using silica gel chromatography eluting with a gradient of hexanes:ethyl acetate from 95:5 to 25:75 and received the desired compound. MS: m/z=443.2 [M+H]. 1H NMR (DMSO) δ 8.21 (s, 1H), 6.80 (s, 2H), 4.24 (s, 3H), 3.44 (d, J=12.0 Hz, 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) .

Example 15

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

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) triethylamine (0.062 ml, 0.45 mmol) and sulfamide (85 mg, 0.89 mmol) were added in 1,4-dioxane (3 ml) and the reaction mixture was heated at 90° C. and stirred for 10 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC eluting with a gradient of 43:57:0.05 to 73:27:0.05 acetonitrile:water:ammonium hydroxide to give the title compound. MS: m/z=417.1 [M+H]. 1 H NMR (400 MHz, CDCl ₃ ): δ 7.67 (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).

Example 16

(2R)-2-[5-(1-Cyclopropyl-1 H-pyrazol-5-ul)-1,3,4-oxadiazol-2-yl]-1,1-difluoro-6azaspiro[2.5] octane-6 -sulfonamide.

Step A. (2R)-2-({2-[(1-Cyclopropyl-1H-pyrazol-5-yl)carbonyl]hydrazinyl}carbonyl)-1,1difluoro-6-azaspiro[2.5]octane-6-sulfonamide.

To a 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) at ambient temperature were added 1-hydroxy-7-azabenzotriazole (24 mg, 0.18 mmol) and 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (91 mg, 0.48 mmol) and reaction the 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 for 18 h at ambient temperature. The reaction mixture was poured into water (30 ml) and the resulting mixture was extracted with ethyl acetate (2x80 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (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].

Step B. (2R)-2-[5-(1-Cyclopropyl-1H-pyrazol-5-yl)-1,3,4-oxadiazol-2-yl]-1,1-difluoro-6azaspiro[2.5] octane-6-sulfonamide.

To a solution of (2R)-2-({2-[(1-Cyclopropyl-1H-pyrazole-5-ul)carbonyl]hydrazinyl}carbonyl)-1,1difluoro-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 heated at 85°C and stirred for 10 hours. The reaction mixture was cooled to ambient temperature and slowly poured into saturated aqueous sodium bicarbonate (30 ml) and the resulting mixture was extracted with ethyl acetate (2x70 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 100:0 to 50:50 hexanes:ethyl acetate to give the title compound. MS: m/z=401.4 [M+H]. 1H NMR (DMSO-d ₆ ) δ 7.62 (d, J=2.0 Hz, 1H), 6.99 (d, J=2.0 Hz, 1H), 6.82 (s, 2H), 4.25 (tt, J=7.4, 3.9 Hz, 1H), 3.58 (d, J=11.8 Hz, 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) .

- 70 042108

Example 17.

(2S)-2-[5-(1-Cyclopropyl-1H-pyrazol-5-yl)-1,3,4-thiadiazol-2-yl]-1,1-difluoro-6-azaspiro[2.5]octane6- sulfonamide.

To a solution of (2R)-2-({2-[(1-cyclopropyl-1H-pyrazol-5-yl)carbonyl]hydrazinyl}carbonyl)-1,1difluoro-6-azaspiro[2.5]octane-6-sulfonamide ( described in example 16) (50 mg, 0.115 mmol) in tetrahydrofuran (1.50 ml) Lawesson's reagent (97 mg, 0.24 mmol) was added and the reaction mixture was heated at 65°C and stirred for 3.5 h. the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of 100:0 to 50:50 hexanes:ethyl acetate to give the title compound. MS: m/z=417.4 [M+H]. ¹ N

NMR (DMSO-d ₆ ) δ 7.57 (d, J=1.9 Hz, 1H), 6.98 (d, J=1.9 Hz, 1H), 6.81 (s, 2H), 4 .18 (tt, J=7.4, 3.9 Hz, 1H), 3.77 (d, J=12.5 Hz, 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) .

Example 18.

(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-6azaspiro[2.5]octane-6-sulfonamide.

To a 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) at ambient temperature, 1-hydroxy-7-azabenzotriazole (27.2 mg, 0.200 mmol) and 1-(3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (57.5 mg, 0.300 mmol) were added successively 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 for 2 h. The reaction mixture was heated at 90°C and stirred for 4 h. The reaction mixture was cooled to ambient temperature, diluted with water, the layers were separated and the organic layer 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=433.2 [M+H]. 1H NMR (DMSO-d6) δ 8.17 (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) .

Example 19.

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

To a 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) at ambient temperature, 1-hydroxy-7-azabenzotriazole (27.2 mg, 0.200 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg, 0.300 mmol) were added in succession and the reaction mixture was stirred for 15 min. (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 for 2 hours at ambient temperature. The reaction mixture was heated at 90°C and stirred for 4 hours. The reaction mixture was cooled to ambient temperature, diluted with water, the layers were separated and the organic layer was purified using silica gel chromatography eluting with a gradient of hexanes:ethyl acetate - from 95:5 to 25:75 and received the desired compound. MS: m/z=443.2 [M+H]. 1H NMR (DMSO-66) δ 8.91 (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).

- 71 042108

Example 20.

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

To a 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) 1-hydroxy-7-azabenzotriazole (27.2 mg, 0.200 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg, 0.300 mmol) were added successively at ambient temperature and the reaction mixture was stirred for 15 minutes. (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6azaspiro[2.5]octane-1-carboximidamide (intermediate 11) (68.2 mg, 0.240 mmol) was added and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was heated at 95° C. and stirred for 3 hours. The reaction mixture was cooled to ambient temperature, diluted with water, the layers were separated and the organic layer was purified by silica gel chromatography eluting with a gradient of 90:10 hexanes:ethyl acetate. up to 0:100 and obtained the desired compound. MS: m/z=415.2 [M+H]. ¹ H NMR (DMSO-66) δ 6.79 (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=7.3 Hz, 2H), 2.43 (p , J=7.4 Hz, 2H), 2.02-1.82 (m, 4H).

Example 21.

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

To a 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) 1-hydroxy-7-azabenzotriazole (77 mg, 0.50 mmol) was added at ambient temperature 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 for 18 h at ambient temperature. The reaction mixture was heated at 95° C. and stirred for 6 hours. The reaction mixture was heated at 105° C. and stirred for 4 hours. 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 95:4:1 to 50:38:12 hexanes:ethyl acetate:ethanol. The product fractions were combined and concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 10:90:0.1 to 95:5:0.1 acetonitrile:water:trifluoroacetic acid to give the title compound. MS: m/z=456.2 [M+H]. ¹ H NMR (DMSO^) δ 8.00-7.91 (m, 2H), 7.77 (t, J=8.1 Hz, 1H), 3.77 (d, J=11.2 Hz, 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).

Example 22.

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

To a 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) at ambient temperature 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 for 1 h at ambient temperature. The reaction mixture was heated at 90°C and stirred for 2 h. The reaction mixture was cooled to ambient temperature, diluted with water, the layers were separated and the organic layer was purified by silica gel chromatography eluting with a gradient

- 72 042108 ent mode with a mixture of hexanes: ethyl acetate: ethanol - from 96:3:1 to 52:36:12 and received the desired compound. MS: m/z=403.2 [M+H]. ¹ H NMR (DMSO-d ₆ ) δ 6.79 (s, 2H), 4.07 (s, 3H), 3.34 (d, J=12.6 Hz, 1H), 3.233.13 (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).

Example 23.

Η, Ν. .Ν X o o (1R)-1-[4-(3-Cyclopropylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro[2.5] octane-6-sulfonamide.

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 heated at 100°C and stirred for 2 hours. 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 100:0 to 70:30 hexanes:ethyl acetate to give the title compound. MS: m/z=365.1 [M+H]. ¹ H NMR (DMSO-H ₆ ) δ 9.07 (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, 5.0 Hz, 1H), 1.73-1.50 (m, 5 H), 1.21-1.13 (m, 2H), 1.07 -0.98 (m, 2H), 0.90-0.81 (m, 2H).

Example 24.

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

Step A. (2R)-N-[(Dimethylamino)methylidene]-1,1-difluoro-2-{2-[4-fluoro-2-(trifluoromethyl)phenyl]1,3-oxazol-4-yl}- 6-azaspiro[2.5]octane-6-sulfonamide.

To a solution of (2R)-N-[(dimethylamino)methylidene]-1,1-difluoro-2-(iodoacetyl)-6-azaspiro[2.5]octane-6sulfonamide (intermediate 24) (133 mg, 0.296 mmol) in ethyl acetate (1.48 ml) were added 4fluoro-2-(trifluoromethyl)benzamide (77 mg, 0.37 mmol) and silver trifluoromethanesulfonate (95 mg, 0.37 mmol) and the reaction mixture was heated at 60°C and stirred for 3 h The reaction mixture was cooled to ambient temperature and diluted with saturated aqueous sodium chloride (10 ml) and ethyl acetate (10 ml) and the resulting mixture was stirred for 3.5 h. The layers were separated and the aqueous layer was extracted with ethyl acetate (2x). The combined organic extracts were washed successively with saturated aqueous sodium bicarbonate, aqueous HCl (1 M) and saturated aqueous sodium chloride, 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 100:0:0 to 40:45:15 hexanes:ethyl acetate:ethanol to give the title compound. MS: m/z=511.2 [M+H].

Step B: (2R)-1,1-Difluoro-2-{2-[4-fluoro-2-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-6azaspiro[2.5]octan-6- sulfonamide.

To a solution of (2R)-N-[(dimethylamino)methylidene]-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) hydrazine (0.0443 ml, 1.41 mmol) was added and the reaction mixture was heated at 60°C and stirred over 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of 100:0:0 to 40:45:15 hexanes:ethyl acetate:ethanol to give the title compound. MS: m/z=456.2 [M+H]. ¹ H NMR (500 MHz, CDCl3) δ 7.95 (dd, J=8.6, 5.4 Hz, 1H), 7.66 (s, 1H), 7.53 (dd, J=8.9 , 2.5 Hz, 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=13.7 Hz, 1H), 2.03 (m, 1H), 1.89 (m, 1H), 1.78 (m, 1H), 1.65 ( m, 1H).

Example 25.

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

To a solution of 1-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylic acid (intermediate product

- 73 042108

20) (33.2 mg, 0.200 mmol) in 1,2-dichloroethane (0.90 ml) and dimethyl sulfoxide (0.10 ml) at ambient temperature was added 1-hydroxy-7-azabenzotriazole (30.8 mg, mmol) and 1-(3dimethylaminopropyl)-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-6azaspiro[2.5]octane-1-carboximidamide (intermediate 11) (62.5 mg, 0.220 mmol) was added and the reaction mixture was stirred for 16 h at ambient temperature. The reaction mixture was heated at 90°C and stirred for 3 hours. The reaction mixture was cooled to ambient temperature, diluted with water, the layers were separated and the organic layer 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 the title compound. MS: m/z=415.3 [M+H]. 1H NMR (DMSO-d ₆ ) δ 7.91 (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).

Example 26.

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

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 heated at 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 heated at 120°C and stirred for 16 hours, 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 96:3:1 to 52:36:12 hexanes:ethyl acetate:ethanol to give the racemic title compound. The mixture was separated by SFC using a ChiralPak AS-H column and eluting with methanol:carbon dioxide 25:75. The first main eluting peak corresponded to 1-[5-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]-6(methylsulfonyl)-6-azaspiro[2.5]octane, enantiomer A, desired compound, and the second main eluting peak 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]. 1H NMR (DMSO-d ₆ ) δ 7.94 (d, J=2.7 Hz, 1H), 7.71 (dd, J=9.0, 2.7 Hz, 1H), 7.33 (d , J=9.1 Hz, 1H), 3.93 (s, 3H), 3.36-3.27 (m, 1H), 3.21 (t, J=5.4 Hz, 2H), 3 .11 (ddd, J=11.1, 7.3, 3.5 Hz, 1H), 2.98 (ddd, J=11.1, 7.0, 3.3 Hz, 1H), 2.87 (s, 3H), 2.19 (dd, J=7.9, 6.2 Hz, 1H), 1.77-1.56 (m, 3H), 1.26-1.13 (m, 2H ).

Example 27.

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

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 heated at 50°C and stirred for 2 h. mg, 0.201 mmol) and the reaction mixture was heated at 90° C. and stirred for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by HPLC eluting with a gradient of 5:95:0.1 to 95:5:0.1 acetonitrile:water:trifluoroacetic acid to give the title compound. MS: m/z=367.3 [M+H]. 1H NMR (DMSO-d ₆ ) δ 6.74 (s, 1H), 6.72 (s, 2H), 4.18 (q, J=7.4 Hz, 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=7.2 Hz, 3H), 1.21-1.12 (m, 2H).

Example 28.

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

- 74 042108

Step A. (1R)-N-[2-(3-Cyclopropyl-5-methylisoxazol-4-yl)-2-oxoethyl]-6-sulfamoyl-6azaspiro[2.5]octane-1-carboxamide.

Triphenylphosphine (200 mg, 0.761 mmol) ) and the reaction mixture was stirred for 2 h at ambient temperature. Water (0.05 ml) was added and the reaction mixture was stirred for 1 h at ambient temperature. 4 A molecular sieves were added and the reaction mixture was stirred for 15 minutes at ambient temperature. (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) and the reaction mixture was stirred for 18 h at ambient temperature. The reaction mixture was poured into water (50 ml) and the resulting mixture was extracted with ethyl acetate (2x80 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (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].

Step B. (1R)-1-[5-(3-Cyclopropyl-5-methylisoxazol-4-yl)-1,3-oxazol-2-yl]-6azaspiro[2.5]octane-6-sulfonamide.

To a solution of (1R)-N-[2-(3-cyclopropyl-5-methylisoxazol-4-yl)-2-oxoethyl]-6-sulfamoyl-6azaspiro[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 heated at 85°C and stirred for 2 hours. The reaction mixture was cooled to ambient temperature and poured into saturated aqueous sodium bicarbonate (20 ml) and the resulting mixture was extracted with ethyl acetate (2x40 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (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 100:0 to 50:50 hexanes:ethyl acetate to give the title compound. MS: m/z=379.1 [M+H]. 1H NMR (DMSO) δ 7.33 (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, 5.6 Hz, 1H), 1.99 (dd, J= 13.3, 8.2, 5.0 Hz, 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, 2.5 Hz, 2H), 0.88-0.79 (m, 2H).

Example 29.

(2R)-2-{5-[1-Cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro6-azaspiro [2.5]octane-6-sulfonamide.

To a 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) 1-hydroxy-7-azabenzotriazole (40.8 mg, 0.300 mmol) and 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86.0 mg, 0.450 mmol) were added at ambient temperature and the reaction mixture was stirred for 15 minutes. (1R)-2,2-difluoro-N'-hydroxy-6-sulfamoyl-6azaspiro[2.5]octane-1-carboximidamide (intermediate 11) (102 mg, 0.360 mmol) was added and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was heated at 95°C and stirred for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with water, the layers were separated and the organic layer 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 the title compound. MS: m/z=469.2 [M+H]. 1H NMR (DMSO-d ₆ ) δ 7.74 (s, 1H), 6.80 (s, 2H), 4.31 (dt, J=7.1, 3.6 Hz, 1H), 3.39 (d, J=11.7 Hz, 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).

Example 30.

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

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)

- 75 042108 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) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was heated at 110° C. and stirred for 2.5 hours. The reaction mixture was allowed to cool to ambient temperature and filtered, and the filtrate was concentrated in a stream of nitrogen. The residue was purified by HPLC eluting with a gradient of 20:80 to 95:5 acetonitrile:water to give the title compound. MS: m/z=425.2 [M+H]. ¹ H NMR (DMSO-d ₆ ) δ 7.76 (s, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H) , 6.81 (s, 2H), 3.33 (s, 1H), 3.16 (s, 1H), 3.11-3.01 (m, 2H), 2.89 (d, J=6 .6 Hz, 1H), 2.61-2.53 (m, 1H), 2.35 (s, 3H), 1.97 (d, J=6.9 Hz, 3H), 1.95-1 .88 (m, 1H), 0.97 (d, J=8.5 Hz, 2H), 0.70 (q, J=5.8 Hz, 2H).

Example 31.

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

Step A. (2R)-2-[2-(3-Cyclopropylisoxazol-4-yl)-1,3-oxazol-4-yl]-N[(dimethylamino)methylidene]-1,1-difluoro-6-azaspiro [2.5]octane-6-sulfonamide.

To a solution of (2R)-N-[(dimethylamino)methylidene]-1,1-difluoro-2-(iodoacetyl)-6-azaspiro[2.5]octane-6sulfonamide (intermediate 24) (74.5 mg, 0.166 mmol) in ethyl acetate (0.83 ml) 3-cyclopropylisoxazole-4-carboxamide (31.5 mg, 0.207 mmol) and silver trifluoromethanesulfonate (53.3 mg, 0.207 mmol) were added and the reaction mixture was heated at 60°C and stirred for 2 h. The mixture was diluted with saturated aqueous sodium chloride (10 ml) and ethyl acetate (10 ml) and the mixture was stirred for 4 hours. The resulting mixture was filtered, washed with ethyl acetate, the filtrate layers were separated and the aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2x), aqueous HCl (1 M) 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 100:0:0 to 60:30:10 hexanes:ethyl acetate:ethanol to give the title compound. MS: m/z=456.3 [M+H].

Step B. (2R)-2-[2-(3-Cyclopropylisoxazol-4-yl)-1,3-oxazol-4-yl]-1,1-difluoro-6azaspiro[2.5]octane-6-sulfonamide.

To a solution of (2R)-2-[2-(3-cyclopropylisoxazol-4-yl)-1,3-oxazol-4-yl]-N[(dimethylamino)methylidene]-1,1-difluoro-6-azaspiro[ 2.5]octane-6-sulfonamide (42 mg, 0.092 mmol) in methanol (0.92 ml) hydrazine (0.0289 ml, 0.922 mmol) was added and the reaction mixture was heated at 50°C and stirred for 2 h. concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of 100:0:0 to 70:23:7 hexanes:ethyl acetate:ethanol to give the title compound. MS: m/z=401.2 [M+H]. 1H NMR (500 MHz, CDCl ₃ ) δ 8.82 (s, 1H), 7.54 (s, 1H), 4.34 (s, 2H), 3.45 (m, 1H), 3.333.24 ( m, 2H), 3.11 (m, 1H), 2.55-2.52 (m, 1H), 2.49 (d, J=13.8 Hz, 1H), 1.97 (m, 2H ), 1.79-1.70 (m, 1H), 1.711.63 (m, 1H), 1.17-1.07 (m, 4H).

Example 32.

R

A ^Me \

Me _x -Ν. J G /

X

OO Me

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

Basically following the procedures described in Example 21, but using N'-hydroxy-2,5dimethylbenzenecarboximidamide instead of 4-fluoro-N'-hydroxy-2-(trifluoromethyl)benzimidamide, the title compound was obtained. MS: m/z=39S.3 [M+H].

1H NMR (DMSO-d ₆ ) δ 7.70 (s, 1H), 7.29 (s, 2H), 3.69 (d, J=11.4 Hz, 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).

Example 33.

- 76 042108 (1R)-1-[5-(2-Methylphenyl)-1,2,4-oxadiazol-3-yl]-6-azacniro[2.5]octane-6-sulfonamide.

Basically following the procedures described in Example 1, but using 2-methylbenzoic acid instead of 2-methyl-5-(trifluoromethyl)benzoic acid, the title compound was obtained. MS: m/z=349.1 [M+H]. Ή NMR (DMSO-d ₆ ) δ 8.00 (d, J=7.8 Hz, 1H), 7.56 (t, J=7.4 Hz, 1H), 7.46 (d, J=7 .6 Hz, 1H), 7.42 (t, J=7.5 Hz, 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=6.9 Hz, 1H), 1.80-1.73 (m, 1H), 1.72- 1.59 (m, 3H), 1.20 (d, J=7.0 Hz, 2H).

Example 34.

R, F

7h ^Me \ h ₂ n ^ JU y K / F ^N -o O O Me (2R) -2- [5- (2,5-Dimethylphenyl) -1,2,4-oxadiazol-3-yl] -1, 1-difluoro-6-azaspiro[2.5]octane-6sulfonamide.

Basically following the procedures described in Example 30, but using 2,5-dimethylbenzoic acid instead of 2-cyclopropyl-5-methylbenzoic acid, the title compound was obtained. MS: m/z=399.2 [M+H]. ¹ H NMR (DMSO-06) δ 7.85 (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).

Example 35.

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

Basically following the procedures described in Example 24, but using 2(difluoromethoxy)pyridine-4-carboxamide (intermediate 29) instead of 4-fluoro-2(trifluoromethyl)benzamide, the title compound was obtained. MS: m/z=437.2 [M+H]. lH NMR (500 MHz, CDCl ₃ ) δ 8.31 (d, J=5.2 Hz, 1H), 7.67 (d, J=5.3 Hz, 1H), 7.65 (s, 1H) , 7.64-7.36 (t, J=74.5 Hz, 1H), 7.46 (s, 1H), 4.36 (s, 2H), 3.48-3.44 (m, 1H ), 3.41-3.18 (m, 2H), 3.14-3.09 (m, 1H), 2.50 (d, J=13.6 Hz, 1H), 2.04-1, 92 (m, 2H), 1.78-1.73 (m, 1H) 1.67-1.60 (m, 1H).

Example 36.

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

To a solution of 1,1-difluoro-2-{1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}-6azaspiro[2.5]octane hydrochloride (intermediate 31) (23.7 mg, 0.0576 mmol) in 1,4-dioxane (2 ml) were added sulfamide (24.3 mg, 0.253 mmol) and triethylamine (0.04 ml, 0.25 mmol) and the reaction mixture was heated at 100°C and stirred 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 (2x5 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 36:64:0.1 to 66:34:0.1 acetonitrile:water:ammonium hydroxide to give the title compound. MS: m/z=454.9 [M+H]. 1H NMR (400 MHz, CD ₃ OD) δ 7.80 (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).

Example 37.

Oh Oh

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

To a solution of 1,1-difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}-6azaspiro[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

- 77 042108 was heated at 95°C and stirred for 12 hours, the Reaction mixture was cooled to ambient temperature and diluted with water (5 ml). The resulting mixture was extracted with ethyl acetate (3x5 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 petroleum ether:ethyl acetate-50:50 to give the title compound. MS: m/z=472.8 [M+H]. 1H NMR (400 MHz, CDCl3): δ 7.71 (dd, J1=8.4 Hz, J2=5.6 Hz, 1H), 7.58 (dd, J1=8.8 Hz, J2=2, 0 Hz, 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=12.8 Hz, 1H), 2.13-2.19 (m, 2H), 1.99- 2.01 (m, 2H).

Compounds of the examples indicated in the following tables were obtained by analogy with the above examples, as described, or obtained by analogous transformations with modifications known to those skilled in the art. The necessary starting materials are described in the present invention, commercially available, known in the literature or easily synthesized by a person skilled in the art. In some cases, obvious strategies for the use of protecting groups have been used.

EX-A table x x

Example X ^{R1 R2 R3 R4 R3} MS [M+H] A1 H OME Η Η Cl Η 399.1 A2 F H Η Η Η Η 371.1 AZ F _CF3 Η F Η Η 457.1 A4 H _CF3 Η Η F Η 421.1 A5 H Η ochf ₂ Η Η Η 401.2 Ab H Η F Η Η Η 389.2 A7 H F Η F Η Η 407.2 A8 H Η Η _CMe2OH Η Η 429.2

- 78 042108

EX-B table

Example R A note on stereochemistry MS [M+H] IN 1 ^{0 0} Racemic 475.2 AT 2 ⁵ “L Al 0 0 Racemic 466.2 VZ [1 o o mixture of isomers 482.3 AT 4 Me-N 3% N^sA 0 0 Racemic 464.2 AT 5 ο ^{ζ h} o Racemic 488.3 wb 'ο-Ν 0 0 Racemic 502.2 AT 7 λα οό Racemic 517.2 AT 8 0 Α® F ₃ C 0 Ρ'Ν ^Ζ ν K λ U/dA NO 0 0 Racemic 482.2 [M] AT 9 n "Me^N^X. MeI Π Me 0 Racemic 419.2 AT 10 ⁿ _h kA 0 Racemic 445.3 VP oh oh Racemic 490.2 AT 12 Ns H _h vA^N'sA- 0 Racemic 460.2 B13 kA n . kA/MhD O Racemic 453.3 B14 me. RF o o ^o Racemic 398.2

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EX-C table

h ₂ n

Example X Z R A note on stereochemistry MS [M+H] Cl n n Me HN An νΌ Racemic 365.2 C2 n n 0 Racemic 405.3 sz F n Me v-O Me Racemic 390.2 C4 H n Λ' R 366.1 C5 F n T Me R 416.2

- 80 042108

C6 F H R 377.2 C7 F H Me V=Nv-O R 386.2 C8 F H _CF3vO R 440.2 C9 F H oF vC/ ^F R 438.1 CIO F H VpJ Me R 415.2 joint venture F H R 411.2 C12 H H . l /\ II o-z R 434.19 C13 H H MeO Cl Racemic 399.1 C14 F H i n-n R 401.3 C15 F H z-q V—7 R 470.2 C16 F H Z-O // R 470.2 C17 Cl H F ₃ C Racemic 488.8 C18 F Me Me 1-¾ Me Racemic 413.0

- 81 042108

Table EX-D n

Example X ^{R1 R2 R3 R4 R3} MS [M+H] DI H H _CF3 H H H 403.1 D2 H ome H H Cl H 399.1 D3 H CN H H H H 360.1 D4 H OCHF ₂ H H H H 401.1 D5 H H H _CF3 H H 403.1 D6 H _CF3 H H Br H 483.0 D7 H _CF3 H Cl H 437.1 D8 H H H H H H 335.2 D9 H OCHF2 H _CF3 H H 469.1 DIO H OCHF2 H Cl H H 435.1 Dll H H OCHF2 H H H 401.1 D12 H F H H H _CF3 421.1 D13 H H H ome H H 365.2 D14 H H H OCHF2 H H 401.2 D15 H F H F H H 371.3 D16 H _CF3 H F H H 421.2 D17 H _CF3 H H H H 403.1 D18 H _{OCH2CF3 _} H H H H 433.1 D19 H Me H Me H H 363.2 D20 H OCF ₃ H H H H 419.1 D21 H OCF ₃ H H F H 437.1 D22 H OCF ₃ H H Cl H 453.1 D23 H H H _CMe2OH H H 393.3 D24 H OCHF2 H F H H 419.1 D25 H Me H Me Me H 377.2 D26 F cPr H H H H 411.3 D27 H ome H Cl H H 383.2

- 82 042108

Table EX-E x x

Example X R A note on stereochemistry MS [M+H] E1 H Me R 428.2 E2 n Me\=N W R 350.2 E3 n Me Me mixture of isomers 355.2 E4 n \P ^F 3 FO R 435.1 E5 n c/ O F ₃ C R 435.2 E6 n __, Me UCH> Me—<? R 377.2 E7 n Me mixture of isomers 355.2 E8 n Me v< C'-O mixture of isomers 397.1

- 83 042108

E9 Η ^CF ₃ H F R 435.2 EY Η R 425.2 El Η mixture of isomers 367.2 E12 Η QF R 435.1 E13 Η LL mixture of isomers 393.1 E14 Η LL-SRz R 443.2 E15 Η v-C^O mixture of isomers 389.2 E16 Η Me F Me R 364.2 E17 Η CF ₃ N=\ R 404.1 E18 Η W R 434.2 E19 Η Me CF ₃ R 418.2 E20 Η R 353.2

- 84 042108

E21 Η Me ( Ν-Ν ^Me R 367.3 E22 Η R 407.2 E23 Η F ₃ C An R 394.1 E24 Η Me An R 354.2 E25 Η N^ _n ^CF ₃ R 407.2 E26 Η λ R 366.2 E27 Η Me u \__Me R 354.2 E28 Η —h Me Me-\-° R 368.2 E29 Η z-q R 394.1 EZO Η I Ν-Ν v-V R 365.2 E31 Η c? v-0 F ₃ C R 470.2 E32 Η Me An V^yU F ₃ C R 407.2

- 85 042108

E3Z F Uy R 428.3 E34 F I N'N Hu R 401.3 E35 F me me n-n Hu R 417.2 E36 F Me R 425.2 E37 F Λ 1 V-N-^Me R 429.2 E38 F ^F 3\ Me 1 VN R 443.2 E39 F F ₃ ^C R 485.2 E40 F R 415.2 E41 F I n-n Hu Me R 415.2 E42 F ci R 401.3 E43 F Me _t / ^N ' ⁿ Hu R 375.2

- 86 042108

E44 F Kb Φ R 415.3 E45 F Me R 443.2 E46 F Me 'n- _n ^CF ₃ R 469.2 E47 F 7. 75 R 455.2 E48 F , ⁿ 'N F ₃ C R 469.2 E49 F \=N Uj R 413.2 E50 H 4+U R 377.2 E51 F Me oA .__/ Me V-O R 430.2 E52 H Me n-n v-y Me R 353.0 E53 F R 419.1

- 87 042108

E54 F Me Φ F ₃ C R 483.2 E55 F F ₃ C R 470.2 E56 F yQ R 372.2 E57 H F ₃ C R 404.1 E58 H F ₃ C \=N R 404.1 E59 H V=N R 434.2 E60 H R 434.2 E61 H Me V=N v-o 'cF, R 418.2 E62 H Me Me—ζ N'N vAj ¹ R 367.3 E63 H F ₃ C /=N ) NG R 434.2 E64 H V-yj> Me R 379.0

- 88 042108

E65 Η Me N'N rs R 393.3 E66 F Me 'N'N R 429.2 E67 F R 372.3 E68 F F ₃ C R 430.2 E69 H R 375.2 E70 H _cf z ^CF 3 R 469.1 E71 H F b R 427.1 E72 H +cP R 389.2 E73 H 0vb R 400.1 E74 H F V-Cj R 429.2 E75 H CN R 400.1 E76 H QvO R 413.1 E77 H O R 401.2 E78 H /—CF ₃ 0 R 434.2

- 89 042108

Table EX-F x x

Example X A R MS [M+H] fl Η 0 F ₃ C 421.1 F2 Η 0 _CF3vO 403.1 F3 Η 0 O'CF _3nb 419.1 F4 Η S R F 387.1 F5 Η 0 Me t-Q F 367.1

- 90 042108

F6 H 0 /-CF ₃ o Λ 433.2 F7 H s ^CF ₃ O 449.1 F8 H s Me 365.2 F9 H s F ₃ C 437.2 F10 H s F p-{ v-c5 417.2 Fil H 0 Me 380.2 F12 H s Me 396.2 F13 F 0 Me 385.1 F14 F s Me Λ 401.1

Table EX-G

- 91 042108

G1 H 334.2 G2 H νλs 381.0 G3 H Me // Me 352 G4 F A' 417.2 G5 F F ₃ C A-H aVf Iru 456.1 G6 F F p-4 /=4 ^F 436.9 G7 F A^n /= n Me 414.0 G8 F A^\ /= N V^\__Z 1 λ 7 VO °N 401.0 G9 F F ₃ CAA N'O'-- 456.0 GIO F A^n A. _f Υηγ 456.1 Gil F F ₃ G W ^S N 472.0

- 92 042108

Table EX-H x x

Example X R MS [M+H] H1 H Meo ί AA Ο-N A CI 399.1 H2 F F ₃ C AV F 457.1 NZ F AO θ'Ν ⁴ — 377.2 H4 F F Ο-n ⁴ - ¹ 389.2 H5 F Me AAI) n ~ _n ^z 385.1 H6 F Me Ab nA 401.1

Table EX-I

Example ^{x1 x2} Y ¹ Y 2 R A note on stereochemistry MS [M+H] eleven H H F H One isomer 419.2

- 93 042108

12 Η Η F Η F F-4 0 Χ_Ν ΧΑ One isomer 419.2 13 Η Η F F Χ^ν ΧΑ One isomer 371.2 14 Η Η F F Me Χ^Ν Χα Me One isomer 399.3 15 Η Η Me Η F ₃ C-\ O Ο-n ⁴ - One isomer 448.3 16 Η Η F Η Χ^,Ν /= Ν xrx One isomer 384.2 17 Η Η F Η αΧ One isomer 384.1 18 Η Η F Η l t One isomer 384.1 19 Η Η F Η ya O-n One isomer 384.2 BY Η Η F Η XsAl /= Nx^ One isomer 384.2 Ill F F F Η m-l χχχ mixture of isomers 420.2

- 94 042108

112 F F F H z-o mixture of isomers 420.2 113 F F F H z-o V One isomer 420.2 114 F F F H Λ T /=n One isomer 420.1 115 F F F H ^F 3 ^C x / Vf X "kJ ON '— mixture of isomers 475.3 116 F F F H ^F 3<\ A_N V\ _F mixture of isomers 475.2 117 F F F H ^F ₃ C A_N / VF mixture of isomers 475.2 118 F F F H ^F 3 ^C A^N /V _F θ'Ν ^λ — mixture of isomers 475.2 119 F H H H ^F 3 ^C X A^ /Vf TH/ On ⁴ ' Racemic 473.0 120 Me H H H ^F aC A_^N LL F θ'Ν ^λ — mixture of isomers 439.0 121 Me Me H H ^F 3 ^C X A+l / VF VVV ^F One isomer 435.0 122 F F H H f ₃ c A+JV\ _F VVV ^f Racemic 449.2

Table EX-J

x ¹ x ²

Example ^{x1 x2} W R Note about stereochemistry MS [M+H] L n n 2 o _h 7 'co °'u Meo A_,N /V 1-GM CI Racemic 398.1 J2 F F H ₂ K X o' ^A o A_a GA Ύ V-Ch / N-s Racemic 394.0

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EX-K table

Me

Me

Example R Note about stereochemistry MS [M+H] K1 Η ₂ Ν θ' o One isomer 425.2 K2 f co ² ζ ^P O SM I mixture of isomers 413.0

The utility of the compounds of the present invention as a positive allosteric modulator of α7 nicotinic acetylcholine receptor activity can be demonstrated by methodology known in the art. Direct activation of α7 (agonism) and increase in acetylcholine-induced α7 currents were studied as follows.

Automatic technique for local fixation of the potential.

Functional analysis (analysis A).

Automated local clamping technique was performed using IonFlux HT (Fluxion Biosciences Inc., San Francisco, CA) using population clamped whole cells. Test compounds were tested for their ability to modulate α7 nicotinic acetylcholine receptor function in the presence and absence of a suitable α7 acetylcholine agonist.

A HEK cell line stably expressing human RIC-3 and human α7 (PrecisION hnAChR a7/RIC-3, Eurofins Pharma, St. Charles, MO) was grown in 175 cm ² three-layer tissue growth mats until no more than 90% confluence in medium for growing DMEM/F-12 supplemented with 10% heat-inactivated fetal bovine serum, 1% essential amino acids, 0.625 µg/ml puromycin, and 400 µg/ml geneticin. Immediately prior to analysis, cells were separated by aspirating growth media, rinsed with Dulbecco's phosphate buffered saline, and then 10 ml of Accutase (Innovative Cell Technologies, San Diego, CA) was added to the flask and then incubated at 37°C for 5 min. The detached cells were then reconstituted by adding 40 ml of serum-free CHO media supplemented with 25 mM HEPES and gently shaking in a 50 ml conical tube for 20 minutes and then subjected to local clamp assay. After recovery, the cells were pelletized by centrifugation at 1000 rpm for 1 min in a compact bench top centrifuge; reducing media was aspirated and cells were resuspended in external measurement solution (150 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 12 mM dextrose) to a density of 5.0 x 10 ⁶ cells/ml. The cell suspension was introduced into the cell injection wells of the IonFlux HT population clamp plate, which was pre-washed and primed with deionized H2O. Test compounds were serially diluted in DMSO and then resuspended to the final test concentration in external measurement solution with or without the addition of 40 μM acetylcholine; then, test compounds were transferred to an IonFlux HT population clamp plate. The internal measurement solution (110 mM TrisPO ₄ , 28 mM TrisBase, 0.1 mM CaCl ₂ , 2 mM MgCl ₂ , 11 mM EGTA, 4 mM MgATP) was injected into the internal measurement wells of the IonFlux HT plate clamps, into which the cells and test compounds were pre-placed, and the plate was inserted into the IonFlux HT instrument. In the IonFlux HT, a cell capture, cell separation, and whole cell assay configuration was performed; the cells were clamped at a holding potential of -60 mV for the duration of the experiment, all experiments were performed at room temperature and the IonFlux HT injection pressure was ⁸ psig for the injection solution. After establishing the configuration of whole cells, the external measurement solution was injected into the recording chambers for 120 s and then 40 μM acetylcholine was injected for 1 s and immediately flushed with the external measurement solution for 60 s. The α7 current evoked by 40 μM acetylcholine acted as a response current to which the subsequent test compound in the presence or absence of 40 μM acetylcholine reacted and quantified. Then, for the studied compounds at different concentrations, the ability to induce or modulate the response currents α7 was investigated; three increasing concentrations of test compound were examined. To assess the agonistic activity of the

- 96 042108 of the following compound, the test compound, diluted with the solution for external measurements, was studied, starting with the lowest concentration of the test compound, for 58 s; the first 20 s of the 58 s of the compound administration period coincided with a 20 s data acquisition period and data was collected at a rate of 5000 samples/s. To determine the positive allosteric modulating activity of the test compound, immediately after the administration of the test compound for 58, at the same concentration of the test compound, diluted with a solution for external measurements containing 40 μM acetylcholine, was administered for 1 s; thus, the test compound and the natural acetylcholine receptor agonist were co-administered, and an activation-enhancing effect of the test compounds was observed. 1 s administration of test compound diluted with external measurement solution containing 40 μM acetylcholine coincided with a 20 s data collection period and data was collected at a rate of 5000 samples/s followed by 42 s administration of external measurement solution alone . After these 42 seconds, washing with external measurement solution only, test compound was administered at the next higher concentration in the absence and then in the presence of acetylcholine as previously described, and data was collected as previously described. The agonistic and positive allosteric modulating activity was then evaluated at three increasing concentrations of the test compound, the experiment was terminated, and the leakage current was subtracted using the IonFlux HT data analysis software. Area under the curve (AUC) peak current amplitudes were quantified for each current sweep using proprietary software, and test compound effects were quantified as follows.

The agonist activity of the test compound was calculated as follows.

Agonism, %=(Y/X)x100

The enhancing activity of the test compound was calculated as follows.

Gain, %=[(Z/X)x100]-100

X=peak current amplitude (or AUC) due to 40 μM acetylcholine.

Y=Peak current amplitude (or AUC) due to test compound diluted with external measurement solution.

Z=Peak current amplitude (or AUC) due to test compound diluted with external measurement solution containing 40 μM acetylcholine.

On their own, test compounds that produced the same current amplitude as 40 μM acetylcholine alone should have a calculated agonism, %, of 100%. Test compounds administered together with 40 μM acetylcholine, which result in a current amplitude equal to 2x the current amplitude due to 40 μM acetylcholine alone, should have a calculated gain, %, equal to 100%, and test compounds administered together with 40 μM acetylcholine, which result in a current amplitude as high as 40 μM acetylcholine alone should be characterized as not leading to an increase.

Agonism and gain data derived from peak current amplitude or area under the curve (AUC) are presented graphically and fitted with a 4-parameter logistic relationship based on the Levenberg-Marquardt algorithm, where y=A+((BA)/(1+( (C/x) ^Λ D))), where

A=minimum, B=maximum, C=EC ₅ 0, D=slope, x=test compound concentration, y=agonism, % or enhancement, %.

Activity data for selected compounds of the present invention, according to the automatic method of functional analysis of local clamping potential (analysis A) are shown in the table below.

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Example α7 nAChR activity

1 A 2 A 3 WITH 4 IN 5 WITH 6 IN 7 WITH 8 IN 9 A 10 IN eleven A 12 IN 13 A 14 A 15 IN 16 IN 17 WITH 18 WITH 19 IN 20 A

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21 WITH 22 A 23 WITH 24 A 25 IN 26 IN 27 WITH 28 IN 29 IN thirty A 31 IN 32 WITH 33 IN 34 A 35 IN 36 WITH 37 WITH Al IN A2 IN AZ IN A4 WITH A5 WITH Ab IN A7 IN A8 WITH Bl WITH AT 2 WITH VZ WITH AT 4 WITH AT 5 With wb With AT 7 With AT 8 With AT 9 D

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bio C vp C B12 C B13 D B14 C Cl C C2 C C3 IN C4 C C5 A C6 IN C7 C C8 C C9 IN CIO A joint venture C C12 IN C13 C C14 IN C15 A C16 A C17 C C18 C DI C D2 A D3 D D4 IN D5 C D6 IN D7 C D8 C D9 C DIO A Dll C

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D12 WITH D13 WITH D14 With D15 With D16 V D17 With D18 V D19 V D20 V D21 V D22 V D23 With D24 V D25 V D26 A D27 With El V E2 With E3 With E4 D E5 WITH E6 WITH E7 WITH E8 With E9 With EY With El With E12 With E13 With E14 With E15 With E16 With E17 With E18 With

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E19 IN E20 WITH E21 IN E22 With E23 With E24 With E25 With E26 With E27 With E28 With E29 With EZO With E31 With E32 V E3Z V E34 V E35 V E36 With E37 A E38 V E39 V E40 With E41 A E42 WITH E43 V E44 V E45 With E46 With E47 V E48 A E49 IN E50 WITH E51 WITH E52 WITH

- 102042108

E53 WITH E54 IN E55 A E56 WITH E57 WITH E58 WITH E59 IN E60 WITH E61 With E62 With E63 With E64 With E65 V E66 V E67 With E68 With E69 A E70 WITH E71 V E72 V E73 With E74 V E75 D E76 WITH E77 WITH E78 WITH fl WITH F2 WITH F3 With F4 With F5 V F6 With F7 V F8 With

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F9 c F10 V Fil V F12 With F13 V F14 V G1 With G2 With G3 With G4 V G5 A G6 A G7 WITH G8 A G9 A GIO A Gil IN Hl D H2 WITH H3 WITH H4 WITH H5 WITH H6 WITH II WITH 12 WITH 13 WITH 14 WITH 15 WITH 16 WITH 17 WITH 18 D 19 WITH IIO WITH Ill WITH

- 104 042108

112 IN 113 WITH 114 IN 115 WITH 116 WITH 117 WITH 118 IN 119 With 120 With 121 With 122 With L With J2 With K1 A K2 IN

* Activity is defined as A (EC ₅ o<0.1 μM); B (0.1 μM<EC ₅ o<0.5 μM); C (0.5 μM<EC ₅₀ <5 μM); D (5 μM<EC ₅₀ <50 μM).

The electrophysiological values of EC ₅ o for selected compounds of the present invention, according to the automatic method of functional analysis of local potential clamping (analysis A) are shown in the table below.______________________________________________

Example a7 nAChR EC ₅₀ (nM) 1 98 2 82 3 1300 4 350 5 1200 6 280 7 1100 8 230 9 75 10 220 eleven 58 12 220 13 73 14 49

- 105 042108

- 106 042108

- 107 042108

- 108 042108

- 109 042108

- 110 042108

It should be understood that the various features and functions discussed above and other features and functions, or alternatives thereof, may be combined to provide many other systems or applications, if desired. In addition, unforeseen or unexpected alternatives, modifications, changes or improvements may be made by those skilled in the art and are also included in the appended claims.

Claims (29)

CLAIM 1. A compound selected from the group consisting of (1R)-1-{5-[2-Methyl-5-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[ 2.5]octane-6sulfonamide; (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-6sulfonamide, diastereoisomer WITH; 1-{3-[3-(Difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6sulfonamide, diastereoisomer E; (1R)-1-{3-[4-Fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxαdiazol-5-yl}-6-azaspuro[2.5]octane-6sulfonamide; 1-{3-[4-Fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-4-methyl-6-azaspiro[2.5]octane-6sulfonamide, diastereoisomer D; (1R)-1-{2-[3-(Trifluoromethoxy)phenyl]-1,3-thiazol-4-yl}-6-azaspyro[2.5]octane-6-sulfonamide; (1R)-1-{5-[4-Methyl-1-(2,2,2-trifluoroethyl)-1 H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-6azaspiro [2.5]octane-6-sulfonamide; - 111 042108 (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-6azaspiro[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) -1 H-pyrazol-5-yl] -1,2,4-oxadiazol-5 -yl} -6azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{5-[2-(Difluoromethoxy)-5-methylpyridin-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6azaspiro [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}-6azaspiro [ 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-6azaspiro [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]octane6- 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-6azaspiro [2.5]octane-6-sulfonamide; (2R)-1,1 - Difluoro-2- {5-[1 -methyl-3 -(trifluoromethyl)-1 H-pyrazol-4-yl] -1,2,4-oxadiazol-3 -yl} -6azaspiro [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-3yl]- 6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1-Difluoro-2-[5-(1,3,4-trimethyl-1 H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6azaspiro [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-6sulfonamide; (2R)-2-[5-(1-Cyclopropyl-4-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6azaspiro [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-6sulfonamide; (1R)-1-[5-(3-Cyclopropyl-5-methylisoxazol-4-yl)-1,3-oxazol-2-yl]-6-azaspiro[2.5]octane-6sulfonamide; (2R)-2-{5-[1-Cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro6-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-6sulfonamide; (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-6sulfonamide; (2R)-2-{2-[2-(Difluoromethoxy)pyridin-4-yl]-1,3-oxazol-4-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6sulfonamide; 1,1-Difluoro-2-{1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; 1,1-Difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (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} -6azaspiro [2.5] octane-6-sulfonamide ; (1R)-1-{3-[5-Fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6sulfonamide; (1R)-1-{3-[3-(Difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6sulfonamide; (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-6sulfonamide; (2R)-1,1 - Difluoro-2- {3-[4-(2-hydroxypropan-2-yl)phenyl] -1,2,4-oxadiazol-5 -yl} -6azaspiro [2.5] octane-6 -sulfonamide; - 112 042108 1-{3-[2-(Pyrrolidin-1-yl)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6sulfonamide; 2-[3-(3,5-Dimethylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6-azaspiro[2.5]octane-6sulfonamide; (1R)-1-[3-(3-Cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-6-azaspiro[2.5]octane-6sulfonamide; (2R)-2-[3-(3-Cyclopropyl-5-methylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6azaspiro[2.5]octan-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-6sulfonamide; (2R)-1,1-Difluoro-2-{3-[2-(trifluoromethyl)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-6azaspiro[2.5]octane-6-sulfonamide ; (2R)-2-{3-[2-(Difluoromethoxy)pyridin-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6azaspiro[2.5]octane-6-sulfonamide ; (2R)-2-[3-(1-Cyclopropyl-4-methyl-1 H-pyrazol-5-yl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6azaspiro [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-6sulfonamide; (1R)-1-{3-[5-Cyclopropyl-3-(trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-5-yl}-6azaspiro[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-1 H-pyrazol-5-yl)-1,2,4-oxadiazol-5-yl]-1,1-difluoro-6azaspiro[2.5]octane-6 -sulfonamide; (2R)-2-{3-[3-Cyclopropyl-5-(trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6azaspiro[2.5]octane -6-sulfonamide; (2R)-2-{3-[5-Cyclopropyl-3-(trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-5-yl}-1,1-difluoro-6azaspiro[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-6sulfonamide; (1R)-1-{5-[3-(Trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6-sulfonamide; (R)-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-6sulfonamide; (1R)-1-{5-[4-Chloro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (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}-6azaspiro[2.5]octane-6-sulfonamide; (1R)-1-{5-[4-Chloro-2-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (1R)-1-{5-[3-(Difluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (1R)-1-{5-[2-Fluoro-6-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (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-6sulfonamide; (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-6sulfonamide; (1R)-1-[5-(2,4-Dimethylphenyl)-1,2,4-oxαdiαzol-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-6sulfonamide; (1R)-1-{5-[5-Chloro-2-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; - 113 042108 (1R)-1-{5-[4-(2-Hydroxypropan-2-yl)phenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (1R)-1-{5-[2-(Difluoromethoxy)-4-fluorophenyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (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-6sulfonamide; (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-6sulfonamide; (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-6sulfonamide; (1R)-1-{5-[2-Fluoro-6-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (1R)-1-{5-[2-Fluoro-5-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (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-[1-(2,5-Difluorophenyl)cyclobutyl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (1R)-1-[5-(Spiro[2.5]oct-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-6sulfonamide; (1R)-1-[5-(4-Fluoro-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane- 6sulfonamide; (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-6sulfonamide; (1R)-1-{5-[2-(2,2,2-Trifluoroethoxy)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide ; (1R)-1-{5-[3-Methyl-6-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (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-6sulfonamide; (1R)-1-{5-[1-(2,2,2-Trifluoroethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5] octane-6sulfonamide; (1R)-1-{5-[4-(Trifluoromethyl)-1,3-oxazol-5-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (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-6sulfonamide; (1R)-1-[5-(3-Cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6sulfonamide; (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-6sulfonamide; (1R)-1-{5-[3-(Trifluoromethyl)isoxazol-4-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (1R)-1-[5-(1-Cyclopropyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane-6sulfonamide; (1R)-1-{5-[2-(1H-Imidazol-1-yl)-5-(trifluoromethyl)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}-6azaspiro [2.5 ] octane-6-sulfonamide; (1R)-1-{5-[1-Methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-6azaspiro [2.5]octan-6- sulfonamide; (2R)-2-{5-[2-(Cyclopropyloxy)pyridin-4-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro-6azaspiro[2.5]octane-6-sulfonamide ; - 114 042108 (2R)-2-[5-(1-Cyclopropyl-1 H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl] -1,1-difluoro-6azaspiro [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-а]pyridin-7-yl)-1,2,4-oxadiazol-3-yl]-6azaspiro [2.5] octane-6-sulfonamide; (2R)-2-[5-(3-Cyclopropyl-1-ethyl-1 H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6azaspiro [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}-6azaspiro [ 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- 6azaspiro[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 ]-6azaspiro[2.5]octane-6-sulfonamide; (2R)-2-[5-(1-Cyclopropyl-4-methyl-1 H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-1,1-difluoro-6azaspiro [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-6azaspiro[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- 6sulfonamide; (2R)-1,1-Difluoro-2-[5-(1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-1,2,4-oxadiazol-3yl]- 6-azaspiro[2.5]octane-6-sulfonamide; (2R)-1,1 - Difluoro-2- {5-[1 -methyl-3 -(trifluoromethyl)-1 H-pyrazol-5-yl] -1,2,4-oxadiazol-3 -yl} -6azaspiro [2.5] octane-6-sulfonamide; (2R)-2-{5-[1-Cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro6-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- difluoro6-azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{5-[1-Cyclopropyl-4-(trifluoromethyl)-1 H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-1,1-difluoro6-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-6sulfonamide; (2R)-1,1 - Difluoro-2- {5-[2-(propan-2-yloxy)pyridin-4-yl] -1,2,4-oxadiazol-3-yl} -6azaspiro [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-6sulfonamide; (2R)-1,1-Difluoro-2-[5-(4H-pyrazolo[1,5-c] [1,3]thiazol-3-yl)-1,2,4-oxadiazol-3-yl] -6azaspiro[2.5]octane-6-sulfonamide; (2R)-2-{5-[1-Cyclopropyl-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl} -1,1difluoro - 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-6azaspiro[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-6sulfonamide; (1R)-1-{5-[4-(Trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (1R)-1-{5-[2-(Trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (1R)-1-{5-[2-(2,2,2-Trifluoroethoxy)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide ; (1R)-1-{5-[5-(2,2,2-Trifluoroethoxy)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide ; (1R)-1-{5-[2-Methyl-5-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; (1R)-1-{5-[1-(Propan-2-yl)-1H-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane- 6sulfonamide; (1R)-1-{5-[6-(2,2,2-Trifluoroethoxy)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide ; (1R)-1-[5-(1-Cyclopropyl-4-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]-6-azaspiro[2.5]octane 6-sulfonamide; - 115 042108 (1R)-1 -[5-(2-Methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-1,2,4-oxadiazol-3-yl]-6azaspiro [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 ]-6azaspiro[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}-6azaspiro[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-6sulfonamide; (1R)-1-(5-{3-[5-(Trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1,2,4-oxadiazol-3-yl)-6azaspiro[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-6sulfonamide; (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'-Fluoro-biphenyl-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-6sulfonamide; (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-6sulfonamide ; (1R)-1-{5-[4-Fluoro-2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-6-azaspiro[2.5]octane-6sulfonamide; (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-6sulfonamide; (1R)-1-{5-[2-(2,2,2-Trifluoroethoxy)phenyl]-1,3,4-thiadiazol-2-yl}-6-azaspiro[2.5]octane-6sulfonamide; (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-6sulfonamide; (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-6sulfonamide; (1R)-1-[5-(3-Cyclopropyl-5-methylisoxazol-4-yl)-1,3,4-thiadiazol-2-yl]-6-azaspiro[2.5]octane-6sulfonamide; (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-6sulfonamide; (2R)-2-{3-[2-(Difluoromethoxy)pyridin-4-yl]isoxazol-5-yl}-1,1-difluoro-6-azaspiro[2.5]octane-6sulfonamide; (2R)-2-[4-(3-Cyclopropylisoxazol-4-yl)-1-methyl-1H-imidazol-2-yl]-1,1-difluoro-6azaspiro[2.5]octane-6-sulfonamide; (2R)-2-(3'-Cyclopropyl-3,4'-biisoxazol-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-6sulfonamide; (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}-6azaspiro[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-oxad iazol-5-yl]-6-azaspiro[2.5]octane-6sulfonamide; (25)-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; - 116 042108 1-{3-[3-(Difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4-fluoro-6-azaspiro[2.5]octane-6sulfonamide; 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-6sulfonamide; 2-[3-(3-Cyclopropylisoxazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,1,4-trifluoro-6-azaspiro[2.5]octane-6sulfonamide; 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-Fluoro-2-{3-[4-fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-6-azaspiro[2.5]octane-6sulfonamide; 1-{3-[4-Fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-2-methyl-6-azaspiro[2.5]octane-6sulfonamide; 2-{3-[4-Fluoro-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-1,1-dimethyl-6-azaspiro[2.5]octane-6sulfonamide; 1,1-Difluoro-2-{5-[4-fluoro-2-(trifluoromethyl)phenyl]isothiazol-3-yl}-6-azaspiro[2.5]octane-6sulfonamide; 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-6sulfonamide; or a pharmaceutically acceptable salt thereof. 2. A pharmaceutical composition containing (i) a pharmaceutically acceptable carrier and (ii) a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 3. Pharmaceutical composition according to claim 2, additionally containing a second therapeutic agent selected from the group consisting of acetylcholinesterase inhibitors; NMDA receptor antagonists; antipsychotics; MAO-B inhibitors; and levodopa. 4. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in therapy to modulate a7 nAChR activity. 5. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cognitive impairment associated with Alzheimer's disease, Parkinson's disease and schizophrenia in a patient in need thereof. 6. The use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the treatment of a patient with cognitive impairment associated with Alzheimer's disease, Parkinson's disease and schizophrenia. 7. The use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in a method of treating a patient with cognitive impairment associated with Alzheimer's disease, Parkinson's disease and schizophrenia. 8. The compound that is or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 8, which is 10. A pharmaceutical composition containing (i) a pharmaceutically acceptable carrier and (ii) a compound according to claim 9. 11. A compound that is - 117 042108 or a pharmaceutically acceptable salt thereof. 12. The compound according to claim 11, which is 13. A pharmaceutical composition containing (i) a pharmaceutically acceptable compound according to claim 12. 14. Compound which is a carrier (ii) or a pharmaceutically acceptable salt thereof. 15. The compound according to claim 14, which is 16. A pharmaceutical composition containing (i) a pharmaceutically acceptable compound according to claim 15. 17. Compound which is a carrier (ii) or a pharmaceutically acceptable salt thereof. 18. The compound according to claim 17, which is 19. A pharmaceutical composition containing (i) a pharmaceutically acceptable compound according to claim 18. 20. Compound which is a carrier (ii) or a pharmaceutically acceptable salt thereof. 21. The compound according to claim 20, which is 22. A pharmaceutical composition containing (i) a pharmaceutically acceptable compound according to claim 21. 23. Compound which is a carrier (ii) - 118 042108 or a pharmaceutically acceptable salt thereof. 24. The compound according to claim 23, which is 25. A pharmaceutical composition containing (i) a pharmaceutically acceptable carrier and (p) a compound according to claim 24. 26. A compound that is or a pharmaceutically acceptable salt thereof. 27. The compound according to claim 26, which is 28. A pharmaceutical composition containing (i) a pharmaceutically acceptable carrier and (p) a compound according to claim 27. 29. The use of a compound according to any one of claims 8, 9, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26 or 27, or a pharmaceutically acceptable salt thereof, in a method of treating a patient with Alzheimer's dementia from weak to moderate.