5-oxa-2-azaspiro [3.4] octane derivatives as M4 agonists

Abstract

Provided herein are compounds according to Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R5 and R7 are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of formula (I) and the use of such compounds as M4 receptor agonists. # imgabs0 #

Description

[0001] This application is a divisional application of Chinese patent application 202080070235.1, with an application date of October 7, 2020, a priority date of October 9, 2019, and an invention name of “5-oxa-2-azaspiro[3.4]octane derivatives as M4 agonists”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 912,986, filed on October 9, 2019, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0004] Provided herein are novel 2-azaspiro[3.4]octane compounds that act as M4 receptor agonists, and pharmaceutical compositions thereof, for use in treating conditions, diseases and disorders associated with the M4 receptor, including but not limited to psychosis, hyperkinetic movement disorders, cognitive dysfunction and substance use disorders. Background Art

[0005] Acetylcholine is the major neurotransmitter in the central and peripheral nervous systems, signaling through activation of its ionotropic (nicotinic) receptors and G protein-coupled (muscarinic) receptors. Five muscarinic receptors (M1-M5) have been identified with differential expression and signaling. The M1, M3, and M5 receptors are coupled to Gq proteins that activate phospholipase C. Phospholipase C hydrolyzes membrane phosphoinositides to inositol triphosphate (IP 3 ) and diacylglycerol (DAG), which elevate intracellular calcium and activate many signaling pathways. M2 and M4 receptors interact with G i / oProtein coupling, which inhibits adenylate cyclase production and reduces cyclic adenosine monophosphate (cAMP) levels (having an inhibitory effect on cellular function). M1 receptors are expressed primarily in the forebrain (cortex, hippocampus, striatum and thalamus) and on the salivary glands (Brain Res Mol Brain Res [Brain Research and Molecular Brain Research] 2005, 133(1):6-11; Br. J. Pharmacol [British Journal of Pharmacology] 2006, 148, 565-578; Pharmacol Ther [Journal of Ophthalmic Pharmacology and Therapeutics] 2008, 117:232-243). M2 receptors are expressed in the brain and are also highly expressed in the heart, where they mediate vagal innervation and may affect heart rate (Br. J. Pharmacol [British Journal of Pharmacology] 2006, 148, 565-578; Pharmacol [Journal of Ophthalmic Pharmacology and Therapeutics] 2008, 117: 232-243). M3 receptors are primarily expressed in the smooth muscle of peripheral tissues, including the gastrointestinal tract, bladder, eyes, sweat glands, and salivary glands (Br. J. Pharmacol [British Journal of Pharmacology] 2006, 148, 565-578). M4 receptors are abundant in the brain and are primarily expressed in the striatum, a brain region involved in dopamine release and signaling (J Neurosci 1994 14(5):3351-3363; Proc Natl Acad Sci USA 1999, 96(18):10483-10488; Pharmacol Ther 2008, 117:232-243). M5 receptors are expressed on the vascular system, including the cerebral vessels (Proc Natl Acad Sci USA 2001, 98(24):14096-14101).

[0006] In the central nervous system, muscarinic receptors have been shown to play a key role in the regulation of cognition and dopaminergic signaling (Neuron 2017, 94 (3): 431-446). Of particular interest is the M4 receptor, which is highly expressed in the striatum. Genetic deletion of the M4 receptor causes an excessive dopaminergic phenotype in rodents. M4 knockout mice have been shown to have elevated striatal dopamine levels and increased motor activity (Proc Natl Acad Sci USA 1999, 96 (18): 10483-10488.; FASEB J 2004, 18 (12): 1410-1412). Consistent with these observations, pharmacological activation of the M4 receptor reduced amphetamine-induced dopamine release and reversed amphetamine-induced hyperlocomotion in mice (Neuropsychopharm [Journal of Neuropsychopharmacology] 2004, 39: 1578-1593). Therefore, these results show that the M4 receptor can serve as a negative regulator of dopamine release and signaling in the striatum.

[0007] Increased dopamine tone in the striatum is closely associated with psychotic symptoms in schizophrenia and other diseases, including psychotic depression, bipolar disorder, Huntington's disease, and Alzheimer's disease (Lancet 1988, 2: 119-125; Schizophr Bull 2009, 35: 549-562). Current antipsychotic drugs work primarily by blocking the action of dopamine at D2 receptors. However, they have limited efficacy and severe side effects, including drug-induced parkinsonism, tardive dyskinesia, Q-Tc prolongation, weight gain, and metabolic syndrome, which lead to poor patient compliance (N Engl J Med 2005, 353: 1209-23).

[0008] Activation of the muscarinic M4 receptor has been shown to downregulate striatal dopamine signaling and thus may provide an alternative approach to treating psychosis. Supporting this concept, the muscarinic agonist xanomeline showed strong antipsychotic efficacy when tested in two clinical trials in patients with Alzheimer's disease (Arch Neurol 1997, 54(4):465-473) and schizophrenia (Am J Psychiatry 2008, 165(8):1033-1039). However, its treatment is associated with a number of side effects, including nausea, vomiting, excessive salivation, indigestion, and chills, which discontinued its clinical studies. Xanomeline is a pan-muscarinic agonist that activates all muscarinic receptor subtypes. Studies have shown that the antipsychotic efficacy of xanomeline is primarily mediated by activation of the M4 receptor. M4 receptors are highly expressed in the human striatum (Schizophr Res 2015, 169:83-88.) and the antipsychotic-like effects of xanomeline on dopamine-mediated behaviors are abolished in M4 knockout mice (Eur J Pharmacol 2009, 603:147-149; J Neurosci 2011, 31(16):5905-5908.). In contrast, the side effects of xanomeline are most likely due to activation of M2 and M3 receptors expressed in the heart, digestive tract, and salivary glands (CNS Drug Review 2003, 9:159-186; Br. J. Pharmacol 2006, 148, 565-578). Therefore, M4-selective agonists may preserve the antipsychotic efficacy of xanomeline without causing cholinergic side effects.

[0009] Therefore, compounds that act as M4 receptor agonists are useful in treating M4-related disorders. Summary of the invention

[0010] In one embodiment, provided herein is a compound according to formula (I)

[0011]

[0012]

[0013] or a pharmaceutically acceptable salt thereof, wherein

[0014] R 1 is a halogen or hydrogen;

[0015] R 2 is a halogen or hydrogen;

[0016] R3 yes

[0017] Optionally substituted C 1-3 alkyl, which is optionally substituted with a 4- to 6-membered heterocycloalkyl,

[0018] Optionally substituted 5- to 6-membered heteroaryl, the heteroaryl group is optionally substituted with one C 1-3 alkyl, 4 to 6 membered heterocycloalkyl, or

[0019] -OR 4 ;

[0020] R 4 yes

[0021] Optionally substituted C 1-5 Alkyl, the alkyl group is optionally replaced by one or two R 6 replace,

[0022] An optionally substituted 3 to 9 membered heterocycloalkyl group, the heterocycloalkyl group being optionally substituted by one or two R 6 Replace, or

[0023] An optionally substituted 4- to 6-membered cycloalkyl group, the cycloalkyl group being optionally substituted by one, two or three R 6 replace;

[0024] R 5 is a halogen or hydrogen;

[0025] Each R 6 Independently

[0026] halogen,

[0027] -OH,

[0028] -OCH 3 ,

[0029] -C(CH 3 ) 2 OH,

[0030] -CH 2 OH,

[0031] Cyano,

[0032] Optionally substituted C 1 -C 4 alkyl, said alkyl being optionally substituted with -OH,

[0033] Optionally substituted 4 to 7 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted with one or two substituents independently selected from the group consisting of halogen, -OH, -OCH 3 and C 1-3 Alkyl, or

[0034] Optionally substituted 5- to 6-membered heteroaryl, the heteroaryl group is optionally substituted with one C 1-3 Alkyl substituted; and

[0035] R 7 It is a 5-membered heteroaryl.

[0036] In one embodiment, provided herein is a compound according to formula (Ia)

[0037]

[0038] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0039] In one embodiment, provided herein is a compound according to formula (Ib)

[0040]

[0041] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0042] In one embodiment, R 1 is selected from the group consisting of: H, chlorine and fluorine. In another embodiment, R 1 It's fluorine.

[0043] In one embodiment, R 2 It is H or fluorine.

[0044] In one embodiment, R 5 It is H or fluorine.

[0045] In one embodiment, R 1 , R 2 and R 5 It's H.

[0046] In one embodiment, R 2 and R 5 It's H.

[0047] In one embodiment, R 3 Selected from the group consisting of: In some embodiments, R 3 Yes-OR 4 .

[0048] In one embodiment, R 4 Selected from the group consisting of: CH 3 、-CH 2 CH 2 C(CH 3 ) 2 OH, -CH 2CH 2 C(CH 3 ) 2 OCH 3 、-CH 2 CH 2 OCH 3 and -CH 2 C(CH 3 ) 2 OH. In some embodiments, R 4 Selected from the group consisting of:

[0049]

[0050] In another embodiment, R 4 It is C 1 -C 5 Alkyl and R 6 are independently cyano, -OH, -OCH 3 ,

[0051] In one embodiment, R 7 Selected from the group consisting of:

[0052] In one embodiment, provided herein is a compound according to formula (I)

[0053]

[0054] or a pharmaceutically acceptable salt thereof, wherein

[0055] R 1 is a halogen or hydrogen;

[0056] R 2 is a halogen or hydrogen;

[0057] R 3 yes

[0058] Optionally substituted C 1-3 alkyl, which is optionally substituted with a 4- to 6-membered heterocycloalkyl,

[0059] Optionally substituted 5- to 6-membered heteroaryl, the heteroaryl group is optionally substituted with one C 1-3 Alkyl substitution,

[0060] optionally substituted 4 to 6 membered heterocycloalkyl, said heterocycloalkyl being optionally substituted with one -OH,

[0061] An optionally substituted 4- to 6-membered cycloalkyl group, the cycloalkyl group being optionally substituted with one -OH or

[0062] -OR 4 ;

[0063] R 4 yes

[0064] Optionally substituted C 1-5 Alkyl, the alkyl group is optionally replaced by one or two R 6 replace,

[0065] An optionally substituted 3 to 9 membered heterocycloalkyl group, the heterocycloalkyl group being optionally substituted by one or two R 6 Replace, or

[0066] An optionally substituted 4- to 6-membered cycloalkyl group, the cycloalkyl group being optionally substituted by one, two or three R 6 replace;

[0067] R 5 is a halogen or hydrogen;

[0068] Each R 6 Independently

[0069] halogen,

[0070] -OH,

[0071] -OCH 3 ,

[0072] -C(CH 3 ) 2 OH,

[0073] -CH 2 OH,

[0074] Cyano,

[0075] Optionally substituted C 1 -C 4 alkyl, said alkyl being optionally substituted with -OH,

[0076] Optionally substituted 4 to 7 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted with one or two substituents independently selected from the group consisting of halogen, -OH, -OCH 3 and C 1-3 Alkyl, or

[0077] Optionally substituted 5- to 6-membered heteroaryl, the heteroaryl group is optionally substituted with one C 1-3 Alkyl substituted; and

[0078] R 7 It is a 5-membered heteroaryl.

[0079] In one embodiment, provided herein is a compound according to formula (Ia)

[0080]

[0081] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0082] In one embodiment, provided herein is a compound according to formula (Ib)

[0083]

[0084] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0085] In one embodiment, R 1 is selected from the group consisting of: H, chlorine and fluorine. In another embodiment, R 1 It's fluorine.

[0086] In one embodiment, R 2 It is H or fluorine.

[0087] In one embodiment, R 5 It is H or fluorine.

[0088] In one embodiment, R 1 , R 2 and R 5 It's H.

[0089] In one embodiment, R 2 and R 5 It's H.

[0090] In one embodiment, R 3 Selected from the group consisting of: In some embodiments, R 3 Yes-OR 4 .

[0091] In one embodiment, R 4 Selected from the group consisting of: CH 3 、-CH 2 CH 2 C(CH 3 ) 2 OH, -CH 2 CH 2 C(CH 3 ) 2 OCH 3 、-CH 2 CH 2 OCH 3 and -CH 2 C(CH 3 ) 2 OH. In some embodiments, R4 Selected from the group consisting of:

[0092]

[0093] In another embodiment, R 4 It is C 1 -C 5 Alkyl and R 6 are independently cyano, -OH, -OCH 3 ,

[0094] In one embodiment, R 7 Selected from the group consisting of:

[0095] In one embodiment, provided herein is a compound selected from the group consisting of:

[0096] (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0097] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0098] 5-((S)-7-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylic acid ethyl ester;

[0099] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0100] (S)-3-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2,2-dimethylpropionitrile;

[0101] (S)-7-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0102] (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0103] (S)-7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0104] (S)-7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0105] (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0106] (S)-7-(4-(5-fluoro-2-(3-methoxy-3-methylbutyloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0107] (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0108] (S)-7-(4-(2-((1,3-dioxan-5-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0109] (S)-4-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylbutan-2-ol;

[0110] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0111] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0112] (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0113] (S)-7-(4-(4,5-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0114] (S)-7-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0115] (S)-4-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-5-fluorophenoxy)-2-methylbutan-2-ol;

[0116] (S)-1-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylpropan-2-ol;

[0117] (S)-7-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0118] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(pyrimidin-5-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0119] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(oxazol-2-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0120] (S)-7-(4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0121] (S)-7-(4-(5-fluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0122] (S)-7-(4-(5-fluoro-2-((3-methyloxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0123] (S)-7-(4-(5-fluoro-2-(((R)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate;

[0124] (S)-7-(4-(5-fluoro-2-(((S)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate;

[0125] (S)-7-(4-(5-fluoro-2-(((R)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate;

[0126] (S)-7-(4-(5-fluoro-2-(((S)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate;

[0127] (S)-7-(4-(5-fluoro-2-((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0128] (S)-7-(4-(5-fluoro-2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0129] (S)-7-(4-(5-fluoro-2-((3-methylisoxazol-5-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0130] (S)-7-(4-(5-fluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0131] (S)-7-(4-(5-fluoro-2-(pyrimidin-2-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0132] (S)-7-(4-(5-fluoro-2-((3-fluorooxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0133] (S)-7-(4-(5-fluoro-2-((3-methyloxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0134] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0135] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0136] (S)-7-(4-(2-(((R)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0137] (S)-7-(4-(2-(((S)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0138] (S)-7-(4-(2-(((R)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0139] (S)-7-(4-(2-(((S)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0140] (S)-7-(4-(2-((3-ethyloxetan-3-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0141] (S)-7-(4-(5-fluoro-2-(((S)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0142] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0143] (S)-7-(4-(5-fluoro-2-(((S)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0144] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0145] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0146] (S)-7-(4-(2-((5-ethyl-1,3,4-thiadiazol-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0147] (S)-3-((2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)methyl)oxetan-3-ol;

[0148] 2-((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol;

[0149] 2-((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol;

[0150] 2-((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol;

[0151] 2-((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol;

[0152] (S)-7-(4-(5-fluoro-2-((S)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0153] (S)-7-(4-(5-fluoro-2-((R)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0154] (S)-7-(4-(5-fluoro-2-((S)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0155] (S)-7-(4-(5-fluoro-2-((R)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0156] (7S)-7-(4-(2-((3-oxabicyclo[3.1.0]hexan-6-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0157] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-3,5-difluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0158] (S)-7-(4-(3,5-difluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0159] (S)-7-(4-(3,5-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0160] (S)-7-(4-(3,5-difluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0161] (S)-7-(4-(3,5-difluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0162] (S)-7-(4-(4,5-difluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0163] (S)-7-(4-(4,5-difluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0164] ((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol;

[0165] ((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol;

[0166] ((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol;

[0167] ((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol;

[0168] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0169] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0170] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0171] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0172] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0173] (S)-7-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0174] (S)-7-(4-(5-fluoro-2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0175] (S)-7-(4-(5-fluoro-2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0176] (S)-7-(4-(5-fluoro-2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0177] (S)-7-(4-(5-fluoro-2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0178] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0179] (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol;

[0180] (1S,4r)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol;

[0181] (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol;

[0182] (1S,4r)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol;

[0183] (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol;

[0184] (1S,4r)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol;

[0185] (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol;

[0186] (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0187] (S)-7-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0188] (S)-2-(oxazol-2-yl)-7-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0189] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0190] (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0191] (S)-2-(Oxazol-2-yl)-7-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0192] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0193] (S)-2-(Oxazol-2-yl)-7-(4-(2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0194] (S)-7-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0195] (S)-2-(oxazol-2-yl)-7-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0196] (S)-1-(4-fluoro-2-(1-(2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol;

[0197] (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0198] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0199] (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0200] (S)-7-(4-(4,5-difluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0201] (S)-7-(4-(4,5-difluoro-2-((3-fluorooxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0202] (S)-7-(4-(4,5-difluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0203] (S)-2-(oxazol-2-yl)-7-(4-(2-(pyrimidin-5-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0204] (S)-7-(4-(4-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0205] 2-((1R,3s)-3-(4-fluoro-2-(1-((S)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)cyclobutyl)propan-2-ol;

[0206] 2-((1S,3r)-3-(4-fluoro-2-(1-((S)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)cyclobutyl)propan-2-ol;

[0207] 2-((1R,3s)-3-(4-fluoro-2-(1-((S)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)cyclobutyl)propan-2-ol;

[0208] 2-((1S,3r)-3-(4-fluoro-2-(1-((S)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)cyclobutyl)propan-2-ol;

[0209] (S)-2-(Oxazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0210] (S)-7-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0211] (S)-7-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octane;

[0212] (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octane;

[0213] (S)-1-(2-(1-(2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylpropan-2-ol;

[0214] (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octane;

[0215] (S)-7-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octane;

[0216] (S)-7-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0217] (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0218] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0219] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0220] (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0221] (S)-7-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0222] (S)-7-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0223] (S)-7-(4-(4,5-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0224] (S)-7-(4-(5-fluoro-2-(3-methoxy-3-methylbutyloxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0225] (S)-7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0226] (S)-4-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylbutan-2-ol;

[0227] (S)-7-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane carboxylate;

[0228] (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0229] (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0230] (S)-7-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0231] (S)-1-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylpropan-2-ol;

[0232] (S)-4-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-5-fluorophenoxy)-2-methylbutan-2-ol;

[0233] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0234] (S)-7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0235] (S)-1-(2-(1-(2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol;

[0236] (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,2,4-oxadiazol-3-yl)-5-oxa-2-azaspiro[3.4]octane;

[0237] (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,2,4-oxadiazol-3-yl)-5-oxa-2-azaspiro[3.4]octane; and

[0238] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,2,4-oxadiazol-3-yl)-5-oxa-2-azaspiro[3.4]octane, or a pharmaceutically acceptable salt thereof.

[0239] In one embodiment, the compound is selected from the group consisting of:

[0240] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure:

[0241]

[0242] (R)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure:

[0243]

[0244] (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure:

[0245] as well as

[0246] (S)-2-(Oxazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure:

[0247] or a pharmaceutically acceptable salt thereof.

[0248] In certain embodiments, the compound is (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)

[0249]

[0250] In certain embodiments, the compound is (R)-7-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure:

[0251] or a pharmaceutically acceptable salt thereof.

[0252] In certain embodiments, the compound is (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure:

[0253] or a pharmaceutically acceptable salt thereof.

[0254] In certain embodiments, the compound is (S)-2-(oxazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure:

[0255] or a pharmaceutically acceptable salt thereof.

[0256] In one embodiment, provided herein is a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof.

[0257] In one embodiment, provided herein is a method for treating an M4-related condition, disease or disorder, comprising administering a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0258] In one embodiment, a method for treating a psychosis is provided herein, comprising administering a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof to a patient in need of treatment thereof. In some embodiments, the psychosis is associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, or frontotemporal dementia. In another embodiment, the psychosis is associated with Alzheimer's disease.

[0259] In one embodiment, a method for treating cognitive dysfunction is provided herein, comprising administering a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof to a subject in need of treatment thereof. In some embodiments, the cognitive dysfunction is associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, or frontotemporal dementia. In another embodiment, the cognitive dysfunction is associated with Alzheimer's disease.

[0260] In one embodiment, a method for treating a hyperkinetic movement disorder is provided herein, the method comprising administering a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof to a subject in need of treatment thereof. In some embodiments, the hyperkinetic movement disorder is associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, or frontotemporal dementia. In another embodiment, the hyperkinetic movement disorder is associated with Alzheimer's disease. In some embodiments, the hyperkinetic movement disorder is Tourette syndrome, chorea, or tardive dyskinesia.

[0261] In one embodiment, provided herein is a method for treating a substance use disorder, comprising administering a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0262] In one embodiment, provided herein is a method of treating a condition, disease or disorder that is treated with an M4 receptor agonist, the method comprising administering a therapeutically effective amount of an antidepressant and a compound provided herein or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0263] In one embodiment, provided herein is a method for treating a condition, disease or disorder treated with an M4 receptor agonist, the method comprising administering a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof in combination with computer-assisted psychosocial or behavioral therapy.

[0264] In one embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy. In further embodiments, the therapy is selected from a condition, disease or disorder treated by an M4 receptor agonist.

[0265] In another embodiment, provided herein is the use of a compound having formula (I) or a pharmaceutically acceptable salt thereof in an M4-related condition, disease or disorder.

[0266] In another embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a psychotic disorder. In some embodiments, the psychotic disorder is associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, or frontotemporal dementia. In another embodiment, the psychotic disorder is associated with Alzheimer's disease.

[0267] In one embodiment, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in cognitive dysfunction. In some embodiments, the cognitive dysfunction is associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, or frontotemporal dementia. In another embodiment, the cognitive dysfunction is associated with Alzheimer's disease.

[0268] In one embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a hyperkinetic movement disorder. In some embodiments, the hyperkinetic movement disorder is associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, or frontotemporal dementia. In another embodiment, the hyperkinetic movement disorder is associated with Alzheimer's disease. In some embodiments, the hyperkinetic movement disorder is Tourette syndrome, chorea, or tardive dyskinesia.

[0269] In one embodiment, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in substance use disorders.

[0270] In one embodiment, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a condition, disease or disorder treated by an M4 receptor agonist. In certain embodiments, the use is combined with computer-assisted psychosocial or behavioral therapy.

[0271] In one embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. In another embodiment, the medicament is used to treat a condition, disease or disorder treated by an M4 receptor agonist. In another embodiment, the condition, disease or disorder is a psychotic disorder, including but not limited to a psychotic disorder associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease and frontotemporal dementia.

[0272] In one embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a dyskinesia with hyperkinesia. In some embodiments, the dyskinesia with hyperkinesia is associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, or frontotemporal dementia. In another embodiment, the dyskinesia with hyperkinesia is associated with Alzheimer's disease.

[0273] In one embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cognitive dysfunction. In some embodiments, the cognitive dysfunction is associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, or frontotemporal dementia. In another embodiment, the cognitive dysfunction is associated with Alzheimer's disease.

[0274] In one embodiment, provided herein is the use of a compound having formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a substance use disorder. BRIEF DESCRIPTION OF THE DRAWINGS

[0275] Figure 1 Using the mouse amphetamine-induced hyperactivity test, Example 1A and Example 2L are shown to have an effect on hyperactivity induced by the stimulant d-amphetamine in mice.

[0276] Figure 2 Using the mouse amphetamine-induced hyperactivity test, Example 3C and Example 3D show the effects of the stimulant d-amphetamine-induced hyperactivity in mice.

[0277] Figure 3 Using the mouse amphetamine-induced hyperactivity test, Example 4A and Example 5G show the effects of the stimulant d-amphetamine-induced hyperactivity in mice. DETAILED DESCRIPTION

[0278] 1. Definition

[0279] As used herein, "alkyl" refers to a monovalent saturated hydrocarbon chain having a specified number of carbon atoms. 1-3 Alkyl refers to an alkyl group having from 1 to 3 carbon atoms. The alkyl group may optionally be substituted by one or more substituents defined in formula (I). The alkyl group may be straight or branched. Representative branched alkyl groups have one, two or three branches. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl.

[0280] As used herein, "cycloalkyl" refers to a saturated hydrocarbon ring system having a specified number of carbon atoms. Cycloalkyl is a monocyclic or bicyclic ring system. For example, C 3-7 Cycloalkyl refers to a cycloalkyl having from 3 to 7 carbon atoms. The cycloalkyl may optionally be substituted with one or more substituents as defined in formula (I). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0281]

[0066] "Halo" or "halogen" as used herein refers to a fluoro, chloro, or bromo group.

[0282] As used herein, "haloalkyl" refers to an alkyl group having a specific number of carbon atoms, wherein at least one hydrogen atom attached to a carbon atom within the alkyl group is replaced by a halo group. The number of halo substituents includes, but is not limited to, 1, 2, 3, 4, 5, or 6 substituents. Haloalkyl groups include, but are not limited to, monofluoromethyl, difluoroethyl, and trifluoromethyl.

[0283] As used herein, "heteroaryl" refers to an aromatic ring system containing one or more heteroatoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. The heteroaryl group may be optionally substituted with one or more substituents as defined in formula (I). The heteroaryl group may be a monocyclic ring system or a fused bicyclic ring system. The monocyclic heteroaryl ring has from 5 to 6 ring atoms. The bicyclic heteroaryl ring has from 8 to 10 member atoms. Bicyclic heteroaryl rings include those ring systems in which the heteroaryl ring is fused to a phenyl ring. Heteroaryl includes, but is not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl (including 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl), thiazolyl, isothiazolyl, thiadiazolyl (including 1,3,4-thiadiazolyl), furanyl, furazanyl, thienyl, triazolyl, pyridyl (including 2-, 3- and 4-pyridyl), pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, tetrazolyl, Indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, benzimidazolyl, benzopyranyl, benzopyranyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, naphthyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, imidazo[2,1-b][1,3,4]thiadiazolyl, and the like.

[0284] As used herein, "5-6 membered heteroaryl" refers to a heteroaryl group as defined above having 5 or 6 ring atoms and containing 1 to 4 heteroatoms. Examples of 5-6 membered heteroaryl groups include, but are not limited to, thiazole, oxazole, isoxazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,5-thiadiazole, 1H-imidazole, 1H-pyrazole, pyridine, pyrimidine, 1,3,5-triazine, and the like.

[0285] As used herein, "heteroatom" refers to a nitrogen, oxygen or sulfur atom.

[0286] "Heterocycle" or "heterocycloalkyl" refers to a saturated or unsaturated monocyclic or bicyclic ring containing from 1 to 4 heteroatoms. Heterocyclic ring systems are not aromatic. Heterocyclic groups containing more than one heteroatom may contain different heteroatoms. Heterocycles include those in which the sulfur atom is oxidized to the form SO or SO 2The ring system of the heterocyclic group. The heterocyclic group may be optionally substituted by one or more substituents as defined in formula (I). The heterocyclic group is a monocyclic, bicyclic, spiral or fused or bridged bicyclic ring system. The ring of the monocyclic heterocyclic ring has 3 to 7 ring atoms. Examples of monocyclic heterocyclic groups include pyranyl, tetrahydropyranyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dithianyl, oxathianyl, thiomorpholinyl, tetrahydro-thiopyran 1,1-dioxide, 1,4-diazepanyl, etc. Examples of bicyclic heterocyclic groups include 3-oxabicyclo[3.1.0]hexane, etc. Examples of bridged heterocyclic groups include 2-azabicyclo[2.2.1]heptyl, etc. Examples of spiroheterocyclic groups include 2-oxaspiro[3.3]heptyl, etc.

[0287] "4- to 6-membered heterocycle" or "4- to 6-membered heteroaryl" refers to a heterocyclic group as defined above having from 4 to 6 ring atoms and containing from 1 to 3 heteroatoms. Examples of 4- to 6-membered heterocycles include, but are not limited to, oxetanyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, 1,4-diazepanyl, 3-oxabicyclo[3.1.0]hexanyl, and the like.

[0288] "5- to 6-membered heterocycle" or "5- to 6-membered heteroaryl" refers to a heterocyclic group as defined above having from 5 to 6 ring atoms and containing from 1 to 3 heteroatoms. Examples of 5- to 6-membered heterocycles include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, 1,4-diazepanyl, 3-oxabicyclo[3.1.0]hexanyl, and the like.

[0289] "3- to 9-membered heterocycle" or "3- to 9-membered heteroaryl" refers to a heterocyclic group as defined above having from 3 to 9 ring atoms and containing from 1 to 3 heteroatoms. Examples of 3- to 9-membered heterocycles include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, 1,4-diazepanyl, 2-oxaspiro[3.3]heptyl, 3-oxabicyclo[3.1.0]hexanyl, and the like.

[0290] As used herein, "optionally substituted" means that groups such as alkyl, heteroaryl and heterocycle may be unsubstituted or the group may be substituted with one or more substituents as defined in formula (I).

[0291] As used herein, "salts (salt or salts)" refers to acid addition salts or base addition salts of compounds provided herein. "Salts" particularly include "pharmaceutically acceptable salts". As used herein, "pharmaceutically acceptable salts" refer to salts that retain the biological effectiveness and characteristics of compounds according to formula (I) and are typically not biologically or otherwise undesirable. In many cases, due to the presence of amino and / or carboxyl groups or groups similar thereto, compounds according to formula (I) are able to form acid and / or base salts. It will be appreciated by those skilled in the art that salts of compounds according to formula (I) can be prepared, including pharmaceutically acceptable salts. These salts can be prepared in situ during the final separation and purification of the compound, or prepared separately by reacting the purified compound in the form of free acid or free base with a suitable base or acid, respectively.

[0292] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc.

[0293] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases, such as carboxylates, sulfonates and phosphates.

[0294] In certain embodiments, provided herein are compounds according to formula (I) in the form of acetate, ascorbate, adipate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, decanoate, chloride / hydrochloride, chlortheophyllonate, citrate, edisylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide. In certain embodiments, the compounds of formula (I) are provided herein as formate or citrate salts.

[0295] "Isomers" refer to different compounds according to Formula (I) that have the same molecular formula but differ in arrangement and configuration of the atoms.

[0296] "Optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound provided herein and includes geometric isomers. It is understood that substituents may be attached at chiral centers of carbon atoms. Thus, the compounds provided herein include enantiomers, diastereomers, or racemates of the compounds.

[0297] Depending on the choice of starting materials and procedures, compounds according to formula (I) can exist in one possible stereoisomeric form or as a mixture thereof (e.g., as pure optical isomers or as stereoisomer mixtures, such as racemates and diastereomeric mixtures), depending on the number of asymmetric carbon atoms. Compounds according to formula (I) provided herein are meant to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-stereoisomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents can be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents can have a cis or trans configuration. All tautomeric forms are also included.

[0298] Any asymmetric atom (e.g., carbon, etc.) of a compound according to formula (I) can exist in racemic or enantiomeric enrichment, such as (R)-, (S)-, or (R, S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess (R)- or (S)-configuration. If possible, substituents on atoms with unsaturated double bonds can exist in cis-(Z)- or trans-(E)-forms.

[0299] Thus, the compounds provided herein may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

[0300] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the components, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0301] Any resulting racemate of a compound according to formula (I) or its intermediate can be split into optical antipodes by known methods, for example, by separating its diastereomeric salts obtained with optically active acids or bases, and releasing optically active acidic or basic compounds. In particular, therefore, the compound according to formula (I) can be split into their optical antipodes using an alkaline moiety, for example, by fractional crystallization with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, two-O, O'-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid salts are split. According to the racemic compound or racemic intermediate of formula (I), it can also be split by chiral chromatography (for example, using high pressure liquid chromatography (HPLC) of chiral adsorbent).

[0302] Any formula given herein is also intended to represent the unlabeled form and isotope-labeled form of the compound. Isotope-labeled compounds have the structure represented by the formula given herein, except that one or more atoms are replaced by atoms with selected atomic mass or mass number. The isotopes that can be incorporated into the compound according to formula (I) include, for example, isotopes of hydrogen.

[0303] In addition, the incorporation of certain isotopes, especially deuterium (i.e. 2 H or D) can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improvements in therapeutic index or tolerance. It should be understood that deuterium in this context is considered to be a substituent of a compound provided herein. The concentration of deuterium can be defined by an isotopic enrichment factor. As used herein, "isotopic enrichment factor" refers to the ratio between isotopic abundance and the natural abundance of a particular isotope. If a substituent in a compound provided herein indicates deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation on each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0304] For example, formula (I) may be deuterated, as shown in formula (Ic):

[0305]

[0306] or a pharmaceutically acceptable salt thereof, wherein R 3and R 7 As defined in formula (I); and R D1 , R D2 , R D5 and R D8 -R D27 Each is independently D or halogen.

[0307] Other examples of isotopes that may be incorporated into the compounds according to formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 3 H. 11 C. 13 C. 14 C. 15 N. 18 F. 31 P. 32 P. 35 S. 36 Cl, 123 I. 124 I. 125 I. Thus, it will be understood that compounds according to formula (I) include those incorporating one or more of any of the aforementioned isotopes (including, for example, radioisotopes (such as 3 H and 14 C)) or a compound in which a non-radioactive isotope (such as 2 H and 13 C). Such isotope-labeled compounds can be used for metabolic studies (using 14 C) reaction kinetics studies (e.g. 2 H or 3 H), detection or imaging techniques (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays), or radiation therapy for patients. In particular, 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds according to formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations, using an appropriate isotopically labeled reagent in place of the unlabeled previously used reagent.

[0308] As used herein, "administration," "administering," and "administer" refer to the manner in which a compound provided herein (eg, a compound according to Formula (I)) is presented to a subject.

[0309] As used herein, "subject" or "patient" refers to a living organism suffering from one or more diseases or disorders described herein that can be treated by administering a pharmaceutical composition as described herein. Examples of subjects include mammals (e.g., humans and animals such as dogs, cows, horses, monkeys, pigs, guinea pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals). In certain embodiments, the subject is a primate. In certain embodiments, the subject is a human, such as a person suffering from a disease described herein, at risk of suffering from a disease described herein, or potentially susceptible to a disease described herein. In a specific embodiment, the subject is an adult of at least 18 years old. In a specific embodiment, the subject is an adult of about 18 to about 75 years old. In some embodiments, the subject is a human child of up to about 18 years old.

[0310] As used herein, "treatment" of any disease or disorder refers to mitigation, alleviation, delay, reduction, reversal or improvement of the symptoms of at least one disorder of the subject. The term "treatment" may also mean prevention, delay of onset (i.e., the time period before the clinical manifestation of the disease) and / or reduction of the risk of disease development or disease exacerbation. In certain embodiments, the term "treatment" refers to mitigation, alleviation, delayed progression, reduction, reversal or improvement of at least one symptom selected from the following disorders: psychosis, including psychosis associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, Parkinson's disease, post-traumatic stress disorder and frontotemporal dementia, hyperkinetic movement disorders, including but not limited to Tourette syndrome, chorea and tardive dyskinesia, cognitive dysfunction, including but not limited to cognitive dysfunction associated with schizophrenia, Alzheimer's disease, frontotemporal dementia, schizoaffective disorder and depression; and / or substance use disorders.

[0311] As used herein, "prevent," "preventing," or "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0312] As used herein, "pharmaceutical composition" refers to a compound provided herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier in a form suitable for oral or parenteral administration.

[0313] As used herein, "pharmaceutically acceptable carrier" refers to a substance that can be used to prepare or use a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavorings, dyes, and combinations thereof, as known to those skilled in the art (see, e.g., Remington The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press, 2013, pp. 1049-1070).

[0314] A "therapeutically effective amount" of a compound provided herein refers to an amount of a compound that will cause a biological or medical response in a subject (e.g., increase enzyme or protein activity) or improve symptoms, alleviate symptoms, slow or delay disease progression, or prevent disease, etc. In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound provided herein that, when administered to a subject, is effective to (1) at least partially alleviate, prevent and / or improve (i) a condition or disorder or disease mediated by M4, or (ii) associated with M4 activity, or (iii) characterized by the activity (normal or abnormal) of M4: or (2) increase M4 activity. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound provided herein that, when administered to a cell, or tissue, or non-cellular biological material or medium, is effective to increase the activity of M4.

[0315] As used herein, "inhibit," "inhibition," or "inhibiting" refers to reducing or suppressing a given condition, symptom, or disorder, or disease, or significantly reducing the baseline activity of a biological activity or process.

[0316] A subject is "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0317] As used herein, "substance use disorder" or "SUD" is defined with reference to DSM-5 criteria (i.e., according to Diagnostic and Statistical Manual of Mental Disorders. [Diagnostic and Statistical Manual of Mental Disorders] 5th edition, Washington, DC: American Psychiatric Association, 2013, hereinafter referred to as "DSM-5"), the entire contents of which are incorporated herein by reference. As used herein, the term "substance use disorder" is defined as clinically and functionally severe impairment, such as health problems, disability, and inability to assume primary responsibilities at work, school, or home when alcohol and / or drugs are repeatedly used. According to DSM-5, the diagnosis of substance use disorder is based on evidence of impaired control, social damage, dangerous use, and pharmacological criteria. Substance use disorders include, for example, alcohol use disorder, tobacco use disorder, marijuana use disorder, stimulant use disorder, hallucinogen use disorder, and opioid use disorder.

[0318] As used herein, "psychosocial or behavioral therapy" refers to, but is not limited to, cognitive behavioral therapy (e.g., as described in Arch. Gen. Psychiatry 1999; 56:493-502), interpersonal therapy (e.g., as described in Psychol Addict Behav 2009; 23(1):168-174), contingency management-based therapy (e.g., as described in Psychol Addict Behav 2009; 23(1):168-174; J. Consul. Clin. Psychol. 2005; 73(2):354-59; or Case Reports in Psychiatry, Vol. 2012, Article No. 731638), community reinforcement approach-based therapy (e.g., as described in Drug Alcohol Depend [Drug Alcohol Depend] 2004; 74: 1-13), motivational interviewing-based therapy (e.g. as described in J. Consul. Clin. Psychol. [Clinical Psychology] 2001; 69 (5): 858-62), motivational reinforcement-based therapy (e.g. as described in Drug Alcohol Depend [Drug Alcohol Depend] 2007, 91: 97-101) or meditation-based therapy, such as transcendental meditation therapy (e.g. as described in Addiction [Addiction] 2004; 99 (7): 862-874 or J. Consul. Clin. Psychol. [Clinical Psychology] 2000; 68 (3): 515-52); in particular, contingency management-based therapy.

[0319] As used herein, "standardized psychotherapy" or "standardized psychological support" refers to standard counseling sessions, for example once a week, particularly counseling focused on cocaine consumption.

[0320] As used herein, "computer-assisted" or "computer-assisted" refers to psychosocial or behavioral therapies that involve the use of electronic or digital tools, such as online tools, smartphones, laptops, tablets, wireless devices, or health apps.

[0321] Unless otherwise indicated, "a compound provided herein" or "compounds provided herein" refers to compounds having formula (I) and subformulae thereof (including formula (Ia), (Ib) and (Ic)), as well as any exemplified compounds and salts thereof, and all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterated substitutions), as well as inherently formed moieties.

[0322] As used herein, “a,” “an,” “the,” and similar terms (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0323] In this specification and the claims that follow, unless the context requires otherwise, the word "comprise" or variations thereof (such as its third person and present tense forms) will be understood to imply a stated integer or step or group of integers or steps but not to exclude any other integer or step or group of integers or steps.

[0324] If there is a discrepancy between a depicted structure and the chemical name given for that structure, the depicted structure shall prevail. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated, for example, by bold or dashed lines, that structure or portion of that structure shall be interpreted as encompassing all stereoisomers of that structure or portion of that structure.

[0325] All methods described herein can be performed in any suitable order, unless otherwise specified herein or otherwise clearly contradictory to the context. The application of any and all examples or exemplary language (e.g., "such as") provided herein is only intended to better illustrate the present invention, without limiting the scope of the present invention otherwise claimed.

[0326] 2. Compounds

[0327] In one embodiment, provided herein is a compound according to formula (I)

[0328]

[0329] or a pharmaceutically acceptable salt thereof, wherein

[0330] R 1 is a halogen or hydrogen;

[0331] R 2 is a halogen or hydrogen;

[0332] R 3 yes

[0333] Optionally substituted C 1-3 alkyl, which is optionally substituted with a 4- to 6-membered heterocycloalkyl,

[0334] Optionally substituted 5- to 6-membered heteroaryl, the heteroaryl group is optionally substituted with one C 1-3 Alkyl substitution,

[0335] optionally substituted 4 to 6 membered heterocycloalkyl, said heterocycloalkyl being optionally substituted with one -OH,

[0336] An optionally substituted 4- to 6-membered cycloalkyl group, the cycloalkyl group being optionally substituted with one -OH or

[0337] -OR 4 ;

[0338] R 4 yes

[0339] Optionally substituted C 1-5 Alkyl, the alkyl group is optionally replaced by one or two R 6 replace,

[0340] An optionally substituted 3 to 9 membered heterocycloalkyl group, the heterocycloalkyl group being optionally substituted by one or two R 6 Replace, or

[0341] An optionally substituted 4- to 6-membered cycloalkyl group, the cycloalkyl group being optionally substituted by one, two or three R 6 replace;

[0342] R 5 is a halogen or hydrogen;

[0343] Each R 6 Independently

[0344] halogen,

[0345] -OH,

[0346] -OCH 3 ,

[0347] -C(CH 3 ) 2 OH,

[0348] -CH 2 OH,

[0349] Cyano,

[0350] Optionally substituted C 1 -C 4 alkyl, said alkyl being optionally substituted with -OH,

[0351] Optionally substituted 4 to 7 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted with one or two substituents independently selected from the group consisting of halogen, -OH, -OCH 3 and C 1-3 Alkyl, or

[0352] Optionally substituted 5- to 6-membered heteroaryl, the heteroaryl group is optionally substituted with one C 1-3 Alkyl substituted; and

[0353] R 7 It is a 5-membered heteroaryl.

[0354] In one embodiment, provided herein is a compound according to formula (Ia)

[0355]

[0356] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0357] In one embodiment, provided herein is a compound according to formula (Ib)

[0358]

[0359] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0360] In one embodiment, R 1 is selected from the group consisting of: H, chlorine and fluorine. In another embodiment, R 1 It's fluorine.

[0361] In one embodiment, R 2 It is H or fluorine.

[0362] In one embodiment, R 5 It is H or fluorine.

[0363] In one embodiment, R 1 , R 2 and R 5 It's H.

[0364] In one embodiment, R 2 and R 5 It's H.

[0365] In one embodiment, R 3 Selected from the group consisting of: In some embodiments, R 3 Yes-OR 4 .

[0366] In one embodiment, R 4 Selected from the group consisting of: CH 3 、-CH 2 CH 2 C(CH 3 ) 2 OH, -CH 2 CH 2 C(CH 3 ) 2 OCH 3 、-CH 2 CH 2 OCH 3 and -CH 2 C(CH 3 ) 2 OH. In some embodiments, R 4 Selected from the group consisting of:

[0367]

[0368]

[0369] In another embodiment, R 4 It is C 1 -C 5 Alkyl and R 6 are independently cyano, -OH, -OCH 3 ,

[0370] In one embodiment, R 7 Selected from the group consisting of:

[0371] In one embodiment, provided herein is a compound selected from the group consisting of:

[0372] (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0373] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0374] 5-((S)-7-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylic acid ethyl ester;

[0375] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0376] (S)-3-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2,2-dimethylpropionitrile;

[0377] (S)-7-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0378] (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0379] (S)-7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0380] (S)-7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0381] (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0382] (S)-7-(4-(5-fluoro-2-(3-methoxy-3-methylbutyloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0383] (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0384] (S)-7-(4-(2-((1,3-dioxan-5-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0385] (S)-4-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylbutan-2-ol;

[0386] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0387] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0388] (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0389] (S)-7-(4-(4,5-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0390] (S)-7-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0391] (S)-4-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-5-fluorophenoxy)-2-methylbutan-2-ol;

[0392] (S)-1-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylpropan-2-ol;

[0393] (S)-7-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0394] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(pyrimidin-5-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0395] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(oxazol-2-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0396] (S)-7-(4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0397] (S)-7-(4-(5-fluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0398] (S)-7-(4-(5-fluoro-2-((3-methyloxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0399] (S)-7-(4-(5-fluoro-2-(((R)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate;

[0400] (S)-7-(4-(5-fluoro-2-(((S)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate;

[0401] (S)-7-(4-(5-fluoro-2-(((R)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate;

[0402] (S)-7-(4-(5-fluoro-2-(((S)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate;

[0403] (S)-7-(4-(5-fluoro-2-((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0404] (S)-7-(4-(5-fluoro-2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0405] (S)-7-(4-(5-fluoro-2-((3-methylisoxazol-5-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0406] (S)-7-(4-(5-fluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0407] (S)-7-(4-(5-fluoro-2-(pyrimidin-2-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0408] (S)-7-(4-(5-fluoro-2-((3-fluorooxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0409] (S)-7-(4-(5-fluoro-2-((3-methyloxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0410] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0411] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0412] (S)-7-(4-(2-(((R)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0413] (S)-7-(4-(2-(((S)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0414] (S)-7-(4-(2-(((R)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0415] (S)-7-(4-(2-(((S)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0416] (S)-7-(4-(2-((3-ethyloxetan-3-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0417] (S)-7-(4-(5-fluoro-2-(((S)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0418] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0419] (S)-7-(4-(5-fluoro-2-(((S)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0420] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0421] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0422] (S)-7-(4-(2-((5-ethyl-1,3,4-thiadiazol-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0423] (S)-3-((2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)methyl)oxetan-3-ol;

[0424] 2-((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol;

[0425] 2-((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol;

[0426] 2-((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol;

[0427] 2-((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol;

[0428] (S)-7-(4-(5-fluoro-2-((S)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0429] (S)-7-(4-(5-fluoro-2-((R)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0430] (S)-7-(4-(5-fluoro-2-((S)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0431] (S)-7-(4-(5-fluoro-2-((R)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0432] (7S)-7-(4-(2-((3-oxabicyclo[3.1.0]hexan-6-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0433] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-3,5-difluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0434] (S)-7-(4-(3,5-difluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0435] (S)-7-(4-(3,5-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0436] (S)-7-(4-(3,5-difluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0437] (S)-7-(4-(3,5-difluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0438] (S)-7-(4-(4,5-difluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0439] (S)-7-(4-(4,5-difluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0440] ((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol;

[0441] ((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol;

[0442] ((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol;

[0443] ((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol;

[0444] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0445] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0446] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0447] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0448] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0449] (S)-7-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0450] (S)-7-(4-(5-fluoro-2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0451] (S)-7-(4-(5-fluoro-2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0452] (S)-7-(4-(5-fluoro-2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0453] (S)-7-(4-(5-fluoro-2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0454] (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0455] (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol;

[0456] (1S,4r)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol;

[0457] (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol;

[0458] (1S,4r)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol;

[0459] (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol;

[0460] (1S,4r)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol;

[0461] (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol;

[0462] (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0463] (S)-7-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0464] (S)-2-(oxazol-2-yl)-7-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0465] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0466] (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0467] (S)-2-(Oxazol-2-yl)-7-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0468] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0469] (S)-2-(Oxazol-2-yl)-7-(4-(2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0470] (S)-7-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0471] (S)-2-(oxazol-2-yl)-7-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0472] (S)-1-(4-fluoro-2-(1-(2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol;

[0473] (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0474] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0475] (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0476] (S)-7-(4-(4,5-difluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0477] (S)-7-(4-(4,5-difluoro-2-((3-fluorooxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0478] (S)-7-(4-(4,5-difluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0479] (S)-2-(oxazol-2-yl)-7-(4-(2-(pyrimidin-5-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0480] (S)-7-(4-(4-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0481] 2-((1R,3s)-3-(4-fluoro-2-(1-((S)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)cyclobutyl)propan-2-ol;

[0482] 2-((1S,3r)-3-(4-fluoro-2-(1-((S)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)cyclobutyl)propan-2-ol;

[0483] 2-((1R,3s)-3-(4-fluoro-2-(1-((S)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)cyclobutyl)propan-2-ol;

[0484] 2-((1S,3r)-3-(4-fluoro-2-(1-((S)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)cyclobutyl)propan-2-ol;

[0485] (S)-2-(Oxazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0486] (S)-7-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0487] (S)-7-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octane;

[0488] (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octane;

[0489] (S)-1-(2-(1-(2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylpropan-2-ol;

[0490] (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octane;

[0491] (S)-7-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octane;

[0492] (S)-7-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0493] (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0494] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0495] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0496] (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0497] (S)-7-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0498] (S)-7-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0499] (S)-7-(4-(4,5-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0500] (S)-7-(4-(5-fluoro-2-(3-methoxy-3-methylbutyloxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0501] (S)-7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0502] (S)-4-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylbutan-2-ol;

[0503] (S)-7-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane carboxylate;

[0504] (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0505] (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0506] (S)-7-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0507] (S)-1-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylpropan-2-ol;

[0508] (S)-4-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-5-fluorophenoxy)-2-methylbutan-2-ol;

[0509] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0510] (S)-7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane;

[0511] (S)-1-(2-(1-(2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol;

[0512] (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,2,4-oxadiazol-3-yl)-5-oxa-2-azaspiro[3.4]octane;

[0513] (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,2,4-oxadiazol-3-yl)-5-oxa-2-azaspiro[3.4]octane; and

[0514] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,2,4-oxadiazol-3-yl)-5-oxa-2-azaspiro[3.4]octane, or a pharmaceutically acceptable salt thereof.

[0515] In one embodiment, the compound is selected from the group consisting of:

[0516] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure:

[0517]

[0518] (R)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure:

[0519]

[0520] (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure:

[0521] as well as

[0522] (S)-2-(Oxazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure:

[0523] or a pharmaceutically acceptable salt thereof.

[0524] In certain embodiments, the compound is (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure: or a pharmaceutically acceptable salt thereof.

[0525] In certain embodiments, the compound is (R)-7-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure:

[0526]

[0527] In certain embodiments, the compound is (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure:

[0528] or a pharmaceutically acceptable salt thereof.

[0529] In certain embodiments, the compound is (S)-2-(oxazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure:

[0530] or a pharmaceutically acceptable salt thereof.

[0531] In one embodiment, provided herein is a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof.

[0532] 3. Pharmaceutical Composition

[0533] In one embodiment, a pharmaceutical composition is provided herein, comprising a compound provided herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, a pharmaceutical composition is provided herein, comprising a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, a pharmaceutical composition is provided herein, comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for a specific route of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration) and rectal administration. Topical administration may also involve inhalation or intranasal application. The pharmaceutical composition provided herein may be in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including but not limited to solutions, suspensions or emulsions). Tablets may be coated with a film coating or an enteric coating according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule comprising an active ingredient and one or more of the following:

[0534] a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0535] b) lubricants, such as silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; in the case of tablets, also

[0536] c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone; if desired,

[0537] d) disintegrants, for example starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and

[0538] e) Adsorbents, colorants, flavoring agents and sweeteners.

[0539] For a subject of about 50-70kg, the pharmaceutical composition provided herein can be a unit dose of one or more active ingredients of about 1-1000mg, or a unit dose of about 1-500mg, or about 1-250mg, or about 1-150mg, or about 0.5-100mg, or about 1-50mg of an active ingredient. The therapeutically effective dose of a compound or its pharmaceutical composition depends on the individual condition, its disorder or disease or severity of the subject's species, body weight, age, and treatment. A physician, clinician, or veterinarian with ordinary skills can easily determine the effective amount of each active ingredient necessary for preventing, treating, or suppressing disorder or disease progression.

[0540] The above dosage characteristics can be demonstrated in in vitro and in vivo tests using advantageous mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues and preparations. The compounds provided herein can be administered in vitro in the form of solutions (e.g., aqueous solutions), and in vivo enterally, parenterally (advantageously, intravenously), for example, as a suspension or in aqueous solution. In vitro doses can be administered at about 10 -3 Moore and 10 -9 Depending on the route of administration, the in vivo therapeutically effective amount may be in the range of between about 0.1-500 mg / kg, or between about 1-100 mg / kg.

[0541] 4. Usage

[0542] In one embodiment, the compounds provided herein are in free form or in a pharmaceutically acceptable salt form and have activity as a muscarinic M4 receptor agonist. In a specific embodiment, compounds according to formula (I) are provided herein, which are in free form or in a pharmaceutically acceptable salt form, and have activity as a muscarinic M4 receptor agonist. The significant advantage of the compounds provided herein is that they are highly selective for the M4 receptor relative to the M1, M2 and M3 receptor subtypes, and are therefore believed to maintain their desired activity in the brain without producing unwanted cholinergic side effects. The CHRM4 Ca described in Section 8.2 below can be used ++ Flux Assays The muscarinic activity of the compounds provided herein was determined.

[0543] By virtue of their M4 receptor agonist activity, the compounds provided herein are useful for the treatment of:

[0544] Psychosis, including psychosis associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, Parkinson's disease, post-traumatic stress disorder, and frontotemporal dementia;

[0545] Hyperkinetic movement disorders, including but not limited to Tourette syndrome, chorea, and tardive dyskinesia;

[0546] Cognitive dysfunction, including but not limited to that associated with schizophrenia, Alzheimer's disease, frontotemporal dementia, schizoaffective disorder, and depression; and / or

[0547] Substance use disorder.

[0548] In one embodiment, provided herein is a method for treating a condition, disease or disorder treated by an M4 receptor agonist, the method comprising administering a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of treatment thereof. In further embodiments, the condition, disease or disorder is a psychotic disorder, including but not limited to a psychotic disorder associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, Parkinson's disease, post-traumatic stress disorder and frontotemporal dementia. In a specific embodiment, the psychotic disorder is associated with Alzheimer's disease.

[0549] In another embodiment, there is provided herein a method for treating a hyperkinetic movement disorder, such as Tourette syndrome, chorea or tardive dyskinesia, the method comprising administering a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of treatment thereof. In some embodiments, the hyperkinetic movement disorder is associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease or frontotemporal dementia. In a specific embodiment, the hyperkinetic movement disorder is associated with Alzheimer's disease.

[0550] In another embodiment, there is provided herein a method for treating cognitive dysfunction, such as cognitive dysfunction associated with schizophrenia, Alzheimer's disease, frontotemporal dementia, schizoaffective disorder or depression, the method comprising administering a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of treatment thereof. In a specific embodiment, the cognitive dysfunction is associated with Alzheimer's disease.

[0551] In another embodiment, provided herein is a method of treating a substance use disorder, comprising administering a therapeutically effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0552] In one embodiment, provided herein is the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof in therapy. In a further embodiment, the therapy is selected from a condition, disease or disorder treated by an M4 receptor agonist. In another embodiment, the condition, disease or disorder is selected from the above list, suitably a psychotic disorder, including but not limited to a psychotic disorder associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, Parkinson's disease, post-traumatic stress disorder and frontotemporal dementia.

[0553] In another embodiment, provided herein is a compound according to formula (I) or a pharmaceutically acceptable salt thereof for use in hyperkinetic movement disorders, such as Tourette syndrome, chorea or tardive dyskinesia. In some embodiments, the hyperkinetic movement disorder is associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease or frontotemporal dementia. In a specific embodiment, the hyperkinetic movement disorder is associated with Alzheimer's disease.

[0554] In another embodiment, provided herein is the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof in cognitive dysfunction, such as cognitive dysfunction associated with schizophrenia, Alzheimer's disease, frontotemporal dementia, schizoaffective disorder or depression. In a specific embodiment, the cognitive dysfunction is associated with Alzheimer's disease.

[0555] In another embodiment, provided herein is the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof in substance use disorders.

[0556] In another embodiment, provided herein is the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. In a further embodiment, the medicament is used to treat a condition, disease or disorder treated by an M4 receptor agonist. In another embodiment, the condition, disease or disorder is a psychotic disorder, including but not limited to a psychotic disorder associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, Parkinson's disease, post-traumatic stress disorder and frontotemporal dementia.

[0557] In another embodiment, provided herein is a compound according to formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating a hyperkinetic movement disorder, such as Tourette syndrome, chorea or tardive dyskinesia. In some embodiments, the hyperkinetic movement disorder is associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease or frontotemporal dementia. In a specific embodiment, the hyperkinetic movement disorder is associated with Alzheimer's disease.

[0558] In another embodiment, provided herein is the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cognitive dysfunction, such as cognitive dysfunction associated with schizophrenia, Alzheimer's disease, frontotemporal dementia, schizoaffective disorder or depression. In a specific embodiment, the cognitive dysfunction is associated with Alzheimer's disease.

[0559] In another embodiment, provided herein is a use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a substance use disorder.

[0560] In another embodiment, provided herein is a compound according to formula (I) or a pharmaceutically acceptable salt thereof for use in treating a condition, disease or disorder treated by an M4 receptor agonist. In a further embodiment, the condition, disease or disorder is selected from the above list, suitably a psychotic disorder, including but not limited to a psychotic disorder associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, Parkinson's disease, post-traumatic stress disorder and frontotemporal dementia. In a specific embodiment, the psychotic disorder is associated with Alzheimer's disease.

[0561] In another embodiment, provided herein is a compound according to formula (I) or a pharmaceutically acceptable salt thereof for use in treating a hyperkinetic movement disorder, such as Tourette syndrome, chorea or tardive dyskinesia. In some embodiments, the hyperkinetic movement disorder is associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease or frontotemporal dementia. In a specific embodiment, the hyperkinetic movement disorder is associated with Alzheimer's disease.

[0562] In another embodiment, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating cognitive dysfunction, such as cognitive dysfunction associated with schizophrenia, Alzheimer's disease, frontotemporal dementia, schizoaffective disorder or depression. In a specific embodiment, the cognitive dysfunction is associated with Alzheimer's disease.

[0563] In another embodiment, provided herein is a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in treating a substance use disorder.

[0564] The compound according to formula (I) or its pharmaceutically acceptable salt can be administered simultaneously with one or more other therapeutic agents, or before or after it. The compound according to formula (I) can be administered separately by the same or different administration routes, or administered together in the same pharmaceutical composition as other medicaments. The therapeutic agent is, for example, a chemical compound, a peptide, an antibody, an antibody fragment or a nucleic acid, which has therapeutic activity or enhances therapeutic activity when administered to a subject in combination with a compound provided herein.

[0565] In the combination therapy provided herein, the compound according to formula (I) and other therapeutic agents can be produced and / or formulated by the same or different manufacturers. In addition, the compound provided herein and another therapeutic agent can form a combination therapy together: (i) before the combination product is revealed to the physician (e.g., in the case of a medicine box comprising the compound provided herein and another therapeutic agent); (ii) shortly before administration, by the physician himself (or under the guidance of a physician); (iii) in the patient himself, for example, during the sequential administration of the compound provided herein and another therapeutic agent.

[0566] The compound according to formula (I) or a pharmaceutically acceptable salt thereof can be administered with an antipsychotic, suitably a first generation antipsychotic, such as thorazine, haloperidol, mesoridazine, thioridazine, thiothioxanthene, pimozide, fluphenazine or perphenazine, a second generation antipsychotic, such as clozapine, olanzapine, risperidone, quetiapine, aripiprazole, asenapine, epiprazole, cariprazine, iloperidone, ziprasidone, lurasidone, pimavanserin or paliperidone. In certain embodiments, the compound according to formula (I) or a pharmaceutically acceptable salt thereof can be administered with an antipsychotic and a cholinesterase inhibitor, such as donepezil, rivastigmine tartrate, galantamine, tacrine or memantine. In certain embodiments, the compound according to formula (I) or a pharmaceutically acceptable salt thereof may be administered together with an antipsychotic and a mood stabilizer, such as lithium, divalproex sodium, carbamazepine or lamotrigine.

[0567] The compound according to formula (I) or a pharmaceutically acceptable salt thereof may be administered together with an antidepressant, suitably a selective serotonin reuptake inhibitor such as sertraline, fluoxetine, fluvoxamine, escitalopram, paroxetine or citalopram, a serotonin-norepinephrine reuptake inhibitor such as vortioxetine, venlafaxine, desvenlafaxine, milnacipran, duloxetine or levmilnacipran, a phenylpiperazine antidepressant such as nefazodone, vilazodone or trazodone, a reversible monoamine oxidase inhibitor such as moclobemide, a melatonin agonist such as agomelatine, a serotonin agonist such as mirtazapine, an N-methyl-D-aspartate receptor antagonist such as esketamine and ketamine, and a monoamine oxidase inhibitor such as tranylcypromine, phenelzine, transdermal selegiline or isocarboxazid.

[0568] The compound according to formula (I) or its pharmaceutically acceptable salt can be co-administered with standardized psychotherapy, for example in terms of individual or group therapy. In another embodiment, the compound according to formula (I) or its pharmaceutically acceptable salt can be co-administered with standardized psychotherapy or by computer-assisted and social psychology or behavioral therapy. In certain embodiments, computer-assisted is by means of digital or electronic devices such as online tools, smart phones, laptops, tablet computers, wireless devices or health apps.

[0569] In further embodiments, provided herein is a method of treating a condition, disease or disorder treated with an M4 receptor agonist, the method comprising administering a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof and an antipsychotic to a subject in need of treatment thereof. In certain embodiments, provided herein is a method of treating a condition, disease or disorder treated with an M4 receptor agonist, the method comprising administering a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof, an antipsychotic and a cholinesterase inhibitor to a subject in need of treatment thereof. In certain embodiments, provided herein is a method of treating a condition, disease or disorder treated with an M4 receptor agonist, the method comprising administering a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof, an antipsychotic and a mood stabilizer to a subject in need of treatment thereof.

[0570] In further embodiments, provided herein is a method of treating a condition, disease or disorder that is treated with an M4 receptor agonist, the method comprising administering a therapeutically effective amount of an antidepressant and a compound according to formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0571] In further embodiments, provided herein are uses of compounds according to formula (I) or pharmaceutically acceptable salts thereof in conditions, diseases or disorders treated with M4 receptor agonists, wherein the uses are combined with antipsychotics. In certain embodiments, provided herein are uses of compounds according to formula (I) or pharmaceutically acceptable salts thereof in conditions, diseases or disorders treated with M4 receptor agonists, wherein the uses are combined with antipsychotics and cholinesterase inhibitors. In certain embodiments, provided herein are uses of compounds according to formula (I) or pharmaceutically acceptable salts thereof in conditions, diseases or disorders treated with M4 receptor agonists, wherein the uses are combined with antipsychotics and mood stabilizers.

[0572] In further embodiments, provided herein is the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof in a condition, disease or disorder treated with an M4 receptor agonist, wherein the use is in combination with an antidepressant.

[0573] In further embodiments, provided herein are compounds according to formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of drugs for treating conditions, diseases or disorders treated with M4 receptor agonists, wherein the use is combined with antipsychotics. In certain embodiments, provided herein are compounds according to formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of drugs for treating conditions, diseases or disorders treated with M4 receptor agonists, wherein the use is combined with antipsychotics and cholinesterase inhibitors. In certain embodiments, provided herein are compounds according to formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of drugs for treating conditions, diseases or disorders treated with M4 receptor agonists, wherein the use is combined with antipsychotics and mood stabilizers.

[0574] In further embodiments, provided herein is the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a condition, disease or disorder treated with an M4 receptor agonist, wherein the use is combined with an antidepressant.

[0575] In further embodiments, provided herein is the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof in a condition, disease or disorder treated with an M4 receptor agonist, wherein the use is combined with computer-assisted psychosocial or behavioral therapy.

[0576] In further embodiments, provided herein is a method for treating a condition, disease or disorder that is treated with an M4 receptor agonist, the method comprising administering a therapeutically effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof in combination with computer-assisted psychosocial or behavioral therapy.

[0577] In a further embodiment, provided herein is the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a condition, disease or disorder treatable by an M4 receptor agonist, wherein the use is combined with computer-assisted psychosocial or behavioral therapy.

[0578] 5. Preparation Method

[0579] The compounds provided herein can be prepared by a variety of methods including standard chemistry. Suitable synthetic routes are depicted in the following schemes.

[0580] Compounds provided herein can be prepared by methods known in the art of organic synthesis, as described in part by the following synthesis scheme. In the scheme described below, it is well understood that, according to general principles or chemistry, protective groups of sensitive groups or reactive groups are used when necessary. Protective groups are operated according to standard methods for organic synthesis (see TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley, New York 1999). These groups are removed at a convenient stage of compound synthesis using methods that are obvious to those skilled in the art. The selection process and reaction conditions and their order of implementation should be consistent with the preparation of compounds provided herein.

[0581] Those skilled in the art will recognize whether there is a stereocenter in the compounds provided herein. Therefore, the compounds provided herein include possible stereoisomers and include not only racemic compounds but also individual enantiomers and / or diastereomers. When it is necessary to provide a compound as a single enantiomer or diastereomer, it can be obtained by stereoselective synthesis or by splitting the final product or any convenient intermediate. The splitting of the final product, intermediate or starting material can be carried out by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Elel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0582] The compounds provided herein can be prepared according to the sequence shown in Scheme 1 below.

[0583] Solution 1

[0584]

[0585] In Scheme 1, phenols (such as 1) can be protected as benzyl ethers and to give protected phenols (such as 2). The aldehyde can then be bisallylated with allyltrimethylsilane in the presence of an activated Lewis acid (such as ytterbium chloride). The resulting diene (such as 3) can then be oxidized by ozone gas and subsequently reduced with a reducing agent (such as sodium borohydride) to give diols (such as 4). These alcohols can then be activated as p-toluenesulfonates to give activated diols (such as 5), which can be displaced by amines (such as 6) to give tertiary amines (such as 7). The benzyl protecting group can be removed by palladium catalysis in the presence of hydrogen to give free phenols (such as 8), which can then be alkylated by aliphatic halides or tosylates in the presence of a base such as cesium carbonate to give substituted phenols (such as 9). The amine can then be deprotected with an acid such as TFA to give the free amine, which can be reacted with a heteroaromatic halide under Buchwald Hartwig or nucleophilic aromatic substitution conditions to give examples such as 12. Alternatively, the amine such as 10 can be reacted with a heteroaromatic halide containing an ester to produce a heteroaromatic compound such as 11. The ester can then be hydrolyzed with an aqueous base such as lithium hydroxide, and the resulting acid can be decarboxylated with an aqueous acid such as HCl to give examples such as 12.

[0586] Solution 2

[0587]

[0588] In Scheme 2, phenols (such as 9) can be deprotected with acids (such as TFA), and the resulting amines can react with heteroaromatic halides under Buchwald Hartwig or nucleophilic aromatic substitution conditions to give heteroaromatic compounds (such as 15). Alternatively, amines can react with heteroaromatic halides containing ethyl esters to give esters (such as 14). The esters can then be hydrolyzed with aqueous bases such as lithium hydroxide, and the resulting acids can be decarboxylated with acids such as HCl to give heteroaromatic halides (such as 15). Alternatively, compounds provided herein can be prepared as shown in Scheme 3.

[0589] Solution 3

[0590]

[0591] In Scheme 3, arylboronic acids (such as 17) can react with unsaturated lactones (such as 18) under rhodium catalysis to give saturated lactones (such as 19). The lactones can then be reduced with a reducing agent (such as lithium aluminum hydride) to give diols (such as 4). These diols can then be further processed as depicted in Scheme 1 or Scheme 2. Alternatively, the compounds provided herein can be prepared as shown in Scheme 4 below.

[0592] Solution 4

[0593]

[0594] In Scheme 4, an arylboronic acid (such as 20) can be reacted with an unsaturated lactone (such as 19) under rhodium catalysis, and the resulting saturated lactone 21 can be reduced with a reducing agent such as lithium borohydride to give a diol (such as 22). The resulting diol can then be reacted with a boronate ester (such as 23) under Suzuki-Miyaura conditions to give an unsaturated ring (such as 24). The olefin can then be reduced with palladium catalysis in the presence of hydrogen to give a saturated ring (such as 25), and the hydroxyl group can then be activated with tosyl chloride to give an activated diol (such as 26). The tosyl group can then be replaced with an amine (such as 6) in the presence of a base (such as potassium phosphate) to give a tertiary amine (such as 27). The amine can be deprotected with an acid such as TFA, and the resulting amine 28 can be reacted with a heteroaromatic halide under Buchwald Hartwig or nucleophilic aromatic substitution conditions to give an example (such as 30). Alternatively, the amine can be reacted with a heteroaromatic halide containing an ester to give an ethyl ester (such as 29), and the ester can be hydrolyzed with an aqueous acid (such as lithium hydroxide), and the resulting acid can be decarboxylated with an aqueous acid (such as HCl) to give an example (such as 30). Alternatively, the compounds provided herein can be prepared as shown in Scheme 5 shown below.

[0595] Solution 5

[0596]

[0597] In Scheme 5, an unsaturated ester (such as 31) can be reacted with diethyl malonate in the presence of a reducing metal (such as sodium) to give a triester (such as 32). The ester can then be hydrolyzed and decarboxylated with an acid (such as HCl) to give a diacid (such as 33). The acid can then be reduced with borane to give a diol (such as 35). Alternatively, the ester can be decarboxylated to give a diester (such as 34), and these esters can be reduced with a reducing agent (such as lithium borohydride) to give a diol (such as 35). The diol (such as 35) can then be activated to a tosylate with tosyl chloride, and the activated diol 36 can react with an amine (such as 6) to give a tertiary amine (such as 37). Bromides (such as 37) can react with pinacol borate to give an unsaturated ring (such as 38). The olefin can then be reduced with hydrogen and palladium catalysis to give a saturated ring (such as 39), and the amine can then be deprotected with an acid such as TFA. The free amine (such as 40) can then react with a heteroaromatic halide under Buchwald Hartwig or nucleophilic aromatic substitution conditions to give an example (such as 42). Alternatively, the free amine can react with a heteroaromatic halide containing an ethyl ester. The ester (such as 41) can then be hydrolyzed with an aqueous acid (such as lithium hydroxide) to give an acid, which can then be decarboxylated with an acid (such as HCl) to generate an example (such as 42). Alternatively, the compounds provided herein can be prepared as described in Scheme 6 below.

[0598] Solution 6

[0599]

[0600] In scheme 6, aryl bromide (such as 43) can be combined with pinacol borate (such as 44) under Suzuki-Miyaura cross-coupling conditions to produce unsaturated rings (such as 45). Alcohol can then be deprotected with a fluoride source (such as TBAF) to give free alcohol (such as 46), and olefins can then be reduced with hydrogen and palladium catalysis to produce saturated rings (such as 47). Amine can then be deprotected with acid such as TFA, and then free amine can react with heteroaromatic halides under Buchwald Hartwig or nucleophilic aromatic substitution conditions to give examples (such as 50). Alternatively, free amine (such as 48) can react with heteroaromatic halides containing ethyl esters to give esters (such as 49). Ester can then be hydrolyzed with aqueous bases such as lithium hydroxide, and then the resulting acid can be decarboxylated with aqueous acids such as HCl to give examples (such as 50). Alternatively, provided herein is a compound that can be prepared as described in scheme 7 below.

[0601] Solution 7

[0602]

[0603] In scheme 7, phenol (such as 8) can be activated in the presence of a base (such as pyridine) such as with trifluoromethanesulfonic anhydride to generate a sulfonyl ester (such as 51). Then the trifluoromethylsulfonyl ester can be converted into boric acid with tetrahydroxy diboron in the presence of a palladium catalyst, and the corresponding boric acid can react with a halide in the presence of a base to generate an olefin (such as 52). Subsequently, the compound can be reduced with hydrogen under palladium catalysis to give a saturated compound (such as 53), and then the compound can be deprotected with an acid (such as TFA) to give an amine (such as 54). The amine can react with an aryl halide under Buchwald-Hartwig or nucleophilic aromatic substitution conditions to generate an example (such as 56). Alternatively, an amine (such as 51) can react with a heteroaromatic halide containing an ethyl ester to give an ester (such as 55). The ester can then be hydrolyzed with an aqueous base such as lithium hydroxide, and the resulting acid can be decarboxylated with an aqueous acid such as HCl to generate an example (such as 56). Alternatively, the compound provided herein can be prepared as shown in the following scheme 8.

[0604] Solution 8

[0605]

[0606] In scheme 8, phenol (such as 8) can be activated to trifluoromethylsulfonyl ester (such as 57) using trifluoromethanesulfonic anhydride. Then the obtained activated ester can be converted into boric acid using tetrahydroxy diboron in the presence of palladium, and the obtained boric acid can react with heteroaromatic halides under Suzuki-Miyaura conditions to generate heteroaromatic compounds (such as 58). Then the amine can be deprotected with acid (such as TFA), and the obtained free amine (such as 59) can react with heteroaromatic halides such as under Buchwald Hartwig or nucleophilic aromatic substitution conditions to generate heteroaromatic compounds (such as 61). Alternatively, amine (such as 59) can react with heteroaromatic halides containing ethyl esters to give esters (such as 60). Then the ester can be hydrolyzed with aqueous bases such as lithium hydroxide, and then the obtained acid can be decarboxylated with aqueous acids such as HCl to generate heteroaromatic compounds (such as 61). Alternatively, compounds provided herein can be prepared as shown in scheme 9 below.

[0607] Solution 9

[0608]

[0609] In Scheme 9, a free amine (such as 9) can be alkylated with a reagent such as cyanogen bromide to give a nitrile (such as 62). The nitrile can then react with hydroxylamine to give a hydroxylamine (such as 63), which can then be condensed with a dehydrating agent such as diethylphenyl orthoformate and toluenesulfonic acid to give an oxadiazole (such as 64). Alternatively, compounds can be prepared as shown in Scheme 10 below.

[0610] Solution 10

[0611]

[0612] In scheme 10, substituted phenols (such as 9) can be chlorinated with a chlorinating agent such as 2-chloro-1,3-bis(methoxycarbonyl)guanidine to give aryl chlorides (such as 65). The Boc group can then be removed with an acid (such as TFA) to generate a free amine (such as 56), which can then be further reacted with a heteroaryl halide under nucleophilic aromatic substitution or Buchwald-Hartwig conditions to generate a compound (such as 68). Alternatively, the amine can react with a heteroaromatic halide containing an ethyl ester to give an ester (such as 67). The ester can be hydrolyzed with an aqueous base such as lithium hydroxide, and the resulting acid can be decarboxylated with an acid such as HCl to give an example (such as 68). Alternatively, the compounds provided herein can be prepared as shown in the following scheme 11.

[0613] Solution 11

[0614]

[0615] In Scheme 11, piperidine (such as 69) can react with ketone (such as 70) under reductive amination conditions (such as zinc chloride and sodium cyanoborohydride) to generate a carbon-nitrogen bond, as found in 71. The phenol can then be protected as a benzyl group with benzyl bromide and a base such as cesium carbonate, and the amine can then be deprotected with an acid such as TFA. The free amine (such as 73) can then react with a heteroaromatic halide under nucleophilic aromatic substitution conditions or Buchwald-Hartwig conditions. Alternatively, the free amine (such as 73) can react with an ester-containing heteroaromatic halide to generate an ester (such as 74). The ester can then be hydrolyzed with an aqueous base such as lithium hydroxide, and the resulting acid can be decarboxylated with an acid such as HCl to give a heteroaromatic compound (such as 75). The benzyl group can then be removed by catalytic hydrogenation with palladium, and the resulting phenol 76 can react with a halide or tosylate in the presence of a base such as cesium carbonate. The racemic mixture can then be separated to yield the single enantiomers 77 and 78 using, for example, chiral chromatography.

[0616] 7. Incorporation by Reference

[0617] The entire disclosure of each patent document and scientific article cited herein is incorporated by reference for all purposes.

[0618] 8. Examples

[0619] This disclosure will be further illustrated by the following examples, which are intended to be illustrative only and not limiting in any way. It should be understood that various other embodiments, modifications and their equivalents that may be proposed by those skilled in the art may be adopted without departing from the spirit of this disclosure and / or the scope of the appended claims.

[0620] 1. Synthesis of intermediates and examples

[0621] The abbreviations used are those conventional in the art or the following:

[0622]

[0623] AcOH Acetic acid

[0624] aq water-based

[0625] ATP Adenosine triphosphate

[0626] AUC Area under the curve

[0627] BOC tert-Butyloxycarbonyl

[0628] tBu tert-butyl

[0629] C degrees Celsius

[0630] CDI Carbonyldiimidazole

[0631] CMBG 2-Chloro-1,3-bis(methoxycarbonyl)guanidine

[0632] DCE 1,2-Dichloroethane

[0633] DCM dichloromethane

[0634] DIPEA N,N-Diisopropylethylamine

[0635] DME 1,4-dimethoxyethane

[0636] DMEM Dulbecco's Modified Eagle's Medium

[0637] DMF N,N-Dimethylformamide

[0638] DMSO dimethyl sulfoxide

[0639] DPBS Dulbecco's Phosphate Buffered Saline

[0640] EtOAc Ethyl acetate

[0641] EtOH

[0642] FBS Fetal Bovine Serum

[0643] FCC flash column chromatography

[0644] g

[0645] hr hours

[0646] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0647] HBSS Hank's Balanced Salt Solution

[0648] HBTU 1-[Bis(dimethylamino)methylene]-1H-benzotriazolium hexafluorophosphate (1-)3-oxide

[0649] Hz Hertz

[0650] HOBt 1-Hydroxy-7-azabenzotriazole

[0651] HPLC High Pressure Liquid Chromatography

[0652] IP intraperitoneal

[0653] IPA Isopropyl Alcohol

[0654] J coupling constant

[0655] kg kilogram

[0656] L Liter

[0657] LCMS Liquid chromatography and mass spectrometry

[0658] LED Light Emitting Diode

[0659] Me Methyl

[0660] MHz

[0661] mM millimole

[0662] MTBE Methyl tert-butyl ether

[0663] MS mass spectrometry

[0664] min

[0665] mg milligram

[0666] mL milliliters

[0667] mmol millimole

[0668] m / z mass-to-charge ratio

[0669] nm nanometer

[0670] nM nanomolar

[0671] NMR Nuclear Magnetic Resonance

[0672] Pd / C, Pd-C carbon supported palladium

[0673] Pd(dba) 2 Bis(dibenzylideneacetone)palladium(0)

[0674] Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium(0)

[0675] Pd(dppf)Cl 2 Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)

[0676] PO Oral (oral administration)

[0677] psi pounds per square inch

[0678] pTSCl p-Toluenesulfonyl chloride

[0679] rac racemic RB round bottom

[0680] rpm revolutions per minute

[0681] RT Room temperature

[0682] Rt retention time

[0683] SFC Supercritical Fluid Chromatography

[0684] SC Subcutaneous

[0685] TBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate

[0686] TC tissue culture

[0687] TEA Triethylamine

[0688] TFA Trifluoroacetic acid

[0689] THF Tetrahydrofuran

[0690] TPGS-750-M DL-α-Tocopheryl Methoxy Polyethylene Glycol Succinate Solution

[0691] TTMSS tris(trimethylsilyl)silane

[0692] μL microliter

[0693] μM micromolar

[0694] UPLC Ultra-Performance Liquid Chromatography

[0695] UV

[0696] Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0697] XPhosPd G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0698] General procedure:

[0699] In the case where no preparation route is described, the material is commercially available. Commercial reagents were used without further purification unless otherwise stated. Room temperature (RT) was approximately 20°C-25°C. Recorded at 400 MHz on a Bruker instrument 1 H NMR and processed with mNOVA. Chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane and coupling constants (J) are reported in Hertz. Abbreviations for multiplicity are: s = singlet, d = doublet, t = triplet, q = quartet, dd = double of doublets, dt = double of triplets, br = broad.

[0700] LCMS Method 1:

[0701] Instrument: Waters Acquity UPLC, photodiode array detector; Column: AcQuity UPLC BEH C 18 1.7 μm, 21 x 30 mm; 2 min run time, 2% solvent B from 0 to 0.1 min, 2% → 98% solvent B: solvent A (from 0.1 to 1.8 min), 98% solvent B for 0.2 min. Solvents: solvent A = 0.1% formic acid in water (v / v), solvent B = 0.1% formic acid in acetonitrile (v / v). Injection volume 2-5 uL; UV detection array 210-400, mass detection 120-1250 (electrospray ionization); column at 50°C; flow rate 1.0 mL / min.

[0702] LCMS method 2:

[0703] Instrument: Waters Acquity UPLC, photodiode array detector; Column: AcQuity UPLC BEH C 18 1.7 μm 21 x 50 mm; 2 min run time, 2% solvent B from 0 to 0.1 min, 2% → 98% solvent B: solvent A (from 0.1 to 1.8 min), 98% solvent B for 0.2 min. Solvents: solvent A = 5 mM ammonium hydroxide in water, solvent B = 5 mM ammonium hydroxide in acetonitrile. Injection volume 2-5 uL; UV detection array 210-400, mass detection 120-1250 (electrospray ionization); column at 50 °C; flow rate 1.0 mL / min.

[0704] LCMS method 3:

[0705] Instrument: Waters Acquity UPLC, photodiode array detector; column: AcQuity UPLC BEH C 18 1.7 μm, 21 x 30 mm; 5.2 min run time, 2% → 98% solvent B: solvent A (from 0 to 5.15 min), 98% solvent B from 5.15 to 5.20 min. Solvents: solvent A = 0.1% formic acid in water (v / v), solvent B = 0.1% formic acid in acetonitrile (v / v). Injection volume 2-5 uL; UV detection array 210-400, mass detection 120-1600; column, at 50 °C, flow rate 1.0 mL / min.

[0706] LCMS Method 4:

[0707] Instrument: Waters Acquity UPLC, photodiode array detector; column: AcQuity UPLC BEH C 181.7 μm, 21 x 30 mm; 5.2 min run time, 2% → 98% solvent B: solvent A (from 0 to 5.15 min), 98% solvent B from 5.15 to 5.20 min. Solvents: solvent A = 5 mM ammonium hydroxide in water, solvent B = 5 mM ammonium hydroxide in acetonitrile). Injection volume 2-5 uL; UV detection array 210-400, mass detection 120-1600; column at 50°C, flow rate 1.0 mL / min.

[0708] Intermediate 1A: 3-(2-(Benzyloxy)phenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

[0709]

[0710] Step 1: 4-(2-(Benzyloxy)phenyl)tetrahydro-2H-pyran-2-one

[0711] Potassium hydroxide (3.95 g, 70.3 mmol) in water (17.50 mL) was added dropwise to [RhCl(COD)] at 0 °C over a period of 2 minutes. 2 (0.347 g, 0.703 mmol), (2-(benzyloxy)phenyl)boronic acid (commercially available, 22.46 g, 98 mmol) and 5,6-dihydro-2H-pyran-2-one (commercially available, 6.06 mL, 70.3 mmol) in 1,4-dioxane (175 mL). The temperature of the reaction was then raised to 35 °C and stirred for 16 h. The reaction was diluted with EtOAc and 2M HCl. The aqueous solution was separated and back extracted with EtOAc. The combined organic layers were purified by MgSO 4 Dry and remove the solvent under reduced pressure.The crude mixture was then purified by FCC (0%→60% EtOAc / heptane) to give the title compound (19.49 g, 68.3 mmol).

[0712] LCMS: Rt = 1.03 min (LCMS method 1); MS m / z 281.3 [M+H] + .

[0713] 1 H NMR (400MHz, CD 3OD)δ7.49-7.27(m,5H),7.20(ddd,J=14.8,7.5,1.8Hz,2H),7.05(dd,J=8.1,1.2Hz,1H),6.99-6.89(m,1H),5.13(s, 2H),4.49-4.27(m,2H),3.71-3.50(m,1H),2.85(dd,J=17.2,6.4Hz,1H),2.68(dd,J=17.2,9.8Hz,1H),2.10(m,2H).

[0714] Step 2: 3-(2-(Benzyloxy)phenyl)pentane-1,5-diol

[0715] Lithium aluminum hydride (76 mL, 76 mmol, 1 M in THF) was added to a stirred solution of 4-(2-(benzyloxy)phenyl)tetrahydro-2H-pyran-2-one (19.49 g, 69.0 mmol) in anhydrous THF (400 mL) at 0°C and the reaction mixture was then stirred for 2 h at 0°C. The reaction was quenched by water at -5°C until gas evolution ceased and then a solution of NaOH (25 g) in water (25 mL) was added portionwise to the mixture at 0°C. Next, Na 2 SO 4 (300 g) was added to the reaction mixture and stirred for 60 min. The mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by FCC (0%-10% MeOH / DCM) to give the title compound (19.3 g, 64.1 mmol).

[0716] LCMS: Rt = 0.85 min (LCMS method 1); MS m / z 287.3 [M+H] + .

[0717] 1 H NMR (400 MHz, CDCl 3 )δ7.51-7.31(m,5H),7.26-7.16(m,2H),7.07-6.95(m,2H),5.11(s,2H),3.61-3.35(m,5H),1.92(m,4H),1.66(s,2H).

[0718] Step 3: 3-(2-(Benzyloxy)phenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

[0719] To a solution of 3-(2-(benzyloxy)phenyl)pentane-1,5-diol (19.31 g, 67.4 mmol) and triethylamine (41.4 mL, 297 mmol) in MeCN (40 mL) was added pTsCl (28.3 g, 148 mmol) and DMAP (0.824 g, 6.74 mmol) at -5 °C. After the addition, the reaction was stirred at RT overnight. The solvent was removed under reduced pressure. The crude product was dissolved in DCM and washed with water and brine, then purified by Na 2 SO 4 Dried and filtered. DCM was removed under reduced pressure and the crude was purified by FCC (0%→50% EtOAc / heptane) to give the title compound.

[0720] LCMS: Rt=1.37min

[0721] 1 H NMR (400 MHz, CDCl 3 )δ7.74-7.63(m,4H),7.46-7.33(m,5H),7.30(s,4H),7.20-7.13(m,1H),6.99-6.72(m,3 H),5.00(s,2H),4.01-3.61(m,4H),3.15(m,1H),2.45(s,6H),2.03(m,2H),1.89(m,2H).

[0722] Intermediate 1B: 3-(2-(Benzyloxy)-5-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

[0723]

[0724] Step 1: 4-(2-(Benzyloxy)-5-fluorophenyl)tetrahydro-2H-pyran-2-one

[0725] (5-(Benzyloxy)-2-fluorophenyl)boronic acid (commercially available, 24 g, 98 mmol), 5,6-dihydro-2H-pyran-2-one (commercially available, 6.06 mL, 70.3 mmol) and [RhCl(COD)] 24-[4-(4-(4-(4-(4-oxo-1-yl)-2-nitropropene)-2-nitropropene]-4-nitropropene)-2-nitropropene (0.5 g, 1.014 mmol) was dissolved in dioxane (180 mL) and cooled to -10 ° C. Then, potassium hydroxide (4.38 g, 78 mmol) was dissolved in water (17.8 mL) and added dropwise to the dioxane solution within 10 min. The reaction was then warmed to 35 ° C and stirred for 2 hours. The reaction was neutralized with 1M HCl (to pH 3) and then concentrated under vacuum to remove dioxane. The residue was then diluted with water and extracted with EtOAc, and the organic matter was combined and concentrated under vacuum. The crude product was purified by FCC (0% → 100% EtOAc / heptane) to produce the title compound (19.65 g, 78 mmol).

[0726] LCMS: RT = 1.07 min (LCMS method 2); MS m / z 301.4 [M+H] + .

[0727] Step 2: 3-(2-(Benzyloxy)-5-fluorophenyl)pentane-1,5-diol

[0728] Lithium aluminum hydride (31.2 mL, 71.8 mmol) was added to a stirred solution of 4-(2-(benzyloxy)-5-fluorophenyl)tetrahydro-2H-pyran-2-one (19.6 g, 65.3 mmol) in dry THF (384 mL) at 0°C. The reaction mixture was stirred at -5°C under N 2 The reaction was stirred at -5 °C for 2 h. 2 O (10 mL) was quenched until gas evolution ceased and then a solution of NaOH (25 g) in water (25 mL) was added portionwise to the mixture at 0°C. 2 SO 4 (300 g) was added to the reaction mixture and stirred for 60 min. The mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by FCC (0%-10% MeOH / DCM) to give the title compound (17.8 g, 55.6 mmol).

[0729] LCMS: Rt = 0.90 min (LCMS method 2); MS m / z 304.4 [M+H] + .

[0730] 1 H NMR (400 MHz, CDCl 3 )δ7.47-7.33(m,5H),6.97-6.84(m,3H),5.06(s,2H),3.60-3.47(m,2H),3.41(m,2H),2.06-1.91(m,3H),1.77(m,2H).

[0731] Step 3: 3-(2-(Benzyloxy)-5-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

[0732] 3-(2-(Benzyloxy)-5-fluorophenyl)pentane-1,5-diol (17.8 g, 58.5 mmol) and TEA (35.9 mL, 257 mmol) were dissolved in MeCN (200 mL) and cooled to -5 °C. pTsCl (24.53 g, 129 mmol) and DMAP (0.714 g, 5.85 mmol) were added and the reaction was warmed to RT and stirred overnight. The solvent was removed under reduced pressure. The crude product was dissolved in DCM and washed with water and brine, and purified by Na 2 SO 4 Dry, filter and concentrate.The crude product was purified by FCC (0%→50% EtOAc / heptane) to give the title compound (22.8 g, 37.2 mmol).

[0733] LCMS Rt = 1.37 min (LCMS method 2); MS m / z 630.4 [M+NH 4 ] + .

[0734] Intermediate 1C: 3-(2-(Benzyloxy)-4-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

[0735]

[0736] Step 1: 2-(Benzyloxy)-4-fluoro-1-(hept-1,6-dien-4-yl)benzene

[0737] 2-(Benzyloxy)-4-fluorobenzaldehyde (commercially available, 23.90 g, 104 mmol) was loaded into a 250 mL round-bottom flask, followed by the addition of nitromethane (250 mL). Then, ytterbium (III) chloride (7.25 g, 26.0 mmol) was added to the reaction and the mixture was stirred at RT for 15 min. After stirring for 15 minutes, allyltrimethylsilane (41.2 mL, 260 mmol) was slowly added in 5 min. The mixture was stirred overnight at RT. The reaction was concentrated, and the crude product was purified by FCC (0% → 30% EtOAc / heptane) to produce the title compound (22.64 g, 72.6 mmol) as a clear, colorless oil.

[0738] LCMS: Rt = 1.43 min (LCMS method 1).

[0739] 1 H NMR (400 MHz, CDCl3 )δ7.38-7.19(m,5H),6.97(dd,1H),6.61-6.47(m,2H),5.57(m,2H),4.95(s,2H),4.90-4.78(m,4H),3.19(t,1H),2.29(m,4H).

[0740] Step 2: 3-(2-(Benzyloxy)-4-fluorophenyl)pentane-1,5-diol

[0741] 2-(Benzyloxy)-4-fluoro-1-(hept-1,6-dien-4-yl)benzene (22.64 g, 76 mmol) was dissolved in MeOH (450 mL) and cooled to -78 °C. Next, ozone was bubbled through the reaction mixture for 120 min, during which time the reaction turned a light purple. Nitrogen was then bubbled through the reaction for 20 min and then it was warmed to 0 °C and NaBH 4 (28.9 g, 764 mmol) was added portionwise to the reaction over 4 h and the reaction was then stirred at RT for 16 h. The reaction was then poured into DCM and saturated NH 4 Cl, and the mixture was stirred at RT for 1 h. The organic layer was separated and washed with water and brine, then with Na 2 SO 4 Dry and filter. The solvent was removed under reduced pressure. The obtained product (15.22 g, 50.0 mmol) was used without further purification.

[0742] LCMS: Rt = 0.90 min (LCMS method 1); MS m / z 305.2 [M+H] + .

[0743] 1 H NMR (400 MHz, CDCl 3 )δ7.36-7.22(m,6H),7.03(m,1H),6.64-6.57(m,2H),4.95(s,2H),3.42(m,2H),3.31(m,2H),1.92-1.81(m,2H),1.79-1.64(m,2H).

[0744] Step 3: 3-(2-(Benzyloxy)-4-fluorophenyl)pentane-1,5-diyl bis(4-methylbenzenesulfonate)

[0745] 3-(2-(Benzyloxy)-4-fluorophenyl)pentane-1,5-diol (6.96 g, 22.87 mmol) was dissolved in MeCN (150 mL) and TEA (13.63 mL, 98 mmol) was added and the reaction was cooled to 0 °C. The reaction was incubated for 10 min and then pTsCl (9.59 g, 50.3 mmol) and DMAP (0.559 g, 4.57 mmol) were added. The reaction was slowly warmed to RT and stirred overnight. The reaction was then diluted with water and extracted with DCM. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was then purified by FCC (0% → 60% EtOAc / heptane) to produce the title compound (8.91 g, 14.54 mmol).

[0746] LCMS: Rt = 1.35 min (LCMS method 1); MS m / z 630.3 [M+NH 4 ] + .

[0747] 1 H NMR (400 MHz, CDCl 3 )δ7.68-7.61(m,4H),7.42-7.32(m,5H),7.27(m,4H),6.57(dd,J=10.9,2.4Hz,1H),6.46(td,J=8.3,2.4Hz, 1H),4.93(s,2H),3.90-3.80(m,2H),3.74(m,2H),3.08(m,1H),2.43(s,6H),1.98(m,3H),1.92-1.80(m,2H).

[0748] Intermediate 1D: 3-(2-(Benzyloxy)-4,5-difluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

[0749]

[0750] Step 1: 4,5-difluoro-2-(hept-1,6-dien-4-yl)phenol

[0751] YbCl was added to a 1L three-necked flask. 3 6H 2O (20g, 51mmol), which was dehydrated by heating under vacuum. Then 4,5-difluoro-2-hydroxybenzaldehyde (20g, 126mmol) in nitromethane (200mL) was added to the flask at 25°C. After stirring for 30min, allyltrimethylsilane (51g, 443mmol) was added dropwise at 25°C. The mixture was then warmed to 60°C and stirred for 16h. Next, the reaction was cooled to 25°C, filtered and concentrated. MeCN (200mL) and 2NHCl (200mL) were then added to the crude reaction and the resulting solution was stirred at 25°C for 30min. MeCN was removed in vacuo, and the remaining aqueous phase was extracted with EtOAc, filtered through Na 2 SO 4 Dried, filtered and concentrated.The crude was purified by FCC (0%-10% EtOAc / petroleum ether) to give the title compound (14.5 g, 64.66 mmol) as a yellow liquid.

[0752] 1 H NMR (400 MHz, CDCl 3 )δ6.90(dd,J=8.9,11.6Hz,1H),6.62(dd,J=6.8,11.2Hz,1H),5.68(m,2H),5.56(br s,1H),5.07-4.92(m,4H),3.16-3.03(m,1H),2.48-2.24(m,4H).

[0753] Step 2: 3-(4,5-difluoro-2-hydroxyphenyl)pentane-1,5-diol

[0754] For a stirred solution of 4,5-difluoro-2-(hept-1,6-dien-4-yl)phenol (14.5 g, 64.66 mmol) in MeOH (150 mL) at -78 °C, ozone was bubbled through the reaction mixture for 3 h until the starting material was consumed and the reaction turned pale purple. The ozone bubbling was stopped and the mixture was heated to 40 °C by N 2 Excess ozone in the reaction mixture was removed by bubbling through the reaction mixture for 10 min. The reaction was then warmed to -20 °C and NaBH was added portionwise. 4 (14.68 g, 387.96 mmol), and the reaction was warmed to 0 °C and stirred for 2 h. 4 Cl was quenched and MeOH was removed under reduced pressure. The aqueous layer was then extracted with EtOAc and the combined organic layers were purified by Na 2 SO 4Dried, filtered and concentrated. The residue was purified by FCC (0%-75% EtOAc / petroleum ether). The isolated material was then further purified (0%-5% MeOH / DCM) to give the title compound (3.1 g, 13.35 mmol) as a yellow solid.

[0755] 1 H NMR (400 MHz, DMSO-d 6 )δ9.58(s,1H),7.09(dd,J=9.5,12.1Hz,1H),6.70(dd,J=7.3,12.4Hz,1H) ,4.28(t,J=5.1Hz,2H),3.27-3.18(m,3H),3.07(m,1H),1.76-1.64(m,3H).

[0756] Step 3: 3-(2-(Benzyloxy)-4,5-difluorophenyl)pentane-1,5-diol

[0757] 3-(4,5-difluoro-2-hydroxyphenyl)pentane-1,5-diol (3.46 g, 14.90 mmol) was added to a 250 mL round bottom flask and dissolved in acetone (100 mL). K 2 CO 3 To the 4-thiazolinyl ether (3.09 g, 22.35 mmol) and benzyl bromide (1.86 mL, 15.64 mmol) was added 4-thiazolinyl ether (3.09 g, 22.35 mmol) and benzyl bromide (1.86 mL, 15.64 mmol) and the reaction was refluxed for 3 h. The reaction was then cooled to RT and acetone was evaporated under reduced pressure. The residue was dissolved in DCM and washed with water, and then the aqueous layer was stripped with DCM. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was then purified by FCC (0%-10% MeOH / DCM) to produce the title compound (4.75 g, 14.74 mmol).

[0758] LCMS: Rt = 0.89 min (LCMS method 2); MS m / z 321.2 [MH] - .

[0759] Step 4: 3-(2-(Benzyloxy)-4,5-difluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

[0760] 3-(2-(Benzyloxy)-4,5-difluorophenyl)pentane-1,5-diol (4.72 g, 14.64 mmol) and pTsCl (6.42 g, 33.7 mmol) were dissolved in MeCN (70 mL) at room temperature. DMAP (0.179 g, 1.464 mmol) and triethylamine (8.16 mL, 58.6 mmol) were then added to the solution and the reaction was stirred at room temperature for 16 h. MeCN was then evaporated and the residue was diluted with water and extracted with DCM. The organic extracts were combined, washed with brine, and purified by MgSO 4 Dry, filter and concentrate.The crude was purified by FCC (0%-10% MeOH / DCM) to give the title compound (7.47 g, 11.8 mmol).

[0761] LCMS: Rt = 1.36 min (LCMS method 1); MS m / z 648.6 [M+NH 4 ] + .

[0762] Intermediate 1E: 3-(2-(tetrahydro-2H-pyran-4-yl)phenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

[0763]

[0764] Step 1: 4-(2-bromophenyl)tetrahydro-2H-pyran-2-one

[0765] A solution of potassium hydroxide (5.15 g, 92 mmol) in water (10 mL) was added dropwise to [RhCl(COD)] at 0 °C over a period of 10 min. 2 (0.452 g, 0.917 mmol), (2-bromophenyl)boronic acid (27.6 g, 138 mmol) and 5,6-dihydro-2H-pyran-2-one (8.78 mL, 92 mmol) in 1,4-dioxane (200 mL). The temperature of the reaction was then raised to 35 °C and the reaction was stirred for 16 hours. The reaction was diluted with EtOAc and 3M HCl. The aqueous solution was separated and back extracted with EtOAc. The combined organic layers were purified by MgSO 4 Dry and remove the solvent under reduced pressure.The residue was purified by FCC (0%-60% EtOAc / heptane) to give the title compound (12.9 g, 50.4 mmol).

[0766] LCMS: Rt = 0.85 min (LCMS method 2); MS m / z 255.3 [M+H] + .

[0767] 1H NMR (400 MHz, CDCl 3 )δ7.53(t,J=6.9Hz,1H),7.34-7.21(m,1H),7.17(dd,J=7.8,2.2Hz,1H),7.09(q,J=6.9Hz ,1H),4.39(m,2H),3.66(m,1H),2.93(m,1H),2.57-2.47(m,1H),2.16(m,1H),1.98(m,1H).

[0768] Step 2: 3-(2-Bromophenyl)pentane-1,5-diol

[0769] A solution of lithium borohydride (16.66 mL, 33.3 mmol, 2 M in THF) was added to a stirred solution of 4-(2-bromophenyl)tetrahydro-2H-pyran-2-one (5.00 g, 19.60 mmol) in a mixture of THF (50 mL) and MeOH (0.50 mL) at 0 ° C. The reaction mixture was slowly warmed to RT and stirred for 18 h. THF was then removed under reduced pressure, and the reaction mixture was diluted with EtOAc and water. The pH of the aqueous phase was adjusted to 7 with acetic acid and then extracted with EtOAc. The combined organic layers were then purified by MgSO 4 Dry, filter and concentrate.The crude product was purified by FCC (0%-10% MeOH / DCM) to give the title intermediate (4.70 g, 18.1 mmol).

[0770] LCMS: Rt = 1.27 min (LCMS method 3); MS m / z 241.2 [MH 2 O] + .

[0771] 1 H NMR (400 MHz, DMSO-d 6 )δ7.55(d,J=7.7Hz,1H),7.39-7.31(m,2H),7.11(dt,J=8.6,4.4Hz,1H),4.35(t,J=4.9Hz,2H),3.34-3.14(m,5H),1.85-1.66(m,4H).

[0772] Step 3: 3-(2-(3,6-dihydro-2H-pyran-4-yl)phenyl)pentane-1,5-diol

[0773] 3-(2-Bromophenyl)pentane-1,5-diol (14.0 g, 54.0 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17.02 g, 81 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (1.761 g, 2.70 mmol) and tripotassium phosphate (20.64 g, 97 mmol) were suspended in degassed 1,4-dioxane (150 mL) and water (15.00 mL) and the reaction was stirred at RT for 16 h. The reaction was then diluted with water and extracted with EtOAc. The organic layer was purified by MgSO 4 Dried, filtered and concentrated.The crude was purified by FCC (0%-10% MeOH / DCM) and further purified by recrystallization from EtOAc / heptane (1:1) to give the title compound (9.85 g, 37.5 mmol) as a white solid.

[0774] LCMS: Rt = 0.70 min (LCMS method 2); MS m / z 261.3 [MH] - .

[0775] 1 H NMR (400 MHz, DMSO-d 6 )δ7.25(d,J=7.6Hz,2H),7.12(t,J=7.5Hz,1H),7.02(d,J=7.7Hz,1H),5.51(s,1H),4.27(t,J=5.0Hz, 2H), 4.15 (q, J = 2.9Hz, 2H), 3.79 (t, J = 5.3Hz, 2H), 3.19 (m, 4H), 3.04 (m, 1H), 2.24 (m, 2H), 1.71 (m, 4H).

[0776] Step 4: 3-(2-(Tetrahydro-2H-pyran-4-yl)phenyl)pentane-1,5-diol

[0777] 3-(2-(3,6-dihydro-2H-pyrans-4-yl)phenyl)pentane-1,5-diol (7.60g, 29.0mmol) was dissolved in MeOH (75mL) and 10% carbon-supported palladium (3.08g, 2.90mmol) was added. The flask was purged with 3 hydrogen balloons and then the reaction was stirred under a hydrogen balloon for 18h. The reaction was filtered through a diatomaceous earth pad and concentrated to obtain a crude product as a white solid. This material was combined with a parallel reaction of starting 3-(2-(3,6-dihydro-2H-pyrans-4-yl)phenyl)pentane-1,5-diol (3.30g, 12.6mmol) for recrystallization. The combined solid was recrystallized from EtOH / heptane to produce the title compound (9.95g, 37.6mmol) as a white solid.

[0778] LCMS: 1.29 min (LCMS method 3); MS m / z 265.3 [M+H] + .

[0779] 1 H NMR (400 MHz, CDCl 3 )δ7.26-7.18(m,2H),7.14(m,2H),3.93(dd,J=11.1,3.6Hz,2H),3.43(t,J=11.6,3H), 3.31(bs,1H),3.30-3.20(m,3H),3.15(m,3H),1.79(m,2H),1.68(m,4H),1.56(m,2H).

[0780] Step 4: 3-(2-(Tetrahydro-2H-pyran-4-yl)phenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

[0781] 3-(2-(Tetrahydro-2H-pyran-4-yl)phenyl)pentane-1,5-diol (7050 mg, 26.7 mmol) was suspended in MeCN (70 mL) and THF (70 mL) and cooled to 0 °C. Next, DMAP (326 mg, 2.67 mmol) and TEA (16.4 mL, 117 mmol) were added. The reaction was cooled to 0 °C and stirred for 15 minutes, and then toluenesulfonic anhydride (19.19 g, 58.7 mmol) was added in four portions, and the heterogeneous tan reaction was slowly warmed to RT and stirred for 16 h. Next, additional toluenesulfonic anhydride (4.5 g, 13.8 mmol) was added and the reaction was stirred for another hour. The reaction was then concentrated and the residue was dissolved in EtOAc, and the organic phase was washed with water and brine. The combined aqueous washes were stripped with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated on celite. The crude was then purified by FCC (0% - 60% EtOAc / heptane) to give the title intermediate as a pale yellow solid (10336 mg, 18.05 mmol).

[0782] LCMS: Rt = 2.96 min (LCMS method 3); MS m / z 573.3 [M+H] + .

[0783] 1 H NMR (400 MHz, DMSO-d 6 )δ7.73-7.65(m,4H),7.44(d,J=8.3Hz,4H),7.23(d,J=7.4Hz,1H),7.21-7.07(m,3H),3.86(m,4H),3.69(m,2H),3.35(d,J=10.3 Hz,5H),3.23(s,1H),2.97(t,J=11.6Hz,1H),2.41(s,6H),1.91(m,2H),1.86-1.73(m,2H),1.62(m,2H),1.41(d,J=12.1Hz,2H).

[0784] Intermediate 1F: 3-(2-(Benzyloxy)-3,5-difluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

[0785]

[0786] Step 1: 4-(2-(Benzyloxy)-3,5-difluorophenyl)tetrahydro-2H-pyran-2-one

[0787] In a round-bottom flask, 5,6-dihydro-2H-pyran-2-one (0.298 mL, 3.47 mmol), (3,5-difluoro-2-methoxyphenyl)boronic acid (0.915 g, 3.47 mmol) and [RhCl(COD)] 2 A solution of (0.034 g, 0.069 mmol) in 1,4-dioxane (8.6 mL) was cooled to 0 ° C, and a solution of potassium hydroxide (0.194 g, 3.47 mmol) in water (0.9 mL) was added dropwise. The reaction was then warmed to 35 ° C and stirred for 15 minutes. The reaction was then diluted with EtOAc and 1M HCl. The layers were separated and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with MgSO 4 Dried, filtered and concentrated, and the crude was purified by FCC (0% - 100% EtOAc / heptane) to give the title intermediate as a clear, colorless oil (784 mg, 2.46 mmol).

[0788] LCMS: Rt: 1.07 min (LCMS method 1); MS m / z 319.2 [M+H] + .

[0789] Step 2: 3-(2-(Benzyloxy)-3,5-difluorophenyl)pentane-1,5-diol

[0790] To a solution of 4-(2-(benzyloxy)-3,5-difluorophenyl)tetrahydro-2H-pyran-2-one (0.533 g, 1.674 mmol) in THF (10 mL) under nitrogen at -5 °C in a round bottom flask was added LiAlH 4 (1.0 M in THF, 1.84 mL, 1.842 mmol). After stirring for 35 min, the reaction was quenched with water (0.25 mL) at -5 °C until gas evolution ceased, then a solution of NaOH (614 mg) in water (0.614 mL) was added dropwise, followed by the addition of Na 2 SO 4 (7.38 g). The reaction was stirred for 1 hour and then filtered through celite, rinsed with THF, and the filtrate was concentrated. The crude product was purified by FCC (0%-20% MeOH (10% NH 4 Purification by HPLC-MS / MS (500 ng / ml / min) / dCM (4% paraformaldehyde) gave the title intermediate (501 mg, 1.55 mmol) as a clear, colorless oil.

[0791] LCMS: Rt: 0.90 min (LCMS method 1); MS m / z 323.5 [M+H] + .

[0792] Step 3: 3-(2-(Benzyloxy)-3,5-difluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

[0793] In a round bottom flask, triethylamine (1.08 mL, 7.77 mmol) and pTsCl (0.741 g, 3.89 mmol) and DMAP (0.019 g, 0.155 mmol) were added to a solution of 3-(2-(benzyloxy)-3,5-difluorophenyl)pentane-1,5-diol (0.501 g, 1.554 mmol) in acetonitrile (9.0 mL) in a round bottom flask. The reaction was stirred for 16 hours and then the reaction was concentrated and the residue was dissolved in DCM (50 mL) and washed with water (2 x 10 mL) and brine (1 x 10 mL), MgSO 4 Dried, filtered and concentrated.The residue was purified by FCC (0%-80% EtOAc / heptane) to give the title compound (772 mg, 1.22 mmol) as a yellow oil.

[0794] LCMS: Rt: 1.38 min (LCMS method 1); MS m / z 648.5 [M+NH 4 ] + .

[0795] 1 H NMR (400MHz, CD 3 OD) δ7.71-7.60 (m, 4H), 7.47-7.32 (m, 9H), 6.88 (m, 1H), 6.58 (dt, J = 9.3, 2.5 Hz, 1H), 3.83 (m, 2H), 3.69 (m, 2H), 3.22 (m, 1H), 2.45 (s, 6H), 1.92-1.66 (m, 4H). Two protons were masked by the solvent.

[0796] Intermediate 1G: 3-(2-bromo-5-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

[0797]

[0798] Step 1: Triethyl 2-(2-bromo-5-fluorophenyl)propane-1,1,3-tricarboxylate

[0799] Sodium metal (25.25 g, 1.10 mol) was added in several batches under N 2Under air flow, add in EtOH (1.5L) and stir reaction mixture at 25 DEG C until solid dissolves. Next, diethyl malonate (176g, 1.10mol) is added to the mixture and stirred at 25 DEG C for 30 minutes, (E)-3-(2-bromo-5-fluorophenyl) ethyl acrylate (150g, 0.55mol; Org.Biomol.Chem. [Organic Biomolecules and Chemistry] 2012, 10, Preparation in 3655-3661) is added to reaction mixture and the reaction is stirred at 80 DEG C for 16 hours. Then reaction mixture is concentrated and residue is purified by FCC (2%-10% EtOAc / petroleum ether) as title intermediate (140g, 323mmol) in colorless oil.

[0800] 1 H NMR (400 MHz, CDCl 3 )δ7.51(dd,J=5.5,8.8Hz,1H),7.02(dd,J=3.1,9.8Hz,1H),6.83(m,1H),4.38(q,J=7.4Hz,1H),4.24-4.18( m, 2H), 4.10-3.97 (m, 4H), 3.92 (m, 1H), 2.91 (d, J = 7.1Hz, 2H), 1.23 (t, J = 7.2Hz, 3H), 1.13 (t, J = 7.2Hz, 6H).

[0801] Step 2: 3-(2-Bromo-5-fluorophenyl)glutaric acid

[0802] Triethyl 2-(2-bromo-5-fluorophenyl)propane-1,1,3-tricarboxylate (140 g, 323 mmol) was dissolved in HCl (36.5%, 1 L) and stirred at 100° C. for 48 h. The solution was concentrated to give the title intermediate as a light yellow solid (109 g, 358 mmol, crude) which was used without further purification.

[0803] 1 H NMR (400 MHz, DMSO-d 6 )δ7.61(m,1H),7.47-7.28(m,1H),7.20-6.98(m,1H),3.91-3.80(m,1H),2.61(m,4H).

[0804] Step 3: 3-(2-Bromo-5-fluorophenyl)pentane-1,5-diol

[0805] To a solution of 3-(2-bromo-5-fluorophenyl)pentanedioic acid (105 g, crude) in THF (1000 mL) was added dropwise B at 0°C. 2 H6 To 4-nitropropene (10mL) ethyl acetate (172mL, 17.2mmol, 10M in dimethyl sulfide). The solution was then warmed to RT and stirred for 2 hours. The reaction was cooled to 0 ° C and quenched with MeOH (500mL) and HCl (250mL, 4M in EtOAc), and then the solution was concentrated. The residue was purified by FCC (5%-100% EtOAc: DCM (3: 1) / petroleum ether) to give the title intermediate (43.3g, 156mmol) as a white solid.

[0806] 1 H NMR (400MHz, CD 3 OD)δ7.58-7.54(m,1H),7.12(m,1H),6.89(m,1H),3.55-3.38(m,5H),2.00-1.79(m,4H).

[0807] Step 4: 3-(2-bromo-5-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

[0808] 3-(2-bromo-5-fluorophenyl)pentane-1,5-diol (5000mg, 18.04mmol) is added to a 250mL RB flask and dissolved in MeCN (100mL). Next, TEA (11.1mL 79mmol) and DMAP (220mg, 1.804mmol) are added and the reaction and reaction are cooled to 0 ° C. The reaction is stirred at 0 ° C for 10 minutes, and then toluenesulfonic anhydride (13000mg, 39.8mmol) is added and the reaction is slowly warmed to RT and the reaction is stirred overnight. Next, the material is concentrated on diatomaceous earth for purification by FCC (0%-60% EtOAc / heptane) to produce the title intermediate (9700mg, 16.57mmol) in a light brown oil.

[0809] LCMS: Rt: 3.00 min (LCMS method 1); MS m / z 604.1 [M+H] + .

[0810] 1 H NMR (400 MHz, CDCl 3 )δ7.75-7.67(m,4H),7.42(dd,J=8.8,5.5Hz,1H),7.31(d,J=8.0Hz,4H),6.78(m,1H),6.73-6.62(m,1H) ,3.88(m,2H),3.80(dt,J=10.1,6.9Hz,2H),3.34(s,1H),2.44(s,6H),2.05-1.93(m,2H),1.89(bs,2H).

[0811] Intermediate 1H: 3-(2-bromophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

[0812]

[0813] Step 1: Triethyl 2-(2-bromophenyl)propane-1,1,3-tricarboxylate

[0814] Na (27.04 g, 1180 mmol) was added in several batches under N 2 Under air flow, add in EtOH (1.5L) and stir reaction mixture at 25 DEG C until solid disappears.Then diethyl malonate (188mg, 1180mmol) is added and the reaction is stirred at 25 DEG C for 30min.Next, (E) -3- (2- bromophenyl) ethyl acrylate (150g, 588mmol) is added to the mixture.Then the mixture is stirred at 80 DEG C for 16 hours.Then the reaction mixture is concentrated and the residue is purified by FCC (providing the residue purified by column chromatography (2%-20% EtOAc / petroleum ether)) to produce the title compound (133g, 320mmol) as colorless oil.

[0815] 1 H NMR (400 MHz, CDCl 3 )δ7.57-7.48(m,1H),7.30-7.18(m,2H),7.11-7.00(m,1H),4.48-4.36(m,1H),4.24-4. 13(m,2H),4.07-3.90(m,5H),3.00-2.84(m,2H),1.26-1.20(m,3H),1.13-0.99(m,6H).

[0816] Step 2: Diethyl 3-(2-bromophenyl)glutarate

[0817] To a solution of triethyl 2-(2-bromophenyl)propane-1,1,3-tricarboxylate (133 g, 320 mmol) in DMSO (500 mL) was added NaCl (56 g, 960 mmol) and H 2 O (17 g, 960 mmol). The mixture was stirred at 160 °C for 6 h. The reaction mixture was then treated with H 2 O (500 mL) and extracted with MTBE (3 x 500 mL) and the combined organic phases were washed with brine (500 mL), then dried over sodium sulfate, filtered and concentrated to give the title compound as a yellow oil (used without further purification) (105 g, 305 mmol).

[0818] 1 H NMR (400 MHz, CDCl 3 )δ7.58-7.55(m,1H),7.28-7.25(m,2H),7.10-7.08(m,1H),4.20-4.15(m,1H),4.09-4.04(m,4H),2.79-2.70(m,4H),1.19-1.15(m,6H).

[0819] Step 3: 3-(2-bromophenyl)pentane-1,5-diol

[0820] To a suspension of lithium aluminum hydride (29g, 765mmol) in THF (800mL) was added dropwise a solution of 3-(2-bromophenyl) diethyl glutarate (105g, 305mmol) in THF (200mL) at 0°C. The reaction mixture was stirred at 25°C for 2 hours, and then the reaction mixture was added dropwise to a solution of 2N HCl (2L) and then extracted with EtOAc (3x 500mL). The combined organic phases were washed with brine (500mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by FCC (10%-100% EtOAc / DCM (3:1) / petroleum ether) to give a white solid. The solid was then ground and filtered with EtOAc (100mL), and the filter cake was washed with cold EtOAc (2x 50mL) to provide the title compound (47.2g, 182mmol) as a white solid.

[0821] 1 H NMR (400MHz, CD 3 OD)δ7.55-7.53(m,1H),7.33-7.32(m,2H),7.10-7.06(m,1H),3.47-3.39(m,5H),1.96-1.86(m,4H).

[0822] Step 4: 3-(2-bromophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

[0823] 3-(2-bromophenyl)pentane-1,5-diol (10g, 38.6mmol) and DMAP (0.471g, 3.86mmol) are added to 500mL RB flask and dissolved in MeCN (200mL). The reaction is cooled to 0 ° C and TEA (32.1ml, 232mmol) is added, and the reaction is stirred for 10 minutes and then pTsCl (16.92g, 89mmol) is added. The reaction is then slowly warmed to RT and stirred overnight. The reaction is concentrated and the residue is dissolved in DCM and washed with 1N HCl (4x50mL), and the combined water layer is stripped with 1x 50mL DCM (1x 50mL). The combined organic layer is washed with brine (1x 10mL), dried over sodium sulfate and concentrated. The crude was then purified by FCC (0%-50% EtOAc / heptane) to give the title compound (19.52 g, 34.4 mmol) as a yellow oil.

[0824] 1 H NMR (400 MHz, DMSO-d 6 )δ7.70-7.62(m,4H),7.49(dd,J=8.2,1.4Hz,1H),7.41(d,J=8.2Hz,4H),7.25(m,1H),7.20-7.13(m,1H),7.13-7.07(m,1H ), 3.83 (dt, J = 9.8, 5.9 Hz, 2H), 3.70 (dt, J = 9.9, 6.6 Hz, 2H), 3.20 (dd, J = 14.0, 7.0 Hz, 1H), 2.40 (s, 6H), 1.97-1.77 (m, 4H).

[0825] Intermediate 2A: (S)-7-amino-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester hydrochloride

[0826]

[0827] 7-Oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (commercially available, 200 g, 0.88 mol), isopropylamine hydrochloride (845 g, 8.89 mol) and 5'-pyridoxal phosphate hydrate (10 g, 0.04 mol) were dissolved in DMSO (800 mL) and 0.1 M borate buffer (6200 mL, pH 9.0). The reaction was then warmed to 40°C and a solution of ATA412 (Codexis, 20 g) in 0.1 M borate buffer (400 mL, pH 9.0) was added. N 2The solution is bubbled and stirred to react until complete conversion is achieved.Then the reaction is cooled to 26 ° C and citric acid is added until pH reaches 4.88.DCM (1500mL) is added and the DCM layer is filtered through microcrystalline cellulose to remove enzyme.NaCl (1200mg, 20.5mol) is used for water layer and pH is adjusted to 9.9 with 32% NaOH solution.DCM (3x 2000mL) is extracted for water layer.DCM extract and filtrate are merged and concentrated under reduced pressure, and residue is absorbed in EtOAc (1500mL) and washed with saline (2x 100mL).Then EtOAc is concentrated to dryness, and residue is suspended in EtOAc (1000mL) and filtered to remove NaCl and enzyme.EtOAc is concentrated to obtain the free alkali (146.9g, 0.643mol) of title compound. The free base is dissolved in EtOAc (870mL), and HCl (2M, 390mL) in EtOAc is added in one hour. The reaction is stirred for 2 hours, then filtered, and the filter cake is washed with EtOAc (100mL). The filter cake is then dried to give the title intermediate (169g, 0.639mmol).

[0828] [α] D 25 =-0.478°(c=1.0330w / v%,CH 3 OH).

[0829] 1 H NMR (400MHz, CD 3 OD) δ4.11(d,J=4.8Hz,2H),4.01-3.89(m,5H),2.71(m,1H),2.27-2.17(m,1H),1.46(s,9H).

[0830] Intermediate 3A: (S)-tert-butyl 7-(4-(2-(benzyloxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[0831]

[0832] 3-(2-(Benzyloxy)-5-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate) (Intermediate 1B, 35.41 g, 54.8 mmol) and (S)-7-amino-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester hydrochloride (Intermediate 2, 14.50 g, 54.8 mmol) were suspended in MeCN (500 mL) and tripotassium phosphate (34.9 g, 164 mmol) was added to the solution. The reaction was stirred at 90 ° C for 72 hours. Next, the solvent was removed in vacuo and the solid residue was suspended in EtOAc. The slurry was filtered and the filtrate was concentrated to obtain a crude product as an orange oil. The crude product was purified by FCC (0%-10% MeOH (1% NH 4 OH) / DCM) to give the title compound (17.09 g, 33.9 mmol).

[0833] LCMS: Rt = 1.33 min (LCMS method 2); MS m / z 497.2 [M+H] + .

[0834] 1 H NMR (400MHz, CD 3 OD)δ7.47-7.26(m,5H),7.23-7.09(m,2H),7.04-6.84(m,1H),5.09(s,2H),4.11-3.78(m,5H),3.70(dd,J=8.7,7.4Hz,2H),3.05(m ,3H),2.96-2.72(m,1H),2.42(dd,J=12.9,7.5Hz,1H),2.18(m,2H),2.03(dd,J=12.9,8.5Hz,1H),1.91-1.60(m,4H),1.43(s,9H).

[0835] The following compounds in Table 1 were prepared using similar procedures and related starting materials:

[0836] Table 1: Intermediates 3B to 3H:

[0837]

[0838]

[0839] Intermediate 4A: (S)-tert-butyl 7-(4-(5-fluoro-2-hydroxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[0840]

[0841] To a stirred solution of (S)-7-(4-(2-(benzyloxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (Intermediate 3A, 7.67 g, 15.44 mmol) in ethanol (150 mL) was added 10% palladium on carbon (213 mg, 0.201 mmol). The reaction was then stirred under a hydrogen balloon for 5 hours. The reaction was then filtered through a pad of celite and the solvent was removed under reduced pressure to give a clear oil. Diethyl ether (100 mL) was added and the solvent was removed in vacuo. This was repeated twice more to give the title compound (5.48 g, 13.48 mmol) as a white solid.

[0842] LCMS: Rt = 2.24 min (LCMS method 4); MS m / z 407.2 [M+H] + .

[0843] 1 H NMR (400MHz, CD 3 OD)δ6.90-6.80(m,1H),6.79-6.66(m,2H),4.15-3.81(m,5H),3.74(dd,J=8.7,7.4Hz,1H),3.16-2.81(m,4H ), 2.45(dd,J=12.9,7.5Hz,1H),2.23(m,2H),2.07(dd,J=12.9,8.5Hz,1H),1.93-1.61(m,4H),1.46(s,9H).

[0844] The following compounds in Table 2 were prepared using similar procedures and related starting materials:

[0845] Table 2: Intermediates 4B to 4E:

[0846]

[0847]

[0848] Intermediate 4F: (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol

[0849]

[0850] (S)-7-(4-(2-(Benzyloxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazole-2-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 8B, 1680 mg, 3.62 mmol) was dissolved in ethanol (200 mL) and 10% Pd / C (43 mg, 0.362 mmol) was added. The flask was then stirred under a hydrogen-filled balloon for six hours. The slurry was then filtered through a pad of celite and the cake was rinsed with DCM. The filtrate was concentrated under reduced pressure to produce the title intermediate (1300 mg, 3.47 mmol).

[0851] LCMS: Rt: 0.75 min (LCMS method 2); MS m / z 375.3 [M+H] + .

[0852] Intermediate 5A: (2-oxaspiro[3.3]heptane-6-yl)methyl 4-methylbenzenesulfonate

[0853]

[0854] To a solution of (2-oxaspiro[3.3]heptane-6-yl)MeOH (50 mg, 0.390 mmol), DMAP (4.77 mg, 0.039 mmol) and triethylamine (0.136 mL, 0.975 mmol) in DCM (5 mL) was added pTsCl (78 mg, 0.410 mmol). The reaction was stirred at RT overnight and then diluted with DCM and washed with 1N HCl solution, saturated NaHCO 3 solution, water and brine, and then washed with Na 2 SO 4 Dry.The solvent was removed under reduced pressure and the crude product was purified by FCC (0%-60% EtOAc / heptane) to give the title compound (71 mg, 0.226 mmol).

[0855] LCMS: Rt: 0.92 min (LCMS method 1).

[0856] 1 H NMR (400MHz, CD 3 OD)δ7.80(d,J=8.5Hz,2H),7.47(d,J=8.4Hz,2H),4.66(s,2H),4.54(s,2H) ,3.95(d,J=5.9Hz,2H),2.48(s,3H),2.46-2.27(m,3H),2.01-1.89(m,2H).

[0857] The following compounds in Table 3 were prepared using similar procedures and related starting materials:

[0858] Table 3: Intermediates 5B to 5T:

[0859]

[0860]

[0861] Intermediate 6A: (S)-tert-butyl 7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[0862]

[0863] (S)-tert-Butyl 7-(4-(5-fluoro-2-hydroxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 4A, 549 mg, 1.35 mmol), cesium carbonate (1.32 g, 4.05 mmol) and oxetan-3-yl 4-methylbenzenesulfonate (commercially available, 308 mg, 1.35 mmol) were dissolved in DMF (5.6 mL) and the reaction was stirred at 80 °C overnight. The mixture was diluted with EtOAc and washed with water and purified by MgSO 4 Dry and concentrate in vacuo.The residue was purified by FCC (0%-10% MeOH / DCM) to afford the title intermediate (412 mg, 0.891 mmol).

[0864] LCMS: Rt: 1.08 min (LCMS method 2); MS m / z 463.3 [M+H] + .

[0865] The following compounds in Table 4 were prepared using similar procedures and related starting materials:

[0866] Table 4: Intermediates 6B to 6AA:

[0867]

[0868]

[0869]

[0870]

[0871] Intermediate 6Z: (S)-tert-butyl 7-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[0872]

[0873] (S)-tert-Butyl 7-(4-(5-fluoro-2-hydroxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 4A, 200 mg, 0.49 mmol) was dissolved in THF (4.9 mL) and anhydrous MeOH (975 μL, 24.1 mmol) was added followed by triphenylphosphine resin (3 mmol / g, 821 mg, 2.46 mmol) and di-tert-butyl azodicarboxylate (566 mg, 2.460 mmol). The reaction was stirred at room temperature for 3 days, filtered and rinsed with EtOAc. The filtrate was concentrated and purified by FCC (0%-10% MeOH / DCM) to provide the title intermediate (216 mg, 0.49 mmol).

[0874] LCMS: Rt: 1.18 min (LCMS method 2); MS m / z 421.2 [M+H] + .

[0875] The following compounds in Table 5 were prepared in a similar manner using the relevant starting materials:

[0876] Table 5: Intermediates 6BB to 6DD

[0877]

[0878] Intermediate 7A: (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[0879]

[0880] (S)-tert-Butyl 7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 6A, 825 mg, 1.78 mmol) was dissolved in DCM (18 mL), cooled to 0 °C and TFA (1.3 mL, 17 mmol) was added. The mixture was stirred at room temperature overnight, concentrated in vacuo and the residue was dissolved in DCM, washed with 1 N NaOH and brine, purified by MgSO 4 Drying, filtration and concentration afforded the title intermediate (582 mg, 1.61 mmol).

[0881] LCMS: Rt: 0.44 min (LCMS method 1); MS m / z 363.3 [M+H] + .

[0882] Intermediate 7B: (S)-7-(4-(2-(Benzyloxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[0883]

[0884] To a stirred solution of (S)-7-(4-(2-(benzyloxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (intermediate 3A, 2000 mg, 4.03 mmol) in DCM (5 mL) was added TFA (6.2 mL). The reaction was stirred at RT for 3 hours and then the solvent was removed under reduced pressure. The residue was diluted in EtOAc and water and the pH of the aqueous phase was adjusted to 8-9 with 4N NaOH. The layers were separated and the aqueous phase was extracted with EtOAc, and the combined organic layers were dried over magnesium sulfate, filtered and concentrated. The resulting brown foam was used without further purification (1500 mg, 3.78 mmol).

[0885] LCMS: Rt: 0.61 min (LCMS method 1); MS m / z 397.4 [M+H] + .

[0886] The following compounds in Table 6 were prepared in a similar manner using the relevant starting materials:

[0887] Table 6: Intermediates 7C to 7QQ

[0888]

[0889]

[0890]

[0891]

[0892]

[0893]

[0894] Intermediate 8A: (S)-2-(1-(2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol

[0895]

[0896] (S)-tert-Butyl 7-(4-(5-fluoro-2-hydroxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate fluorophenol (Intermediate 4A, 619 mg, 1.523 mmol) was dissolved in DCM (3 mL) and TFA (1.0 mL) was added. The reaction was stirred at RT for one hour and additional TFA (1.0 mL) was added and the reaction was stirred at RT for another hour. The reaction was then concentrated and the crude was dissolved in 2% aqueous TPGS-750-M (6.8 mL) and THF (0.76 mL) and K was added. 3 PO 4 (970 mg, 4.57 mmol) and 2-bromo-1,3,4-thiadiazole (503 mg, 3.05 mmol). The reaction was stirred at 60 °C for 40 min and then the reaction was cooled to RT and washed with saturated aqueous NaHCO 3 The combined organic layers were diluted and extracted with EtOAc. 4 Dry, filter and concentrate. The crude product was purified by FCC (0%-10% MeOH (10% NH 4 OH) / DCM) to give the title intermediate as a white solid (78 mg, 0.200 mmol).

[0897] LCMS: Rt = 0.75 min (LCMS method 2); MS m / z 391.1 [M+H] + .

[0898] 1 H NMR (CD 3 OD)δ8.66(s,1H),6.90-6.79(m,1H),6.77-6.62(m,2H),4.36-4.03(m,5H),3.84-3.72(m,1H),3.17-3.0 5(m,3H),3.03-2.82(m,2H),2.62-2.50(m,1H),2.35-2.13(m,3H),1.93-1.79(m,2H),1.79-1.61(m,2H).

[0899] Intermediate 8B: (S)-7-(4-(2-(benzyloxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[0900]

[0901] (S)-7-(4-(2-(Benzyloxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7B, 1.00 g, 2.52 mmol) was dissolved in THF (25 mL). The reaction solution was cooled at -5 °C in an acetone-ice bath. DIPEA (0.97 mL, 5.55 mmol) was added followed by ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (0.725 g, 3.28 mmol) as a solid. The mixture was stirred at -5 °C for 30 min and the reaction was then concentrated under reduced pressure. EtOAc was added to the residue and the organic phase was washed with water and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried over sodium sulfate and concentrated. The residue was dissolved in THF (25 mL) and treated with LiOH (0.36 g, 15.1 mmol) dissolved dropwise in water (8.3 mL) within 3 minutes. The reaction mixture was then stirred overnight at RT. Next, the reaction was cooled to -10 °C and aqueous 1M HCl was added over a 3 hour period until pH 2 was reached. The reaction was then poured into EtOAc and 2M Na 2 CO 3 The organic layer was separated and dried over magnesium sulfate, filtered and concentrated. The residue was then purified by FCC (0%-10% MeOH (1% NH 4 OH) / DCM) to give the title intermediate (655 mg, 1.325 mmol).

[0902] LCMS: Rt: 2.60 min (LCMS method 4); MS m / z 465.4 [M+H] + .

[0903] The following compounds in Table 7 were prepared using similar procedures and related starting materials:

[0904] Table 7: Intermediate 8C

[0905]

[0906] Intermediate 9A: (S)-tert-butyl 7-(4-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[0907]

[0908] (S)-tert-Butyl 7-(4-(2-hydroxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 4E, 1.00 g, 2.60 mmol) was dissolved in DCM (10 mL) and pyridine (0.42 mL, 5.2 mmol) was added and the solution was cooled to 0 ° C. The reaction was stirred at 0 ° C for 10 min, and then trifluoromethanesulfonic anhydride (2.337 mL, 2.337 mmol, 1 M in DCM) was added dropwise. The mixture was warmed to room temperature and then stirred for 2 hours. Additional pyridine (0.21 mL, 2.6 mmol) was added and the reaction was cooled to 0 ° C and stirred for 10 min. Trifluoromethanesulfonic anhydride (1.17 mL, 1.17 mmol, 1 M in DCM) was then added dropwise. The reaction was stirred at room temperature for 30 minutes, then pyridine (0.21 mL, 2.6 mmol) was added and the reaction was cooled to 0 °C and stirred for 10 min. Trifluoromethanesulfonic anhydride (1.17 mL, 1.17 mmol, 1 M in DCM) was added at 0 °C and the reaction was warmed and stirred at room temperature for 20 minutes. The reaction was then cooled to 0 °C, diluted with DCM, and quenched with 10% aqueous HCl. The layers were separated and the DCM layer was washed with saturated aqueous NaHCO 3 , washed with brine, and MgSO 4 Dry, filter and evaporate.The residue was purified by FCC (0%-10% MeOH / DCM) to afford the title intermediate (1.30 g, 2.28 mmol).

[0909] LCMS: Rt: 3.01 min (LCMS method 4); MS m / z 521.5 [M+H] + .

[0910] The following compounds in Table 8 were prepared using similar procedures and related starting materials:

[0911] Table 8: Intermediate 9B

[0912]

[0913] Intermediate 10A: (S)-tert-butyl 7-(4-(2-(pyrimidin-5-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[0914]

[0915] In an oven dried glass microwave vial, XPhos Pd G2 (12 mg, 0.015 mmol), XPhos (15 mg, 0.031 mmol), tetrahydroxydiboron (44 mg, 0.46 mmol) and potassium acetate (37 mg, 0.62 mmol) were added. The vessel was sealed, then evacuated and backfilled with nitrogen (this process was repeated four times). EtOH (3 mL) was added via syringe followed by a solution of (S)-tert-butyl 7-(4-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 9A, 80 mg, 0.15 mmol) in EtOH (3 mL). The reaction mixture was stirred in a microwave at 80 °C for 2 hours. Next, potassium carbonate (64 mg, 0.46 mmol) in water (1 mL, pre-degassed) was added, followed by a solution of 5-bromopyrimidine (37 mg, 0.23 mmol) in THF (2 mL, degassed). The reaction mixture was stirred in a microwave at 80 ° C for 14 hours, then filtered and evaporated under reduced pressure. The residue was purified by FCC (0%-100% EtOAc (1% (10% NH 4 OH)) / heptane) to afford the title intermediate (53 mg, 0.12 mmol).

[0916] LCMS: Rt: 0.97 min (LCMS method 2); MS m / z 451.3 [M+H] + .

[0917] The following compounds in Table 9 were prepared using similar procedures and related starting materials:

[0918] Table 9: Intermediates 10B to 10E:

[0919]

[0920]

[0921] Intermediate 11A: (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carbonitrile

[0922]

[0923] In a round bottom flask, a solution of (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7NN, 0.136 g, 0.338 mmol) in DCM (3.4 mL) was placed under nitrogen. Triethylamine (0.240 mL, 1.689 mmol) was added followed by cyanogen bromide (0.054 g, 0.507 mmol). The reaction was stirred for 2.5 hours and then quenched with 0.1 N NaOH solution to pH>12 and extracted with DCM. The combined organic layers were washed with 0.1 N NaOH solution and brine and washed with MgSO 4 Dry, filter and concentrate. The residue is purified by FCC (0%-100% 10% 7N NH 3 / DCM in MeOH) to give the title intermediate as a white solid (115 mg, 0.269 mmol).

[0924] LCMS: Rt: 0.95 min (LCMS method 2); MS m / z 428.5 [M+H] + .

[0925] The following compounds in Table 10 were prepared in a similar manner using the relevant starting materials:

[0926] Table 10: Intermediates 11B to 11C:

[0927]

[0928]

[0929] Intermediate 12A: (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-N-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid imide amide

[0930]

[0931] To a solution of (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carbonitrile (Intermediate 11A, 115 mg, 0.269 mmol) in THF (2.7 mL) was added K 2 CO 3To the mixture was added 4-(4-(2-hydroxy-1-yl)-2-nitropropene (10-nitropropene ...

[0932] LCMS: Rt: 0.84 min (LCMS method 2); MS m / z 461.4 [M+H] + .

[0933] The following compounds in Table 11 were prepared in a similar manner using the relevant starting materials:

[0934] Table 11: Intermediates 12B to 12C:

[0935]

[0936]

[0937] Example 1A: (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[0938]

[0939] (S)-7-(4-(5-fluoro-2-(oxetane-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7A, 540 mg, 1.49 mmol) was dissolved in 2% aqueous TPGS-750-M (2.6 mL) and THF (0.3 mL). Next, ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (329 mg, 1.49 mmol) and tripotassium phosphate (949 mg, 4.47 mmol) were added. The mixture was stirred at room temperature overnight, and then 2M LiOH (2.2 mL, 4.5 mmol) was added and the reaction was stirred at room temperature overnight. MeOH (6 mL) was added, followed by 4N HCl solution to adjust the reaction to pH = 2; then stirred at room temperature for 4 hours. The reaction was then adjusted to pH>8 and the aqueous layer was extracted with DCM, and the combined organic layers were purified by MgSO 4The residue was purified by FCC (0%-10% MeOH / DCM) and further purified by preparative HPLC (XBridge 30 x 50 mm 5 μm 15%-40% MeCN / H 2 O (5 mM NH 4 OH), 75 mL / min) to afford the title compound (214 mg, 0.495 mmol).

[0940] LCMS: Rt: 1.77 min (LCMS method 4); MS m / z 431.1 [M+H] + .

[0941] 1 H NMR (DMSO-d 6 )δ8.65(s,1H),7.04(dd,J=9.8,2.9Hz,1H),6.98-6.86(m,1H),6.56(dd,J=8.9,4.6H z,1H),5.30-5.19(m,1H),4.91(t,J=6.6Hz,2H),4.59-4.47(m,2H),4.22(d,J=8.7Hz , 1H), 4.18-4.09 (m, 2H), 4.02 (d, J = 8.6 Hz, 1H), 3.94 (t, J = 7.6 Hz, 1H), 3.62 (t, J = 7.8 Hz, 1H), 3.05-2.74 (m, 4H), 2.45-2.36 (m, 1H), 2.17-2.00 (m, 3H), 1.81-1.51 (m, 4H). Example 1B: (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[0942]

[0943] (S)-tert-Butyl 7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 6B, 217 mg, 0.442 mmol) was dissolved in DCM (4.4 mL) and TFA (0.68 mL, 8.85 mmol) was added. The reaction was stirred for 4 hours and then it was concentrated and the residue was dissolved in DCM. The organic phase was washed with 1 N NaOH and brine and concentrated. A portion of this material (97 mg, 0.248 mmol) was then dissolved in THF (0.05 mL) and 2% aqueous TPGS-750-M (0.45 mL) and ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (54 mg, 0.248 mmol) and K were added. 3 PO 4 (52.7 mg, 0.248 mmol). The reaction was worked up similarly to Example 1A and the crude product was purified by FCC (0%-7% MeOH / DCM) and by preparative HPLC (C18 OBD 30 x 50 mm 5 μm column, 75 mL / min, 25-50% MeCN / H 2 O (5 mM NH 4 OH)) to give the title compound (43 mg, 0.092 mmol).

[0944] LCMS: Rt: 2.05 min (LCMS method 4); MS m / z 459.1 [M+H] + .

[0945] 1 H NMR (DMSO-d 6 )δ:8.64(s,1H),6.92-7.02(m,3H),4.22(d,J=8.8Hz,1H),4.13(dd,J=8.6,2.7Hz,2H),4.02(d ,J=8.3Hz,1H),3.98-3.91(m,2H),3.90-3.80(m,2H),3.76(td,J=8.1,5.4Hz,1H),3.72-3.65( m,1H),3.65-3.58(m,1H),3.53(dd,J=8.3,5.9Hz,1H),3.04-2.91(m,2H),2.89-2.74(m,2H),2 .70-2.61(m,1H),2.45-2.37(m,1H),2.13-1.97(m,4H),1.74-1.63(m,3H),1.63-1.51(m,2H).

[0946] Example 1C: Ethyl 5-((S)-7-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylate

[0947]

[0948] (S)-7-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7C, 84 mg, 0.21 mmol) was dissolved in 2% aqueous TPGS-750-M (372 μL) and THF (41 μL). Ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (46 mg, 0.21 mmol) and tripotassium phosphate (44 mg, 0.21 mmol) were added and the reaction was processed in a similar manner to Example 1A. The crude product was purified by FCC (0%-7% MeOH / DCM) and by preparative HPLC (XBridge 30 x 50 mm 5 μm 25%-50% MeCN / H2O (5 mM NH4OH), 75 mL / min) to afford the title compound (28 mg, 0.058 mmol).

[0949] LCMS: Rt: 1.90 min (LCMS method 4); MS m / z 475.2 [M+H] + .

[0950] 1 H NMR (DMSO-d 6 )δ8.64(s,1H),7.02-6.92(m,3H),4.22(d,J=8.8Hz,1H),4.13(dd,J=8.3,3.9Hz, 2H),4.04-3.89(m,4H),3.81-3.88(m,2H),3.80-3.74(m,1H),3.71-3.65(m,1H), 3.64-3.58(m,2H),3.53-3.43(m,2H),3.03-2.92(m,2H),2.88-2.75(m,2H),2.41 (dd,J=12.7,7.3Hz,1H),2.12-2.01(m,3H),1.75-1.66(m,2H),1.65-1.51(m,2H).

[0951] Example 1D: (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[0952]

[0953] (S)-7-(4-(2-(((R)-1,4-dioxane-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7D, 84 mg, 0.21 mmol) was dissolved in 2% aqueous TPGS-750-M (372 μL) and THF (41 μL). Ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (46 mg, 0.21 mmol) and tripotassium phosphate (44 mg, 0.21 mmol) were added and the reaction was processed similarly to Example 1A. The crude product was purified by FCC (0%-7% MeOH / DCM) followed by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH), 75 mL / min) to afford the title compound (36 mg, 0.058 mmol).

[0954] LCMS: Rt: 1.91 min (LCMS method 4); MS m / z 445.1 [M+H] + .

[0955] 1 H NMR (400 MHz, DMSO-d 6 )δ8.65(s,1H),7.07-6.88(m,3H),5.01(t,J=5.3Hz,1H),4.22(d,J=8.7Hz, 1H),4.18-4.09(m,2H),4.02(d,J=8.4Hz,1H),3.93(t,J=7.6Hz,1H),3.89- 3.71(m,4H),3.67-3.57(m,1H),3.03-2.90(m,2H),2.80(t,J=12.7Hz,2H), 2.40(dd,J=12.8,7.9Hz,1H),2.18(m,1H),2.12-1.89(m,4H),1.63(m,4H).

[0956] Example 1E: (S)-3-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2,2-dimethylpropionitrile

[0957]

[0958] (S)-3-(2-(1-(5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2,2-dimethylpropionitrile (Intermediate 7E, 20 mg, 0.052 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (14 mg, 0.062 mmol) and tripotassium phosphate (13 mg, 0.062 mmol) were dissolved in 2% aqueous TPGS-750-M (0.7 mL) and THF (0.18 mL). The reaction was stirred at room temperature for 4 days, then 0.5 mL of MeOH and LiOH monohydrate (13 mg, 0.31 mmol) were added and the reaction was stirred at room temperature for 1 hour. 6 M HCl was added to adjust the pH to 4 and the reaction was stirred at room temperature for 1 hour. The reaction was then basified with a solution of sodium bicarbonate, extracted with EtOAc and concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge 30 x 50 mm 5 μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH), 75 mL / min) to afford the title compound (2.8 mg, 0.0060 mmol).

[0959] LCMS: Rt: 2.09 min (LCMS method 4); MS m / z 456.3 [M+H] + .

[0960] 1 H NMR (CD 3 OD)δ8.39(s,1H),7.02-6.81(m,3H),4.35-4.24(m,2H),4.23-4.12(m,2H),4.11-4.03(m,1H),3.95(s,2H),3.81-3.71(m,1H),3.12-3.0 4(m,3H),2.95-2.85(m,1H),2.62-2.51(m,1H),2.34-2.20(m,2H),2.18-2.08(m,1H),1.98-1.85(m,2H),1.77-1.62(m,2H),1.50(s,6H).

[0961] Example 1F: (S)-7-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[0962]

[0963] (S)-7-(4-(2-(((S)-1,4-dioxane-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7F, 84 mg, 0.21 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (46 mg, 0.21 mmol) and tripotassium phosphate (44 mg, 0.21 mmol) were dissolved in 2% aqueous TPGS-750-M (0.37 mL) and THF (0.041 mL). The reaction was processed similarly to Example 1A. The crude product was purified by FCC (0%-10% MeOH / DCM) and further purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH), 75 mL / min) to afford the title compound (29 mg, 0.059 mmol).

[0964] LCMS: Rt: 1.90 min (LCMS method 4); MS m / z 475.1 [M+H] + .

[0965] 1 H NMR (DMSO-d 6 )δ8.64(s,1H),7.03-6.92(m,3H),4.22(d,J=8.8Hz,1H),4.16-4.09(m,2H ),4.05-3.89(m,4H),3.88-3.80(m,2H),3.80-3.74(m,1H),3.72-3.58(m, 3H),3.53-3.43(m,2H),3.03-2.92(m,2H),2.88-2.75(m,2H),2.41(dd,J= 13.0,7.1Hz,1H),2.13-2.01(m,3H),1.78-1.63(m,2H),1.63-1.51(m,2H).

[0966] Example 1G: (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[0967]

[0968] (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7G, 70 mg, 0.18 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (40 mg, 0.18 mmol) and tripotassium phosphate (38 mg, 0.18 mmol) were dissolved in 2% aqueous TPGS-750-M (0.32 mL) and THF (0.036 mL). The reaction was processed similarly to Example 1A and the crude product was purified by FCC (0%-10% MeOH / DCM) and further purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (21 mg, 0.044 mmol).

[0969] LCMS: Rt: 1.58 min (LCMS method 4); MS m / z 459.3 [M+H] + .

[0970] 1 H NMR (DMSO-d 6)δ8.64(s,1H),7.07-6.90(m,3H),4.53(m,1H),4.22(d,J=8.8Hz,1H),4.15-4.10(m ,2H),4.02(d,J=8.3Hz,1H),3.94(dd,J=8.3,6.8Hz,1H),3.85-3.76(m,2H),3.66-3. 59 (m, 1H), 3.50 (m, 2H), 3.02-2.93 (m, 2H), 2.92-2.77 (m, 2H), 2.40 (dd, J = 12.7, 7.3 Hz, 1H), 2.12-2.02 (m, 3H), 1.98-1.88 (m, 2H), 1.75-1.65 (m, 2H), 1.64-1.53 ​​(m, 4H). Example 1H: (S)-7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[0971]

[0972] (S)-tert-Butyl 7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 7H, 91 mg, 0.24 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (53 mg, 0.24 mmol) and tripotassium phosphate (51 mg, 0.24 mmol) were dissolved in 2% aqueous TPGS-750-M (0.44 mL) and THF (0.048 mL). The reaction was processed similarly to Example 1A and the crude product was purified by FCC (0%-10% MeOH / DCM) and further purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH), 75 mL / min) to give the title compound (42 mg, 0.092 mmol).

[0973] LCMS: Rt: 1.91 min (LCMS method 4); MS m / z 445.1 [M+H] + .

[0974] 1 H NMR (400 MHz, DMSO-d 6)δ8.65(s,1H),7.04-6.90(m,3H),5.05-4.98(m,1H),4.22(d,J=8.8Hz,1H), 4.15-4.09(m,2H),4.02(d,J=8.5Hz,1H),3.96-3.90(m,1H),3.89-3.82(m,1H ),3.82-3.71(m,3H),3.66-3.57(m,1H),3.02-2.91(m,2H),2.85-2.74(m,2H) ,2.42-2.36(m,1H),2.26-2.12(m,1H),2.10-1.90(m,4H),1.75-1.48(m,4H).

[0975] Example II: (S)-7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[0976]

[0977] (S)-7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7J, 81 mg, 0.21 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (46 mg, 0.21 mmol) and tripotassium phosphate (44 mg, 0.21 mmol) were dissolved in a mixture of 2% aqueous TPGS-750-M (0.37 mL) and THF (0.042 mL) and the reaction was processed similarly to Example 1A. The residue was purified by FCC (0%-10% MeOH / DCM) and further purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH), 75 mL / min) to afford the title compound (30 mg, 0.064 mmol).

[0978] LCMS: Rt: 2.05 min (LCMS method 4); MS m / z 459.5 [M+H] + .

[0979] 1 H NMR (DMSO-d 6)δ8.64(s,1H),7.01-6.93(m,3H),4.21(d,J=8.8Hz,1H),4.12(dd,J=8.3,2.4Hz,2H),4.02(d, J=8.3Hz,1H),3.97-3.91(m,2H),3.90-3.80(m,2H),3.79-3.73(m,1H),3.72-3.65(m,1H),3.6 4-3.58(m,1H),3.52(dd,J=8.6,6.1Hz,1H),3.01-2.92(m,2H),2.88-2.76(m,2H),2.71-2.59( m,1H),2.40(dd,J=13.0,7.1Hz,1H),2.11-1.96(m,4H),1.75-1.63(m,3H),1.62-1.51(m,2H).

[0980] Example 1J: (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[0981]

[0982] (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7I, 197 mg, 0.453 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (120 mg, 0.54 mmol) and DIPEA (0.16 mL, 0.91 mmol) were dissolved in THF (2.3 mL). The reaction was stirred for 2 h and then evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with water, purified by MgSO 4 The product was stirred for 1 hour at room temperature, and then aqueous 6M HCl (0.76mL) was added to adjust the pH to 2 and the reaction was stirred for 1h at room temperature. Subsequently, the reaction was alkalized (pH>8) with saturated sodium carbonate solution. The residue was diluted with EtOAc, washed with brine and evaporated under reduced pressure. The residue was purified by FCC (0%-10% MeOH (10% NH 4 OH) / DCM) to afford the title compound (157 mg, 0.33 mmol).

[0983] LCMS: Rt: 2.16 min (LCMS method 4); MS m / z 473.7 [M+H] + .

[0984] 1 H NMR (400MHz, CD 3 OD)δ8.38(s,1H),6.88(m,3H),4.29(q,J=8.8Hz,2H),4.16(q,J=8.6Hz,2H),4.10-4.03(m,1H),3.99(dd,J=10.8,3.4Hz,2H),3.83(d,J=6.0Hz, 2H),3.78-3.71(m,1H),3.52-3.43(m,2H),3.14-2.84(m,4H),2.54(dd, J=12.9,7.4Hz,1H),2.28-1.99(m,4H),1.91-1.59(m,6H),1.51(m,2H).

[0985] Example 1K: (S)-7-(4-(5-fluoro-2-(3-methoxy-3-methylbutyloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[0986]

[0987] (S)-7-(4-(5-fluoro-2-(3-methoxy-3-methylbutyloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7M, 79 mg, 0.19 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (43 mg, 0.19 mmol) and K 3 PO 4 Dissolved in a mixture of 2% aqueous TPGS-750-M (0.35 mL) and THF (0.039 mL). The reaction was processed similarly to Example 1A and then purified by preparative HPLC (XBridge 30 x 50 mm 5 μm 10%-30% MeCN / H 2 O (5 mM NH 4 OH), 75 mL / min) to afford the title compound (11 mg, 0.022 mmol).

[0988] LCMS: Rt: 2.38 min (LCMS method 4); MS m / z 475.4 [M+H] + .

[0989] 1 H NMR (DMSO-d6 )δ8.64(s,1H),7.01-6.9(m,3H),4.21(d,J=8.8Hz,1H),4.12(dd,J=8.6,2.2H z,2H),4.05-3.97(m,3H),3.93(dd,J=8.3,6.8Hz,1H),3.61(t,J=7.8Hz,1H), 3.11(s,3H),3.01-2.90(m,2H),2.90-2.75(m,2H),2.40(dd,J=12.7,7.3Hz,1 H), 2.10-1.98 (m, 3H), 1.91 (t, J = 6.8Hz, 2H), 1.73-1.51 (m, 4H), 1.17 (s, 6H).

[0990] Example 1L: (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[0991]

[0992] To a solution of (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7N, 61 mg, 0.17 mmol) in a mixture of 2% aqueous TPGS-750-M (0.30 mL) and THF (0.034 mL) was added ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (37 mg, 0.17 mmol) followed by tripotassium phosphate (36 mg, 0.17 mmol). The reaction was processed similarly to Example 1A and the crude product was purified by preparative HPLC (XBridge 30 x 50 mm 5 μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH), 75 mL / min) to afford the title compound (16 mg, 0.036 mmol).

[0993] LCMS: Rt: 1.95 min (LCMS method 4); MS m / z 433.2 [M+H] + .

[0994] 1 H NMR (400 MHz, DMSO-d 6)δ8.64(s,1H),7.04-6.91(m,3H),4.27-3.89(m,7H),3.71-3.57(m,3H),3.33(s,3H),3.0 1-2.74(m,4H),2.40(dd,J=12.8,7.3Hz,1H),2.04(m,3H),1.77-1.65(m,2H),1.56(m,2H).

[0995] Example 1M: (S)-7-(4-(2-((1,3-dioxan-5-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[0996]

[0997] To a solution of (S)-7-(4-(2-((1,3-dioxan-5-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7W, 99 mg, 0.25 mmol) in a mixture of 2% aqueous TPGS-750-M (0.454 mL) and THF (0.05 mL) was added ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (56 mg, 0.25 mmol) followed by tripotassium phosphate (161 mg, 0.757 mmol). The reaction was worked up similarly to Example 1A and the crude product was purified by FCC (0%-7% MeOH / DCM) and further purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (9.0 mg, 0.018 mmol).

[0998] LCMS: Rt: 0.87 min (LCMS method 4); MS m / z 461.5 [M+H] + .

[0999] 1 H NMR (DMSO-d 6)δ8.64(s,1H),7.03-6.93(m,3H),4.99-4.85(m,2H),4.41-4.33(m,1H),4.21(d ,J=8.3Hz,1H),4.16-4.09(m,2H),4.05-3.99(m,4H),3.98-3.90(m,1H),3.76-3 .68(m,1H),3.61(t,J=7.8Hz,1H),3.02-2.90(m,2H),2.88-2.75(m,2H),2.40(d d,J=13.2,7.3Hz,1H),2.12-1.98(m,3H),1.77-1.65(m,2H),1.64-1.49(m,2H).

[1000] Example 1N: (S)-4-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylbutan-2-ol

[1001]

[1002] To a solution of (S)-4-(2-(1-(5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylbutan-2-ol (Intermediate 70, 147 mg, 0.38 mmol) in a mixture of 2% aqueous TPGS-750-M (0.674 mL) and THF (75 μL) was added ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (83 mg, 0.38 mmol) followed by tripotassium phosphate (79 mg, 0.38 mmol). The reaction was worked up similarly to Example 1A and the crude was then purified by FCC (0%-10% MeOH / DCM) and further purified by preparative HPLC (XBridge 30x 50mm 5μm 10%-30% MeCN / H 2 O(5mMNH 4 OH) 75 mL / min) to afford the title compound (88 mg, 0.19 mmol).

[1003] LCMS: Rt: 1.93 min (LCMS method 4); MS m / z 461.2 [M+H] + .

[1004] 1 H NMR (400MHz, CD 3OD)δ8.38(s,1H),7.02-6.77(m,3H),4.36-4.22(m,2H),4.17(q,J=8.7Hz, 2H),4.07(dd,J=8.7,6.9Hz,1H),3.76(d,J=4.7Hz,3H),3.08(m,3H),2.90 (d,J=11.3Hz,1H),2.55(dd,J=13.0,7.4Hz,1H),2.24(m,2H),2.14(dd,J= 13.0, 8.4Hz, 1H), 1.85 (d, J = 10.9Hz, 2H), 1.80-1.60 (m, 2H), 1.34 (s, 6H).

[1005] Example 10: (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1006]

[1007] To a solution of (S)-7-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7P, 179 mg, 0.499 mmol) in a mixture of 2% aqueous TPGS-750-M (890 μL) and THF (100 μL) was added ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (110 mg, 0.499 mmol) followed by tripotassium phosphate (106 mg, 0.499 mmol). The reaction was worked up similarly to Example 1A and the crude product was purified by FCC (0%-10% MeOH / DCM) and further purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (58 mg, 0.13 mmol).

[1008] LCMS: Rt: 1.87 min (LCMS method 4); MS m / z 427.2 [M+H] + .

[1009] 1 H NMR (DMSO-d 6)δ8.64(s,1H),7.20-7.10(m,2H),6.96-6.85(m,2H),5.07-5.00(m,1H),4.22(d,J=8.8 Hz,1H),4.12(dd,J=8.3,2.9Hz,2H),4.02(d,J=8.3Hz,1H),3.97-3.85(m,2H),3.84-3.7 2(m,3H),3.62(t,J=7.8Hz,1H),3.01-2.91(m,2H),2.87-2.74(m,2H),2.40(dd,J=12.7, 7.3Hz,1H),2.26-2.15(m,1H),2.12-2.00(m,3H),2.00-1.92(m,1H),1.74-1.51(m,4H).

[1010] Example 1P: (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1011]

[1012] To a solution of (S)-7-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7Q, 97 mg, 0.28 mmol) in a mixture of 2% aqueous TPGS-750-M (510 μL) and THF (60 μL) was added ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (62 mg, 0.28 mmol) followed by tripotassium phosphate (60 mg, 0.28 mmol). The reaction was processed similarly to Example 1A and the crude was then purified by FCC (0%-10% MeOH / DCM) and further purified by preparative HPLC (XBridge 30x 50mm 5μm 15%-40% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (27 mg, 0.062 mmol).

[1013] LCMS: Rt: 1.74 min (LCMS method 4); MS m / z 413.2 [M+H] + .

[1014] 1 H NMR (DMSO-d 6)δ8.65(s,1H),7.24-7.18(m,1H),7.15-7.07(m,1H),6.98-6.88(m,1H),6.53(d,J=8.3Hz,1H) ,5.32-5.22(m,1H),4.93(t,J=6.6Hz,2H),4.58-4.47(m,2H),4.27-4.19(m,1H),4.17-4.09(m, 2H),4.16-4.00(m,1H),3.98-3.91(m,J=7.6,7.6Hz,1H),3.69-3.59(m,1H),3.04-2.85(m,3H), 2.85-2.77(m,1H),2.46-2.37(m,1H),2.17-2.02(m,3H),1.81-1.68(m,2H),1.68-1.56(m,2H).

[1015] Example 1Q: (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1016]

[1017] To a solution of (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7X, 81 mg, 0.27 mmol) in a mixture of 2% aqueous TPGS-750-M (480 μL) and THF (50 μL) was added ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (59 mg, 0.27 mmol) followed by tripotassium phosphate (57 mg, 0.27 mmol). The reaction was processed similarly to Example 1A and the crude product was purified by FCC (0%-10% MeOH / DCM) and further purified by preparative HPLC (XBridge 30x 50mm 5μm 15%-40% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (10 mg, 0.026 mmol).

[1018] LCMS: Rt: 1.94 min (LCMS method 4); MS m / z 371.0 [M+H] + .

[1019] 1 H NMR (DMSO-d 6)δ8.64(s,1H),7.22-7.11(m,2H),6.99-6.83(m,2H),4.22(d,J=8.8Hz,1H),4. 13(dd,J=8.1,3.2Hz,2H),4.02(d,J=8.3Hz,1H),3.93(dd,J=8.3,6.8Hz,1H),3. 77(s,3H),3.62(t,J=7.8Hz,1H),3.03-2.91(m,2H),2.90-2.81(m,1H),2.80-2 .73(m,1H),2.39(dd,J=12.7,7.3Hz,1H),2.12-1.97(m,3H),1.74-1.47(m,4H).

[1020] Example 1R: (S)-7-(4-(4,5-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1021]

[1022] To a solution of (S)-7-(4-(4,5-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7R, 96 mg, 0.24 mmol) in a mixture of 2% aqueous TPGS-750-M (440 μL) and THF (50 μL) was added ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (54 mg, 0.24 mmol) followed by tripotassium phosphate (52 mg, 0.24 mmol). The reaction was worked up similarly to Example 1A and the crude product was purified by FCC (0%-7% MeOH / DCM) and further purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O(5mMNH 4 OH) 75 mL / min) to afford the title compound (35 mg, 0.073 mmol).

[1023] LCMS: Rt: 2.01 min (LCMS method 4); MS m / z 463.1 [M+H] + .

[1024] 1 H NMR (400 MHz, DMSO-d 6)δ8.64(s,1H),7.22(dd,J=12.1,9.2Hz,1H),7.12(dd,J=12.8,7.2Hz,1H),5.08-5.01(m,1H),4.21 (d,J=8.7Hz,1H),4.12(dd,J=8.5,2.5Hz,2H),4.02(d,J=8.4Hz,1H),3.93(dd,J=8.5,6.6Hz,1H),3. 86(dd,J=10.3,4.4Hz,1H),3.83-3.71(m,3H),3.60(dd,J=8.6,7.0Hz,1H),3.01-2.91(m,2H),2.82- 2.70(m,2H),2.39(dd,J=12.9,7.2Hz,1H),2.27-2.14(m,1H),2.09-1.89(m,4H),1.72-1.48(m,4H).

[1025] Example 1S: (S)-7-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1026]

[1027] To a solution of (S)-7-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7Y, 279 mg, 0.87 mmol) in a mixture of 2% aqueous TPGS-750-M (1.6 mL) and THF (175 μL) was added ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (192 mg, 0.87 mmol) followed by tripotassium phosphate (185 mg, 0.87 mmol). The mixture was treated similarly to Example 1A and the crude product was purified by FCC (0%-7% MeOH / DCM) and further purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (105 mg, 0.27 mmol).

[1028] LCMS: Rt: 2.04 min (LCMS method 4); MS m / z 389.2 [M+H] + .

[1029] 1 H NMR (DMSO-d 6)δ8.64(s,1H),7.16(dd,J=8.3,7.3Hz,1H),6.84(dd,J=11.2,2.4Hz,1H),6 .74-6.62(m,1H),4.22(d,J=8.8Hz,1H),4.16-4.08(m,2H),4.02(d,J=8.3Hz ,1H),3.97-3.89(m,1H),3.78(s,3H),3.68-3.56(m,1H),3.03-2.89(m,2H), 2.86-2.72(m,2H),2.43-2.36(m,1H),2.13-1.95(m,3H),1.74-1.51(m,4H).

[1030] Example 1T: (S)-4-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-5-fluorophenoxy)-2-methylbutan-2-ol

[1031]

[1032] To a solution of (S)-4-(2-(1-(5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-5-fluorophenoxy)-2-methylbutan-2-ol (Intermediate 7S, 141 mg, 0.36 mmol) in a mixture of 2% aqueous TPGS-750-M (0.65 mL) and THF (70 μL) was added ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (79 mg, 0.36 mmol) followed by tripotassium phosphate (76 mg, 0.36 mmol). The reaction was processed similarly to Example 1A and the crude was purified by FCC (0%-10% MeOH / DCM) and further purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (44 mg, 0.094 mmol).

[1033] LCMS: Rt: 1.97 min (LCMS method 4); MS m / z 461.4 [M+H] + .

[1034] 1 H NMR (DMSO-d 6)δ8.60-8.67(m,1H),7.20-7.09(m,1H),6.89-6.79(m,1H),6.71-6.63( m,1H),4.41-4.34(m,1H),4.27-3.99(m,7H),3.98-3.88(m,1H),3.67-3. 57(m,1H),3.30-3.28(m,1H),3.05-2.89(m,2H),2.87-2.71(m,2H),2.4 5-2.36(m,1H),2.13-1.96(m,3H),1.75-1.48(m,4H),1.22-1.12(m,6H).

[1035] Example 1U: (S)-1-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylpropan-2-ol

[1036]

[1037] (S)-1-(2-(1-(5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylpropan-2-ol (Intermediate 7U, 67 mg, 0.18 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (39 mg, 0.18 mmol) and tripotassium phosphate (38 mg, 0.18 mmol) were suspended in a mixture of 2% aqueous TPGS-750-M (1.6 mL) and THF (0.16 mL). The reaction was processed similarly to Example 1A and the crude product was purified by preparative HPLC (XBridge 30x 50mm5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (6.2 mg, 0.013 mmol).

[1038] LCMS: Rt: 1.85 min (LCMS method 4); MS m / z 447.6 [M+H] + .

[1039] 1 H NMR (400MHz, CD 3OD)δ8.38(s,1H),6.94-6.83(m,3H),4.35-4.24(m,2H),4.17(q,J=8.7Hz, 2H),4.07(dd,J=8.7,6.9Hz,1H),3.76(d,J=4.7Hz,3H),3.15-3.04(m,3H) ,2.90(d,J=11.3Hz,1H),2.55(dd,J=13.0,7.4Hz,1H),2.24(m,2H),2.14( dd,J=13.0,8.4Hz,1H),1.93-1.81(m,2H),1.77-1.62(m,2H),1.34(s,6H).

[1040] Example 1V: (S)-7-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1041]

[1042] (S)-7-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7DD, 116 mg, 0.362 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (80 mg, 0.362 mmol) and tripotassium phosphate (77 mg, 0.362 mmol) were dissolved in a mixture of 2% aqueous TPGS-750-M (0.65 mL) and THF (0.07 mL). The reaction was processed similarly to Example 1A and the residue was purified by FCC (0%-10% MeOH / DCM) and further purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (39 mg, 0.097 mmol).

[1043] LCMS: Rt: 1.98 min (LCMS method 4); MS m / z 389.3 [M+H] + .

[1044] 1 H NMR (400 MHz, DMSO-d 6)δ8.64(s,1H),7.13-6.82(m,3H),4.22(d,J=8.6Hz,1H),4.15-4.09(m,2H),4.02(d,J=8.4Hz,1H),3.93(dd,J=8.6,6.8Hz,1H),3.76(s,3 H),3.62(dd,J=8.5,7.1Hz,1H),3.04-2.90(m,2H),2.90-2.72(m,2H),2.39(dd,J=12.9,7.3Hz,1H),2.12-1.99(m,3H),1.73-1.51(m,4H).

[1045] Example 1W: (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(pyrimidin-5-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1046]

[1047] (S)-7-(4-(2-(pyrimidin-5-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7FF, 34 mg, 0.097 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (28 mg, 0.13 mmol) and tripotassium phosphate (31 mg, 0.15 mmol) were dissolved in a mixture of 2% aqueous TPGS-750-M (0.30 mL) and THF (0.030 mL). The reaction was processed similarly to Example 1A and the residue was purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-40% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (17 mg, 0.041 mmol).

[1048] LCMS: Rt: 1.52 min (LCMS method 4); MS m / z 419.4 [M+H] + .

[1049] 1 H NMR (400MHz, CD 2 Cl 2)δ9.23(s,1H),8.72(s,2H),7.96(s,1H),7.49(m,2H),7.41-7.30(m,1H),7.22(dd,J=7.6,1 .2Hz,1H),4.21(s,2H),4.20-4.07(m,2H),4.00(dd,J=8.5,6.7Hz,1H),3.73(t,J=8.0Hz,1H) ,3.07-2.90(m,2H),2.85-2.68(m,1H),2.54(m,1H),2.40(dd,J=12.9,7.1Hz,1H),2.13(dd, J=12.6,8.1Hz,1H),1.96(q,J=11.1,10.6Hz,2H),1.84(d,J=13.2Hz,2H),1.77-1.67(m,2H).

[1050] Example 1X: (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(oxazol-2-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1051]

[1052] (S)-7-(4-(2-(oxazol-2-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7GG, 25 mg, 0.074 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (21 mg, 0.096 mmol) and tripotassium phosphate (20 mg, 0.096 mmol) were dissolved in a mixture of 2% aqueous TPGS-750-M (0.30 mL) and THF (0.030 mL). The reaction was processed similarly to Example 1A and the crude product was purified by preparative HPLC (XBridge 30 x 50 mm 5 μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (13 mg, 0.032 mmol).

[1053] LCMS: Rt: 1.78 min (LCMS method 4); MS m / z 408.6 [M+H] + .

[1054] 1 H NMR (400MHz, CD 3OD)δ8.38(s,1H),8.01(s,1H),7.76(d,J=7.3Hz,1H),7.49(d,J=4.0Hz,2H),7. 38-7.22(m,2H),4.36-4.23(m,2H),4.16(q,J=8.6Hz,2H),4.06(dd,J=8.7,6.9H z,1H),3.76(dd,J=8.6,7.4Hz,1H),3.55-3.40(m,1H),3.09(m,2H),2.88(dd,J= 11.5, 2.3Hz, 1H), 2.53 (dd, J = 13.1, 7.4Hz, 1H), 2.30-2.05 (m, 3H), 1.82 (m, 4H).

[1055] Example 1Y: (S)-7-(4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1056]

[1057] (S)-7-(4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7HH, 7.0 mg, 0.020 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (5.7 mg, 0.026 mmol) and tripotassium phosphate (5.5 mg, 0.026 mmol) were dissolved in a mixture of 2% aqueous TPGS-750-M (0.60 mL) and THF (0.060 mL). The reaction was processed similarly to Example 1A and the crude product was purified by preparative HPLC (XBridge Peptide BEH C18 5 μm 19 x 150 mm 25%-40% MeCN / H 2 O (5 mM NH 4 OH) 30 mL / min) to afford the title compound (1 mg, 0.002 mmol).

[1058] LCMS: Rt: 1.58 min (LCMS method 4); MS m / z 423.2 [M+H] + .

[1059] 1 H NMR (400MHz, CD 3OD)δ8.38(s,1H),7.81(d,J=8.2Hz,1H),7.63-7.48(m,2H),7.38(m,1H),4. 36-4.24(m,2H),4.18(t,J=8.7Hz,2H),4.07(dd,J=8.8,6.9Hz,1H),3.77(dd ,J=8.7,7.4Hz,1H),3.62-3.45(m,1H),3.18-3.03(m,2H),2.96-2.83(m,1H) ,2.63(s,3H),2.55(dd,J=13.0,7.4Hz,1H),2.33-2.07(m,3H),1.86(m,4H).

[1060] Example 2A: (S)-7-(4-(5-fluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1061]

[1062] (S)-2-(1-(2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 8A, 11 mg, 0.028 mmol), 3-(iodomethyl)oxetane (14 mg, 0.070 mmol) and cesium carbonate (14 mg, 0.042 mmol) were dissolved in MeCN (0.5 mL). The reaction was stirred at 60 °C overnight and then concentrated under reduced pressure, and the crude product was purified by preparative HPLC (X-bridge C18 OBD 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (6.2 mg, 0.013 mmol).

[1063] LCMS: Rt: 1.91 min (LCMS method 4); MS m / z 461.1 [M+H] + .

[1064] 1 H NMR (CD 3OD)δ8.66(s,1H),6.94(d,J=4.4Hz,3H),4.92-4.87(m,2H),4.71-4.59(m,2H),4.33-4.01(m,7H),3.86-3.73(m,1H),3.53-3. 41(m,1H),3.15-2.95(m,3H),2.93-2.84(m,1H),2.61-2.47(m,1H),2.32-2.11(m,3H),1.93-1.79(m,2H),1.78-1.58(m,2H).

[1065] Example 2B: (S)-7-(4-(5-fluoro-2-((3-methyloxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1066]

[1067] (S)-2-(1-(2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 8A, 15 mg, 0.038 mmol) was dissolved in acetonitrile (0.75 mL) and 3-(bromomethyl)-3-methyloxetane (13 mg, 0.077 mmol) was added followed by cesium carbonate (19 mg, 0.058 mmol). The reaction was stirred at 60 °C overnight, concentrated under reduced pressure and purified by preparative HPLC (X-bridge C18 OBD 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (4.5 mg, 0.0093 mmol).

[1068] LCMS: Rt: 2.08 min (LCMS method 4); MS m / z 475.2 [M+H] + .

[1069] 1 H NMR (CD 3OD)δ8.66(s,1H),7.03-6.82(m,3H),4.73-4.66(m,2H),4.51-4.43(m,2H),4.33-4.05(m,5H),4.01(s,2H),3.83-3.72(m,1H), 3.16-2.98(m,3H),2.95-2.85(m,1H),2.65-2.47(m,1H),2.30-2.08(m,3H),1.94-1.81(m,2H),1.79-1.60(m,2H),1.45(s,3H).

[1070] Example 2C: (S)-7-(4-(5-fluoro-2-(((R)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate or (S)-7-(4-(5-fluoro-2-(((S)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate And Example 2D: (S)-7-(4-(5-fluoro-2-(((R)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate or (S)-7-(4-(5-fluoro-2-(((S)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate

[1071]

[1072] (S)-2-(1-(2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 8A, 30 mg, 0.077 mmol) was dissolved in acetonitrile (1.2 mL) and 2-(bromomethyl)oxetane (10 mg, 0.066 mmol) and cesium carbonate (38 mg, 0.12 mmol) were added. The reaction was stirred at 60 °C overnight, then additional 2-(bromomethyl)oxetane (20 mg, 0.13 mmol) was added and the reaction was heated at 60 °C overnight. Additional 2-(bromomethyl)oxetane (40 mg, 0.077 mmol) was added followed by cesium carbonate (25 mg, 0.077 mmol) and the reaction was heated at 75 °C overnight. The reaction was concentrated under reduced pressure and purified by preparative HPLC (XBridge Peptide BEH C18 5 μm 19 x 150 mm 30%-45% MeCN / H 2 O (10 mM NH 4 OH) 30 mL / min) to provide separated diastereomers as TFA salts: Peak 1 (Example 2C, 4.5 mg, 0.0093 mmol) and Peak 2 (Example 2D, 3.6 mg, 0.0061 mmol).

[1073] Example 2C:

[1074] LCMS: Rt: 1.92 min (LCMS method 4); MS m / z 461.2 [M+H] + .

[1075] 1 H NMR (CD 3 OD)δ8.66(s,1H),6.96-6.90(m,2H),6.90-6.83(m,1H),4.33-4.21(m,2H),4.20-4.03(m,5H),3.82-3.73(m,1H),3.18 -2.97(m,4H),2.95-2.86(m,1H),2.85-2.79(m,1H),2.61-2.51(m,2H),2.30-2.02(m,4H),1.98-1.79(m,3H),1.70(br s,2H).

[1076] Example 2D:

[1077] LCMS: Rt: 2.02 min (LCMS method 4); MS m / z 461.6 [M+H] + .

[1078] 1 H NMR (CD 3 OD)δ8.66(s,1H),6.99-6.92(m,2H),6.91-6.83(m,1H),5.25-5.09(m, 1H),4.79-4.63(m,2H),4.32-4.21(m,2H),4.19-4.03(m,5H),3.83-3.7 3(m,1H),3.18-3.05(m,3H),2.96-2.88(m,1H),2.87-2.69(m,2H),2.62 -2.50(m,1H),2.30-2.10(m,3H),1.99-1.82(m,2H),1.79-1.62(m,2H).

[1079] Example 2E: (S)-7-(4-(5-fluoro-2-((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1080]

[1081] (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 4F, 14 mg, 0.037 mmol) was dissolved in acetonitrile (1 mL) and 2-(chloromethyl)-5-methyl-1,3,4-thiadiazole (7.2 mg, 0.049 mmol) was added followed by cesium carbonate (18 mg, 0.056 mmol). The reaction was stirred at room temperature for 18 hours and then concentrated under reduced pressure and purified by preparative HPLC (XBridge 30x 50mm 5μm 15%-40% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to give the title compound (9.8 mg, 0.020 mmol) as a white solid.

[1082] LCMS: Rt: 1.78 min (LCMS method 4); MS m / z 487.3 [M+H] + .

[1083] 1 H NMR (CD 3OD)δ8.39(s,1H),7.09-7.04(m,1H),7.01-6.95(m,1H),6.95-6.87(m,1H), 5.49(d,J=3.4Hz,2H),4.35-4.23(m,2H),4.22-4.12(m,2H),4.10-4.02(m, 1H),3.81-3.70(m,1H),3.17-2.95(m,3H),2.94-2.86(m,1H),2.79(s,3H), 2.61-2.47(m,1H),2.29-2.08(m,3H),1.93-1.78(m,2H),1.77-1.61(m,2H).

[1084] Example 2F: (S)-7-(4-(5-fluoro-2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1085]

[1086] (S) -2- (1- (2- (1,3,4- oxadiazole -2- bases) -5- oxa -2- azaspiro [3.4] octane -7- bases) piperidin -4- bases) -4- fluorophenol (intermediate 4F, 20.2mg, 0.054mmol) was dissolved in DMF (0.5mL) and 2- (chloromethyl) -5- methyl -1,3,4- oxadiazole (8.9mg, 0.065mmol) and cesium carbonate (35.2mg, 0.108mmol) were added. The resulting reaction mixture was stirred at room temperature for 18 hours. It was then diluted with EtOAc and washed with water, and the organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge 30x 50mm 5μm 15% -40% MeCN / H 2 O (5 mM NH 4 OH), 75 mL / min) to give the title compound (15 mg, 0.032 mmol).

[1087] LCMS: Rt: 0.87 min (LCMS method 3), MS m / z 471.3 [M+H] + .

[1088] 1 H NMR (400MHz, CD 3OD)δ8.38(s,1H),7.08(dd,J=9.0,4.6Hz,1H),6.97(dd,J=9.7,3.1Hz,1H),6.93-6 .86(m,1H),5.29(s,2H),4.34-4.23(m,2H),4.16(q,J=8.6Hz,2H),4.05(dd,J=8.6, 7.0Hz,1H),3.75(dd,J=8.4,7.6Hz,1H),3.13-2.94(m,3H),2.87(d,J=10.8Hz,1H), 2.56(s,3H),2.55-2.48(m,1H),2.26-2.09(m,3H),1.80(m,2H),1.76-1.62(m,2H).

[1089] Example 2G: (S)-7-(4-(5-fluoro-2-((3-methylisoxazol-5-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1090]

[1091] (S) -2- (1- (2- (1,3,4- oxadiazole -2- bases) -5- oxa -2- azaspiro [3.4] octane -7- bases) piperidin -4- bases) -4- fluorophenol (intermediate 4F, 18.6mg, 0.050mmol) was dissolved in DMF (0.5mL) and then 5- (chloromethyl) -3- methylisoxazole (8.26mg, 0.060mmol) and cesium carbonate (32.4mg, 0.099mmol) were added. The resulting reaction mixture was stirred at room temperature for 18 hours. The reaction was then diluted with EtOAc and washed with water, and the organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to give the title compound (13.8 mg, 0.029 mmol).

[1092] LCMS: Rt: 1.08 min (LCMS method 3); MS m / z 470.2 [M+H] + .

[1093] 1 H NMR (400MHz, CD 3OD)δ8.38(s,1H),7.03(dd,J=9.0,4.6Hz,1H),6.97-6.84(m,2H),6.33(s,1H),5.17( s,2H),4.34-4.24(m,2H),4.16(q,J=8.8Hz,2H),4.06(dd,J=8.6,7.0Hz,1H),3.75(dd ,J=8.5,7.6Hz,1H),3.14-3.03(m,2H),2.98(m,1H),2.87(d,J=10.6Hz,1H),2.53(dd ,J=13.0,7.4Hz,1H),2.28(s,3H),2.25-2.08(m,3H),1.84-1.75(m,2H),1.68(m,2H).

[1094] Example 2H: (S)-7-(4-(5-fluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1095]

[1096] (S) -2- (1- (2- (1,3,4- oxadiazole -2- bases) -5- oxa -2- azaspiro [3.4] octane -7- bases) piperidin -4- bases) -4- fluorophenol (intermediate 4F, 18.3mg, 0.049mmol) was dissolved in 0.5mL of DMF and 3- (iodomethyl) oxetane (19.36mg, 0.098mmol) and cesium carbonate (31.8mg, 0.098mmol) were added. The resulting reaction mixture was stirred at room temperature for 18h. The reaction was then diluted with EtOAc and washed with water, and concentrated under reduced pressure. The residue was then purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to give the title compound (12.1 mg, 0.027 mmol).

[1097] LCMS: Rt: 0.97 min (LCMS method 3); MS m / z 445.4 [M+H] + .

[1098] 1 H NMR (400MHz, CD 3OD)δ8.38(s,1H),7.02-6.78(m,3H),4.88(dd,J=8.0,6.1Hz,2H),4.64(t,J=6.0H z,2H),4.34-4.23(m,2H),4.17(dd,J=8.9,7.4Hz,4H),4.06(dd,J=8.6,7.0Hz,1H ),3.75(dd,J=8.4,7.6Hz,1H),3.47(m,1H),3.14-2.97(m,3H),2.88(d,J=10.8Hz ,1H),2.53(dd,J=13.0,7.4Hz,1H),2.27-2.08(m,3H),1.84(m,2H),1.68(m,2H). Example 2I: (S)-7-(4-(5-fluoro-2-(pyrimidin-2-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1099]

[1100] (S)-2-(1-(2-(1,3,4-oxadiazole-2-yl)-5-oxa-2-azaspiro[3.4]octane-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 4F, 20.5 mg, 0.055 mmol) was dissolved in 0.5 mL of DMF and then 2-(chloromethyl)pyrimidine (8.89 mg, 0.066 mmol) and cesium carbonate (35.7 mg, 0.110 mmol) were added. The resulting reaction mixture was stirred at room temperature for 18 hours and then diluted with EtOAc, washed with water and concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge 30x 50mm 5μm 15%-40% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to give the title compound (16 mg, 0.034 mmol).

[1101] LCMS: Rt: 0.92 min (LCMS method 3); MS m / z 467.4 [M+H] + .

[1102] 1 H NMR (400MHz, CD 3OD)δ8.81(d,J=4.9Hz,2H),8.38(s,1H),7.44(t,J=4.9Hz,1H),6.97-6.90(m, 2H),6.81(m,1H),5.27(s,2H),4.34-4.23(m,2H),4.16(q,J=8.6Hz,2H),4.05 (dd,J=8.6,7.0Hz,1H),3.80-3.70(m,1H),3.10(m,3H),2.87(d,J=10.7Hz,1H ), 2.53 (dd, J = 13.0, 7.4Hz, 1H), 2.28-2.08 (m, 3H), 1.88 (m, 2H), 1.69 (m, 2H).

[1103] Example 2J: (S)-7-(4-(5-fluoro-2-((3-fluorooxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1104]

[1105] (S)-2-(1-(2-(1,3,4-oxadiazole-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 4F, 17.4 mg, 0.046 mmol) was dissolved in DMF (0.5 mL) and then 3-fluorooxetane-3-yl)methyl 4-methylbenzenesulfonate (commercially available, 13.3 mg, 0.051 mmol) and cesium carbonate (30.3 mg, 0.093 mmol) were added. The resulting reaction mixture was stirred at 50 °C overnight and then diluted with EtOAc, washed with water and concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O(5mMNH 4 OH) 75 mL / min) to give the title compound (2.7 mg, 0.0058 mmol).

[1106] LCMS: Rt: 1.01 min (LCMS method 3); MS m / z 463.7 [M+H] + .

[1107] 1 H NMR (400MHz, CD 3OD)δ8.38(s,1H),7.03-6.84(m,3H),4.84-4.72(m,4H),4.39-4.23(m,4H),4.16(q,J=8.6Hz,2H),4.06(dd,J=8.6,7.0Hz,1H),3.75(dd,J=8.4, 7.6Hz,1H),3.13-3.04(m,2H),2.97(m,1H),2.89(d,J=10.9Hz,1H),2.5 4(dd,J=13.0,7.4Hz,1H),2.27-2.07(m,3H),1.84(m,2H),1.67(m,2H).

[1108] Example 2K: (S)-7-(4-(5-fluoro-2-((3-methyloxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1109]

[1110] (S) -2- (1- (2- (1,3,4- oxadiazole -2- bases) -5- oxa -2- azaspiro [3.4] octane -7- bases) piperidin -4- bases) -4- fluorophenol (intermediate 4F, 19mg, 0.051mmol) was dissolved in acetonitrile (1.0mL) and 3- (bromomethyl) -3- methyloxetane (16.8mg, 0.101mmol) and cesium carbonate (25mg, 0.076mmol) were added. The reaction was stirred at 80 ° C overnight. It was then concentrated under reduced pressure and purified by preparative HPLC (XBridge 30x 50mm 5μm 25% -50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to give the title compound (10.7 mg, 0.023 mmol).

[1111] LCMS: Rt: 2.00 min (LCMS method 4); MS m / z 459.2 [M+H] + .

[1112] 1 H NMR (CD 3OD)δ8.39(s,1H),6.81-7.02(m,3H),4.66-4.72(m,2H),4.48(s,2H),4. 24-4.35(m,2H),4.12-4.21(m,2H),4.03-4.10(m,1H),4.01(s,2H),3.7 1-3.80(m,1H),2.98-3.17(m,3H),2.83-2.95(m,1H),2.47-2.60(m,1H) ,2.08-2.29(m,3H),1.80-1.93(m,2H),1.59-1.76(m,2H),1.45(s,3H).

[1113] Example 2L: (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1114]

[1115] Step 1: 2-Oxaspiro[3.3]heptane-6-yl 4-methylbenzenesulfonate

[1116] To a solution of 2-oxaspiro[3.3]heptan-6-ol (500 mg, 4.38 mmol), DMAP (53 mg, 0.438 mmol) and triethylamine (1.53 mL, 10.95 mmol) in DCM (15 mL) at 0°C was added 4-toluene-1-sulfonyl chloride (877 mg, 4.60 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was then washed with 1N HCl solution, filtered through MgSO 4 Dry and concentrate under reduced pressure.The residue was purified by FCC (0%→60% EtOAc / heptane) to afford the title intermediate as a white solid (1.04 g, 3.68 mmol).

[1117] LCMS: Rt: 0.87 min (LCMS method 2); MS m / z 269.3 [M+H] + .

[1118] Step 2: (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1119] To a solution of (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 4F, 100 mg, 0.267 mmol) and 2-oxaspiro[3.3]heptane-6-yl 4-methylbenzenesulfonate (79 g, 0.294 mmol) in MeCN (5 mL) was added Cs 2 CO 3 (348 mg, 1.07 mmol). The resulting mixture was stirred at 80 °C for 18 hours. The crude was concentrated under reduced pressure and then diluted with EtOAc and washed with water. The combined organics were concentrated under reduced pressure and the crude was purified by FCC (0%-8% MeOH (1% NH 4 The isolated material was dissolved in 3:7 MeCN:water and freeze-dried to give the title compound as a white solid (52 mg, 0.105 mmol). The stereochemistry of this compound was confirmed by X-ray crystallography.

[1120] [α] D 25 =-11.04°(c=1.0400w / v%,CH 3 OH).

[1121] LCMS: Rt: 1.96 min (LCMS method 4); MS m / z 471.4 [M+H] + .

[1122] 1 H NMR (400MHz, CD 3 OD)δ8.38(s,1H),6.90(dd,J=9.8,3.0Hz,1H),6.82(td,J=8.5,3.1Hz,1H),6.70(dd,J=9.0,4.6 Hz,1H),4.75,(s,2H),4.68(s,2H),4.53(p,J=6.6Hz,1H),4.38-4.23(m,2H),4.16(q,J=8.6Hz,2 H),4.06(dd,J=8.7,6.9Hz,1H),3.76(t,J=8.0Hz,1H),3.17-3.04(m,2H),3.03-2.85(m,2H),2.8 5-2.75(m,2H),2.54(dd,J=13.2,7.6Hz,1H),2.36-2.09(m,5H),1.87-1.74(m,2H),1.67(m,2H).

[1123] Example 2M: (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1124]

[1125] Step 1: (R)-(Tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate

[1126] (R)-(tetrahydrofuran-2-yl)methanol (400 mg, 3.92 mmol) was dissolved in DCM (6 mL) and 4-methylbenzenesulfonyl chloride (896 mg, 4.70 mmol), triethylamine (0.82 mL, 5.9 mmol) and DMAP (24 mg, 0.20 mmol) were added. The reaction was stirred at room temperature for 18 hours. The reaction was washed with saturated NH 4 The solution was neutralized with Cl and extracted with DCM. The combined DCM layers were washed with MgSO 4 Dried, filtered and concentrated in vacuo.The residue was purified by FCC (0%-50% EtOAc / heptane) to afford the title intermediate as a colorless oil (925 mg, 3.61 mmol).

[1127] LCMS: Rt: 0.92 min (LCMS method 1), MS m / z 257.1 [M+H] + .

[1128] Step 2: (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1129] (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 4F, 15 mg, 0.040 mmol) was dissolved in acetonitrile (1 mL) and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (13 mg, 0.052 mmol) was added followed by cesium carbonate (20 mg, 0.060 mmol). The reaction was stirred at 75 °C for 18 hours. The reaction was concentrated under reduced pressure and purified by preparative HPLC (XBridge 30x 50mm5μm10%-30% MeCN / H 2 O (0.1% formic acid) 75 mL / min) to give the title compound (4.9 mg, 0.0011 mol) as a white solid.

[1130] LCMS: Rt: 2.09 min (LCMS method 4); MS m / z 459.4 [M+H] + .

[1131] 1 H NMR (CD 3 OD)δ8.39(s,1H),6.99-6.77(m,3H),4.35-4.23(m,3H),4.21-4.12(m,2H),4.11-4.04(m,1H),4.02-3.89(m,3H), 3.87-3.72(m,2H),3.15-2.98(m,3H),2.94-2.85(m,1H),2.60-2.50(m,1H),2.29-1.80(m,9H),1.76-1.59(m,2H).

[1132] Example 2N: (S)-7-(4-(2-(((R)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane or (S)-7-(4-(2-(((S)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane And Example 2O: (S)-7-(4-(2-(((R)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane or (S)-7-(4-(2-(((S)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1133]

[1134] To a solution of (S)-2-(1-(2-(1,3,4-oxadiazole-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 4F, 100 mg, 0.267 mmol) and cesium carbonate (261 mg, 0.801 mmol) in DMF (1.1 mL) was added 5,5-dimethyltetrahydrofuran-3-yl 4-methylbenzenesulfonate (Intermediate 5N, 72.2 mg, 0.267 mmol). The resulting mixture was stirred at 80 °C for 18 hours. The crude product was diluted with EtOAc, washed with water and concentrated under reduced pressure. The residue was purified by FCC (0%-10% MeOH / DCM) and then by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min). The two diastereomers were then separated by preparative SFC (ChiralPakIG 21 x 250 mm column, 30% IPA, flow rate: 80 g / min). Peak 1 was isolated and concentrated to give Example 2N (19 mg, 0.039 mmol) and Peak 2 was isolated to give Example 2O (9 mg, 0.019 mmol)

[1135] Example 2N:

[1136] SFC: Rt: 3.29 min (Chiralpak IG 4.6 x 100 mm 5 μm, 5% → 55% with 10 mM NH 4 IPA / CO of OH 2 , 5 mL / min). LCMS: Rt: 2.21 min (LCMS method 4); MS m / z 473.3 [M+H] + .

[1137] 1 H NMR (400 MHz, DMSO-d 6)δ8.65(s,1H),7.04 - 6.86(m,3H),5.01(m,1H),4.22(d,J=8.9Hz,1H),4.13(dd,J=8.3,2.7Hz,2H),4.09 - 3.99(m,2H),3.94(dd,J=8.5,6.6Hz,1H),3.83 - 3.74(m,1H),3.68 - 3.57(m,1H),3.06 - 2.91(m,2H),2.91 - 2.75(m,2H),2.41(dd,J=12.9,7.2Hz,1H),2.13(dd,J=13.7,6.7Hz,1H),2.09 - 1.98(m,3H),1.89(dd,J=13.8,1.6Hz,1H),1.76 - 1.65(m,2H),1.59(m,2H),1.31(s,3H),1.22(s,3H).

[1138] Example 2O:

[1139] SFC: Rt: 3.41 min (Chiralpak IG 4.6x100 mm 5μm, 5%→55% IPA / CO with 10 mM NH 4 OH 2 , 5 mL / min). LCMS: Rt: 2.23 min (LCMS method 4); MS m / z 473.5 [M + H] + .

[1140] 1 1H NMR (400 MHz, DMSO - d 6 )δ8.65(s,1H),7.12 - 6.80(m,3H),5.01(m,1H),4.22(d,J=8.7Hz,1H),4.13(dd,J=8.5,4.6Hz,2H),4.08 - 3.98(m,2H),3.94(dd,J=8.5,6.7Hz,1H),3.78(dt,J=10.1,1.3Hz,1H),3.65 - 3.57(m,1H),2.95(p,J=7.0Hz,2H),2.92 - 2.75(m,2H),2.41(dd,J=12.9,7.2Hz,1H),2.13(dd,J=13.6,6.6Hz,1H),2.09 - 1.97(m,3H),1.94 - 1.85(m,1H),1.70(m,2H),1.57(m,2H),1.31(s,3H),1.22(s,3H).

[1141] Example 2P: (S)-7-(4-(2-((3-ethyloxetan-3-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1142]

[1143] (S)-2-(1-(2-(1,3,4-oxadiazole-2-yl)-5-oxa-2-azaspiro[3.4]octane-7-yl)piperidin-4-yl)-4-fluorophenol (intermediate 4F, 16 mg, 0.042 mmol) was dissolved in acetonitrile (1.0 mL) and (3-ethyloxetane-3-yl)methyl 4-methylbenzenesulfonate (intermediate 5N, 15 mg, 0.055 mmol) and cesium carbonate (21 mg, 0.064 mmol) were added. The reaction was stirred at 80 ° C for 18 hours and then the reaction was concentrated under reduced pressure. The residue was dissolved in DCM and saturated sodium bicarbonate solution. The layers were separated and the water layer was extracted with DCM, and the combined organic matter was concentrated under reduced pressure. The residue was then purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O(5mMNH 4 OH) 75 mL / min) to afford the title compound (13.4 mg, 0.027 mmol) as a white solid.

[1144] LCMS: Rt: 2.18 min (LCMS method 4); MS m / z 473.5 [M+H] + .

[1145] 1 H NMR (CD 3 OD)δ8.39(s,1H),7.03-6.82(m,3H),4.67-4.61(m,2H),4.54-4.47(m,2 H),4.34-4.24(m,2H),4.21-4.12(m,2H),4.08(s,3H),3.80-3.70(m,1H ),3.16-2.96(m,3H),2.94-2.85(m,1H),2.60-2.48(m,1H),2.28-2.09( m, 3H), 1.91 (d, J = 7.3Hz, 4H), 1.76-1.59 (m, 2H), 0.98 (t, J = 7.6Hz, 3H).

[1146] Example 2Q: (S)-7-(4-(5-fluoro-2-(((S)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane or (S)-7-(4-(5-fluoro-2-(((R)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane and Example 2R: (S)-7-(4-(5-fluoro-2-(((S)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane or (S)-7-(4-(5-fluoro-2-(((R)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1147]

[1148] (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 4F, 100 mg, 0.267 mmol) was dissolved in DMF (1.1 mL) and cesium carbonate (261 mg, 0.801 mmol) was added followed by tetrahydro-2H-pyran-3-yl 4-methylbenzenesulfonate (Intermediate 5L, 68.5 mg, 0.267 mmol). The resulting mixture was stirred at 80 °C for 18 hours and then diluted with EtOAc, washed with water and concentrated under reduced pressure. The residue was purified by FCC (0%-10% MeOH / DCM) and further purified by preparative HPLC (XBridge 30x50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH), 75 mL / min). The diastereomers were then separated by SFC (ChiralPak IG 21 x 250 mm column, 21% MeOH, flow rate: 80 g / min). Peak 1 was isolated to give Example 2Q (8.0 mg, 0.017 mmol) and Peak 2 was isolated to give Example 2R (7.0 mg, 0.015 mmol)

[1149] Example 2Q:

[1150] SFC: Rt: 3.14 min (Chiralpak IA 4.6 x 100 mm 5 μm, 5% → 55% with 10 mM NH4 OH in MeOH / CO 2 , 5 mL / min). LCMS: Rt: 2.10 min (LCMS method 4); MS m / z 459.5 [M+H] + .

[1151] 1 H NMR (DMSO-d 6 )δ8.64(s,1H),7.03-6.90(m,3H),4.36-4.28(m,1H),4.24-4.19(m,1H),4. 15-4.10(m,2H),4.05-4.00(m,1H),3.97-3.90(m,1H),3.75-3.69(m,1H),3 .65-3.54(m,3H),3.54-3.47(m,1H),3.03-2.84(m,3H),2.83-2.74(m,1H), 2.45-2.36(m,1H),2.11-1.93(m,4H),1.86-1.65(m,4H),1.65-1.46(m,3H).

[1152] Example 2R:

[1153] SFC: Rt: 3.35 min (Chiralpak IA 4.6 x 100 mm 5 μm, 5% → 55% with 10 mM NH 4 OH in MeOH / CO 2 , 5 mL / min). LCMS: Rt: 2.09 min (LCMS method 4); MS m / z 459.1 [M+H] + .

[1154] 1 H NMR (DMSO-d 6 )δ8.66-8.62(m,1H),7.04-6.89(m,3H),4.27-4.28(m,1H),4.25-4.19(m,1H ),4.16-4.09(m,2H),4.05-4.00(m,1H),3.97-3.90(m,1H),3.76-3.70(m,1H) ,3.65-3.55(m,3H),3.55-3.47(m,1H),3.01-2.84(m,3H),2.84-2.75(m,1H) ,2.45-2.37(m,1H),2.11-1.93(m,4H),1.87-1.64(m,4H),1.64-1.47(m,3H).

[1155] Example 2S: (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1156]

[1157] (S)-2-(1-(2-(1,3,4-oxadiazole-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 4F, 40 mg, 0.11 mmol), cesium carbonate (139 mg, 0.427 mmol) and (2-oxaspiro[3.3]heptane-6-yl)methyl 4-methylbenzenesulfonate (Intermediate 5A, 36.2 mg, 0.128 mmol) were dissolved in DMF (10 mL). The resulting mixture was stirred at 80 °C for 16 hours. The crude product was diluted with EtOAc, washed with water, and the organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge 30x 50mm 5μm 35%-60% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (23 mg, 0.047 mmol).

[1158] LCMS: Rt: 2.18 min (LCMS method 4); MS m / z 485.5 [M+H] + .

[1159] 1 H NMR (400MHz, CD 3 OD)δ8.29(s,1H),6.89-6.64(m,3H),4.66(s,2H),4.54(s,2H),4.20(d,J=10.3Hz,2H),4.07(d,J=8.6Hz,2H),4.02-3. 92(m,1H),3.82-3.60(m,3H),3.07-2.73(m,4H),2.56-2.40(m,2H),2.33(m,2H),2.19-1.97(m,5H),1.80-1.48(m,4H). Example 2T: (S)-7-(4-(2-((5-ethyl-1,3,4-thiadiazol-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1160]

[1161] (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 4F, 13 mg, 0.035 mmol) was dissolved in acetonitrile (1.0 mL) and 2-(chloromethyl)-5-ethyl-1,3,4-thiadiazole (11.3 mg, 0.069 mmol) and cesium carbonate (17 mg, 0.052 mmol) were added. The reaction was stirred at room temperature for 16 hours and then the solvent was concentrated under reduced pressure and the residue was purified by preparative HPLC (XBridge 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (4.0 mg, 0.0080 mmol) as a white solid.

[1162] LCMS: Rt: 1.93 min (LCMS method 4); MS m / z 501.7 [M+H] + .

[1163] 1 H NMR (CD 3 OD)δ8.39(s,1H),7.10-7.04(m,1H),7.01-6.96(m,1H),6.95-6.88(m,1H),5. 49(s,2H),4.37-4.25(m,2H),4.22-4.13(m,2H),4.11-4.02(m,1H),3.82-3.7 2(m,1H),3.18(s,4H),3.06-2.95(m,1H),2.93-2.84(m,1H),2.62-2.48(m,1H ),2.30-2.10(m,3H),1.93-1.79(m,2H),1.77-1.62(m,2H),1.48-1.38(m,3H).

[1164] Example 2U: (S)-3-((2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)methyl)oxetan-3-ol

[1165]

[1166] (S)-2-(1-(2-(1,3,4-oxadiazole-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 4F, 36 mg, 0.096 mmol) was dissolved in MeCN (1.5 mL) and (3-hydroxyoxetane-3-yl)methyl 4-methylbenzenesulfonate (Intermediate 5J, 30 mg, 0.12 mmol) and cesium carbonate (47 mg, 0.14 mmol) were added. The reaction was stirred at 70 ° C for 3 days and then the solvent was removed under reduced pressure. The residue was washed with DCM and saturated NaHCO 3 The layers were separated and the aqueous layer was extracted with DCM and the combined organic layers were concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge 30 x 50 mm 5 μm 15%-40% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (12.4 mg, 0.027 mmol) as a white solid.

[1167] LCMS: Rt: 1.54 min (LCMS method 4); MS m / z 461.4 [M+H] + .

[1168] 1 H NMR (CD 3OD)δ8.39(s,1H),7.05-6.83(m,3H),4.74-4.69(m,2H),4.68-4.63(m,2H),4.36-4.25(m,2H),4.22-4.13(m,2H),4.12-4.03(m,3H), 3.81-3.72(m,1H),3.15-3.04(m,3H),2.94-2.83(m,1H),2.60-2.49(m,1H),2.33-2.06(m,3H),1.94-1.80(m,2H),1.77-1.60(m,1H). Example 2V: 2-((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol or 2-((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol and Example 2W 2-((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol or 2-((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol

[1169]

[1170] Step 1: (S)-3-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutane-1-carboxylic acid methyl ester

[1171] (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 4F, 50 mg, 0.13 mmol) and methyl 3-(tosyloxy)cyclobutane-1-carboxylate (Intermediate 5Q, 102 mg, 0.200 mmol) were dissolved in acetonitrile (2 mL) and cesium carbonate (218 mg, 0.668 mmol) was added. The reaction was stirred at 80 °C for 16 hours and then concentrated and diluted with EtOAc, washed with water and concentrated under reduced pressure. The residue was purified by FCC (0%-5% MeOH / DCM) to provide the title intermediate (56 mg, 0.11 mmol).

[1172] LCMS: Rt: 0.97 min (LCMS method 2); MS m / z 487.4 [M+H] + .

[1173] Step 2: 2-((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol or 2-((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol

[1174] (S)-3-(2-(1-(2-(1,3,4-oxadiazole-2-yl)-5-oxa-2-azaspiro[3.4]octane-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutane-1-carboxylic acid methyl ester (50 mg, 0.078 mmol) was dissolved in THF (2 mL) at -10 °C, and methylmagnesium chloride (0.057 mL, 0.173 mmol, 3M THF) was added. The reaction was slowly warmed to 0 °C and stirred for 1 hour. The reaction was then neutralized with saturated ammonium chloride solution and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and the residue was purified by preparative HPLC (X-Bridge 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to provide separated diastereomers. The initial peak is Example 2V (5.0 mg, 0.0099 mmol) and the tailing peak is Example 2W (8 mg, 0.016 mmol).

[1175] Example 2V:

[1176] LCMS: Rt: 2.11 min (LCMS method 4); MS m / z 487.5 [M+H] + 。

[1177] 1 H NMR (400 MHz, CD 3 OD) δ 8.38 (s, 1H), 6.97 - 6.75 (m, 2H), 6.64 (dd, J = 9.0, 4.6 Hz, 1H), 4.63 (m, 1H), 4.41 - 4.26 (m, 2H), 4.23 - 4.14 (m, 2H), 4.07 (dd, J = 8.7, 6.9 Hz, 1H), 3.77 (dd, J = 8.7, 7.4 Hz, 1H), 3.17 - 2.86 (m, 4H), 2.64 - 2.53 (m, 1H), 2.51 - 2.33 (m, 3H), 2.31 - 2.09 (m, 5H), 1.95 - 1.59 (m, 4H), 1.16 (s, 6H).

[1178] Example 2W:

[1179] LCMS: Rt: 2.14 min (LCMS method 4); MS m / z 487.4 [M+H] + 。

[1180] 1 H NMR (400 MHz, CD 3 OD) δ 8.38 (s, 1H), 6.97 - 6.65 (m, 3H), 4.59 - 4.40 (m, 1H), 4.37 - 4.24 (m, 2H), 4.17 (q, J = 8.6 Hz, 2H), 4.06 (dd, J = 8.6, 7.0 Hz, 1H), 3.76 (dd, J = 8.6, 7.3 Hz, 1H), 3.17 - 2.79 (m, 4H), 2.54 (dd, J = 13.0, 7.4 Hz, 1H), 2.40 (m, 2H), 2.28 - 2.10 (m, 3H), 2.09 - 1.92 (m, 3H), 1.83 (m, 2H), 1.68 (m, 2H), 1.12 (s, 6H).

[1181] Example 2X: (S)-7-(4-(5-fluoro-2-((S)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane or (S)-7-(4-(5-fluoro-2-((R)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane And Example 2Y: (S)-7-(4-(5-fluoro-2-((S)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane or (S)-7-(4-(5-fluoro-2-((R)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1182]

[1183] (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 4F, 73 mg, 0.20 mmol), 1-(tetrahydro-2H-pyran-4-yl)ethyl 4-methylbenzenesulfonate (Intermediate 5R, 83 mg, 0.29 mmol) were dissolved in acetonitrile (8 mL) and cesium carbonate (127 mg, 0.390 mmol) was added. The reaction was stirred at 80 °C for 16 hours and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (0%-100% EtOAc (0.1% 7N NH 3 ) / DCM; then 0%-3% DCM / MeOH). These diastereomers were then purified by chiral SFC (ChiralPak IF 21 x 250 mm column, 30% MeOH:IPA 1:1 (with 10 mM NH 4 OH), flow rate: 80 g / min). The initial peak was isolated to give Example 2X (17 mg, 0.034 mmol) and the tailing peak was isolated to give Example 2Y (17 mg, 0.034 mmol).

[1184] Example 2X:

[1185] SFC: Rt: 2.78 min (Chiralpak IF 3x 100 mm 5 μm, 5% → 55% MeOH:IPA 1:1 (with 10 mM NH4 OH) / CO 2 , 2.5mL / min).

[1186] LCMS: Rt: 2.28 min (LCMS method 4); MS m / z 487.3 [M+H] + .

[1187] 1 H NMR (400MHz, CD 3 OD)δ8.38(s,1H),7.06-6.56(m,3H),4.35-4.21(m,3H),4.17(q,J=8.6Hz,2H),4.11-3.94(m,3H),3.76(dd,J=8.5,7.4Hz,1H),3.44(m ,2H),3.21-2.85(m,4H),2.55(dd,J=12.9,7.3Hz,1H),2.32-2.07(m,3H),1.92-1.77(m,4H),1.76-1.42(m,5H),1.21(d,J=6.0Hz,3H).

[1188] Example 2Y:

[1189] SFC: Rt: 2.93 min (Chiralpak IF 3x 100 mm 5 μm, 5% → 55% MeOH:IPA 1:1 (with 10 mM NH 4 OH / CO 2 ), 2.5mL / min).

[1190] LCMS: Rt: 2.33 min (LCMS method 4); MS m / z 487.4 [M+H] + .

[1191] 1H NMR (400MHz, CD 3 OD)δ8.38(s,1H),7.31-6.49(m,3H),4.38-4.22(m,3H),4.17(q,J=8.6Hz,2H),4.10-3.92(m,3H),3.76(dd,J=8.7,7.4Hz,1H),3.44(m ,2H),3.22-2.75(m,4H),2.55(dd,J=13.1,7.3Hz,1H),2.38-2.08(m,3H),2.01-1.79(m,4H),1.76-1.43(m,5H),1.22(d,J=6.0Hz,3H).

[1192] Example 2Z: (7S)-7-(4-(2-((3-oxabicyclo[3.1.0]hexan-6-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1193]

[1194] (S)-2-(1-(2-(1,3,4-oxadiazole-2-yl)-5-oxa-2-azaspiro[3.4]octane-7-yl)piperidin-4-yl)-4-fluorophenol (Intermediate 4F, 38 mg, 0.10 mmol) and (3-oxabicyclo[3.1.0]hexane-6-yl)methyl 4-methylbenzenesulfonate (Intermediate 5K, 55 mg, 0.15 mmol) were dissolved in acetonitrile (2 mL) and cesium carbonate (66 mg, 0.20 mmol) was added. The reaction was stirred at 80 ° C for 16 hours and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (X-bridge C18 OBD 30x 50mm 5μm column 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (19 mg, 0.040 mmol).

[1195] LCMS: Rt: 2.11 min (LCMS method 4); MS m / z 471.4 [M+H] + .

[1196] 1 H NMR (400MHz, CD 3 OD)δ8.38(s,1H),7.03-6.29(m,3H),4.36-4.23(m,2H),4.17(q,J=8.5Hz,2H),4.07(dd,J=8.7,6.9Hz,1H),3.96-3.84(m,4H),3.81-3.6 4(m,3H),3.17-2.96(m,3H),2.90(m,1H),2.55(dd,J=13.1,7.3Hz,1H),2.31-2.07(m,3H),1.84(m,2H),1.77-1.59(m,4H),1.16(m,1H).

[1197] Example 2AA: (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-3,5-difluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1198]

[1199] In a 40 mL vial, to a solution of (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4,6-difluorophenol (Intermediate 4C, 0.082 g, 0.209 mmol) in MeCN (2.1 mL) under nitrogen was added a solution of 2-oxaspiro[3.3]heptan-6-yl 4-methylbenzenesulfonate (from Step 1 of Example 2K, 0.062 g, 0.230 mmol) in MeCN (0.5 mL) followed by the addition of Cs 2 CO 3 (0.272 g, 0.836 mmol) and stirred at 80 °C for 6 hours. The reaction was then cooled to RT and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc and the combined organic layers were washed with MgSO 4 Dry, filter and concentrate. The residue is purified by FCC (0%-15% MeOH (10% NH 4 0.4% paraformaldehyde (EtOAc) / 0.1% paraformaldehyde (EtOAc) to give the title compound as a white solid.

[1200] LCMS: Rt: 1.20 min (LCMS method 3); MS m / z 489.3 [M+H] + .

[1201] 1 H NMR (400MHz, CD 3 OD)δ8.38(s,1H),6.89-6.74(m,2H),4.67(d,J=1.8Hz,4H),4.42-4.24(m,3H) ,4.17(q,J=8.6Hz,2H),4.06(dd,J=8.8,6.9Hz,1H),3.77(dd,J=8.8,7.3Hz,1H ),3.17-3.05(m,2H),3.05-2.86(m,2H),2.69(m,2H),2.55(dd,J=13.0,7.4Hz, 1H), 2.39 (ddd, J=10.2, 7.2, 3.4Hz, 2H), 2.31-2.09 (m, 3H), 1.85-1.58 (m, 4H).

[1202] Example 2BB: (S)-7-(4-(3,5-difluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1203]

[1204] (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4,6-difluorophenol (Intermediate 4C, 32 mg, 0.082 mmol), tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate (23 mg, 0.090 mmol) and cesium carbonate (106 mg, 0.326 mmol) were suspended in acetonitrile (0.8 mL). The reaction was stirred at 80 °C overnight and then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by FCC (0%-20% MeOH (10% NH 4 OH) / EtOAc) and purified by preparative HPLC (X-bridge C18 OBD 30x 50mm 5μm column 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (27 mg, 0.058 mmol) as a white solid.

[1205] LCMS: Rt: 1.98 min (LCMS method 4); MS m / z 477.4 [M+H] + .

[1206] 1 H NMR (400MHz, CD 3 OD)δ8.38(s,1H),6.90-6.77(m,2H),4.35-4.12(m,5H),4.06(dd,J=8.6,6.9Hz,1H),3.97(dt,J=12.0,4.3Hz,2H),3.76(dd,J=8.7,7.3Hz ,1H),3.48(m,2H),3.16-3.01(m,3H),2.90(m,1H),2.54(dd,J=12.9,7.4Hz,1H),2.27-2.09(m,3H),2.03-1.93(m,2H),1.87-1.58(m,6H).

[1207] Example 2CC: (S)-7-(4-(3,5-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1208]

[1209] (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4,6-difluorophenol (Intermediate 4C, 32 mg, 0.082 mmol), (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (Intermediate 5C, 22 mg, 0.090 mmol) and cesium carbonate (106 mg, 0.326 mmol) were suspended in acetonitrile (0.8 mL). The reaction was stirred at 80 °C for 80 minutes, then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by FCC (0%-20% MeOH (10% NH 4 OH) / EtOAc) to afford the title compound (27 mg, 0.058 mmol) as a white solid.

[1210] LCMS: Rt: 1.98 min (LCMS method 4); MS m / z 463.2 [M+H] + .

[1211] 1 H NMR (400MHz, CD 3 OD)δ8.38(s,1H),6.94-6.75(m,2H),5.03-4.94(m,1H),4.35-4.23(m,2H),4.17(q,J=8.6Hz,2H),4.10-3.99(m,2H),3.96-3.86(m ,2H),3.80-3.69(m,2H),3.15-2.98(m,3H),2.95-2.84(m,1H),2.55(dd,J=13.0,7.4Hz,1H),2.27-2.08(m,5H),1.85-1.56(m,4H).

[1212] Example 2DD: (S)-7-(4-(3,5-difluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1213]

[1214] (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4,6-difluorophenol (Intermediate 4C, 32 mg, 0.082 mmol), oxetan-3-ylmethyl 4-methylbenzenesulfonate (22 mg, 0.090 mmol) and cesium carbonate (106 mg, 0.326 mmol) were suspended in acetonitrile (0.8 mL). The reaction was stirred at 80 °C for 20 minutes, then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by FCC (0%-20% MeOH (10% NH 4 OH) / EtOAc) to afford the title compound (23 mg, 0.049 mmol) as a white solid.

[1215] LCMS: Rt: 1.89 min (LCMS method 4); MS m / z 463.5 [M+H] + .

[1216] 1 H NMR (400MHz, CD 3 OD)δ8.38(s,1H),6.92-6.77(m,2H),4.88(dd,J=8.0,6.1Hz,2H),4.63(t,J =6.0Hz,2H),4.35-4.23(m,2H),4.23-4.12(m,4H),4.06(dd,J=8.7,6.8Hz,1 H),3.76(dd,J=8.7,7.2Hz,1H),3.44(m,1H),3.17-2.95(m,3H),2.95-2.86 (m,1H),2.54(dd,J=13.1,7.4Hz,1H),2.28-2.09(m,3H),1.88-1.62(m,4H).

[1217] Example 2EE: (S)-7-(4-(3,5-difluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1218]

[1219] (S)-2-(1-(2-(1,3,4-oxadiazole-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4,6-difluorophenol (Intermediate 4C, 32 mg, 0.082 mmol), oxetane-3-yl 4-methylbenzenesulfonate (commercially available, 20 mg, 0.090 mmol) and cesium carbonate (106 mg, 0.326 mmol) were suspended in acetonitrile (0.8 mL). The reaction was stirred at 80 °C for 6 hours, then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by FCC (0%-20% MeOH (10% NH 4 OH) / EtOAc) to afford the title compound (15 mg, 0.033 mmol) as a white solid.

[1220] LCMS: Rt: 1.87 min (LCMS method 4); MS m / z 449.5 [M+H] + .

[1221] 1 H NMR (400MHz, CD 3 OD)δ8.38(s,1H),6.93-6.75(m,2H),5.15-5.00(m,1H),4.91(dd,J=7.5,6.1Hz,2H ),4.83-4.77(m,2H),4.35-4.22(m,2H),4.17(q,J=8.7Hz,2H),4.06(dd,J=8.8,6.9 Hz,1H),3.77(dd,J=8.8,7.3Hz,1H),3.16-2.95(m,3H),2.95-2.85(m,1H),2.54(dd ,J=13.0,7.4Hz,1H),2.23(m,2H),2.14(dd,J=13.0,8.3Hz,1H),1.86-1.59(m,4H).

[1222] Example 2FF: (S)-7-(4-(4,5-difluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1223]

[1224] (S)-2-(1-(2-(1,3,4-oxadiazole-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4,5-difluorophenol (Intermediate 4D, 28 mg, 0.071 mmol), oxetane-3-yl 4-methylbenzenesulfonate (21 mg, 0.093 mmol) and cesium carbonate (70 mg, 0.21 mmol) were suspended in acetonitrile (2 mL). The reaction was stirred at 80 °C overnight, cooled to room temperature, filtered and concentrated. The residue was purified by preparative HPLC (X-bridge C18 OBD 30x 50mm5μm column 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min), and then by preparative HPLC (X-bridge C18 OBD30x 50mm 5μm column 10%-30% MeCN / H 2 D(0.1% formic acid) 75 mL / min) to afford the title compound as a formate salt (6 mg, 0.012 mmol).

[1225] LCMS: Rt: 1.87 min (LCMS method 4); MS m / z 449.3 [M+H] + .

[1226] 1 H NMR (400MHz, CD 3 OD)δ8.38(d,J=6.3Hz,1H),7.13(dd,J=11.7,8.9Hz,1H),6.53(dd,J=12.2,6. 8Hz,1H),5.26(m,1H),5.02(t,J=6.8Hz,2H),4.67(dd,J=7.5,4.8Hz,2H),4.4 2-4.00(m,5H),3.86(dd,J=9.1,6.7Hz,1H),3.29-2.78(m,4H),2.61(dd,J=13 .3,7.5Hz,1H),2.43(m,2H),2.22(dd,J=13.3,7.8Hz,1H),1.96-1.51(m,4H).

[1227] Example 2GG: (S)-7-(4-(4,5-difluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1228]

[1229] (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4,5-difluorophenol (Intermediate 4D, 28 mg, 0.071 mmol), tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate (commercially available, 24 mg, 0.093 mmol) and cesium carbonate (70 mg, 0.21 mmol) were suspended in acetonitrile (2 mL). The reaction was stirred at 80 °C overnight, then cooled to room temperature, filtered and concentrated. The residue was purified by preparative HPLC (X-bridge C18 OBD 30x 50mm 5μm column 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) and further purified by preparative HPLC (X-bridge C18 OBD 30 x 50 mm 5 μm column 10%-30% MeCN / H 2 O (0.1% formic acid) 75 mL / min) to afford the title compound (14 mg, 0.027 mmol).

[1230] LCMS: Rt: 2.11 min (LCMS method 4); MS m / z 477.3 [M+H] + .

[1231] 1 H NMR (400MHz, CD 3 OD)δ8.39(s,1H),7.07(dd,J=11.8,9.2Hz,1H),7.02-6.88(m,1H),4.54( m,1H),4.40-4.25(m,2H),4.23-4.04(m,3H),4.02-3.77(m,3H),3.61(m,2 H),3.29-3.14(m,2H),3.01(m,2H),2.59(dd,J=13.2,7.4Hz,1H),2.36(m, 2H), 2.19 (dd, J=13.3, 7.9Hz, 1H), 2.03 (m, 2H), 1.87 (m, 2H), 1.72 (m, 4H).

[1232] Example 2HH: ((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol or ((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol and Example 2II ((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol or ((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol

[1233]

[1234] (S)-methyl 3-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutane-1-carboxylate (Example 2U, Step 1, 29 mg, 0.060 mmol) was dissolved in THF (2 mL) and LiBH was added at 0 °C. 4 (2.6 mg, 0.12 mmol). The reaction was slowly warmed to room temperature, stirred overnight and neutralized with saturated ammonium chloride solution, extracted with EtOAc and the combined organic layers were concentrated. The residue was purified by preparative HPLC (XSelect CSH C18 5 μm 19 x 150 mm column 15%-30% MeCN / H 2 O (0.1% TFA, 25 mL / min) to provide peaks 1 and 2. Peak 1 was free-based using a PL-HCO3 MP resin column (eluted with methanol) and concentrated to provide Example 2HH (2.0 mg, 0.0043 mmol). Peak 2 was further purified by preparative HPLC (X-bridge C18 OBD 30x50mm 5μm column 35%-60% MeCN / H 2 O (5 mM NH 4 OH), 75 mL / min) to give Example 2II (2 mg, 0.0043 mmol).

[1235] Example 2HH:

[1236] LCMS: Rt: 1.88 min (LCMS method 4); MS m / z 459.5 [M+H] + 。

[1237] 1 H NMR (400 MHz, CD 3 OD) δ 8.38 (s, 1H), 6.90 (dd, J = 9.8, 3.1 Hz, 1H), 6.81 (td, J = 8.4, 3.1 Hz, 1H), 6.65 (dd, J = 8.9, 4.5 Hz, 1H), 4.73 (p, J = 6.4 Hz, 1H), 4.36 - 4.24 (m, 2H), 4.17 (q, J = 8.7 Hz, 2H), 4.07 (dd, J = 8.7, 6.9 Hz, 1H), 3.76 (dd, J = 8.7, 7.4 Hz, 1H), 3.62 (d, J = 6.7 Hz, 2H), 3.09 (t, J = 7.6 Hz, 2H), 3.06 - 2.94 (m, 1H), 2.90 (d, J = 11.2 Hz, 1H), 2.55 (dd, J = 13.0, 7.5 Hz, 1H), 2.53 - 2.40 (m, 1H), 2.39 - 2.29 (m, 2H), 2.29 - 2.09 (m, 5H), 1.84 (m, 2H), 1.78 - 1.61 (m, 2H).

[1238] Example 2II:

[1239] LCMS: Rt: 1.84 min (LCMS method 4); MS m / z 459.5 [M+H] + 。

[1240] 1 H NMR (400 MHz, CD 3 OD) δ 8.41 (s, 1H), 6.92 (dd, J = 9.8, 3.0 Hz, 1H), 6.84 (td, J = 8.3, 3.1 Hz, 1H), 6.77 (dd, J = 8.9, 4.8 Hz, 1H), 4.58 (p, J = 7.0 Hz, 1H), 4.40 - 4.26 (m, 2H), 4.19 (q, J = 8.7 Hz, 2H), 4.09 (dd, J = 8.8, 6.9 Hz, 1H), 3.85 - 3.75 (m, 1H), 3.57 (d, J = 5.9 Hz, 2H), 3.19 - 3.08 (m, 2H), 3.00 (m, 1H), 2.92 (d, J = 11.4 Hz, 1H), 2.57 (m, 3H), 2.36 - 2.12 (m, 4H), 1.87 (m, 4H), 1.71 (m, 2H).

[1241] Example 3A: (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane or (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane and Example 3B: (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane or (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1242]

[1243] Step 1: (S)-tert-butyl 7-(4-(2-(2,5-dihydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[1244] (S)-tert-Butyl 7-(4-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 9A, 330 mg, 0.634 mmol), 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (124 mg, 0.634 mmol) and tripotassium phosphate (404 mg, 1.90 mmol) were dissolved in a mixture of dioxane (1.4 mL) and water (140 μL). Pd(dppf)Cl was added. 2 ·CH 2 Cl 2 (25 mg, 0.032 mmol) and the mixture was degassed with nitrogen for 2 minutes and stirred at 80 ° C for 5 hours. The solvent was evaporated under reduced pressure and the residue was diluted with a mixture of DCM and water. The layers were separated and the organic phase was washed with water, brine, MgSO 4 Dry, filter and evaporate under reduced pressure.The residue was purified by FCC (0%-40% EtOAc / heptane) to afford the title intermediate (246 mg, 0.558 mmol).

[1245] LCMS: Rt: 1.10 min (LCMS method 2); MS m / z 441.2 [M+H] + .

[1246] Step 2: (S)-7-(4-(2-(2,5-dihydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1247] (S)-tert-Butyl 7-(4-(2-(2,5-dihydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (246 mg, 0.558 mmol) was dissolved in DCM (5.5 mL) and cooled to 0 ° C and stirred for 10 minutes, and then TFA (637 mg, 5.58 mmol) was added and the reaction was stirred at RT for 16 hours. The reaction was then diluted with DCM and washed with 1N NaOH. The DCM layer was dried over sodium sulfate, filtered and concentrated to give the title intermediate (187 mg, 0.549 mmol), which was used without further purification.

[1248] LCMS: Rt: 0.80 min (LCMS method 2); MS m / z 341.1 [M+H] + .

[1249] Step 3: (S)-7-(4-(2-(2,5-dihydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1250] (S)-7-(4-(2-(2,5-dihydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (187 mg, 0.55 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (121 mg, 0.55 mmol) and tripotassium phosphate (350 mg, 1.65 mmol) were dissolved in a mixture of 2% aqueous TPGS-750-M (1.0 mL) and THF (0.11 mL). The reaction was stirred at room temperature overnight. Next, 4N HCl was added to adjust the pH to 2. The reaction was stirred at room temperature for 3 hours and then basified to pH>8 with 2M LiOH. The solution was then extracted with DCM, and the combined organic layers were evaporated under reduced pressure. The residue was purified by FCC (0%-7% MeOH / DCM) to provide the title intermediate (38 mg, 0.089 mmol).

[1251] LCMS: Rt: 1.85 min (LCMS method 4); MS m / z 409.7 [M+H] + .

[1252] Step 4: (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane or (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1253] (S)-7-(4-(2-(2,5-dihydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane (143 mg, 0.35 mmol) and 10% Pd-C (37 mg) were dissolved in MeOH and the reaction was stirred under a hydrogen balloon for 16 hours. The reaction was then filtered and the crude product was purified by preparative HPLC (X-bridge C18 OBD 30x 50mm 5μm column 25%-50% MeCN / H 2 O (5 mM NH 4 The two diastereomers were then purified by chiral SFC (ChiralPak ID 21 x 250 mm column, 40% with 10 mM NH 4 OH in IPA, flow rate: 80 g / min) was separated to give Peak 1 (Example 3A, 32 mg, 0.076 mmol) and Peak 2 (Example 3B, 27 mg, 0.064 mmol).

[1254] Example 3A:

[1255] SFC: Rt: 3.99 min (Chiralpak ID 4.6 x 100 mm 5 μM, 5% → 55% with 10 mM NH 4 IPA / CO of OH 2 , 5 mL / min). LCMS: Rt: 1.81 min (LCMS method 4); MS m / z 411.2 [M+H] + .

[1256] 1 H NMR (DMSO-d 6)δ8.66-8.63(m,1H),7.30-7.20(m,2H),7.19-7.13(m,2H),4.26-4.20(m,1H ),4.16-4.10(m,2H),4.05-3.91(m,4H),3.85-3.77(m,1H),3.69-3.59(m,2H) ,3.58-3.52(m,1H),3.04-2.93(m,2H),2.89-2.75(m,2H),2.44-2.36(m,1H) ,2.31-2.23(m,1H),2.19-2.04(m,3H),1.95-1.83(m,1H),1.72-1.57(m,4H).

[1257] Example 3B:

[1258] SFC: Rt: 4.65 min (Chiralpak ID 4.6 x 100 mm 5 μM, 5% → 55% with 10 mM NH 4 IPA / CO of OH 2 ,5mL / min). LCMS: Rt: 1.82min (LCMS method 4); MS m / z 411.5[M+H] + .

[1259] 1 H NMR (DMSO-d 6 )δ8.64(s,1H),7.31-7.21(m,2H),7.20-7.12(m,2H),4.26-4.20(m,1H),4. 16-4.10(m,2H),4.06-3.90(m,4H),3.86-3.77(m,1H),3.69-3.60(m,2H),3 .58-3.52(m,1H),3.05-2.92(m,2H),2.90-2.75(m,2H),2.44-2.36(m,1H), 2.34-2.22(m,1H),2.19-2.04(m,3H),1.94-1.81(m,1H),1.73-1.59(m,4H)

[1260] Example 3C: (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1261]

[1262] Step 1: (S)-tert-butyl 7-(4-(2-(3,6-dihydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[1263] (S)-tert-butyl 7-(4-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 9A, 237 mg, 0.455 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (143 mg, 0.683 mmol), Cs 2 CO 3 (445 mg, 1.366 mmol) and XPhosPd G2 (35.8 mg, 0.046 mmol) were added to a 40 mL vial. Dioxane (5 mL) and water (1 mL) were added and the solution was evacuated and heated with N 2 The gas was backfilled three times. It was then stirred at 80°C for 4 hours. The reaction was then cooled and extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by FCC (0%-5% MeOH (10% NH 4 OH) / DCM) to give the title intermediate (250 mg, 0.455 mmol).

[1264] LCMS: Rt: 1.16 min (LCMS method 2); MS m / z 455.5 [M+H] + .

[1265] Step 2: (S)-tert-butyl 7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[1266] (S)-tert-butyl 7-(4-(2-(3,6-dihydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (250 mg, 0.55 mmol) and 10% Pd-C (117 mg) were dissolved in EtOH (10 mL). The flask was flushed with hydrogen and the reaction was then stirred under a hydrogen balloon for 16 hours. The solution was filtered and concentrated to produce the title intermediate (250 mg, 0.547 mmol).

[1267] LCMS: Rt: 0.77 min (LCMS method 1); MS m / z 457.5 [M+H] + .

[1268] Step 3: (S)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1269] (S)-tert-butyl 7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (250 mg, 0.547 mmol) was dissolved in DCM (10 mL) and TFA (3 mL, 17.6 mmol) was added. The reaction was stirred for 2 hours and then the solvent was concentrated and the residue was taken up in DCM. The DCM solution was washed with saturated NaHCO 3 The DCM layer was washed and then washed with MgSO 4 Dry and concentrate to give the title intermediate (195 mg, 0.547 mmol).

[1270] LCMS: Rt: 0.50 min (LCMS method 1); MS m / z 357.3 [M+H] + .

[1271] Step 4: (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1272] (S)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (195 mg, 0.547 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (157 mg, 0.711 mmol) and K 3 PO 4 4-(4-(4-(4-(4-piperidin-2-yl)-1-yl)-2-nitropropene (151mg, 0.711mmol) was dissolved in a mixture of 2% aqueous TPGS-750-M (6.0mL) and THF (0.6mL). The reaction was stirred at room temperature overnight, then a solution of 2M LiOH (2.73mL, 5.47mmol) was added, and the reaction was stirred for 2 hours. MeOH and 4N HCl solution were added to adjust the pH to 2. It was stirred at room temperature for 3 hours, then basified with 2M LiOH solution (pH>8), extracted 3 times with DCM, and the combined organic layers were evaporated under reduced pressure. The residue was purified by FCC (0%-7% EtOAc / heptane (with 1% 7N NH 4 OH / MeOH)) and further purified by preparative HPLC (XBridge Peptide BEHC18 5 μm 19 x 150 mm 30%-45% MeCN / H 2 O (5 mM NH4 OH) 30 mL / min) to afford the title compound (59 mg, 0.14 mmol).

[1273] LCMS: Rt: 1.89 min (LCMS method 4); MS m / z 425.5 [M+H] + .

[1274] 1 H NMR (400MHz, CD 3 OD)δ8.39(s,1H),7.34-6.98(m,4H),4.38-4.25(m,2H),4.17(q,J=8.6Hz,2H), 4.11-3.98(m,3H),3.79(dd,J=8.8,7.3Hz,1H),3.60(td,J=11.8,1.9Hz,2H),3 .19-3.06(m,3H),2.92(dd,J=11.7,3.6Hz,2H),2.56(dd,J=13.0,7.5Hz,1H),2 .29(m,2H),2.16(dd,J=13.1,8.3Hz,1H),1.91-1.69(m,6H),1.67-1.56(m,2H).

[1275] Example 3D: (S)-7-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1276]

[1277] Step 1: (S)-tert-butyl 7-(4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[1278] (S)-tert-butyl 7-(4-(5-fluoro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 9B, 300 mg, 0.557 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (117 mg, 0.557 mmol), K 3 PO 4(355 mg, 1.671 mmol) and Pd(dppf)Cl2.CH2Cl2 (22.75 mg, 0.028 mmol) were dissolved in dioxane (1.2 mL) and water (0.12 mL). The vial was evacuated and backfilled with nitrogen and this was repeated twice. The reaction was then stirred at 80°C for 5 hours in a sealed vial. The solvent was concentrated and the residue was taken up in DCM and washed with water and brine, dried over magnesium sulfate, filtered and concentrated (250 mg, 0.529 mmol).

[1279] LCMS: Rt: 1.16 min (LCMS method 1); MS m / z 473.2 [M+H] + .

[1280] Step 2: (S)-tert-butyl 7-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[1281] (S)-tert-Butyl 7-(4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (250 mg, 0.529 mmol) and 10% Pd—C (56 mg) were dissolved in MeOH (5.2 mL) and stirred under a hydrogen atmosphere for 16 hours. The reaction was filtered through a pad of celite and the solvent was removed to give the title compound (231 mg, 0.487 mmol).

[1282] LCMS: Rt: 1.14 min (LCMS method 2); MS m / z 475.6 [M+H] + .

[1283] Step 3: (S)-7-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1284] (S)-tert-Butyl 7-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (231 mg, 0.487 mmol) was dissolved in DCM (4.8 mL) and cooled to 0°C. After incubation at 0°C for 10 min, TFA (0.75 mL, 9.73 mmol) was added and the reaction was warmed to RT and stirred for 16 h. The solution was concentrated and the residue was dissolved in DCM and washed with 1 N NaOH and brine, washed with MgSO 4 Dry, filter and concentrate to give the title intermediate (111 mg, 0.296 mmol).

[1285] LCMS: Rt: 0.53 min (LCMS method 1); MS m / z 375.1 [M+H] + .

[1286] Step 4: (S)-7-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1287] (S)-7-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (111 mg, 0.296 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (66 mg, 0.30 mmol) and K 3 PO 4 (189 mg, 0.889 mmol) was dissolved in a mixture of 2% aqueous TPGS-750-M (0.53 mL) and THF (0.059 mL). The reaction was processed similarly to Example 1A and the crude product was purified by FCC (0%-7% MeOH / DCM) and further purified by preparative HPLC (X-bridge C18 OBD 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (60 mg, 0.13 mmol).

[1288] LCMS: Rt: 1.33 min (LCMS method 4); MS m / z 443.3 [M+H] + .

[1289] 1 H NMR (DMSO-d 6 )δ8.67-8.60(m,1H),7.32-7.23(m,1H),7.06-6.92(m,2H),4.26-4.20(m,1H),4.16-4.10(m,2H),4.06-4.00(m,1H),3.99-3.89(m,3H) ,3.68-3.59(m,1H),3.53-3.42(m,2H),3.06-2.92(m,3H),2.88-2.74(m,2H),2.46-2.36(m,1H),2.19-2.02(m,3H),1.79-1.49(m,8H).

[1290] Example 3E: (S)-7-(4-(5-fluoro-2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane or (S)-7-(4-(5-fluoro-2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane and Example 3F: (S)-7-(4-(5-fluoro-2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane or (S)-7-(4-(5-fluoro-2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1291]

[1292] Step 1: (S)-tert-butyl 7-(4-(2-(2,5-dihydrofuran-3-yl)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[1293] (S)-tert-butyl 7-(4-(5-fluoro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 9B, 250 mg, 0.464 mmol), 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (91 mg, 0.464 mmol) and K 3 PO 4 (296 mg, 1.393 mmol) was suspended in dioxane (1.0 mL) and water (0.1 mL). Pd(dppf)Cl was added 2 ·CH 2 Cl 2 The mixture was stirred for 5 hours at 80 °C. The reaction mixture was concentrated and the residue was dissolved in DCM and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by FCC (0%-40% EtOAc / heptane) to produce the title intermediate (207 mg, 0.451 mmol).

[1294] LCMS: Rt: 1.16 min (LCMS method 2); MS m / z 459.3 [M+H] + .

[1295] Step 2: (7S)-tert-butyl 7-(4-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[1296] (S)-tert-Butyl 7-(4-(2-(2,5-dihydrofuran-3-yl)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (207 mg, 0.451 mmol) and 10% Pd-C (50 mg) were dissolved in MeOH (4.5 mL) and stirred under a hydrogen balloon for 16 hours. The solution was filtered and washed with MeOH, and the filtrate was concentrated to give the title intermediate (171 mg, 0.371 mmol).

[1297] LCMS: Rt: 1.11 min (LCMS method 2); MS m / z 461.6 [M+H] + .

[1298] Step 3: (7S)-7-(4-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1299] (7S)-tert-Butyl 7-(4-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (171 mg, 0.371 mmol) was dissolved in DCM (3.7 mL) and cooled to 0° C. The reaction was stirred for 10 minutes and then TFA (0.5 mL, 2.94 mmol) was added and the reaction was stirred at 0° C. for 5 hours. The reaction was then concentrated and dissolved in DCM and washed with 1 N NaOH and brine, dried over sodium sulfate, filtered and concentrated to give the title intermediate (134 mg, 0.371 mmol).

[1300] LCMS: Rt: 0.49 min (LCMS method 1); MS m / z 361.3 [M+H] + .

[1301] Step 4: (S)-7-(4-(5-fluoro-2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane or (S)-7-(4-(5-fluoro-2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1302] (7S)-7-(4-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (134 mg, 0.371 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (90 mg, 0.41 mmol) and K 3 PO 4 (260 mg, 1.22 mmol) was dissolved in a mixture of 2% aqueous TPGS-750-M (0.73 mL) and THF (0.082 mL) and the reaction was treated similarly to Example 1A. The crude product was purified by FCC (0%-7% MeOH / DCM) and further purified by HPLC (X-bridge C18 OBD 30x 50mm 5μm 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to provide a mixture of diastereomers. The two diastereomers were then purified by SFC (ChiralPak IG 21x250 mm, co-solvent: 35% with 10 mM NH 3 IPA, flow rate: 80 g / min) was separated to give an initial peak Example 3E (18 mg, 0.41 mmol) and a tailing peak Example 3F (17 mg, 0.038 mmol).

[1303] Example 3E:

[1304] SFC: Rt: 3.63 min (Chiralpak IG 4.6 x 100 mm 5 μm, 5% → 55% with 10 mM NH 4 IPA / CO of OH 2 , 5 mL / min). LCMS: Rt: 1.89 min (LCMS method 4); MS m / z 429.5 [M+H] + .

[1305] 1 H NMR (DMSO-d 6)δ8.65(s,1H),7.34-7.28(m,1H),7.06-6.94(m,2H),4.27-4.20(m,1H),4.17-4 .10(m,2H),4.06-4.00(m,1H),4.00-3.90(m,3H),3.84-3.75(m,1H),3.68-3.56 (m,2H),3.56-3.50(m,1H),3.06-2.91(m,2H),2.90-2.74(m,2H),2.45-2.35(m, 1H),2.32-2.23(m,1H),2.20-2.02(m,3H),1.92-1.79(m,1H),1.71-1.57(m,4H).

[1306] Example 3F:

[1307] SFC Rt: 3.85 min (Chiralpak IG 4.6 x 100 mm 5 μm, 5% → 55% with 10 mM NH 4 IPA / CO of OH 2 , 5 mL / min). LCMS: Rt: 1.89 min (LCMS method 4); MS m / z 429.3 [M+H] + .

[1308] 1 H NMR (DMSO-d 6 )δ8.62(s,1H),7.35-7.27(m,1H),7.07-6.94(m,2H),4.27-4.20(m,1H),4.17-4 .10(m,2H),4.06-4.00(m,1H),4.00-3.90(m,3H),3.85-3.75(m,1H),3.69-3.56 (m,2H),3.56-3.50(m,1H),3.07-2.90(m,2H),2.90-2.74(m,2H),2.46-2.36(m, 1H),2.31-2.23(m,1H),2.20-2.01(m,3H),1.91-1.79(m,1H),1.71-1.59(m,4H).

[1309] Example 3G: (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1310]

[1311] Step 1: (S)-tert-butyl 7-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[1312] (S)-tert-butyl 7-(4-(2-((tetrahydro-4H-pyran-4-ylidene)methyl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 10D, 80 mg, 0.17 mmol) and Pd(OH) 2 =Toluene (20mL) was added 4-nitropropene (20mL) and 4-nitropropene (20mL) was added to 4-nitropropene (20mL) and 4-nitropropene (20mL) was added to 5 ...

[1313] LCMS: Rt: 1.20 min (LCMS method 2); MS m / z 471.6 m / z [M+H] + .

[1314] Step 2: (S)-7-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1315] (S)-tert-Butyl 7-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (45 mg, 0.096 mmol) was dissolved in DCM (1 mL) and TFA (0.5 mL, 2.94 mmol) was added. The reaction was stirred for 2 hours and then the solvent was removed, and the residue was dissolved in DCM and washed with 1 M NaOH. The DCM layer was concentrated to produce the title intermediate (35 mg, 0.094 mmol).

[1316] LCMS: Rt: 0.51 min (LCMS method 1); MS m / z 371.4 m / z [M+H] + .

[1317] Step 3: (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1318] (S)-7-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane, ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (27 mg, 0.12 mmol) and tripotassium phosphate (26 mg, 0.12 mmol) were dissolved in a mixture of 2% aqueous TPGS-750-M (0.6 mL) and THF (0.06 mL). The reaction was processed similarly to Example 1A and the crude product was purified by preparative HPLC (XBridge Peptide BEH C18 5 μm 19 x 150 mm 40%-55% MeCN / H 2 O (5 mM NH 4 OH) 30 mL / min) and purified by FCC (0%-15% MeOH / DCM) to afford the title compound (13 mg, 0.030 mmol).

[1319] LCMS: Rt: 2.07 min (LCMS method 4); MS m / z 439.6 [M+H] + .

[1320] 1 H NMR (400MHz, CD 3 OD)δ8.38(s,1H),7.30-7.22(m,1H),7.19-7.13(m,1H),7.11-7.05(m,2H),4.37-4.2 6(m,2H),4.18(t,J=8.1Hz,2H),4.07(dd,J=8.8,6.9Hz,1H),3.91(m,2H),3.78(dd,J =8.8,7.3Hz,1H),3.35(dd,J=11.8,2.0Hz,2H),3.19-3.07(m,2H),3.00-2.77(m,2H) ,2.58(m,3H),2.38-2.07(m,3H),1.91-1.63(m,5H),1.56(m,2H),1.46-1.09(m,2H).

[1321] Example 3H: (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexan-1-ol or (1S,4r)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexan-1-ol And Example 3I: (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol or (1S,4r)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol

[1322]

[1323] Step 1: (6R)-tert-butyl 6-(4-(4'-((tert-butyldimethylsilyl)oxy)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

[1324] To a mixture of (R)-6-(4-(2-bromophenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (intermediate 3F, 219 mg, 0.487 mmol), tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-yl)oxy)silane (198 mg, 0.585 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (17.83 mg, 0.024 mmol) and potassium phosphate (310 mg, 1.462 mmol), dioxane (3 mL) and water (0.3 mL) were added. The reaction mixture was stirred at RT for 16 hours and then concentrated. The residue was added to water (50 mL) and extracted with EtOAc (x 3). The organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was then purified by FCC (0%-20% EtOAc (5% 7N NH 3 The material was then further purified by FCC (0%-5% MeOH / DCM) to give the title compound (266 mg, 0.441 mmol) as a glassy solid.

[1325] LCMS: Rt: 1.78 min (LCMS method 2); MS m / z 581.0 [M+H] + .

[1326] Step 2: (7S)-tert-butyl 7-(4-(4-fluoro-4'-hydroxy-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[1327] (7S)-tert-butyl 7-(4-(4'-((tert-butyldimethylsilyl)oxy)-4-fluoro-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (254 mg, 0.423 mmol) was dissolved in THF (3 mL) and TBAF (1 M in THF, 2.114 mL, 2.114 mmol) was added and the reaction was stirred at 40 °C for 16 hours. The reaction was concentrated and the residue was purified by FCC (0%-30% EtOAc (8% 7N NH in aqueous ammonia) 3 ) / heptane) to give the title compound (200 mg, 0.411 mmol) as a yellow oil.

[1328] LCMS: Rt: 1.11 min (LCMS method 2); MS m / z 487.6 [M+H] + .

[1329] Step 3: (S)-tert-butyl 7-(4-(5-fluoro-2-(4-hydroxycyclohexyl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[1330] (7S)-tert-butyl 7-(4-(4-fluoro-4'-hydroxy-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (200 mg, 0.411 mmol) was dissolved in MeOH (1 mL) and Pd-C (4 mg, 0.041 mmol) was added and the reaction was stirred under an atmosphere of hydrogen for 72 hours. The reaction was concentrated and the crude product was purified by FCC (0%-32% EtOAc (8% 7N NH in MeOH) 3 ) / heptane) to give the title compound (107 mg, 0.197 mmol) as a yellow oil.

[1331] LCMS: Rt: 1.11 min (LCMS method 2); MS m / z 489.5 [M+H] + .

[1332] Step 4: (S)-4-(2-(1-(5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol

[1333] To a solution of (S)-tert-butyl 7-(4-(5-fluoro-2-(4-hydroxycyclohexyl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (107 mg, 0.219 mmol) in DCM (750 μL) was added TFA (422 μL, 5.47 mmol). The reaction mixture was stirred at RT for two hours. The reaction mixture was concentrated, diluted with DCM and washed with 1 N NaOH to give the title compound (used without further purification) (91 mg, 0.181 mmol).

[1334] LCMS: Rt: 0.78 min (LCMS method 2); MS m / z 389.4 [M+H] + .

[1335] Step 5: (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol or (1S,4r)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol cyclohexane-1-ol and Example 3I: (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol

[1336] To a solution of (S)-4-(2-(1-(5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol (91 mg, 0.145 mmol) in THF (1 mL) at 0 °C was added 5-bromo-1,3,4-oxadiazole-2-carboxylic acid ethyl ester (48.0 mg, 0.174 mmol) and DIEA (0.056 mL, 0.319 mmol). The resulting suspension was stirred at RT for 2 hours, and then concentrated and diluted with EtOAc. The crude organics were washed with water and brine. The combined organics were then purified by MgSO 4The reaction mixture was dried, filtered and concentrated. The concentrated reaction mixture was diluted in THF (1 mL) and LiOH (36.5 mg, 0.869 mmol) was added in water (1 mL), and the reaction was stirred for 72 hours. Then 6N HCl (0.241 mL, 1.449 mmol) was added to the reaction mixture at -5 °C and the solution became clear. It was stirred for 2 hours at RT and then solid Na 2 CO 3 The solution was stirred for 2 hours until it became basic and then concentrated under vacuum. The residue was diluted with EtOAc and washed with brine, and the organic layer was dried over magnesium sulfate and concentrated. The crude product was purified by FCC (0%-40% EtOAc (10% 7N NH 3 ) / heptane) to give a white solid. The two diastereomers were then separated by preparative HPLC (XBridge C18 30 x 50 mm 10-30% MeCN / H 2 O (1% formic acid), 75 mL / min). The initial peak was isolated as Example 3H (27.9 mg, 0.055 mmol) (as formate salt) and the tailing peak was isolated as Example 3I (1.7 mg, 0.003 mmol) (as formate salt).

[1337] Example 3H:

[1338] LCMS: Rt: 0.97 min (LCMS method 3); MS m / z 457.5 [M+H] + .

[1339] 1 H NMR (400MHz, CD 3 OD)δ8.40(s,1H),8.32(d,J=3.6Hz,1H),7.31(dd,J=8.6,6.1Hz,1H),6.94(dd,J=10.9,2.7Hz,1H) ,6.89(td,J=8.5,2.8Hz,1H),4.41-4.27(m,2H),4.19(q,J=8.7Hz,2H),4.13-4.03(m,2H),3.94(m ,1H),3.45(dt,J=13.6,6.0Hz,1H),3.28(d,J=5.9Hz,1H),3.18-3.09(m,1H),3.03(p,J=7.8Hz,1H ),2.82(m,1H),2.62(m,3H),2.29(m,1H),2.00-1.79(m,8H),1.77-1.62(m,2H),1.53-1.42(m,2H).

[1340] Example 3I:

[1341] LCMS: Rt: 1.10 min (LCMS method 3); MS m / z 457.4 [M+H] + .

[1342] 1 H NMR (400MHz, CD 3 OD)δ8.40(s,1H),8.31(s,1H),7.26(dd,J=8.6,6.0Hz,1H),7.00-6.81(m,2 H),4.46-4.25(m,2H),4.19(q,J=8.7Hz,2H),4.15-4.02(m,2H),3.92(dd,J= 9.3,6.8Hz,1H),3.64(m,1H),3.12(m,1H),3.07-2.94(m,1H),2.91-2.73(m, 1H),2.63(m,3H),2.34-2.18(m,1H),2.13-1.98(m,2H),1.97-1.37(m,12H).

[1343] Example 4A: (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1344]

[1345] (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7A, 200 mg, 0.552 mmol) and 2-bromooxazole (98 mg, 0.66 mmol) were dissolved in dioxane (5.5 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (31.7 mg, 0.055 mmol), XantPhos (38 mg, 0.066 mmol) and sodium tert-butoxide (159 mg, 1.66 mmol). The reaction was stirred at 75 °C overnight, filtered through a celite column, rinsed with EtOAc and concentrated. The residue was purified by FCC (0%-10% MeOH (1% NH 3 ) / DCM) to afford the title compound (63 mg, 0.14 mmol) as a light yellow solid.

[1346] LCMS: Rt: 1.99 min (LCMS method 4); MS m / z 430.4 [M+H] + .

[1347] 1 H NMR (400MHz, CD 3 OD)δ7.40(d,J=1.4Hz,1H),6.96(dd,J=9.8,3.2Hz,1H),6.88-6.78(m,2H),6.49(dd,J=8.8,4.4H z,1H),5.25(m,1H),5.05-4.95(m,2H),4.68(dd,J=7.4,4.8Hz,2H),4.25-4.16(m,2H),4.13-4.0 2(m,3H),3.80-3.73(m,1H),3.16-3.03(m,3H),2.91(d,J=11.5Hz,1H),2.53(dd,J=13.0,7.4Hz, 1H), 2.32-2.19 (m, 2H), 2.13 (dd, J=12.9, 8.4Hz, 1H), 1.86 (t, J=10.2Hz, 2H), 1.81-1.64 (m, 2H).

[1348] Example 4B: (S)-7-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1349]

[1350] (S)-7-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7C, 90 mg, 0.22 mmol) and 2-bromooxazole (39 mg, 0.27 mmol) were dissolved in dioxane (2.2 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (12.7 mg, 0.022 mmol), XantPhos (15 mg, 0.027 mmol) and sodium tert-butoxide (64 mg, 0.66 mmol) and the reaction was stirred at 75 °C overnight. The reaction was filtered through a celite column, rinsed with EtOAc and concentrated. The residue was purified by FCC (0%-10% MeOH (1% NH 3 ) / DCM) to afford the title compound (32 mg, 0.064 mmol) as a light yellow solid.

[1351] LCMS: Rt: 2.12 min (LCMS method 4); MS m / z 474.4 [M+H] + .

[1352] 1 H NMR (400MHz, CD 3 OD)δ7.40(d,J=1.2Hz,1H),6.94-6.83(m,3H),6.81(d,J=1.0Hz,1H),4.26-4.15(m, 2H),4.14-4.03(m,3H),4.02-3.87(m,4H),3.87-3.68(m,4H),3.68-3.50(m,2H),3.1 6-3.06(m,2H),3.06-2.95(m,1H),2.90(d,J=11.4Hz,1H),2.53(dd,J=13.0,7.4Hz,1 H), 2.23 (m, 2H), 2.12 (dd, J = 13.0, 8.5Hz, 1H), 1.92-1.80 (m, 2H), 1.78-1.57 (m, 2H).

[1353] Example 4C: (S)-2-(Oxazol-2-yl)-7-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1354]

[1355] (S)-7-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7Q, 130 mg, 0.38 mmol) and 2-bromooxazole (67 mg, 0.45 mmol) were dissolved in dioxane (3.8 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (22 mg, 0.038 mmol), XantPhos (26 mg, 0.045 mmol) and sodium tert-butoxide (109 mg, 1.13 mmol) and the reaction was stirred at 75 °C overnight. The reaction was filtered through a pad of celite and rinsed with EtOAc and then concentrated. The residue was purified by FCC (0%-10% MeOH (1% NH 3 ) / DCM) to afford the title compound (73 mg, 0.17 mmol) as a light yellow solid.

[1356] LCMS: Rt: 1.96 min (LCMS method 4); MS m / z 412.7 [M+H] + .

[1357] 1 H NMR (400MHz, CD 3OD)δ7.40(d,J=1.0Hz,1H),7.22(dd,J=7.4,1.8Hz,1H),7.11(m,1H),6.93(m,1H),6.84-6.79(m ,1H),6.48(dd,J=8.3,1.0Hz,1H),5.27(m,1H),5.06-4.98(m,2H),4.69(dd,J=7.3,4.8Hz,2H), 4.26-4.16(m,2H),4.14-4.02(m,3H),3.76(dd,J=8.6,7.5Hz,1H),3.16-3.00(m,3H),2.90(m,1 H),2.53(dd,J=12.9,7.4Hz,1H),2.25(m,2H),2.13(dd,J=12.9,8.5Hz,1H),1.91-1.71(m,4H).

[1358] Example 4D: (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1359]

[1360] (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7D, 90 mg, 0.24 mmol) and 2-bromooxazole (42 mg, 0.29 mmol) were dissolved in dioxane (2.4 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (14 mg, 0.024 mmol), XantPhos (17 mg, 0.029 mmol) and sodium tert-butoxide (69 mg, 0.72 mmol) were added and the reaction was stirred at 75 °C overnight. The reaction was filtered through a celite column, rinsed with EtOAc and concentrated. The residue was purified by FCC (0%-10% MeOH (1% NH 3 ) / DCM) to afford the title compound (13 mg, 0.029 mmol) as a light yellow solid.

[1361] LCMS: Rt: 2.14 min (LCMS method 4); MS m / z 444.2 [M+H] + .

[1362] 1 H NMR (400MHz, CD 3OD)δ7.40(d,J=0.9Hz,1H),6.93(dd,J=9.8,2.6Hz,1H),6.90-6.84(m,2H),6.81(d,J=1.2Hz ,1H),5.01(m,1H),4.20(q,J=8.7Hz,2H),4.13-4.01(m,3H),4.01-3.84(m,4H),3.74(dd,J= 8.7,7.4Hz,1H),3.08(m,2H),3.03-2.92(m,1H),2.89(d,J=11.5Hz,1H),2.52(dd,J=12.9,7 .4Hz,1H),2.30-2.16(m,3H),2.11(dd,J=13.1,8.3Hz,2H),1.87-1.74(m,2H),1.67(m,2H).

[1363] Example 4E: (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1364]

[1365] (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7G, 90 mg, 0.23 mmol) and 2-bromooxazole (41 mg, 0.28 mmol) were dissolved in dioxane (2.3 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (13 mg, 0.023 mmol), XantPhos (16 mg, 0.028 mmol) and sodium tert-butoxide (66 mg, 0.69 mmol) were added and the reaction was stirred at 75 °C overnight. The reaction was filtered through a celite column, rinsed with EtOAc and concentrated. The residue was purified by FCC (0%-10% MeOH (1% NH 3 ) / DCM) and purified by preparative HPLC (X-Bridge Peptide BEH C18 5 μm 19 x 150 mm 40%-55% MeCN / H 2 O (10 mM NH 4 OH) 75 mL / min) to afford the title compound (12 mg, 0.026 mmol) as a white powder.

[1366] LCMS: Rt: 2.22 min (LCMS method 4); MS m / z 458.7 [M+H]+ .

[1367] 1 H NMR (400MHz, CD 3 OD)δ7.40(s,1H),6.94(m,2H),6.89-6.80(m,2H),4.52(m,1H),4.20(q,J=8.7Hz,2H),4 .14-4.01(m,3H),3.93(ddd,J=11.6,6.1,3.9Hz,2H),3.79-3.71(m,1H),3.60(ddd,J=11 .7,8.3,3.3Hz,2H),3.16-2.98(m,3H),2.95-2.85(m,1H),2.53(dd,J=12.9,7.4Hz,1H), 2.22(m,2H),2.12(dd,J=12.9,8.4Hz,1H),2.07-1.96(m,2H),1.83(m,2H),1.71(m,4H).

[1368] Example 4F: (S)-2-(Oxazol-2-yl)-7-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1369]

[1370] (S)-7-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7P, 78 mg, 0.22 mmol) and 2-bromooxazole (39 mg, 0.26 mmol) were dissolved in dioxane (2.2 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (13 mg, 0.022 mmol), XantPhos (15 mg, 0.026 mmol) and sodium tert-butoxide (63 mg, 0.65 mmol) and the reaction was stirred at 75 °C overnight. The reaction was filtered through a celite column, rinsed with EtOAc and concentrated. The residue was purified by FCC (0%-10% MeOH (1% NH 3 ) / DCM) to afford the title compound (37 mg, 0.083 mmol) as a light yellow solid.

[1371] LCMS: Rt: 2.10 min (LCMS method 4); MS m / z 426.5 [M+H] + .

[1372] 1H NMR (400MHz, CD 3 OD)δ7.40(d,J=1.0Hz,1H),7.21-7.11(m,2H),6.94-6.86(m,2H),6.81(d,J=1.2Hz ,1H),5.05(m,1H),4.25-4.16(m,2H),4.12-4.02(m,3H),4.00-3.86(m,4H),3.78-3 .71(m,1H),3.15-3.04(m,2H),2.98(m,1H),2.92-2.85(m,1H),2.53(dd,J=12.9,7. 4Hz, 1H), 2.30-2.18 (m, 3H), 2.12 (ddd, J = 13.0, 7.6, 4.8Hz, 2H), 1.87-1.66 (m, 4H).

[1373] Example 4G: (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1374]

[1375] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7NN, 90 mg, 0.22 mmol) and 2-bromooxazole (40 mg, 0.27 mmol) were dissolved in dioxane (2.2 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (13 mg, 0.022 mmol), XantPhos (16 mg, 0.028 mmol) and sodium tert-butoxide (65 mg, 0.67 mmol) and the reaction was stirred at 75 ° C overnight. The reaction was filtered through a celite column, rinsed with EtOAc and concentrated. The residue was purified by preparative HPLC (X-bridge C18 OBD 30x50mm 5μm column 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (10 mg, 0.021 mmol) as a white powder.

[1376] LCMS: Rt: 2.24 min (LCMS method 4); MS m / z 470.5 [M+H] + .

[1377] 1 H NMR (400MHz, CD 3 OD)δ7.40(s,1H),6.90(dd,J=9.8,3.0Hz,1H),6.87-6.77(m,2H),6.70(dd,J=9.0,4.6Hz,1H),4.72 (d,J=30.8Hz,4H),4.53(p,J=6.7Hz,1H),4.20(q,J=8.7Hz,2H),4.13-4.01(m,3H),3.75(dd,J=8.7, 7.4Hz,1H),3.13-3.04(m,2H),2.99-2.85(m,2H),2.85-2.76(m,2H),2.52(dd,J=13.0,7.4Hz,1H), 2.34-2.26(m,2H),2.21(m,2H),2.11(dd,J=12.9,8.5Hz,1H),1.85-1.75(m,2H),1.75-1.61(m,2H).

[1378] Example 4H: (S)-2-(Oxazol-2-yl)-7-(4-(2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1379]

[1380] (S)-7-(4-(2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7H, 78 mg, 0.22 mmol) and 2-bromooxazole (39 mg, 0.26 mmol) were dissolved in dioxane (2.2 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (12 mg, 0.022 mmol), XantPhos (15 mg, 0.026 mmol) and sodium tert-butoxide (63 mg, 0.65 mmol) and the reaction was stirred at 75 °C overnight. The reaction was filtered through a celite column, rinsed with EtOAc and concentrated. The residue was purified by FCC (0%-10% MeOH (1% NH 3 ) / DCM) was purified twice to afford the title compound (18 mg, 0.041 mmol) as a light yellow solid.

[1381] LCMS: Rt: 2.08 min (LCMS method 4); MS m / z 426.3 [M+H] + .

[1382] 1H NMR (400MHz, CD 3 OD)δ7.40(s,1H),7.21-7.12(m,2H),6.94-6.86(m,2H),6.81(s,1H),5.05(m, 1H),4.25-4.16(m,2H),4.13-4.03(m,3H),4.00-3.87(m,4H),3.78-3.72(m,1H ),3.14-3.06(m,2H),2.98(m,1H),2.89(d,J=11.4Hz,1H),2.53(dd,J=13.0,7 .4Hz,1H),2.30-2.17(m,3H),2.12(ddd,J=13.0,7.4,3.8Hz,2H),1.74(m,4H).

[1383] Example 4I: (S)-7-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1384]

[1385] (S)-7-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7DD, 70 mg, 0.22 mmol) and 2-bromooxazole (39 mg, 0.26 mmol) were dissolved in dioxane (2.2 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (12 mg, 0.022 mmol), XantPhos (15 mg, 0.026 mmol) and sodium tert-butoxide (42 mg, 0.44 mmol) and the reaction was stirred at 75 ° C overnight. The reaction was filtered through a celite column, rinsed with EtOAc and acetonitrile and then concentrated. The residue was purified by preparative HPLC (X-bridge C18 OBD 30x 50mm 5μm column 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (45 mg, 0.11 mmol) as a light yellow solid.

[1386] LCMS: Rt: 2.27 min (LCMS method 4); MS m / z 388.8 [M+H] + .

[1387] 1 H NMR (400MHz, CD 3OD)δ7.40(s,1H),6.93-6.85(m,3H),6.81(d,J=1.0Hz,1H),4.20(q,J=8.7Hz, 2H),4.12-4.02(m,3H),3.80(s,3H),3.74(dd,J=8.7,7.4Hz,1H),3.14-3.04( m,2H),2.98(tt,J=12.2,3.7Hz,1H),2.92-2.84(m,1H),2.52(dd,J=13.0,7.4 Hz, 1H), 2.21 (m, 2H), 2.11 (dd, J = 13.0, 8.5Hz, 1H), 1.80 (m, 2H), 1.69 (m, 2H).

[1388] Example 4J: (S)-2-(Oxazol-2-yl)-7-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[1389]

[1390] (S)-7-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 700, 148 mg, 0.40 mmol) and 2-bromooxazole (71 mg, 0.48 mmol) were dissolved in dioxane (5.0 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (23 mg, 0.040 mmol), XantPhos (28 mg, 0.048 mmol) and sodium tert-butoxide (115 mg, 1.19 mmol) were added and the reaction was stirred at 75 °C overnight. The reaction was filtered through a celite column, rinsed with EtOAc, and concentrated. The residue was purified by preparative HPLC (X-bridge C18 OBD 30x 50mm 5μm column 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (68 mg, 0.15 mmol) as a light yellow solid.

[1391] LCMS: Rt: 1.04 min (LCMS method 3); MS m / z 440.4 [M+H] + .

[1392] 1 H NMR (400MHz, CD 3OD)δ7.30(s,1H),7.12-6.99(m,2H),6.90-6.76(m,2H),6.72(d,J=1.0Hz,1H),4.50( tt,J=7.6,3.8Hz,1H),4.11(q,J=8.7Hz,2H),4.05-3.92(m,3H),3.84(ddd,J=11.5,6 .2,3.7Hz,2H),3.70-3.60(m,1H),3.52(ddd,J=11.4,8.1,3.3Hz,2H),3.09-2.87(m, 3H), 2.80 (m, 1H), 2.44 (dd, J = 12.8, 7.4Hz, 1H), 2.24-1.86 (m, 5H), 1.83-1.55 (m, 6H).

[1393] Example 4K: (S)-1-(4-fluoro-2-(1-(2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol

[1394]

[1395] (S)-1-(2-(1-(5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylpropan-2-ol (Intermediate 7U, 45 mg, 0.12 mmol) and 2-bromooxazole (21 mg, 0.14 mmol) were dissolved in dioxane (1.2 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (6.8 mg, 0.012 mmol), XantPhos (8.3 mg, 0.014 mmol) and sodium tert-butoxide (23 mg, 0.24 mmol) were added and the reaction was stirred at 75 °C overnight. The reaction was filtered through a celite column, rinsed with EtOAc and acetonitrile and the filtrate was concentrated. The residue was purified by FCC (0%-10% MeOH (1% NH 3 ) / DCM) to afford the title compound (25 mg, 0.053 mmol) as a light yellow solid.

[1396] LCMS: Rt: 2.09 min (LCMS method 4); MS m / z 446.6 [M+H] + .

[1397] 1 H NMR (400MHz, CD 3OD)δ7.40(s,1H),6.95-6.83(m,3H),6.81(s,1H),4.20(q,J=8.7Hz,2H),4.12-4.03(m,3H),3.75(s,3H),3.14-3.04(m,3H),2.90(dd ,J=11.4,4.4Hz,1H),2.53(dd,J=13.0,7.4Hz,1H),2.24(m,2H),2.11(dd,J=13.0,8.5Hz,1H),1.86(m,2H),1.69(m,3H),1.34(s,6H).

[1398] Example 4L: (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1399]

[1400] (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7N, 65 mg, 0.18 mmol) and 2-bromooxazole (32 mg, 0.21 mmol) were dissolved in dioxane (1.8 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (10 mg, 0.018 mmol), XantPhos (12 mg, 0.021 mmol) and sodium tert-butoxide (34 mg, 0.36 mmol) were added and the reaction was stirred at 75 ° C overnight. The reaction was filtered through a celite column, rinsed with EtOAc and acetonitrile and the filtrate was concentrated. The residue was purified by FCC (0%-7% MeOH / DCM) and by preparative HPLC (X-bridge C18 OBD 30x 50mm 5μm column 35%-60% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (25 mg, 0.057 mmol).

[1401] LCMS: Rt: 2.20 min (LCMS method 4); MS m / z 432.3 [M+H] + .

[1402] 1 H NMR (400 MHz, DMSO-d 6)δ7.57(s,1H),7.03-6.92(m,3H),6.83(d,J=0.6Hz,1H),4.13(d,J=8.5Hz,1H),4.09-4.01(m,5H),3.96-3.89(m,2H),3.68 -3.63(m,2H),3.62-3.56(m,1H),3.03-2.73(m,5H),2.42-2.34(m,1H),2.11-1.96(m,4H),1.80-1.64(m,2H),1.57(m,2H).

[1403] Example 4M: (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1404]

[1405] (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7II, 110 mg, 0.29 mmol) and 2-bromooxazole (51 mg, 0.34 mmol) were dissolved in dioxane (2.9 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (16 mg, 0.029 mmol), XantPhos (20 mg, 0.034 mmol) and sodium tert-butoxide (82 mg, 0.86 mmol) were added and the reaction was stirred at 75 °C overnight. The reaction was filtered through a celite column, rinsed with EtOAc and concentrated. The residue was purified by FCC (0%-10% MeOH (1% NH 3 ) / DCM) and purified by preparative HPLC (X-bridge C18 OBD 30x 50mm 5μm column 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (9.5 mg, 0.021 mmol).

[1406] LCMS: Rt: 2.18 min (LCMS method 4); MS m / z 452.4 [M+H] + .

[1407] 1 H NMR (400MHz, CD 3OD)δ7.40(d,J=1.0Hz,1H),7.19-7.06(m,2H),6.88(dd,J=8.1,6.9Hz,1H),6.81(d,J=1.0Hz,1H) ,6.72(d,J=8.2Hz,1H),4.72(d,J=31.9Hz,4H),4.62-4.52(m,1H),4.21(q,J=8.8Hz,2H),4.11(s, 3H),3.75(t,J=8.1Hz,1H),3.15-3.04(m,2H),3.02-2.85(m,2H),2.85-2.77(m,2H),2.53(dd,J=1 2.9,7.4Hz,1H),2.37-2.26(m,2H),2.26-2.16(m,2H),2.12(dd,J=12.9,8.5Hz,1H),1.76(m,4H).

[1408] Example 4N: (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1409]

[1410] (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7X, 52 mg, 0.17 mmol) and 2-bromooxazole (31 mg, 0.21 mmol) were dissolved in dioxane (1.7 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (9.9 mg, 0.017 mmol), XantPhos (12 mg, 0.021 mmol) and sodium tert-butoxide (31 mg, 0.34 mmol) were added and the reaction was stirred at 75 °C overnight. The reaction was filtered through a celite column, rinsed with EtOAc and acetonitrile and concentrated. The residue was purified by preparative HPLC (X-bridge C18 OBD 30x 50mm 5μm column 35%-60% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (9.4 mg, 0.024 mmol).

[1411] LCMS: Rt: 2.19 min (LCMS method 4); MS m / z 370.3 [M+H] + .

[1412] 1 H NMR (400MHz, CD3 OD)δ7.40(d,J=1.3Hz,1H),7.21-7.10(m,2H),6.89(dd,J=14.1,7.7Hz,2H),6 .81(d,J=1.0Hz,1H),4.32-4.13(m,2H),4.14-4.01(m,3H),3.81(s,3H),3.80- 3.70(m,1H),3.08(t,J=7.7Hz,3H),2.88(d,J=11.9Hz,1H),2.52(dd,J=13.0,7 .4Hz,1H),2.27-2.17(m,2H),2.12(dd,J=13.1,8.4Hz,1H),1.90-1.66(m,4H).

[1413] Example 4O: (S)-7-(4-(4,5-difluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1414]

[1415] (S)-7-(4-(4,5-difluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7JJ, 100 mg, 0.254 mmol) and 2-bromooxazole (45 mg, 0.30 mmol) were dissolved in dioxane (2.5 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (15 mg, 0.025 mmol), XantPhos (18 mg, 0.030 mmol) and sodium tert-butoxide (73 mg, 0.76 mmol) and the reaction was stirred at 75 °C overnight. The reaction was filtered through a celite column, rinsed with EtOAc and concentrated. The residue was purified by FCC (0%-10% MeOH (1% NH 3 ) / DCM) and purified by preparative HPLC (X-bridge C18 OBD 30x 50mm 5μm column 25%-50% MeCN / H 2 O (5 mM NH 4 OH) 75 mL / min) to afford the title compound (20 mg, 0.041 mmol).

[1416] LCMS: Rt: 2.15 min (LCMS method 4); MS m / z 462.3 [M+H] + .

[1417] 1H NMR (400MHz, CD 3 OD)δ7.40(d,J=1.3Hz,1H),7.08(dd,J=11.9,9.1Hz,1H),6.94(dd,J=12.6,6.9Hz,1H),6.81( s,1H),4.93-4.87(m,2H),4.63(t,J=6.1Hz,2H),4.26-4.11(m,4H),4.11-3.99(m,3H),3.74( dd,J=8.7,7.4Hz,1H),3.47(m,1H),3.15-3.04(m,2H),3.04-2.91(m,1H),2.88(m,1H),2.51( dd,J=12.9,7.4Hz,1H),2.21(m,2H),2.11(dd,J=13.0,8.5Hz,1H),1.82(m,2H),1.66(m,2H).

[1418] Example 4P: (S)-7-(4-(4,5-difluoro-2-((3-fluorooxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[1419]

[1420] (S)-7-(4-(4,5-difluoro-2-((3-fluorooxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (Intermediate 7KK, 100 mg, 0.242 mmol) and 2-bromooxazole (43 mg, 0.29 mmol) were dissolved in dioxane (2.5 mL) and the mixture was purged with nitrogen. Pd was added 2 (dba) 3 (14 mg, 0.024 mmol), ...

Claims

1. A compound according to formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is a halogen or hydrogen; R 2 is a halogen or hydrogen; R 3 yes Optionally substituted C 1-3 alkyl, which is optionally substituted with a 4- to 6-membered heterocycloalkyl, Optionally substituted 5- to 6-membered heteroaryl, the heteroaryl group is optionally substituted with one C 1-3 Alkyl substitution, optionally substituted 4 to 6 membered heterocycloalkyl, said heterocycloalkyl being optionally substituted with one -OH, optionally substituted 4 to 6 membered cycloalkyl, said cycloalkyl being optionally substituted with one -OH, or -OR 4 ; R 4 yes Optionally substituted C 1-5 Alkyl, the alkyl group is optionally replaced by one or two R 6 replace, An optionally substituted 3 to 9 membered heterocycloalkyl group, the heterocycloalkyl group being optionally substituted by one or two R 6 Replace, or An optionally substituted 4- to 6-membered cycloalkyl group, the cycloalkyl group being optionally substituted by one, two or three R 6 replace; R 5 is a halogen or hydrogen; Each R 6 Independently halogen, -OH, -OCH3, -C(CH3)2OH, -CH2OH, Cyano, Optionally substituted C1-C4 alkyl, said alkyl being optionally substituted by -OH, An optionally substituted 4 to 7 membered heterocycloalkyl group, the heterocycloalkyl group being optionally substituted by one or two substituents independently selected from the group consisting of halogen, -OH, -OCH3 and C 1-3 Alkyl, or Optionally substituted 5- to 6-membered heteroaryl, the heteroaryl group is optionally substituted with one C 1-3 Alkyl substituted; and R 7 It is a 5-membered heteroaryl.

2. The compound according to claim 1, which has formula (Ia) or a pharmaceutically acceptable salt or stereoisomer thereof.

3. The compound according to claim 1, which has the formula (Ib) or a pharmaceutically acceptable salt or stereoisomer thereof.

4. The compound according to any one of claims 1 to 3, wherein R 1 Selected from the group consisting of: H, chlorine and fluorine.

5. The compound according to any one of claims 1 to 4, wherein R 1 It's fluorine.

6. The compound according to any one of claims 1 to 5, wherein R 2 It is H or fluorine.

7. The compound according to any one of claims 1 to 6, wherein R 5 It is H or fluorine.

8. The compound according to any one of claims 1 to 3, wherein R 1 , R 2 and R 5 It's H.

9. The compound according to any one of claims 1 to 3, wherein R 2 and R 5 It's H.

10. The compound according to any one of claims 1 to 9, wherein R 3 Selected from the group consisting of:

11. The compound according to any one of claims 1 to 9, wherein R 3 is - OR 4 。 12. The compound according to any one of claims 1 to 11, wherein R 4 Selected from the group consisting of CH3, -CH2CH2C(CH3)2OH, -CH2CH2C(CH3)2OCH3, -CH2CH2OCH3 and -CH2C(CH3)2OH.

13. A compound according to any one of claims 1 to 11, wherein R 4 Selected from the group consisting of:

14. A compound according to any one of claims 1 to 11, wherein R 4 is a C1-C5 alkyl group and R 6 are independently cyano, -OH, -OCH3, 15. A compound according to any one of claims 1 to 14, wherein R 7 Selected from the group consisting of:

16. A compound selected from the group consisting of: (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; 5-((S)-7-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylic acid ethyl ester; (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-3-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2,2-dimethylpropionitrile; (S)-7-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(3-methoxy-3-methylbutyloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-((1,3-dioxan-5-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-4-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylbutan-2-ol; (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(4,5-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-4-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-5-fluorophenoxy)-2-methylbutan-2-ol; (S)-1-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylpropan-2-ol; (S)-7-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(pyrimidin-5-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(oxazol-2-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((3-methyloxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(((R)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate; (S)-7-(4-(5-fluoro-2-(((S)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate; (S)-7-(4-(5-fluoro-2-(((R)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate; (S)-7-(4-(5-fluoro-2-(((S)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane trifluoroacetate; (S)-7-(4-(5-fluoro-2-((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((3-methylisoxazol-5-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(pyrimidin-2-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((3-fluorooxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((3-methyloxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-(((R)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-(((S)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-(((R)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-(((S)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-((3-ethyloxetan-3-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(((S)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(((R)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(((S)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(((R)-tetrahydro-2H-pyran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-((5-ethyl-1,3,4-thiadiazol-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-3-((2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)methyl)oxetan-3-ol; 2-((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol; 2-((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol; 2-((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol; 2-((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol; (S)-7-(4-(5-fluoro-2-((S)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((R)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((S)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((R)-1-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (7S)-7-(4-(2-((3-oxabicyclo[3.1.0]hexan-6-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-3,5-difluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(3,5-difluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(3,5-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(3,5-difluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(3,5-difluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(4,5-difluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(4,5-difluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; ((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol; ((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol; ((1S,3r)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol; ((1R,3s)-3-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)methanol; (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((R)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((S)-tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-2-(1,3,4-oxadiazol-2-yl)-7-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol; (1S,4r)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol; (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol; (1S,4r)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol; (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol; (1S,4r)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol; (1R,4s)-4-(2-(1-((S)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexane-1-ol; (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-2-(oxazol-2-yl)-7-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-2-(Oxazol-2-yl)-7-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-2-(Oxazol-2-yl)-7-(4-(2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-2-(Oxazol-2-yl)-7-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-1-(4-fluoro-2-(1-(2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol; (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(4,5-difluoro-2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(4,5-difluoro-2-((3-fluorooxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(4,5-difluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-2-(oxazol-2-yl)-7-(4-(2-(pyrimidin-5-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(4-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; 2-((1R,3s)-3-(4-fluoro-2-(1-((S)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)cyclobutyl)propan-2-ol; 2-((1S,3r)-3-(4-fluoro-2-(1-((S)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)cyclobutyl)propan-2-ol; 2-((1R,3s)-3-(4-fluoro-2-(1-((S)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)cyclobutyl)propan-2-ol; 2-((1S,3r)-3-(4-fluoro-2-(1-((S)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)cyclobutyl)propan-2-ol; (S)-2-(Oxazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-1-(2-(1-(2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylpropan-2-ol; (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(4,5-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(3-methoxy-3-methylbutyloxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-4-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylbutan-2-ol; (S)-7-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane carboxylate; (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-1-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylpropan-2-ol; (S)-4-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-5-fluorophenoxy)-2-methylbutan-2-ol; (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-1-(2-(1-(2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol; (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(1,2,4-oxadiazol-3-yl)-5-oxa-2-azaspiro[3.4]octane; (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,2,4-oxadiazol-3-yl)-5-oxa-2-azaspiro[3.4]octane; and (S)-7-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,2,4-oxadiazol-3-yl)-5-oxa-2-azaspiro[3.4]octane.

17. The compound according to claim 16, wherein The compound is selected from the group consisting of: (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure: (R)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure: (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure: as well as (S)-2-(Oxazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure: or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 16, wherein The compound is (S)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure: or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 16, wherein The compound is (R)-7-(4-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure: or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 16, wherein The compound is (S)-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure: or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 16, wherein The compound is (S)-2-(oxazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane, which has the following structure: or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

23. A method for treating an M4-related condition, disease or disorder, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

24. A method for treating a psychosis, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof to a patient in need of treatment thereof.

25. The method according to claim 24, wherein: The psychosis is associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease or frontotemporal dementia.

26. The method according to claim 25, wherein: The psychosis is associated with Alzheimer's disease.

27. A method for treating cognitive dysfunction, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof to a subject in need of treatment thereof.

28. A method for treating a hyperkinetic movement disorder, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

29. A method for treating a substance use disorder, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof to a subject in need of treatment thereof.

30. A method of treating a condition, disease or disorder that is treated with an M4 receptor agonist, the method comprising administering to a subject in need thereof a therapeutically effective amount of an antidepressant and a compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof.

31. A method for treating a condition, disease or disorder that is treated with an M4 receptor agonist, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof, in combination with a computer-assisted psychosocial or behavioral therapy.

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