RU2820477C1 - 5-oxa-2-azaspiro[3.4]octane derivatives as m4 agonists - Google Patents

Abstract

FIELD: chemistry; pharmaceutics.

SUBSTANCE: invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, where R¹ is halogen or hydrogen; R² is halogen or hydrogen; R³ is optionally substituted C_1-3alkyl, wherein said alkyl is optionally substituted with tetrahydropyranyl, optionally substituted 5–6 membered heteroaryl selected from the group consisting of pyrimidinyl, 1,3,4-oxadiazolyl and oxazolyl, wherein said heteroaryl is optionally substituted with one C_1-3alkyl, optionally substituted 4–6 membered heterocycloalkyl selected from the group consisting of tetrahydrofuranyl and tetrahydropyranyl, wherein said heterocycloalkyl is optionally substituted with one -OH, optionally substituted 4–6 membered cycloalkyl, wherein said cycloalkyl is optionally substituted with one -OH; or -OR⁴; R⁴ is optionally substituted C_1-5alkyl, wherein said alkyl is optionally substituted with one or two R⁶, optionally substituted 3–9 membered heterocycloalkyl selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxanyl and 2-oxaspiro[3.3]heptanyl, wherein said heterocycloalkyl is optionally substituted with one or two R⁶, or optionally substituted 4–6 membered cycloalkyl, wherein said cycloalkyl is optionally substituted with one, two or three R⁶; R⁵ is halogen or hydrogen; each R⁶ independently represents a halogen, -OH, -OCH₃, -C(CH₃)₂OH, -CH₂OH, cyano, optionally substituted C_1-4alkyl, wherein said alkyl is optionally substituted with -OH, optionally substituted 4–7 membered heterocycloalkyl, selected from the group consisting of tetrahydrofuranyl, 1,4-dioxanyl, tetrahydropyranyl, oxetanyl, 2-oxaspiro[3.3]heptanyl and 3-oxabicyclo[3.1.0]hexanyl, wherein said heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, -OH, -OCH₃ and C_1-3 alkyl, or optionally substituted 5–6 membered heteroaryl selected from the group consisting of 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, pyrimidinyl and 1,2,4-oxadiazolyl, wherein said heteroaryl is optionally substituted with one C_1-3alkyl; and R⁷ is 5-membered heteroaryl selected from the group consisting of 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl and 1,2,4-oxadiazolyl. Invention also relates to a pharmaceutical composition containing a compound of formula (I) and to the use of the compound of formula (I) for the treatment of psychosis associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease or frontotemporal dementia.

EFFECT: compound of formula (I) used as an M4 receptor agonist.

24 cl, 3 dwg, 122 ex, 12 tbl

Description

1. CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Application No. 62/912986, filed October 9, 2019, the disclosure of which is incorporated herein by reference in its entirety.

2. TECHNICAL FIELD OF THE INVENTION

Provided herein are novel 2-azaspiro[3.4]octane-based compounds that act as M4 receptor agonists, as well as pharmaceutical compositions thereof, routes of use for the treatment of conditions, diseases and disorders associated with the M4 receptor, which include without limitations psychosis, hyperkinetic movement disorders, cognitive dysfunction and substance use disorders.

3. BACKGROUND OF THE ART

Acetylcholine, a major neurotransmitter in the central and peripheral nervous system, transmits signals by activating its ionotropic (nicotinic) and G protein-coupled (muscarinic) receptors. Five muscarinic receptors (M1-M5) with differences in expression and signal transduction have been identified. M1, M3 and M5 receptors are associated with Gq proteins, which activate phospholipase C. Phospholipase C hydrolyzes membrane phosphoinositides to inositol triphosphate (IP ₃ ) and diacylglycerol (DAG), which increase intracellular calcium and activate a number of signal transduction pathways. M2 and M4 receptors are associated with G _{i /o} proteins, which inhibit the production of adenylate cyclase and reduce cyclic adenosine monophosphate (cAMP) levels, having a suppressive effect on cell function. M1 receptors are predominantly expressed in the forebrain (cerebral cortex, hippocampus, striatum and thalamus) and salivary glands ( Brain Res Mol Brain Res 2005 , 133(1):6-11; Br. J. Pharmacol 2006 , 148, 565- 578; Pharmacol Ther 2008 , 117: 232-243). M2 receptors are expressed in the brain and are also expressed at high levels in the heart, where they mediate innervation of the vagus nerve and can influence heart rate ( Br. J. Pharmacol 2006 , 148, 565-578; Pharmacol Ther 2008 , 117:232 -243). M3 receptors are primarily expressed in smooth muscle of peripheral tissues, including the gastrointestinal tract, bladder, eye, and sweat and salivary glands ( Br. J. Pharmacol 2006 , 148, 565-578). M4 receptors are present in increased numbers in the brain and are primarily expressed in the striatum, a region of the brain involved in dopamine release and dopamine 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 in the vasculature, including cerebral blood vessels ( Proc Natl Acad Sci USA 2001, 98(24):14096-14101).

In the central nervous system, muscarinic receptors have been shown to play a central role in cognitive function and the regulation of dopaminergic signaling ( Neuron 2017 , 94(3): 431-446). Of particular interest are the M4 receptors, which are expressed at high levels in the striatum. Genetic deletion of M4 receptors causes a hyper-dopaminergic phenotype in rodents. M4 knockout mice have been shown to have increased dopamine levels in the striatum and increased locomotor activity ( Proc Natl Acad Sci USA 1999 , 96(18): 10483-10488; FASEB J 2004 , 18(12):1410-1412) . Consistent with such observations, pharmacological activation of M4 receptors reduces amphetamine-induced dopamine release and reverses amphetamine-induced hyperlocomotion in mice ( Neuropsychopharm 2004, 39: 1578-1593). Thus, such results indicate that M4 receptors may act as a negative regulator of dopamine release and dopamine signaling in the striatum.

Elevated dopamine levels in the striatum are strongly associated with psychotic symptoms in schizophrenia and other disorders, including psychotic depression, bipolar disorder, Huntington's disease, and Alzheimer's disease ( Lancet 1988, 2:119-125; Schizophr Bull 2009 , 35:549-562 ). Modern antipsychotic medications work primarily by blocking the effects of dopamine on D2 receptors. However, they are characterized by limited effectiveness and dangerous side effects, including drug-induced parkinsonism, tardive dyskinesia, Q-Tc prolongation, weight gain and metabolic syndrome, which lead to poor patient compliance with drug instructions ( N Engl J Med 2005 , 353:1209-23).

Activation of M4 muscarinic receptors has been shown to suppress dopamine signaling in the striatum and may thereby provide an alternative treatment for psychosis. In support of this idea, the muscarinic receptor agonist xanomeline demonstrated consistent antipsychotic efficacy when tested in two clinical trials in patients suffering from Alzheimer's disease (Arch Neurol 1997, 54(4):465-473) and schizophrenia (Am J Psychiatry 2008, 165(8):1033-1039). However, its treatment was associated with a number of side effects, including nausea, vomiting, excessive salivation, dyspepsia and fever, which stopped its clinical trials. Xanomeline is a general muscarinic receptor agonist that activates all muscarinic receptor subtypes. Research indicates that the antipsychotic efficacy of xanomeline is primarily mediated by activation of M4 receptors. M4 receptors are expressed at high levels in the human striatum (Schizophr Res 2015, 169: 83–88.), and the antipsychotic-like effects of xanomeline on dopamine-mediated behaviors are limited 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, which are expressed in the heart, digestive tract, and salivary glands (CNS Drug Rev 2003, 9:159-186; Br. J. Pharmacol 2006, 148, 565-578). Thus, selective M4 agonists likely retain the antipsychotic efficacy of xanomeline without producing cholinergic side effects.

Therefore, compounds that act as M4 receptor agonists may be useful for treating M4-related conditions.

4. SUMMARY OF THE INVENTION

In one embodiment, provided herein is a compound of formula (I),

(I),

or a pharmaceutically acceptable salt thereof, wherein

R ¹ represents halogen or hydrogen;

R ² represents halogen or hydrogen;

R ³ represents

optionally substituted C _1-3 alkyl, wherein said alkyl is optionally substituted with one 4-6 membered heterocycloalkyl,

optionally substituted 5-6 membered heteroaryl, wherein said heteroaryl is optionally substituted with one C _1-3 alkyl, 4-6 membered heterocycloalkyl or

-OR ⁴ ;

R ⁴ represents

optionally substituted C _1-5 alkyl, wherein said alkyl is optionally substituted with one or two R ⁶ ,

optionally substituted 3-9 membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or two R ⁶ , or

optionally substituted 4-6 membered cycloalkyl, wherein said cycloalkyl is optionally substituted with one, two or three R ⁶ ;

R ⁵ represents halogen or hydrogen;

each R ⁶ independently represents

halogen,

-OH,

-OCH ₃ ,

-C(CH ₃ ) ₂ OH,

-CH ₂ OH,

cyano,

optionally substituted C ₁ -C ₄ alkyl, wherein said alkyl is optionally substituted -OH,

optionally substituted 4-7 membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, -OH, -OCH ₃ and C _1-3 alkyl, or

optionally substituted 5-6 membered heteroaryl, wherein said heteroaryl is optionally substituted with one C _1-3 alkyl; And

R ⁷ is a 5-membered heteroaryl.

In one embodiment, provided herein is a compound of formula (Ia),

(Ia),

or a pharmaceutically acceptable salt or stereoisomer thereof.

In one embodiment, provided herein is a compound of formula (Ib)

(Ib),

or a pharmaceutically acceptable salt or stereoisomer thereof.

In one embodiment, R ¹ is selected from the group consisting of H, chlorine and fluorine. In another embodiment, R ¹ is fluorine.

In one embodiment, R ² is H or fluorine.

In one embodiment, R ⁵ is H or fluorine.

In one embodiment, ^R1 , ^R2 and ^R5 are H.

In one embodiment, ^R2 and ^R5 are H.

In one embodiment, R ³ is selected from the group consisting of: , , , , , , And . In some embodiments, R ³ is -OR ⁴ .

In one embodiment, R ⁴ is 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 is selected from the group consisting of:

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

In another embodiment, R ⁴ is C ₁ -C ₅ alkyl and R ⁶ is an independent cyano group, -OH, -OCH ₃ . , , , , , , , , , , , , , , , , , , And .

In one embodiment, R ⁷ is selected from the group consisting of: , , , And .

In one embodiment, provided herein is a compound of formula (I),

(I),

or a pharmaceutically acceptable salt thereof, wherein

R ¹ represents halogen or hydrogen;

R ² represents halogen or hydrogen;

R ³ represents

optionally substituted C _1-3 alkyl, wherein said alkyl is optionally substituted with one 4-6 membered heterocycloalkyl,

optionally substituted 5-6-membered heteroaryl, wherein said heteroaryl is optionally substituted with one C _1-3 alkyl,

optionally substituted 4-6-membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one -OH,

optionally substituted 4-6 membered cycloalkyl, wherein said cycloalkyl is optionally substituted with one -OH; or

-OR ⁴ ;

R ⁴ represents

optionally substituted C _1-5 alkyl, wherein said alkyl is optionally substituted with one or two R ⁶ ,

optionally substituted 3-9 membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or two R ⁶ , or

optionally substituted 4-6 membered cycloalkyl, wherein said cycloalkyl is optionally substituted with one, two or three R ⁶ ;

R ⁵ represents halogen or hydrogen;

each R ⁶ independently represents

halogen,

-OH,

-OCH ₃ ,

-C(CH ₃ ) ₂ OH,

-CH ₂ OH,

cyano,

optionally substituted C ₁ -C ₄ alkyl, wherein said alkyl is optionally substituted -OH,

optionally substituted 4-7 membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, -OH, -OCH ₃ and C _1-3 alkyl, or

optionally substituted 5-6 membered heteroaryl, wherein said heteroaryl is optionally substituted with one C _1-3 alkyl; And

R ⁷ is a 5-membered heteroaryl.

In one embodiment, provided herein is a compound of formula (Ia),

(Ia),

or a pharmaceutically acceptable salt or stereoisomer thereof.

In one embodiment, provided herein is a compound of formula (Ib)

(Ib),

or a pharmaceutically acceptable salt or stereoisomer thereof.

In one embodiment, R ¹ is selected from the group consisting of H, chlorine and fluorine. In another embodiment, R ¹ is fluorine.

In one embodiment, R ² is H or fluorine.

In one embodiment, R ⁵ is H or fluorine.

In one embodiment, ^R1 , ^R2 and ^R5 are H.

In one embodiment, ^R2 and ^R5 are H.

In one embodiment, R ³ is selected from the group consisting of: , , , , , , And . In some embodiments, R ³ is -OR ⁴ .

In one embodiment, R ⁴ is 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 is selected from the group consisting of:

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

In another embodiment, R ⁴ is C ₁ -C ₅ alkyl and R ⁶ is an independent cyano group, -OH, -OCH ₃ . , , , , , , , , , , , , , , , , , , And .

In one embodiment, R ⁷ is selected from the group consisting of: , , , And .

In one embodiment, provided herein is a compound that is 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;

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-oxadiazol-2-carboxylate;

(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-dimethylpropanenitrile;

(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-methylbutoxy)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;

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

(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-fluoroxetan-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]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazole -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]heptan-6-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazole -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]octane- 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]octane- 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]octane- 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]octane- 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]heptan-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]octane-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]octane-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]octane-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]octane-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)cyclohexan-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)cyclohexan-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)cyclohexan-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)cyclohexan-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)cyclohexan-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)cyclohexan-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)cyclohexan-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]heptan-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]heptan-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-fluoroxetan-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]octane-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]octane-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]octane-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]octane-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-methylbutoxy)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;

formate salt (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;

(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]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-thiadiazole -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-oxapiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,2,4-oxadiazole -3-yl)-5-oxa-2-azaspiro[3.4]octane, or a pharmaceutically acceptable salt thereof.

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

(S)-7-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazole -2-yl)-5-oxa-2-azaspiro[3.4]octane, having the following structure:

;

(R)-7-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazole -2-yl)-5-oxa-2-azaspiro[3.4]octane, having 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 having the following structure:

; And

(S)-2-(oxazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[ 3.4]octane having the following structure:

, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound is (S)-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, having the following structure: , or a pharmaceutically acceptable salt thereof.

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, having the following structure:

, or a pharmaceutically acceptable salt thereof.

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, having the following structure:

, or a pharmaceutically acceptable salt thereof.

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, having the following structure:

, or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a pharmaceutical composition containing a compound provided herein or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a method of 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 of such treatment.

In one embodiment, provided herein is a method of treating psychosis, comprising administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment. 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, psychosis is associated with Alzheimer's disease.

In one embodiment, provided herein is a method of treating cognitive dysfunction, comprising administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment. 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, cognitive dysfunction is associated with Alzheimer's disease.

In one embodiment, provided herein is a method of treating a hyperkinetic movement disorder, comprising administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment. In some embodiments, 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, hyperkinetic movement disorder is associated with Alzheimer's disease. In some embodiments, the hyperkinetic movement disorder is Tourette's syndrome, chorea, or tardive dyskinesia.

In one embodiment, provided herein is a method of treating substance use disorders, comprising administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

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

In one embodiment, provided herein is a method of treating a condition, disease, or disorder that is treatable with an M4 receptor agonist, 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 .

In one embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy. In a further embodiment, the therapy is selected for a condition, disease or disorder that is treatable with an M4 receptor agonist.

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

In another embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in psychosis. 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, psychosis is associated with Alzheimer's disease.

In one embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for 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, cognitive dysfunction is associated with Alzheimer's disease.

In one embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for hyperkinetic movement disorder. In some embodiments, 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, hyperkinetic movement disorder is associated with Alzheimer's disease. In some embodiments, the hyperkinetic movement disorder is Tourette's syndrome, chorea, or tardive dyskinesia.

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

In one embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a condition, disease or disorder that is treatable with an M4 receptor agonist. In embodiments, use is carried out in combination with computer-assisted psychosocial and behavioral therapy.

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 medicinal product. In a further embodiment, the medicinal product is for treating a condition, disease or disorder that is treatable with an M4 receptor agonist. In another embodiment, the condition, disease, or disorder is a psychosis, including, but not limited to, psychosis associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, and frontotemporal dementia.

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 the treatment of hyperkinetic movement disorder. In some embodiments, 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, hyperkinetic movement disorder is associated with Alzheimer's disease.

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 the treatment of 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, cognitive dysfunction is associated with Alzheimer's disease.

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 the treatment of substance use disorders.

5. BRIEF DESCRIPTION OF GRAPHIC MATERIALS

In fig. 1 demonstrates the effect of Example 1A and Example 2L on hyperactivity in mice induced by the stimulant d-amphetamine using an amphetamine-induced hyperlocomotion assay in mice.

In fig. 2 demonstrates the effect of Example 3C and Example 3D on hyperactivity in mice induced by the stimulant d-amphetamine using an amphetamine-induced hyperlocomotion assay in mice.

In fig. 3 demonstrates the effect of Example 4A and Example 5G on the stimulant d-amphetamine-induced hyperactivity in mice using an amphetamine-induced hyperlocomotion assay in mice.

6. DETAILED DESCRIPTION

1. Definitions

"Alkyl" as used herein refers to a monovalent saturated hydrocarbon chain containing the specified number of carbon atoms. For example, C _1-3 alkyl refers to an alkyl group containing from 1 to 3 carbon atoms. Alkyl groups may optionally be substituted with one or more substituents as defined in formula (I). Alkyl groups can be straight or branched. Typical branched alkyl groups contain 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.

"Cycloalkyl" as used herein refers to a saturated hydrocarbon ring system containing the specified number of carbon atoms. Cycloalkyl groups are monocyclic or bicyclic ring systems. For example, C _3-7 cycloalkyl refers to a cycloalkyl group containing from 3 to 7 carbon atoms. Cycloalkyl groups may be optionally substituted with one or more substituents as defined in formula (I). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

"Halogen" or "halogen" as used herein refers to the group of fluorine, chlorine or bromine.

“Haloalkyl” as used herein refers to an alkyl group containing a specified number of carbon atoms, where at least one hydrogen atom attached to the carbon atom in the alkyl group is replaced by a halogen atom. The number of substituents representing a halogen atom includes, but is not limited to, 1, 2, 3, 4, 5 or 6 substituents. Haloalkyl includes, but is not limited to, monofluoromethyl, difluoroethyl and trifluoromethyl.

"Heteroaryl" as used herein refers to an aromatic ring system containing one or more heteroatoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined in formula (I). Heteroaryl groups can be monocyclic ring systems or fused bicyclic ring systems. Monocyclic heteroaryl rings contain 5 to 6 ring atoms. Bicyclic heteroaryl rings contain from 8 to 10 atoms in their composition. Bicyclic heteroaryl rings include those ring systems where 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, furanzanyl, thienyl, triazolyl, pyridinyl (including 2-, 3- and 4-pyridinyl), pyrimidinyl, pyridazinyl, pyrazinyl, trazinyl, tetrazinyl, tetrazolyl, indonyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzimidazolyl, benzopyranyl, benzopyranyl, benzoxazolyl, benzoisoxazolyl, benzofuranyl, benzothiazolyl, benzothienyl, naphthyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, imidazo[ 2,1-b][1,3,4]thiadiazolyl, etc.

“5-6 membered heteroaryl” as used herein refers to a heteroaryl group as defined above having 5 or 6 ring atoms and containing 1-4 heteroatoms. Examples of the 5-6 membered heteroaryl 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, etc.

"Heteroatom" as used herein refers to a nitrogen, oxygen or sulfur atom.

"Heterocyclic group" or "heterocycloalkyl" as used herein 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. Heterocyclic groups include ring systems where the sulfur atom is oxidized to form SO or SO ₂ . Heterocyclic groups may be optionally substituted with one or more substituents as defined in formula (I). Heterocyclic groups are monocyclic, bicyclic, spiro- or fused or bridged bicyclic ring systems. Monocyclic heterocyclic rings contain 3-7 ring atoms. Examples of monocyclic heterocyclic groups include pyranyl, tetrahydropyranyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, tetrahydropyranyl, hydropyranyl , oxathiolanyl, dithiolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dithianyl, oxathianyl, thiomorpholinyl, tetrahydrothiopyran-1,1-dioxide, 1,4-diazepanyl, etc. Examples of bicyclic heterocyclic groups include 3-oxabicyclo[3.1.0]hexane, etc. Examples of bridging heterocyclic groups include 2-azabicyclo[2.2.1]heptanyl, etc. Examples of spiroheterocyclic groups include 2-oxaspiro[3.3]heptanyl, etc. .

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

“5-6 membered heterocyclic group” or “5-6 membered heterocycloaryl” as used herein refers to a heterocyclic group as defined above having 5 to 6 ring atoms and containing 1 to 3 heteroatoms. Examples of the 5-6 membered heterocyclic group include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, 1,4-diazepanyl, 3-oxabicyclo[3.1.0]hexanyl, and the like.

“3-9 membered heterocyclic group” or “3-9 membered heterocycloaryl” as used herein refers to a heterocyclic group as defined above having 3 to 9 ring atoms and containing 1 to 3 heteroatoms. Examples of the 3-9 membered heterocyclic group include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, 1,4-diazepanyl, 2-oxaspiro[3.3]heptanyl, 3-oxabicyclo[3.1.0]hexanyl, and the like.

"Optionally substituted" as used herein indicates that a group, such as an alkyl, heteroaryl and heterocyclic group, may be unsubstituted or the group may be substituted by one or more substituents as defined in formula (I).

“Salt” or “salts” as used herein refer to the acid addition or base addition salt of a compound provided herein. "Salts" include in particular "pharmaceutically acceptable salts". "Pharmaceutically acceptable salts" as used herein refer to salts that retain the biological effectiveness and properties of the compounds of Formula (I) and that are generally not biologically or otherwise undesirable. In many cases, the compounds according to formula (I) are capable of forming salts with an acid and/or a base due to the presence of amino groups and/or carboxyl groups or the like. One skilled in the art will appreciate that salts, including pharmaceutically acceptable salts, of the compounds of formula (I) can be prepared. Such salts may be prepared in situ during the final isolation and purification of the compound or by separately reacting the purified compound in its free acid or base form with a suitable base or acid, respectively.

Pharmaceutically acceptable acid addition salts can be formed using inorganic acids and organic acids. Inorganic acids from which salts can be prepared include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be prepared 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.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases, such as carboxylate, sulfonate and phosphate salts.

In certain embodiments, compounds of formula (I) are provided herein in the salt form of acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenate, trifluoroacetate or xinafoate. In certain embodiments, compounds of formula (I) are provided herein in formate or citrate salt form.

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

"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 a substituent may be attached at the chiral center of the carbon atom. Therefore, the compounds provided herein include enantiomers, diastereomers or racemates of the compound.

Depending on the choice of starting materials and procedures, the compounds according to formula (I) may be in the form of one of the possible stereoisomers or in the form of mixtures thereof, for example, in the form of pure optical isomers, or in the form of mixtures of stereoisomers, such as racemates and mixtures of diastereoisomers , depending on the number of asymmetric carbon atoms. The compounds of formula (I) provided herein are intended to include all such possible stereoisomers, including racemic mixtures, mixtures of diastereoisomers, and optically pure forms. Optically active ( R )- and ( S )-stereoisomers can be prepared using chiral synthons or chiral reagents or isolated using traditional techniques. If the compound contains a double bond, the substituent may have the E- or Z-configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. Inclusion of all tautomeric forms is also intended.

Any asymmetric atom (for example, carbon or the like) of compounds according to formula (I) may be in racemic or enantiomerically enriched form, for example in (R)-, (S)- or (R,S)-configurations. 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 at least 95% enantiomeric excess or at least 99% enantiomeric excess in (R)- or (S)-configurations. Substituents on atoms with unsaturated double bonds may, if possible, be in cis- (Z)- or trance- (E)-form.

Accordingly, the compound provided herein may be in the form of one of possible stereoisomers, rotamers, atropoisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric ( cis or trans ) stereoisomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.

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

Any resulting racemates of compounds according to formula (I) or intermediates thereof can be separated into optical antipodes by known methods, e.g. by separating their diastereomeric salts obtained with an optically active acid or base and isolating the optically active acid or base compound. In particular, the basic fragment can be used in this way to separate compounds according to formula (I) into their optical antipodes, e.g. by fractional crystallization of a salt formed with an optically active acid, e.g. tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-P-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic compounds according to formula (I) or racemic intermediates can also be separated by chiral chromatography, e.g. high pressure liquid chromatography (HPLC) using a chiral adsorbent.

Any formula given herein is intended to also represent both unlabeled forms and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures depicted by the formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that may be included in the compounds of formula (I) include, for example, isotopes of hydrogen.

Additionally, the inclusion of certain isotopes, particularly deuterium (i.e. e. ²H or D) may provide certain therapeutic benefits due to higher metabolic stability, such as increased half-life in vivo, or by reducing the required dose, or by improving the therapeutic index or tolerability. It is known that deuterium in this context is considered as a substitute for the compound provided herein. Deuterium concentration can be determined using the isotope enrichment factor. "Isotope enrichment factor" as used herein means the ratio of the abundance of an isotope to the natural occurrence of that isotope. If the substituent in a compound provided herein is specified as deuterium, then such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (inclusion of 52.5% deuterium for each designated deuterium atom), at least 4000 (60% deuterium inclusion), at least 4500 (67.5% deuterium inclusion), at least 5000 (75% deuterium inclusion), at least 5500 (82.5% deuterium inclusion), at least 6000 (inclusion of 90% deuterium), at least 6333.3 (95% deuterium inclusion), at least 6466.7 (97% deuterium inclusion), at least 6600 (99% deuterium inclusion) or at least 6633.3 (inclusion 99.5% deuterium). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

For example, a compound of formula (I) may be deuterated, as represented by formula (Ic):

(Ic),

or a pharmaceutically acceptable salt thereof, wherein R ³ and R ⁷ are defined in formula (I); and each of R ^D1 , R ^D2 , R ^D5 and R ^D8 -R ^D27 is independently D or halogen.

Other examples of isotopes that can be included in the compounds of 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, respectively. Accordingly, it should be understood that compounds in accordance with formula (I) include compounds that include one or more of any of the above isotopes, including, for example, radioactive isotopes such as ³ H and ¹⁴ C, or compounds in which contain non-radioactive isotopes such as ² H and ¹³ C. Such isotopically labeled compounds are useful in metabolism studies (using ¹⁴ C), reaction kinetics studies (using, for example, ² H or ³ H), detection or imaging techniques , such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including in drug or substrate tissue distribution assays or in radiation therapy of patients. In particular, the ¹⁸ F labeled compound may be particularly suitable for PET or SPECT studies. Isotope-labeled compounds of formula (I) generally can be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the accompanying examples and methods of preparation using suitable isotopically labeled reagents in place of the unlabeled reagent previously used.

“Administering” and “administering” and “administering” as used herein refer to the manner in which a compound provided herein (eg, a compound according to formula (I)) is provided to a subject.

"Subject" or "patient" as used herein refers to a living organism suffering from one or more diseases or disorders described herein, which can be treated by administering a pharmaceutical composition described herein. Examples of subjects include mammals (eg, humans and animals such as dogs, cows, horses, monkeys, pigs, guinea pigs, sheep, goats, cats, mice, rabbits, rats and non-human transgenic animals). In certain embodiments, the subject is a primate. In certain embodiments, the subject is a human, for example, a person who suffers from, is at risk of developing, or has the potential to suffer from a disease described in this document. In specific embodiments, the subject is an adult at least about 18 years of age. In specific embodiments, the subject is an adult between about 18 and about 75 years of age. In specific embodiments, the subject is a human child under approximately 18 years of age.

“Treat,” “treat,” or “treat” any disease or disorder as used herein refers to alleviating, alleviating, delaying, reducing, reversing, or improving at least one symptom of the condition in a subject. The term "treat" can also mean to suspend or delay the onset (i.e., period before the clinical manifestation of the disease) and/or reducing the risk of development or worsening of the condition. In certain embodiments, the term "treat" refers to the attenuation, alleviation, delay of progression, reduction, reversal, or improvement of at least one symptom of a condition selected from 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 disorder including, but not limited to, Tourette's 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.

“Prevent,” “prevent,” or “prevent” any disease or disorder, as used herein, refers to the preventive treatment of a disease or disorder; or providing a delay in the onset or progression of a disease or disorder.

"Pharmaceutical composition" as used herein refers to a compound provided herein, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

A "pharmaceutically acceptable carrier" as used herein refers to a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption retardants, salts, drug stabilizers, binders, fillers, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, coloring agents and combinations thereof, which should be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22^nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

A "therapeutically effective amount" of a compound as used herein refers to an amount of a compound that will produce a biological or medical response in a subject, such as increasing the activity of an enzyme or protein or reducing the severity of symptoms, alleviating conditions, slowing or inhibiting progression disease 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 in (1) at least partially alleviating, preventing and/or reducing the severity of a condition or disorder or disease (i) mediated by M4, or (ii) associated with M4 activity, or (iii) characterized by activity (normal or abnormal) of M4; or (2) increases 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 environment, is effective to increase M4 activity.

“Suppress,” “suppress,” or “suppress,” as used herein, refers to reducing the severity or suppression of a given condition, symptom, or disorder, or disease, or significantly reducing the baseline level of activity of a biological activity or process.

A subject is “in need” of treatment if the subject will benefit biologically, medically, or improve his or her quality of life as a result of such treatment.

“Substance Use Disorder” or “SUD” as used herein is defined based on DSM-5 criteria (i.e., according to the Diagnostic and Statistical Manual of Mental Disorders. 5^th Edition, Washington, DC: American Psychiatric Association, 2013; hereinafter referred to as "DSM-5"), the entire contents of which are incorporated herein by reference. The term “substance use disorder” as used herein refers to a situation in which recurrent use of alcohol and/or drugs causes clinically and functionally significant impairment, such as health problems, impairment of function, and inability to perform basic responsibilities. at work, at school or at home. According to the DSM-5, a diagnosis of substance use disorder is based on evidence of impaired control, decreased social functioning, risky use, and pharmacological criteria. Substance use disorder includes, for example, alcohol use disorder, tobacco use disorder, cannabis use disorder, stimulant use disorder, hallucinogenic substance use disorder, and associated with opioid use.

“Psychosocial or behavioral therapy” as used herein refers, without limitation, 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 Behav2009; 23(1): 168-174), therapy based on positive reinforcement, e.g. as described in Psychol Addict Behav2009; 23(1): 168-174; V J. Consul. Clin. Psychol. 2005; 73(2): 354-59; or in Case Reports in Psychiatry, Vol. 2012, Article ID 731638), therapy based on a community support approach (e.g. as described in Drug Alcohol Depend2004; 74:1-13), therapy based on motivational counseling (e.g. as described in J. Consul. Clin. Psychol. 2001; 69(5): 858-62), therapy based on motivational enhancement (e.g. as described in Drug Alcohol Depend2007, 91:97-101), or meditation-based therapy, such as transcendental meditation-based therapy (eg as described in Addiction 2004; 99(7):862-874 or J. Consul. Clin. Psychol. 2000; 68(3): 515-52); particularly therapy based on positive reinforcement.

“Standardized psychological treatment” or “standardized psychological support” as used herein refers to standard counseling sessions, such as once a week, particularly counseling that focuses heavily on cocaine use.

“Computer-assisted” or “computer-assisted” as used herein refers to psychosocial or behavioral therapy that involves the use of electronic or digital tools, such as online tools, smartphones, laptops, tablets, wireless devices or health applications.

Unless otherwise indicated, “compound provided herein” or “compounds provided herein” refers to compounds of formula (I) and subformulas thereof, including formulas (Ia), (Ib), (Ic), and any illustrative compounds and their salts, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including those substituted by deuterium), as well as naturally occurring moieties.

As used herein, the singular and similar terms used herein (especially in the context of the claims) are to be construed to include both the singular and the plural unless otherwise specified herein or unless clearly consistent with the context.

Throughout this specification and the claims that follow, unless the context otherwise requires, the word “comprise” or variations thereof such as “comprises” or “comprising” should be understood to include the specified integer or step or group integers or stages, but not to the exclusion of any other whole number or stages, or group of integers or stages.

If there is a discrepancy between a depicted structure and the chemical name given to that structure, the depicted structure should be given greater preference. In addition, unless the stereochemistry of a structure or part of a structure is indicated, for example, by bold or dashed lines, the structure or part of a structure should be interpreted as encompassing all stereoisomers of the structure or part of a structure.

All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly inconsistent with the context. Use all possible examples or introductory words before examples (for example, "such as") provided herein are intended solely to better explain the present invention and do not limit the scope of the present invention as otherwise claimed.

2. Connections

In one embodiment, provided herein is a compound of formula (I),

(I),

or a pharmaceutically acceptable salt thereof, wherein

R ¹ represents halogen or hydrogen;

R ² represents halogen or hydrogen;

R ³ represents

optionally substituted C _1-3 alkyl, wherein said alkyl is optionally substituted with one 4-6 membered heterocycloalkyl,

optionally substituted 5-6-membered heteroaryl, wherein said heteroaryl is optionally substituted with one C _1-3 alkyl,

optionally substituted 4-6-membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one -OH,

optionally substituted 4-6 membered cycloalkyl, wherein said cycloalkyl is optionally substituted with one -OH; or

-OR ⁴ ;

R ⁴ represents

optionally substituted C _1-5 alkyl, wherein said alkyl is optionally substituted with one or two R ⁶ ,

optionally substituted 3-9 membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or two R ⁶ , or

optionally substituted 4-6 membered cycloalkyl, wherein said cycloalkyl is optionally substituted with one, two or three R ⁶ ;

R ⁵ represents halogen or hydrogen;

each R ⁶ independently represents

halogen,

-OH,

-OCH ₃ ,

-C(CH ₃ ) ₂ OH,

-CH ₂ OH,

cyano,

optionally substituted C ₁ -C ₄ alkyl, wherein said alkyl is optionally substituted -OH,

optionally substituted 4-7 membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, -OH, -OCH ₃ and C _1-3 alkyl, or

optionally substituted 5-6 membered heteroaryl, wherein said heteroaryl is optionally substituted with one C _1-3 alkyl; And

R ⁷ is a 5-membered heteroaryl.

In one embodiment, provided herein is a compound of formula (Ia),

(Ia),

or a pharmaceutically acceptable salt or stereoisomer thereof.

In one embodiment, provided herein is a compound of formula (Ib)

(Ib),

or a pharmaceutically acceptable salt or stereoisomer thereof.

In one embodiment, R ¹ is selected from the group consisting of H, chlorine and fluorine. In another embodiment, R ¹ is fluorine.

In one embodiment, R ² is H or fluorine.

In one embodiment, R ⁵ is H or fluorine.

In one embodiment, ^R1 , ^R2 and ^R5 are H.

In one embodiment, ^R2 and ^R5 are H.

In one embodiment, R ³ is selected from the group consisting of: , , , , , , And . In some embodiments, R ³ is -OR ⁴ .

In one embodiment, R ⁴ is 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 is selected from the group consisting of:

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

In another embodiment, R ⁴ is C ₁ -C ₅ alkyl and R ⁶ is an independent cyano group, -OH, -OCH ₃ . , , , , , , , , , , , , , , , , , , And .

In one embodiment, R ⁷ is selected from the group consisting of: , , , And .

In one embodiment, provided herein is a compound that is 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;

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-oxadiazol-2-carboxylate;

(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-dimethylpropanenitrile;

(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-methylbutoxy)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;

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

(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-fluoroxetan-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]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazole -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]heptan-6-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazole -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]octane- 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]octane- 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]octane- 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]octane- 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]heptan-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]octane-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]octane-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]octane-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]octane-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)cyclohexan-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)cyclohexan-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)cyclohexan-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)cyclohexan-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)cyclohexan-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)cyclohexan-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)cyclohexan-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]heptan-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]heptan-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-fluoroxetan-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]octane-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]octane-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]octane-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]octane-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-methylbutoxy)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;

formate salt (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;

(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]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-thiadiazole -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-oxapiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,2,4-oxadiazole -3-yl)-5-oxa-2-azaspiro[3.4]octane or a pharmaceutically acceptable salt thereof.

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

(S)-7-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazole -2-yl)-5-oxa-2-azaspiro[3.4]octane, having the following structure:

;

(R)-7-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazole -2-yl)-5-oxa-2-azaspiro[3.4]octane, having 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 having the following structure:

; And

(S)-2-(oxazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[ 3.4]octane having the following structure:

, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound is (S)-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, having the following structure: , or a pharmaceutically acceptable salt thereof.

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, having the following structure:

, or a pharmaceutically acceptable salt thereof.

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, having the following structure:

, or a pharmaceutically acceptable salt thereof.

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, having the following structure:

, or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a pharmaceutical composition containing a compound provided herein or a pharmaceutically acceptable salt thereof.

3. Pharmaceutical compositions

In one embodiment, provided herein is a pharmaceutical composition comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another embodiment, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In a further embodiment, the composition contains at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition may be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g. by injection, infusion, transdermal or topical administration) and rectal administration. Topical administration may also refer to inhalation or intranasal administration. The pharmaceutical compositions provided herein may be prepared in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, without limitation, solutions, suspensions, or emulsions). Tablets can be either film-coated or enteric-coated according to methods known in the art. Typically, pharmaceutical compositions are tablets or gelatin capsules containing the active ingredient together with one or more of the following:

a) thinners, e.g. with lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

b) lubricants, e.g. with silicon dioxide, talc, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; also in the case of tablets

c) binders, e.g. with magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary

d) raising agents, e.g. with types of starch, agar, alginic acid or its sodium salt or effervescent mixtures; And

e) absorbents, coloring agents, flavorings and sweeteners.

The pharmaceutical compositions provided herein may be presented in a single dosage of about 1-1000 mg of active ingredient(s) for a subject weighing about 50-70 kg, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredients. The therapeutically effective dosage of a compound or a pharmaceutical composition based thereon depends on the type of subject, body weight, age and individual condition, disorder or disease being treated or the severity thereof. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients needed to prevent, treat, or inhibit the progression of the disorder or disease.

The above dosage parameters are evident in the tests in vitroAnd in vivousing predominantly mammals, e.g. mice, rats, dogs, non-human apes or isolated organs, tissues and their preparations. The connections provided in this document can be used in vitroin the form of solutions, for example aqueous solutions, and in vivoor parenterally, mainly intravenously, for example, in the form of a suspension or aqueous solution. Dosage in vitromay range in molar concentration from approximately 10^-3 to 10^-9. Depending on the route of administration, the therapeutically effective amount in vivomay be in the range of about 0.1-500 mg/kg or about 1-100 mg/kg.

4. Methods of application

In one embodiment, the compounds provided herein are in free or pharmaceutically acceptable salt form and have M4 muscarinic receptor agonist activity. In a specific embodiment, provided herein are compounds of formula (I), in free or pharmaceutically acceptable salt form, having activity as M4 muscarinic receptor agonists. A significant advantage of the compounds provided herein is that they are highly selective for the M4 receptor over the M1, M2 and M3 receptor subtypes and are thus believed to retain their essential activity in the brain but do not cause to unwanted cholinergic side effects. The activity of the compounds provided herein at muscarinic receptors can be determined using the CHRM4 Ca ⁺⁺ flux assay described below in section 8.2.

Due to their activity as an M4 receptor agonist, the compounds provided herein may be useful for the treatment of:

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's 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

disorders associated with the use of psychoactive substances.

In one embodiment, provided herein is a method of providing treatment for a condition, disease, or disorder that is treatable with an M4 receptor agonist, comprising administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of such treatment. . In a further embodiment, the condition, disease or disorder is a psychosis, including, but not limited to, 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. In a specific embodiment, psychosis is associated with Alzheimer's disease.

In another embodiment, provided herein is a method of treating a hyperkinetic movement disorder, such as Tourette's syndrome, chorea, or tardive dyskinesia, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of such treatment. In some embodiments, 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, hyperkinetic movement disorder is associated with Alzheimer's disease.

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

In another embodiment, provided herein is a method of treating substance use disorders, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

In one embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy. In a further embodiment, the therapy is selected for a condition, disease or disorder that is treatable with an M4 receptor agonist. In another embodiment, the condition, disease or disorder is selected from the foregoing list, in particular psychosis, including, but not limited to, psychosis associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease, Parkinson's disease, post-traumatic stress disorder and frontal depression. -temporal dementia.

In another embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a hyperkinetic movement disorder such as Tourette's syndrome, chorea or tardive dyskinesia. In some embodiments, 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, hyperkinetic movement disorder is associated with Alzheimer's disease.

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

In another embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for substance use disorders.

In another embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicinal product. In a further embodiment, the medicinal product is for treating a condition, disease, or disorder that is treatable with an M4 receptor agonist. In another embodiment, the condition, disease, or disorder is a psychosis, including, but not limited to, 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.

In another 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 the treatment of a hyperkinetic movement disorder such as Tourette's syndrome, chorea or tardive dyskinesia. In some embodiments, 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, hyperkinetic movement disorder is associated with Alzheimer's disease.

In another 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 the treatment of cognitive dysfunction, for example cognitive dysfunction associated with schizophrenia, Alzheimer's disease, frontotemporal dementia, schizoaffective disorder, or depression. In a specific embodiment, cognitive dysfunction is associated with Alzheimer's disease.

In another 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 the treatment of substance use disorders.

In another embodiment, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a condition, disease, or disorder that is treatable with an M4 receptor agonist. In a further embodiment, the condition, disease or disorder is selected from the foregoing list, particularly psychosis including, but not limited to, 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. In a specific embodiment, psychosis is associated with Alzheimer's disease.

In another embodiment, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a hyperkinetic movement disorder such as Tourette's syndrome, chorea or tardive dyskinesia. In some embodiments, 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, hyperkinetic movement disorder is associated with Alzheimer's disease.

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

In another embodiment, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of substance use disorders.

A compound according to formula (I) or a pharmaceutically acceptable salt thereof can be administered either simultaneously with, before or after one or more other therapeutic agents. The compounds of formula (I) may be administered individually by the same or different routes of administration, or together in the same pharmaceutical composition as other agents. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a subject in combination with a compound provided herein.

In the combination therapies provided herein, the compound of Formula (I) and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compounds provided herein and another therapeutic agent may be combined in a combination therapy: (i) prior to distributing the combination product (e.g., in the case of a kit containing a compound provided herein and another therapeutic agent); (ii) by the physicians themselves (or under the direction of a physician) shortly before administration; (iii) by the patients themselves, e.g. during sequential administration of a compound provided herein and another therapeutic agent.

A compound according to formula (I) or a pharmaceutically acceptable salt thereof can be administered with an antipsychotic, in particular a first generation antipsychotic such as chlorpromazine (Thorazine), haloperidol, mesoridazine, thioridazine, thiothixene, pimozide, fluphenazine or perphenazine, with an antipsychotic a second-generation agent such as clozapine, olanzapine, risperidone, quetiapine, aripiprazole, asenapine, brexpiprazole, cariprazine, iloperidone, ziprasidone, lurasidone, pimavanserin, or paliperidone. In certain embodiments, a compound of 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, a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be administered with an antipsychotic and mood stabilizer such as lithium, divalprex sodium, carbamazepine, or lamotrigine.

A compound according to formula (I) or a pharmaceutically acceptable salt thereof can be administered with an antidepressant, in particular a selective serotonin reuptake inhibitor such as sertraline, fluoxetine, fluvoxamine, escitalopram, paroxetine or citalopram, a serotonin-norepinephrine reuptake inhibitor such as such as vortioxetine, venlafaxine, desvenlafaxine, milnacipran, duloxetine or levomilnacipran, with a phenylpiperazine antidepressant such as nefazodone, vilazodone or trazodone, with reversible monoamine oxidase inhibitors such as moclobemide, with melatonin agonists such as agomelatine, with serotonin agonists such as mirtazapine, with N-methyl-D-aspartate receptor antagonists such as esketamine and ketamine, and monoamine oxidase inhibitors such as tranylcypromine, phenelzine, transdermal selegiline or isocarboxazid.

A compound according to formula (I) or a pharmaceutically acceptable salt thereof can be administered in combination with standardized psychological treatment, for example, in individual or group therapy. In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered in combination with psychosocial or behavioral therapy, either through standardized psychological treatment or computer software. In a certain embodiment, the computing is provided through a digital or electronic device, such as online tools, smartphones, laptops, tablets, wireless devices, or health applications.

In a further embodiment, provided herein is a method of treating a condition, disease, or disorder that is amenable to treatment with an M4 receptor agonist, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an antipsychotic agent to a subject in need in such treatment. In certain embodiments, provided herein is a method of treating a condition, disease, or disorder that is treatable with an M4 receptor agonist, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, an antipsychotic, and a cholinesterase inhibitor to a subject in need of such treatment. In certain embodiments, provided herein is a method of treating a condition, disease, or disorder that is treatable with an M4 receptor agonist, comprising administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, an antipsychotic, and a mood stabilizer to a subject, in need of such treatment.

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

In a further embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a condition, disease or disorder that is amenable to treatment with an M4 receptor agonist, where the use is combined with an antipsychotic agent. In certain embodiments, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a condition, disease, or disorder that is amenable to treatment with an M4 receptor agonist, wherein the use is combined with an antipsychotic and a cholinesterase inhibitor. In certain embodiments, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a condition, disease, or disorder that is amenable to treatment with an M4 receptor agonist, wherein the use is combined with an antipsychotic and a mood stabilizer.

In a further embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a condition, disease or disorder that is amenable to treatment with an M4 receptor agonist, where the use is combined with an antidepressant.

In a further 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 the treatment of a condition, disease or disorder that is treatable with an M4 receptor agonist, wherein the use is combined with an antipsychotic agent. In certain embodiments, provided herein is the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a condition, disease, or disorder that is treatable with an M4 receptor agonist, wherein the use is combined with an antipsychotic and cholinesterase inhibitor. In certain embodiments, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a condition, disease, or disorder that is treatable with an M4 receptor agonist, wherein the use is combined with an antipsychotic and normotimic.

In a further 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 the treatment of a condition, disease or disorder that is treatable with an M4 receptor agonist, wherein the use is combined with an antidepressant.

In a further embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a condition, disease or disorder that is amenable to treatment with an M4 receptor agonist, where the use is combined with computer-assisted psychosocial or behavioral therapy.

In a further embodiment, provided herein is a method of treating a condition, disease, or disorder that is treatable with an M4 receptor agonist, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with computerized psychosocial or behavioral intervention. therapy.

In a further 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 the treatment of a condition, disease or disorder that is amenable to treatment with an M4 receptor agonist, wherein the use is combined with computerized psychosocial or behavioral therapy.

5. Methods of obtaining

The compounds provided herein can be prepared through a variety of methods, including standard chemistry. Suitable synthesis routes are indicated in the schemes below.

The compounds provided herein can be prepared by methods known in the art of organic synthesis, set forth in part in the following synthetic schemes. In the schemes described below, it is understood that protecting groups are used for labile or reactive groups as necessary, in accordance with general principles or chemistry. Protective groups are treated in accordance with standard methods of organic synthesis (see, T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis" Third edition, Wiley, New York 1999). Such groups are removed at a suitable stage in the synthesis of the compound using methods obvious to those skilled in the art. Selection methods, as well as reaction conditions and the order in which they are carried out, must be consistent with the preparation of the compounds provided for in this document.

Those skilled in the art will be able to determine the presence of a stereocenter in the compounds provided herein. Accordingly, the compounds provided herein include both possible stereoisomers and also include not only racemic compounds, but also individual enantiomers and/or diastereomers. If a compound provided herein is desired as a single enantiomer or diastereoisomer, it can be obtained by stereospecific synthesis or isolation of the final product or any suitable intermediate. Isolation of the final product, intermediate or starting material can be accomplished by any suitable method known in the art. Cm., for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

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

Scheme 1

In Scheme 1, phenols such as 1 can be subjected to a benzyl ether protecting group reaction and mediate the formation of protected phenols such as 2 . The aldehyde can then be doubly alkylated with an alkyltrimethylsilane in the presence of a Lewis acid activator such as ytterbium chloride. The resulting bis-olefins such as 3 can then be oxidized with ozone gas followed by a reducing agent such as sodium borohydride to produce diols such as 4 . The alcohols can then be activated as para -toluenesulfone esters to produce activated diols such as 5 , which can be replaced by an amine such as 6 to produce 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 with an aliphatic halide or tosylate 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 form free amines, which can react with heteroaromatic halides under Buchwald-Hartwig reaction conditions or under nucleophilic aromatic substitution conditions to give examples such as 12 . Alternatively, amines such as 10 can be reacted with heteroaromatic halides that contain an ester to form heteroaromatics 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 .

Scheme 2

In Scheme 2, phenols such as 9 can be deprotected with an acid such as TFA, and the resulting amine can be reacted with a heteroaromatic halide under Buchwald-Hartwig reaction conditions or nucleophilic aromatic substitution conditions to form heteroaromatic compounds such as like 15 . Alternatively, the amine can be reacted with a heteroaromatic halide that contains an ethyl ester to produce esters such as 14 . 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 produce heteroaromatic halides such as 15 . Alternatively, the connections provided herein can be prepared as shown in Scheme 3.

Scheme 3

In Scheme 3, arylboronic acids such as 17 can be reacted with unsaturated lactones such as 18 under rhodium catalysis conditions to produce saturated lactones such as 19 . The lactone can then be reduced with a reducing agent such as lithium aluminum hydride to produce 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.

Scheme 4

In Scheme 4, arylboronic acids such as 20 can be reacted with an unsaturated lactone such as 19 under rhodium-catalyzed conditions and the resulting saturated lactone 21 can be reduced with a reducing agent such as lithium borohydride to produce diols such as 22 . The resulting diol can then be reacted with a boronic ester such as 23 under Suzuki-Miyaura reaction conditions to form unsaturated rings such as 24 . The olefin can then be reduced by palladium catalysis in the presence of hydrogen to produce saturated rings such as 25 , and the hydroxyl group can then be activated by tosyl chloride to form activated diols such as 26 . The tosyl groups can then be replaced with an amine such as 6 in the presence of a base such as potassium phosphate to produce 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 reaction conditions or nucleophilic aromatic substitution conditions to give examples such as 30 . Alternatively, the amine can be reacted with a heteroaromatic halide that contains the ester to produce ethyl esters 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 solution acid such as HCl to give examples such as 30 . Alternatively, the connections provided herein can be obtained as shown in Scheme 5 shown below.

Scheme 5

In Scheme 5, unsaturated esters such as 31 can be reacted with diethyl malonate in the presence of a reducing metal such as sodium to produce tribasic esters such as 32 . The ester can then be hydrolyzed and decarboxylated with an acid such as HCl to produce diacids such as 33 . The acids can then be reduced with borane to give diols such as 35 . Alternatively, the ester can be decarboxylated to give dibasic esters such as 34 , and the esters can be reduced with a reducing agent such as lithium borohydride to give diols such as 35 . Diols such as 35 can then be activated as tosylates using tosyl chloride and the activated diols 36 can be reacted with an amine such as 6 to produce tertiary amines such as 37 . Bromides such as 37 can then be reacted with pinacolboronic esters to give unsaturated rings such as 38 . The olefin can then be reduced using hydrogen and palladium catalysis to produce saturated rings such as 39 , and the amine can then be deprotected with an acid such as TFA. Free amines such as 40 can then be reacted with a heteroaromatic halide under Buchwald-Hartwig reaction conditions or nucleophilic aromatic substitution conditions to give examples such as 42 . Alternatively, the free amine can be reacted with a heteroaromatic halide that contains an ethyl ester. Esters such as 41 can then be hydrolyzed with an aqueous acid solution such as lithium hydroxide to form an acid, which can then be decarboxylated with an acid such as HCl to form examples such as 42 . Alternatively, the connections provided herein can be prepared as described in Scheme 6 below.

Scheme 6

In Scheme 6, aryl bromides such as 43 can be combined with pinacolboronic esters such as 44 under Suzuki–Miyaura cross-coupling reaction conditions to give unsaturated rings such as 45 . The alcohol can then be subjected to a deprotection reaction using a fluoride source such as TBAF to produce free alcohols such as 46 , and the olefin can then be reduced using hydrogen and palladium catalysis to produce saturated rings such as 47 . The amine can then be deprotected with an acid such as TFA, and the free amine can then be reacted with a heteroaromatic halide under Buchwald-Hartwig reaction conditions or nucleophilic aromatic substitution conditions to give examples such as 50 . Alternatively, free amines such as 48 can be reacted with heteroaromatic halides that contain an ethyl ester to produce esters such as 49 . The ester can then be hydrolyzed with an aqueous base such as lithium hydroxide and the resulting acid can then be decarboxylated with an aqueous acid such as HCl to give examples such as 50 . Alternatively, the connections provided herein can be prepared as described in Scheme 7 below.

Scheme 7

In Scheme 7, phenols such as 8 can be activated, for example, with trifluoromethanesulfonic anhydride in the presence of a base such as pyridine to form a sulfonyl ester such as 51 . The trifluoromethylsulfonyl ester can then be converted to boronic acid using tetrahydroxydiboron in the presence of a palladium catalyst and the corresponding boronic acid can be reacted with a halide in the presence of a base to form an olefin such as 52 . Subsequently, the compound can be reduced with hydrogen via palladium catalysis to produce saturated compounds such as 53 , and the compound can subsequently be deprotected with an acid such as TFA to produce amines such as 54 . The amine can be reacted with an aryl halide under Buchwald–Hartwig reaction conditions or under nucleophilic aromatic substitution conditions to form examples such as 56 . Alternatively, amines such as 51 can be reacted with a heteroaromatic halide containing ethyl ester to produce esters 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 form examples such as 56 . Alternatively, the connections provided herein can be prepared as shown in Scheme 8 below.

Scheme 8

In Scheme 8, phenols such as 8 can be activated as trifluoromethylsulfonyl esters such as 57 using triflate anhydride. The resulting activated ester can then be converted to boronic acid using tetrahydroxydiboron in the presence of palladium, and the resulting boronic acid can be reacted under Suzuki-Miyaura reaction conditions with a heteroaromatic halide to form heteroaromatic compounds such as 58 . The amine can then be deprotected with an acid such as TFA, and the resulting free amines such as 59 can be reacted with a heteroaromatic halide under Buchwald-Hartwig reaction conditions or nucleophilic aromatic substitution conditions to form heteroaromatic compounds such as 61 . Alternatively, amines such as 59 can be reacted with heteroaromatic halides containing ethyl ester to produce esters such as 60 . The ester can then be hydrolyzed with an aqueous base such as lithium hydroxide, and the resulting acid can then be decarboxylated with an aqueous acid such as HCl to form heteroaromatic compounds such as 61 . Alternatively, the connections provided herein can be prepared as shown in Scheme 9 below.

Scheme 9

In Scheme 9, free amines such as 9 can be alkylated with a reagent such as cyanogen bromide to produce nitriles such as 62 . The nitrile can then be reacted with hydroxylamine to produce hydroxylamines such as 63 , which can then be condensed with dehydrating agents such as diethylphenyl orthoformate and tosinic acid to produce oxadiazoles such as 64 . Alternatively, connections can be prepared as shown in Scheme 10 below.

Scheme 10

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 an aryl chloride such as 65 . The Boc group can then be removed with an acid such as TFA to form free amines such as 56 , which can then be further reacted with a heteroaryl halide under nucleophilic aromatic substitution or Buchwald-Hartwig reaction conditions to form compounds such as 68 . Alternatively, the amine can be reacted with a heteroaromatic halide that contains an ethyl ester to produce an ester such as 67 . The ester can be hydrolyzed with an aqueous solution of a base such as lithium hydroxide and the resulting acid can be decarboxylated with an acid such as HCl to give examples such as 68 . Alternatively, the connections provided herein can be prepared as shown in Scheme 11 below.

Scheme 11

In Scheme 11, piperidines such as 69 can be reacted with ketones such as 70 under reductive amination conditions, such as treatment with zinc chloride and sodium cyanoborohydride, to form carbon-nitrogen bonds such as in 71 . The phenol can then be deprotected with a benzyl group using benzyl bromide and a base such as cesium carbonate, and the amine can then be deprotected with an acid such as TFA. Free amines such as 73 can then be reacted with heteroaromatic halides under nucleophilic aromatic substitution or Buchwald-Hartwig reaction conditions. Alternatively, free amines such as 73 can be reacted with an ester containing heteroaromatic halides to form esters 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 produce a heteroaromatic compound such as 75 . The benzyl group can then be removed by hydrogenation using palladium catalysis and the resulting phenol 76 can be reacted with a halide or tosylate in the presence of a base such as cesium carbonate. The racemic mixture can then be separated using, for example, chiral chromatography to form the individual enantiomers 77 and 78 .

7. INCLUSION BY REFERENCE

The entire disclosure of each of the patent documents and scientific articles cited herein is incorporated by reference for all purposes.

8. EXAMPLES

The present invention is 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 equivalents thereof may be contemplated by those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims.

1. Synthesis of intermediates and examples

The abbreviations used are those generally accepted in the art or mean as follows.

Å angstrom(angstroms)

AcOH acetic acid

aq. water

ATP adenosine triphosphate

AUC area under the curve

BOC tert -butyloxycarbonyl

t Bu tert- butyl

C degrees Celsius

CDI carbonyldiimidazole

CMBG 2-chloro-1,3-bis(methoxycarbonyl)guanidine

DCE 1,2-dichloroethane

DCM dichloromethane

DIPEA N, N-diisopropylethylamine

DME 1,4-dimethoxyethane

Dulbecco's Modified Needle Medium DMEM

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

DPBS Dulbecco Phosphate Buffer Saline

EtOAc ethyl acetate

EtOH ethyl alcohol

FBS fetal bovine serum

FCC flash column chromatography

g gram(grams)

h. hour(hours)

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

HBSS Hanks Balanced Salt Solution

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

Hz hertz

HOBt 1-hydroxy-7-azabenzotriazole

HPLC high pressure liquid chromatography

IP intraperitoneal

IPA isopropyl alcohol

J interaction constant

kg kilogram(kilograms)

l liter(liters)

LCMS liquid chromatography and mass spectrometry

LED LED

Me methyl

MHz megahertz

mmol mmol

MTBE methyl tert -butyl ether

MS mass spectrometry

min. minute(s)

mg milligram(milligrams)

ml milliliter(milliliters)

mmol millimole(millimoles)

mass/charge ratio of mass and charge

nm nanometer(nanometers)

nM nmol/l

NMR nuclear magnetic resonance

Pd/C, Pd-C palladium on carbon

Pd(dba) ₂ bis(dibenzylideneacetone)palladium(0)

Pd ₂ (dba) ₃ tris(dibenzylideneacetone)dipalladium(0)

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

PO orally (oral administration)

psi inch psi

p TSCl para- toluenesulfonyl chloride

rac racemic

RB round bottom

rpm rpm

room temperature

RT retention time

SFC supercritical fluid chromatography

SC subcutaneous

TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate

TC tissue culture

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TPGS-750-M DL-α-tocopherol-methoxypolyethylene glycol succinate solution

TTMSS tris(trimethylsilyl)silane

µl microliter(microliters)

µM µmol/l

UPLC ultra performance liquid chromatography

UV ultraviolet radiation

Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

XPhosPd G2 chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

General procedures

If the route of preparation is not described, the material is commercially available. Commercial reagents were used without further purification unless otherwise stated. Room temperature (RT) is approximately 20-25°C. ¹ H NMR was recorded at 400 MHz on a Bruker instrument and processed using mNOVA. Chemical shifts are given in parts per million (ppm) relative to tetramethylsilane, and coupling constants ( J ) are given in hertz. Abbreviations for multiplicity are as follows: s=singlet, d=doublet, t=triplet, q=quartet, dd=doublet of doublets, dt=doublet of triplets, br=broad.

Method 1 LCMS.

Instrument: Waters Acquity UPLC, photodiode array detector; column: AcQuity UPLC BEH C ₁₈ 1.7 µm, 21x30 mm; run time 2 min., 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). The volume of the injected sample is 2-5 µl; matrix for ultraviolet detection 210-400, detectable mass range 120-1250 (electrospray ionization); column at 50°C; flow rate 1.0 ml/min.

Method 2 LCMS.

Instrument: Waters Acquity UPLC, photodiode array detector; column: AcQuity UPLC BEH C ₁₈ 1.7 µm, 21x50 mm; run time 2 min., 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. The volume of the injected sample is 2-5 µl; matrix for ultraviolet detection 210-400, detectable mass range 120-1250 (electrospray ionization); column at 50°C; flow rate 1.0 ml/min.

Method 3 LCMS.

Instrument: Waters Acquity UPLC, photodiode array detector; column AcQuity UPLC BEH C ₁₈ 1.7 µm, 21×30 mm; run time 5.2 min, 2 → 98% solvent B: solvent A 0 to 5.15 min, 98% solvent B 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). The volume of the injected sample is 2-5 µl; matrix for ultraviolet detection 210-400, detectable mass range 120-1600; column at 50°C, flow rate 1.0 ml/min.

Method 4 LCMS.

Instrument: Waters Acquity UPLC, photodiode array detector; column AcQuity UPLC BEH C ₁₈ 1.7 µm, 21×30 mm; run time 5.2 min, 2 → 98% solvent B: solvent A 0 to 5.15 min, 98% solvent B 5.15 to 5.20 min. Solvents: solvent A=5 mM ammonium hydroxide in water, solvent B=5 mM ammonium hydroxide in acetonitrile. The volume of the injected sample is 2-5 µl; matrix for ultraviolet detection 210-400, detectable mass range 120-1600; column at 50°C, flow rate 1.0 ml/min.

Intermediate 1A. 3-(2-(Benzyloxy)phenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

Step 1. 4-(2-(Benzyloxy)phenyl)tetrahydro-2H-pyran-2-one

Potassium hydroxide (3.95 g, 70.3 mmol) in water (17.50 ml) was added dropwise to a solution of [RhCl(COD)] 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 ) at 0°C for a period of 2 minutes. The temperature of the reaction mixture was then raised to 35°C and stirred for 16 hours. The reaction mixture was diluted with EtOAc and 2 M HCl. The aqueous solution was separated and extracted again with EtOAc. The combined organic layers were dried over MgSO ₄ and the solvent was removed under reduced pressure. The crude mixture was then purified with FCC (0→60% EtOAc/heptanes) to give the title compound (19.49 g, 68.3 mmol).

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

¹ H NMR (400 MHz, CD ₃ OD) δ 7.49-7.27 (m, 5H), 7.20 (ddd, J=14.8, 7.5, 1.8 Hz, 2H), 7 .05 (dd, J=8.1, 1.2 Hz, 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, 6.4 Hz, 1H), 2.68 (dd, J=17.2, 9 .8 Hz, 1H), 2.10 (m, 2H).

Step 2. 3-(2-(Benzyloxy)phenyl)pentane-1,5-diol

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 then the reaction mixture was stirred for 2 hours at 0°C. The reaction mixture was quenched with water at -5°C until gas formation ceased, and then a solution of NaOH (25 g) in water (25 ml) was added to the mixture in portions at 0°C. Then Na was added to the reaction mixture₂SO₄ (300 g) and stirred for 60 minutes. The mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified with FCC (0-10% MeOH/DCM) to give the title compound (19.3 g, 64.1 mmol).

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

^1H NMR (400 MHz, CDCl ₃ ) δ 7.51-7.31 (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).

Step 3. 3-(2-(Benzyloxy)phenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

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) at -5 °C p TsCl (28.3 g, 148 mmol) and DMAP (0.824 g, 6.74 mmol) were added. After addition, the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The crude product was dissolved in DCM and washed with water and brine, then dried over Na ₂ SO ₄ and filtered. DCM was removed under reduced pressure and the crude product was purified using FCC (0→50% EtOAc/heptanes) to give the title compound.

LCMS: Rt= 1.37 min.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.74-7.63 (m, 4H), 7.46-7.33 (m, 5H), 7.30 (s, 4H), 7.20- 7.13 (m, 1H), 6.99-6.72 (m, 3H), 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).

Intermediate 1B. 3-(2-(Benzyloxy)-5-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

Step 1. 4-(2-(Benzyloxy)-5-fluorophenyl)tetrahydro-2H-pyran-2-one

(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)] ₂ (0.5 g, 1.014 mmol) were dissolved in dioxane (180 ml) and cooled to -10°C. Potassium hydroxide (4.38 g, 78 mmol) was then dissolved in water (17.8 ml) and added dropwise to the dioxane solution over 10 min. The reaction mixture was then heated to 35°C and stirred for 2 hours. The reaction mixture was neutralized with 1 M HCl (to pH 3), then concentrated in vacuo to remove dioxane. The residue was then diluted with water and extracted with EtOAc, the organics were combined and concentrated in vacuo. The crude product was purified using FCC (0→100% EtOAc/heptanes) to give the title compound (19.65 g, 78 mmol).

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

Step 2. 3-(2-(Benzyloxy)-5-fluorophenyl)pentane-1,5-diol

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 for 2 hours at -5°C under N ₂ atmosphere. The reaction mixture was quenched with H ₂ O (10 ml) at -5°C until gas formation ceased, and then a solution of NaOH (25 g) in water (25 ml) was added in portions to the mixture at 0°C. Na ₂ SO ₄ (300 g) was added to the reaction mixture and stirred for 60 minutes. The mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified with FCC (0-10% MeOH/DCM) to give the title compound (17.8 g, 55.6 mmol).

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

^1H NMR (400 MHz, CDCl ₃ ) δ 7.47-7.33 (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).

Step 3. 3-(2-(Benzyloxy)-5-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

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. Added pTsCl (24.53 g, 129 mmol) and DMAP (0.714 g, 5.85 mmol), and the reaction mixture was warmed to room temperature and stirred overnight. The solvent was removed under reduced pressure. The crude product was dissolved in DCM and washed with water and brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified with FCC (0→50% EtOAc/heptanes) to give the title compound (22.8 g, 37.2 mmol).

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

Intermediate 1C. 3-(2-(Benzyloxy)-4-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

Step 1. 2-(Benzyloxy)-4-fluoro-1-(hepta-1,6-dien-4-yl)benzene

A 250 mL round bottom flask was charged with 2-(benzyloxy)-4-fluorobenzaldehyde (commercially available, 23.90 g, 104 mmol) followed by the addition of nitromethane (250 mL). Ytterbium(III) chloride (7.25 g, 26.0 mmol) was then added to the reaction mixture and the mixture was stirred for 15 minutes. at room temperature. After 15 min. Allyltrimethylsilane (41.2 mL, 260 mmol) was slowly added while stirring over 5 min. The mixture was stirred overnight at RT. The reaction mixture was concentrated and the crude product was purified using FCC (0→30% EtOAc/heptanes) to give the title compound as a clear colorless oil (22.64 g, 72.6 mmol ).

LCMS: Rt= 1.43 min. (LCMS Method 1).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.38-7.19 (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).

Step 2. 3-(2-(Benzyloxy)-4-fluorophenyl)pentane-1,5-diol

2-(Benzyloxy)-4-fluoro-1-(hepta-1,6-dien-4-yl)benzene (22.64 g, 76 mmol) was dissolved in MeOH (450 ml) and cooled to -78°C. Ozone was then bubbled through the reaction mixture for 120 minutes, during which time the reaction mixture turned a pale purple color. Nitrogen was then bubbled through the reaction mixture for 20 minutes. and then heated it to 0°C, and NaBH₄(28.9 g, 764 mmol) was added in portions to the reaction mixture over 4 hours, and then the reaction mixture was stirred for 16 hours at RT. The reaction mixture was then poured into DCM and saturated NH was added₄Cl, and the mixture was stirred at room temperature for 1 hour. The organic layer was separated and washed with water and brine, then dried over Na₂SO₄ and filtered. The solvent was removed under reduced pressure. The resulting product (15.22 g, 50.0 mmol) was carried to the next step without further purification.

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

^1H NMR (400 MHz, CDCl ₃ ) δ 7.36-7.22 (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).

Step 3. 3-(2-(Benzyloxy)-4-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

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 mixture was cooled to 0°C. The reaction mixture was incubated for 10 min. and then added pTsCl (9.59 g, 50.3 mmol) and DMAP (0.559 g, 4.57 mmol). The reaction mixture was slowly heated to room temperature and stirred overnight. The reaction mixture 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 with FCC (0→60% EtOAc/heptanes) to give the title compound (8.91 g, 14.54 mmol).

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

^1H NMR (400 MHz, CDCl ₃ ) δ 7.68-7.61 (m, 4H), 7.42-7.32 (m, 5H), 7.27 (m, 4H), 6.57 ( dd, J=10.9, 2.4 Hz, 1H), 6.46 (td, J=8.3, 2.4 Hz, 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).

Intermediate connection 1D. 3-(2-(Benzyloxy)-4,5-difluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

Step 1. 4,5-Difluoro-2-(hepta-1,6-dien-4-yl)phenol

A 1 L three-neck flask was charged with YbCl ₃ •6H ₂ O (20 g, 51 mmol), which was dehydrated by heating in vacuum. 4,5-difluoro-2-hydroxybenzaldehyde (20 g, 126 mmol) in nitromethane (200 ml) was then added to the flask at 25°C. After stirring for 30 minutes, allyltrimethylsilane (51 g, 443 mmol) was added dropwise at 25°C. The mixture was then heated to 60°C and stirred for 16 hours. The reaction mixture was then cooled to 25°C, filtered and concentrated. MeCN (200 ml) and 2N were then added to the crude reaction mixture. HCl (200 ml) and the resulting solution was stirred for 30 min. at 25°C. MeCN was removed in vacuo and the remaining aqueous phase was extracted with EtOAc, dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified with FCC (0-10% EtOAc/petroleum ether) to give the title compound as a yellow liquid (14.5 g, 64.66 mmol).

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.90 (dd, J=8.9, 11.6 Hz, 1H), 6.62 (dd, J=6.8, 11.2 Hz, 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).

Step 2. 3-(4,5-Difluoro-2-hydroxyphenyl)pentane-1,5-diol

Ozone was bubbled through a stirred solution of 4,5-difluoro-2-(hepta-1,6-dien-4-yl)phenol (14.5 g, 64.66 mmol) in MeOH (150 mL) at -78°C. reaction mixture for 3 hours until the starting material is consumed and the reaction mixture turns pale purple. Ozone sparging was stopped and excess ozone in the reaction mixture was removed by bubbling N ₂ through the reaction mixture for 10 minutes. The reaction mixture was then heated to -20°C and NaBH ₄ (14.68 g, 387.96 mmol) was added in portions, the reaction mixture was heated to 0°C and stirred for 2 hours. The reaction mixture was quenched with a saturated aqueous solution of NH ₄ Cl and MeOH was removed under reduced pressure. The aqueous layer was then extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , 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.

^1H NMR (400 MHz, DMSO _- d6 ) δ 9.58 (s, 1H), 7.09 (dd, J=9.5, 12.1 Hz, 1H), 6.70 (dd, J= 7.3, 12.4 Hz, 1H), 4.28 (t, J=5.1 Hz, 2H), 3.27-3.18 (m, 3H), 3.07 (m, 1H), 1.76-1.64 (m, 3H).

Step 3. 3-(2-(Benzyloxy)-4,5-difluorophenyl)pentane-1,5-diol

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 (3.09 g, 22.35 mmol) and benzyl bromide (1.86 ml, 15.64 mmol) were added and the reaction mixture was refluxed for 3 hours. The reaction mixture was then cooled to room temperature and acetone evaporated under reduced pressure. The residue was dissolved in DCM and washed with water, and then the aqueous layer was extracted again with DCM. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude material was then purified by FCC (0-10% MeOH/DCM) to give the title compound (4.75 g, 14.74 mmol).

LCMS: Rt= 0.89 min. (LCMS method 2); MS mass/charge 321.2 [MH] ^- .

Step 4. 3-(2-(Benzyloxy)-4,5-difluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

3-(2-(Benzyloxy)-4,5-difluorophenyl)pentane-1,5-diol (4.72 g, 14.64 mmol) and pTsCl (6.42 g, 33.7 mmol) was 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 mixture was stirred at room temperature for 16 hours. MeCN was then evaporated and the residue was diluted with water and extracted with DCM . Organic extracts were combined, washed with saline, dried over MgSO₄, filtered and concentrated. The crude material was purified by FCC (0-10% MeOH/DCM) to give the title compound (7.47 g, 11.8 mmol).

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

Intermediate 1E. 3-(2-(Tetrahydro-2H-pyran-4-yl)phenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

Step 1. 4-(2-Bromophenyl)tetrahydro-2H-pyran-2-one

A solution of potassium hydroxide (5.15 g, 92 mmol) in water (10 ml) was added dropwise to a solution of [RhCl(COD)] 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) at 0°C for 10 min. The temperature of the reaction mixture was then raised to 35°C and the reaction mixture was stirred for 16 hours. The reaction mixture was diluted with EtOAc and 3 M HCl. The aqueous solution was separated and extracted again with EtOAc. The combined organic layers were dried over MgSO ₄ and the solvent was removed under reduced pressure. The residue was purified with FCC (0-60% EtOAc/heptanes) to give the title compound (12.9 g, 50.4 mmol).

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

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.53 (t, J=6.9 Hz, 1H), 7.34-7.21 (m, 1H), 7.17 (dd, J=7, 8, 2.2 Hz, 1H), 7.09 (q, J=6.9 Hz, 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).

Step 2. 3-(2-Bromophenyl)pentane-1,5-diol

A solution of lithium borohydride (16.66 ml, 33.3 mmol, 2 M in THF) was added to the 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 room temperature and stirred for 18 hours. 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 dried over MgSO₄, filtered and concentrated. The crude product was purified with FCC (0-10% MeOH/DCM) to give the title intermediate (4.70 g, 18.1 mmol).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.55 (d, J=7.7 Hz, 1H), 7.39-7.31 (m, 2H), 7.11 (dt, J=8, 6, 4.4 Hz, 1H), 4.35 (t, J=4.9 Hz, 2H), 3.34-3.14 (m, 5H), 1.85-1.66 (m, 4H ).

Step 3. 3-(2-(3,6-Dihydro-2H-pyran-4-yl)phenyl)pentan-1,5-diol

3-(2-Bromophenyl)pentan-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 tribasic potassium phosphate (20.64 g, 97 mmol) were suspended in degassed 1,4-dioxane (150 ml) and water (15.00 ml) and the reaction mixture was stirred at room temperature for 16 hours. Then the reaction mixture diluted with water and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated. The crude material was purified by FCC (0-10% MeOH/DCM) and further purified by recrystallization from EtOAc/heptanes (1:1) to give the title compound as a white solid (9.85 g, 37.5 mmol ).

LCMS: Rt= 0.70 min. (LCMS method 2); MS mass/charge 261.3 [MH] ^- .

¹ H NMR (400 MHz, DMSO -d ₆ ) δ 7.25 (d, J=7.6 Hz, 2H), 7.12 (t, J=7.5 Hz, 1H), 7.02 (d , J=7.7 Hz, 1H), 5.51 (s, 1H), 4.27 (t, J=5.0 Hz, 2H), 4.15 (q, J=2.9 Hz, 2H ), 3.79 (t, J=5.3 Hz, 2H), 3.19 (m, 4H), 3.04 (m,1H), 2.24 (m, 2H), 1.71 (m , 4H).

Step 4. 3-(2-(Tetrahydro-2H-pyran-4-yl)phenyl)pentan-1,5-diol

3-(2-(3,6-Dihydro-2H-pyran-4-yl)phenyl)pentan-1,5-diol (7.60 g, 29.0 mmol) was dissolved in MeOH (75 ml) and 10 % palladium on carbon (3.08 g, 2.90 mmol). The flask was purged with hydrogen from 3 bottles and then the reaction mixture was stirred under hydrogen from the bottle for 18 hours. The reaction mixture was filtered through a pad of celite and concentrated to give the crude product as a white solid. This material was combined with a parallel reaction mixture of the starting material 3-(2-(3,6-dihydro-2H-pyran-4-yl)phenyl)pentan-1,5-diol (3.30 g, 12.6 mmol) for recrystallization . The combined solids were recrystallized from EtOH/heptanes to give the title compound (9.95 g, 37.6 mmol) as a white solid.

LCMS: 1.29 min. (LCMS method 3); MS mass/charge 265.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26-7.18 (m, 2H), 7.14 (m, 2H), 3.93 (dd, J=11.1, 3.6 Hz, 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).

Step 4. 3-(2-(Tetrahydro-2H-pyran-4-yl)phenyl)pentan-1,5-diylbis(4-methylbenzenesulfonate)

3-(2-(Tetrahydro-2H-pyran-4-yl)phenyl)pentan-1,5-diol (7050 mg, 26.7 mmol) was suspended in MeCN (70 ml) and THF (70 ml) and cooled to 0°C. DMAP (326 mg, 2.67 mmol) and TEA (16.4 mL, 117 mmol) were then added. The reaction mixture was cooled to 0°C and stirred for 15 minutes, then tosyl anhydride (19.19 g, 58.7 mmol) was added in four portions and the heterogeneous brown reaction mixture was slowly warmed to room temperature and stirred for 16 hours. Additional tosyl anhydride (4.5 g, 13.8 mmol) was then added and the reaction mixture was stirred for an additional hour. The reaction mixture was then concentrated and the residue was dissolved in EtOAc and the organic phase was washed with water and brine. The combined aqueous thin layers were re-extracted with EtOAc and the combined organic layers were dried over sodium sulfate, filtered and concentrated on celite. The crude material was then purified with FCC (0-60% EtOAc/heptanes) to obtain the title intermediate as a pale yellow solid (10336 mg, 18.05 mmol).

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

¹ H NMR (400 MHz, DMSO _- d6 ) δ 7.73-7.65 (m, 4H), 7.44 (d, J=8.3 Hz, 4H), 7.23 (d, J= 7.4 Hz, 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=11.6 Hz, 1H), 2.41 (s, 6H), 1.91 (m, 2H), 1, 86-1.73 (m, 2H), 1.62 (m, 2H), 1.41 (d, J=12.1 Hz, 2H).

Intermediate 1F. 3-(2-(Benzyloxy)-3,5-difluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

Step 1. 4-(2-(Benzyloxy)-3,5-difluorophenyl)tetrahydro-2H-pyran-2-one

In a round bottom flask, a solution of 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 (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 mixture was then heated to 35°C and stirred for 15 minutes. The reaction mixture was then diluted with EtOAc and 1 M HCl. The layers were separated and aq. the phase was extracted with EtOAc (2×50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated, and the crude material was purified with FCC (0-100% EtOAc/heptanes) to give the title intermediate as a clear colorless oil (784 mg, 2.46 mmol).

LCMS: Rt: 1.07 min. (LCMS method 1); MS mass/charge 319.2 [M+H] ⁺ .

Step 2. 3-(2-(Benzyloxy)-3,5-difluorophenyl)pentane-1,5-diol

In a round bottom flask, add a solution of 4-(2-(benzyloxy)-3,5-difluorophenyl)tetrahydro-2H-pyran-2-one (0.533 g, 1.674 mmol) in THF (10 ml) at -5°C under nitrogen atmosphere LiAlH ₄ (1.0 M in THF, 1.84 mL, 1.842 mmol) was added dropwise over ~2 minutes. After stirring for 35 minutes, the reaction mixture was quenched with water (0.25 ml) at -5°C until gas formation 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 mixture was stirred for 1 hour and then filtered through celite, washing with THF, and the filtrate was concentrated. The crude material was purified with FCC (0-20% MeOH (10% NH ₄ OH)/DCM) to give the title intermediate as a clear colorless oil (501 mg, 1.55 mmol).

LCMS: Rt: 0.90 min. (LCMS method 1); MS mass/charge 323.5 [M+H] ⁺ .

Step 3. 3-(2-(Benzyloxy)-3,5-difluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

In a round bottom flask, triethylamine (1.08 mL, 7.77 mmol), and p TsCl (0.741 g, 3.89 mmol), and DMAP (0.019 g, 0.155 mmol). The reaction mixture was stirred for 16 hours and then the reaction mixture was concentrated and the residue was dissolved in DCM (50 ml) and washed with water (2×10 ml) and brine (1×10 ml), dried over MgSO ₄ , filtered and concentrated. The residue was purified with FCC (0-80% EtOAc/heptanes) to give the title compound as a yellow oil (772 mg, 1.22 mmol).

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

¹ H NMR (400 MHz, CD ₃ OD) δ 7.71-7.60 (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 are overlapped by a peak corresponding to the solvent.

Intermediate connection 1G. 3-(2-Bromo-5-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

Step 1. Triethyl 2-(2-bromo-5-fluorophenyl)propane-1,1,3-tricarboxylate

Sodium metal (25.25 g, 1.10 mol) was added in several batches to EtOH (1.5 L) under a stream of N gas₂ and the reaction mixture was stirred at 25°C until the solid dissolved. Then diethyl malonate (176 g, 1.10 mol) was added to the mixture and stirred at 25°C for 30 minutes, ethyl (E)-3-(2-bromo-5-fluorophenyl)acrylate (150 g, 0. 55 mol; preparation according to Org. Biomol. Chem. 2012, 10, 3655-3661) to the reaction mixture and the reaction mixture was stirred for 16 hours at 80°C. The reaction mixture was then concentrated and the residue was purified with FCC (2-10% EtOAc/petroleum ether) to give the title intermediate (140 g, 323 mmol) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.51 (dd, J=5.5, 8.8 Hz, 1H), 7.02 (dd, J=3.1, 9.8 Hz, 1H) , 6.83 (m, 1H), 4.38 (q, J=7.4, Hz, 1H), 4.24-4.18 (m, 2H), 4.10-3.97 (m, 4H), 3.92 (m, 1H), 2.91 (d, J=7.1 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H), 1.13 (t, J=7.2 Hz, 6H).

Step 2. 3-(2-Bromo-5-fluorophenyl)pentanedioic acid

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 hours. The solution was concentrated to give the title intermediate (109 g, 358 mmol, crude) as a light yellow solid, which was used without further purification.

^1H NMR (400 MHz, DMSO _- d6 ) δ 7.61 (m, 1H), 7.47-7.28 (m, 1H), 7.20-6.98 (m, 1H), 3, 91-3.80 (m, 1H), 2.61 (m, 4H).

Step 3. 3-(2-Bromo-5-fluorophenyl)pentane-1,5-diol

To a solution of 3-(2-bromo-5-fluorophenyl)pentanedioic acid (105 g, crude) in THF (1000 ml) was added B ₂ H ₆ (172 ml, 17.2 mmol, 10 M in dimethyl sulfide) dropwise at 0 °C. The solution was then heated to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0°C and quenched with MeOH (500 ml) and HCl (250 ml, 4 M in EtOAc), and then the solution was concentrated. The residue was purified with FCC (5-100% EtOAc:DCM (3:1)/petroleum ether) to give the title intermediate (43.3 g, 156 mmol) as a white solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.58-7.54 (m, 1H), 7.12 (m, 1H), 6.89 (m, 1H), 3.55-3.38 (m, 5H), 2.00-1.79 (m, 4H).

Step 4. 3-(2-Bromo-5-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

3-(2-Bromo-5-fluorophenyl)pentane-1,5-diol (5000 mg, 18.04 mmol) was placed in a 250 ml round bottom flask and dissolved in MeCN (100 ml). TEA (11.1 ml, 79 mmol) and DMAP (220 mg, 1.804 mmol) were then added and the reaction mixture was cooled to 0°C. The reaction mixture was stirred for 10 minutes at 0°C and then tosyl anhydride (13000 mg, 39.8 mmol) was added and the reaction mixture was slowly warmed to room temperature and the reaction mixture was stirred overnight. The material was then concentrated on Celite for purification with FCC (0-60% EtOAc/heptanes) to give the title intermediate as a light brown oil (9700 mg, 16.57 mmol).

LCMS: Rt: 3.00 min. (LCMS method 1); MS mass/charge 604.1 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75-7.67 (m, 4H), 7.42 (dd, J=8.8, 5.5 Hz, 1H), 7.31 (d, J=8.0 Hz, 4H), 6.78 (m, 1H), 6.73-6.62 (m, 1H), 3.88 (m, 2H), 3.80 (dt, J=10 ,1, 6.9 Hz, 2H), 3.34 (s, 1H), 2.44 (s, 6H), 2.05-1.93 (m, 2H), 1.89 (bs, 2H) .

Intermediate 1H. 3-(2-Bromophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

Step 1. Triethyl 2-(2-bromophenyl)propane-1,1,3-tricarboxylate

Na (27.04 g, 1180 mol) was added in several batches to EtOH (1.5 L) under a stream of N ₂ gas and the reaction mixture was stirred at 25°C until no solids disappeared. Diethyl malonate (188 g, 1180 mmol) was then added and the reaction mixture was stirred at 25°C for 30 minutes. Ethyl (E)-3-(2-bromophenyl)acrylate (150 g, 588 mmol) was then added to the mixture. The mixture was then stirred for 16 hours at 80°C. The reaction mixture was then concentrated and the residue was purified by FCC (the residue was purified by column chromatography (2-20% EtOAc/petroleum ether) to give the title compound (133 g, 320 mmol) as a colorless oil.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.57-7.48 (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).

Step 2. Diethyl 3-(2-bromophenyl)pentanedioate

NaCl (56 g, 960 mmol) and H ₂ O (17 g, 960 mmol). The mixture was stirred at 160°C for 6 hours. The reaction mixture was then quenched 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 in as a yellow oil, which was used without further purification (105 g, 305 mmol).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.58-7.55 (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 ).

Step 3. 3-(2-Bromophenyl)pentane-1,5-diol

To a suspension of lithium aluminum hydride (29 g, 765 mmol) in THF (800 ml) was added dropwise a solution of diethyl 3-(2-bromophenyl)pentanedioate (105 g, 305 mmol) in THF (200 ml) at 0°C. The reaction mixture was stirred at 25°C for 2 hours, then the reaction mixture was added dropwise to the 2N solution. HCl (2 L) and then extracted with EtOAc (3x500 ml). The combined organic phases were washed with brine (500 ml), dried over sodium sulfate, filtered and concentrated. The residue was purified with FCC (10-100% EtOAc/DCM (3:1)/petroleum ether) to give a white solid. The solid was then triturated with EtOAc (100 mL) and filtered, the filter cake was washed with cold EtOAc (2 x 50 mL) to give the title compound as a white solid (47.2 g, 182 mmol).

^1H NMR (400 MHz, CD ₃ OD) δ 7.55-7.53 (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).

Step 4. 3-(2-Bromophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

3-(2-Bromophenyl)pentane-1,5-diol (10 g, 38.6 mmol) and DMAP (0.471 g, 3.86 mmol) were added to a 500 mL round bottom flask and dissolved in MeCN (200 mL). The reaction mixture was cooled to 0°C and TEA (32.1 ml, 232 mmol) was added, the reaction mixture was stirred for 10 minutes and then p TsCl (16.92 g, 89 mmol) was added. The reaction mixture was then slowly warmed to room temperature and stirred overnight. The reaction mixture was concentrated, the residue was dissolved in DCM and washed with 1 N. HCl (4x50 ml) and the combined aqueous layers were again extracted with 1x50 ml DCM (1x50 ml). The combined organic layers were washed with brine (1 x 10 ml), dried over sodium sulfate and concentrated. The crude material was then purified with FCC (0-50% EtOAc/heptanes) to give the title compound (19.52 g, 34.4 mmol) as a yellow oil.

¹ H NMR (400 MHz, DMSO _- d6 ) δ 7.70-7.62 (m, 4H), 7.49 (dd, J=8.2, 1.4 Hz, 1H), 7.41 ( d, J=8.2, Hz, 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).

Intermediate connection 2A. rubs -Butyl-( S )-7-amino-5-oxa-2-azaspiro[3.4]octane-2-carboxylate hydrochloride

tert -Butyl-7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (commercially available, 200 g, 0.88 mol), isopropylamine hydrochloride (845 g, 8.89 mol) and pyridoxal- 5'-phosphate hydrate (10 g, 0.04 mol) was dissolved in DMSO (800 ml) and 0.1 M borate buffer (6200 ml, pH 9.0). The reaction mixture was then heated 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 ₂ was bubbled through the solution and the reaction mixture was stirred until complete conversion was achieved. The reaction mixture was then cooled to 26°C and citric acid was added until the pH reached 4.88. DCM (1500 ml) was added and the DCM layer was filtered through microcrystalline cellulose to remove the enzyme. The aqueous layer was treated with NaCl (1200 mg, 20.5 mol) and the pH was adjusted with 32% NaOH to 9.9. The aqueous layer was extracted with DCM (3 x 2000 ml). The DCM extracts and filtrate were combined and concentrated under reduced pressure and the residue was taken up in EtOAc (1500 ml) and washed with brine (2×100 ml). EtOAc was then concentrated to dryness and the residue was suspended in EtOAc (1000 ml) and filtered to remove NaCl and enzyme. EtOAc was concentrated to give the free base of the title compound (146.9 g, 0.643 mol). The free base was dissolved in EtOAc (870 ml) and HCl in EtOAc (2 M, 390 ml) was added over an hour. The reaction mixture was stirred for 2 hours, then filtered and the filter cake was washed with EtOAc (100 ml). The filter cake was then dried to give the title intermediate (169 g, 0.639 mmol).

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

¹ H NMR (400 MHz, CD ₃ OD) δ 4.11 (d, J=4.8 Hz, 2H), 4.01-3.89 (m, 5H), 2.71 (m, 1H), 2.27-2.17 (m, 1H), 1.46 (s, 9H).

Intermediate connection 3A. rubs -Butyl-( S )-7-(4-(2-(benzyloxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

3-(2-(Benzyloxy)-5-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate) (intermediate 1B, 35.41 g, 54.8 mmol) and tert-butyl( S )-7- Amino-5-oxa-2-azaspiro[3.4]octane-2-carboxylate hydrochloride (intermediate 2, 14.50 g, 54.8 mmol) was suspended in MeCN (500 ml) and tribasic potassium phosphate (34, 9 g, 164 mmol). The reaction mixture was stirred at 90°C for 72 hours. The solvent was then removed in vacuo and the solid residue was suspended in EtOAc. The slurry was filtered and the filtrate was concentrated to give the crude product as an orange oil. The crude product was purified with FCC (0-10% MeOH (1% NH ₄ OH)/DCM) to give the title compound (17.09 g, 33.9 mmol).

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

^1H NMR (400 MHz, CD ₃ OD) δ 7.47-7.26 (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, 7.4 Hz, 2H), 3.05 (m, 3H ), 2.96-2.72 (m, 1H), 2.42 (dd, J=12.9, 7.5 Hz, 1H), 2.18 (m, 2H), 2.03 (dd, J=12.9, 8.5 Hz, 1H), 1.91-1.60 (m, 4H), 1.43 (s, 9H).

The following compounds in Table 1 were prepared using a similar procedure and corresponding starting materials.

Table 1. Intermediates 3B - 3H

Intermediate connection Structure Retention time (min.) and
way Expected
weight Observable
weight 3B 1.33
Method 2 LCMS 497.3
[M+H] ⁺ 497.4
[M+H] ⁺ 3C 1.31
Method 2 LCMS 515.3
[M+H] ⁺ 515.4
[M+H] ⁺ 3D 2.61
Method 4 LCMS 457.3
[M+H] ⁺ 457.8
[M+H] ⁺ 3E 1.35
Method 2 LCMS 515.3
[M+H] ⁺ 515.3
[M+H] ⁺ 3F 2.96
Method 4 LCMS 469.2
[M+H] ⁺ 469.5
[M+H] ⁺ 3G 1.33 min.
Method 2 LCMS 479.3
[M+H] ⁺ 479.2
[M+H] ⁺ 3H 0.76 min.
Method 1 LCMS 451.2
[M+H] ⁺ 451.3
[M+H] ⁺

Intermediate connection 4A. rubs -Butyl-( S )-7-(4-(5-fluoro-2-hydroxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

To a stirred solution of tert -butyl-( S )-7-(4-(2-(benzyloxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate ( 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 mixture was then stirred under a hydrogen atmosphere from a balloon for 5 hours. The reaction mixture was then filtered through a pad of celite and the solvent was removed under reduced pressure to obtain a clear oil. Diethyl ether (100 ml) was added and the solvent was removed in vacuo . This was repeated two more times to obtain the title compound as a white solid (5.48 g, 13.48 mmol).

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

^1H NMR (400 MHz, CD ₃ OD) δ 6.90-6.80 (m, 1H), 6.79-6.66 (m, 2H), 4.15-3.81 (m, 5H) , 3.74 (dd, J=8.7, 7.4 Hz, 1H), 3.16-2.81 (m, 4H), 2.45 (dd, J=12.9, 7.5 Hz , 1H), 2.23 (m, 2H), 2.07 (dd, J=12.9, 8.5 Hz, 1H), 1.93-1.61 (m, 4H), 1.46 ( s, 9H).

The following compounds in Table 2 were prepared using a similar procedure and corresponding starting materials.

Table 2. Intermediates 4B - 4E

Intermediate connection Structure Retention time (min.) and
way Expected
weight Observable
weight 4B 1.18
Method 1 LCMS 407.4
[M+H] ⁺ 407.2
[M+H] ⁺ 4C 0.52
Method 1 LCMS 393.4
[M+H] ⁺ 393.2
[M+H] ⁺ 4D 1.02
Method 2 LCMS 425.2
[M+H] ⁺ 425.2
[M+H] ⁺ 4E 0.97
Method 2 LCMS 389.2
[M+H] ⁺ 389.3
[M+H] ⁺

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

(S)-7-(4-(2-(Benzyloxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-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 contents of the flask were then stirred in an atmosphere of hydrogen with which the balloon was filled for six hours. The suspension was then filtered through a pad of celite and the precipitate was washed with DCM. The filtrate was concentrated under reduced pressure to give the title intermediate (1300 mg, 3.47 mmol).

LCMS: Rt: 0.75 min. (LCMS method 2); MS mass/charge 375.3 [M+H] ⁺ .

Intermediate connection 5A. (2-Oxaspiro[3.3]heptan-6-yl)methyl-4-methylbenzenesulfonate

To a solution of (2-oxaspiro[3.3]heptan-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) p TsCl (78 mg, 0.410 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with DCM and washed with 1N. HCl solution, sat. NaHCO ₃ solution, water and saline solution, then dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the crude product was purified using FCC (0-60% EtOAc/heptanes) to give the title compound (71 mg, 0.226 mmol).

LCMS: Rt: 0.92 min. (LCMS method 1).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.80 (d, J=8.5 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 4.66 (s, 2H), 4.54 (s, 2H), 3.95 (d, J=5.9 Hz, 2H), 2.48 (s, 3H), 2.46-2.27 (m, 3H), 2.01-1.89 (m, 2H).

The following compounds in Table 3 were prepared using a similar procedure and corresponding starting materials.

Table 3. Intermediates 5B - 5T

Intermediate connection Structure Retention time (min.) and
way Expected
weight Observable
weight 5B 0.82
Method 2 LCMS 273.1
[M+H] ⁺ 273.0
(M+H) 5C 0.84
Method 1 LCMS 243.1
[M+H] ⁺ 243.1
(M+H) 5D 0.91
Method 1 LCMS 254.1
[M+H] ⁺ 254.2
(M+H) 5E 0.82
Method 1 LCMS 273.1
[M+H] ⁺ 273.0
(M+H) 5F 0.83
Method 2 LCMS 260.1
[M+NH ₄ ] ⁺ 260.3
[M+NH ₄ ] ⁺ 5G 0.86
Method 1 LCMS 257.1
[M+H] ⁺ 257.2
[M+H] ⁺ 5H 0.90
Method 2 LCMS 269.1
[MH] ^- 269.2
[MH] ^- 5I 0.87
Method 1 LCMS 257.1
[M+H] ⁺ 257.2
[M+H] ⁺ 5J 0.70
Method 1 LCMS 259.1
[M+H] ⁺ 259.3
[M+H] ⁺ 5K 0.99
Method 1 LCMS 286.1
[M+NH ₄ ] ⁺ 286.0
[M+NH ₄ ] ⁺ 5L 0.92
Method 1 LCMS 257.1
[M+H] ⁺ 257.2
[M+H] ⁺ 5M 0.87
Method 2 LCMS 269.1
[M+H] ⁺ 269.3
[M+H] ⁺ 5N 0.96
Method 1 LCMS 288.1
[M+NH ₄ ] ⁺ 288.1
[M+NH ₄ ] ⁺ 5O 0.93
Method 1 LCMS 271.1
[M+H] ⁺ 271.2
[M+H] ⁺ 5P 1.02
Method 2 LCMS 273.1
[M+H] ⁺ 273.2
[M+H] ⁺ 5Q 0.84
Method 1 LCMS 278.1
[M+NH ₄ ] ⁺ 278.1
[M+NH ₄ ] ⁺ 5S 0.95
Method 1 LCMS 285.2
[M+H] ⁺ 257.2
[M+H] ⁺ 5T 0.97
Method 2 LCMS 302.2
[M+NH ₄ ] ⁺ 302.1
[M+NH ₄ ] ⁺

Intermediate connection 6A. rubs -Butyl-( S )-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octan-2-carboxylate

tert -Butyl-(S)-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 mixture was stirred at 80°C overnight. The mixture was diluted with EtOAc and washed with water, dried over MgSO ₄ and concentrated in vacuo . The residue was purified with FCC (0-10% MeOH/DCM) to give the title intermediate (412 mg, 0.891 mmol).

LCMS: Rt: 1.08 min. (LCMS method 2); MS mass/charge 463.3 [M+H] ⁺ .

The following compounds in Table 4 were prepared using a similar procedure and corresponding starting materials.

Table 4. Intermediates 6B - 6AA

Intermediate connection Structure Retention time (min.) and
way Expected
weight Observable
weight 6B 1.18
Method 2 LCMS 491.3
[M+H] ⁺ 491.2
[M+H] ⁺ 6C 0.82
Method 1 LCMS 507.3
[M+H] ⁺ 507.3
[M+H] ⁺ 6D 0.83
Method 1 LCMS 477.3
[M+H] ⁺ 477.4
[M+H] ⁺ 6E 1.15
Method 2 LCMS 488.3
[M+H] ⁺ 488.3
[M+H] ⁺ 6F 1.11
Method 2 LCMS 507.3
[M+H] ⁺ 507.4
[M+H] ⁺ 6G 1.16
Method 2 LCMS 491.1
[M+H] ⁺ 491.3
[M+H] ⁺ 6H 1.13
Method 2 LCMS 477.3
[M+H] ⁺ 477.4
[M+H] ⁺ 6I 0.98
Method 2 LCMS 491.3
[M+H] ⁺ 491.4
[M+H] ⁺ 6J 1.18
Method 2 LCMS 505.3
[M+H] ⁺ 505.3
[M+H] ⁺ 6K 1.28
Method 2 LCMS 507.3
[M+H] ⁺ 507.4
[M+H] ⁺ 6L 1.13
Method 2 LCMS 465.3
[M+H] ⁺ 465.4
[M+H] ⁺ 6M 1.27
Method 2 LCMS 499.3
[M+H] ⁺ 499.2
[M+H] ⁺ 6N 1.11
Method 2 LCMS 459.3
[M+H] ⁺ 459.2
[M+H] ⁺ 6O 0.75
Method 1 LCMS 445.3
[M+H] ⁺ 445.2
[M+H] ⁺ 6P 1.16
Method 2 LCMS 495.3
[M+H] ⁺ 495.3
[M+H] ⁺ 6Q 0.75
Method 1 LCMS 493.3
[M+H] ⁺ 492.9
[M+H] ⁺ 6R 1.08
Method 4 LCMS 479.3
[M+H] ⁺ 479.7
[M+H] ⁺ 6S 1.13
Method 2 LCMS 485.3
[M+H] ⁺ 485.2
[M+H] ⁺ 6T 1.11
Method 2 LCMS 495.2
[M+H] ⁺ 495.2
[M+H] ⁺ 6U 1.12
Method 2 LCMS 513.3
[M+H] ⁺ 513.6
[M+H] ⁺ 6V 1.09
Method 2 LCMS 481.2
[M+H] ⁺ 481.5
[M+H] ⁺ 6W 1.09
Method 2 LCMS 463.3
[M+H] ⁺ 463.4
[M+H] ⁺ 6X 1.22
Method 2 LCMS 519.3
[M+H] ⁺ 519.2
[M+H] ⁺ 6Y 1.13
Method 1 LCMS 503.3
[M+H] ⁺ 503.2
[M+H] ⁺ 6Z 0.81
Method 1 LCMS 473.6
[M+H] ⁺ 473.6
[M+H] ⁺ 6AA 1.08
Method 2 LCMS 485.3
[M+H] ⁺ 485.4
[M+H] ⁺

Intermediate connection 6Z. rubs -Butyl-( S )-7-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

( 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 mixture was stirred at room temperature for 3 days, filtered and washed with EtOAc. The filtrate was concentrated and purified with FCC (0-10% MeOH/DCM) to give the title intermediate (216 mg, 0.49 mmol).

LCMS: Rt: 1.18 min. (LCMS method 2); MS mass/charge 421.2 [M+H] ⁺ .

The following compounds in Table 5 were prepared in a similar manner using the appropriate starting materials.

Table 5. Intermediates 6BB - 6DD

Intermediate connection Structure Retention time (min.) and
way Expected
weight Observable
weight 6BB 1.15
Method 2 LCMS 493.3
[M+H] ⁺ 493.3
[M+H] ⁺ 6CC 1.17
Method 2 LCMS 403.3
[M+H] ⁺ 403.3
[M+H] ⁺ 6DD 1.17
Method 2 LCMS 421.2
[M+H] ⁺ 421.6
[M+H] ⁺

Intermediate connection 7A. ( S )-7-(4-(5-Fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

tert -Butyl-( S )-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, dried over MgSO ₄ , filtered and concentrated to give the title intermediate (582 mg, 1.61 mmol).

LCMS: Rt: 0.44 min. (LCMS method 1); MS mass/charge 363.3 [M+H] ⁺ .

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

To a stirred solution of tert -butyl-( S )-7-(4-(2-(benzyloxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate ( intermediate 3A, 2000 mg, 4.03 mmol) in DCM (5 ml) was added TFA (6.2 ml). The reaction mixture was stirred at room temperature for 3 hours and then the solvent was removed under reduced pressure. The residues were diluted in EtOAc and water and the pH of the aqueous phase was adjusted to 8-9 4N. NaOH. The layers were separated and the aqueous phase was extracted with EtOAc, 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).

LCMS: Rt: 0.61 min. (LCMS method 1); MS mass/charge 397.4 [M+H] ⁺ .

The following compounds in Table 6 were prepared in a similar manner using the appropriate starting materials.

Table 6. Intermediates 7C - 7QQ

Intermediate connection Structure Retention time (min.) and
way Expected
weight Observable
weight 7C 0.50
Method 1 LCMS 407.2
[M+H] ⁺ 407.4
[M+H] ⁺ 7D 0.88
Method 2 LCMS 377.2
[M+H] ⁺ 377.2
[M+H] ⁺ 7E 0.54
Method 1 LCMS 388.2
[M+H] ⁺ 388.3
[M+H] ⁺ 7F 0.50
Method 1 LCMS 407.2
[M+H] ⁺ 407.4
[M+H] ⁺ 7G 0.94
Method 2 LCMS 391.2
[M+H] ⁺ 391.2
[M+H] ⁺ 7H 0.45
Method 1 LCMS 377.2
[M+H] ⁺ 377.5
[M+H] ⁺ 7I 0.52
Method 1 LCMS 405.3
[M+H] ⁺ 405.3
[M+H] ⁺ 7J 0.94
Method 2 LCMS 391.2
[M+H] ⁺ 391.2
[M+H] ⁺ 7K 0.60
Method 1 LCMS 379.2
[M+H] ⁺ 379.4
[M+H] ⁺ 7L 0.47
Method 1 LCMS 357.3
[M+H] ⁺ 357.4
[M+H] ⁺ 7M 0.99
Method 2 LCMS 407.3
[M+H] ⁺ 407.2
[M+H] ⁺ 7N 0.92
Method 2 LCMS 365.2
[M+H] ⁺ 365.1
[M+H] ⁺ 7O 0.50
Method 1 LCMS 393.3
[M+H] ⁺ 393.0
[M+H] ⁺ 7P 0.46
Method 1 LCMS 359.2
[M+H] ⁺ 359.6
[M+H] ⁺ 7Q 0.45
Method 1 LCMS 345.2
[M+H] ⁺ 345.2
[M+H] ⁺ 7R 0.85
Method 1 LCMS 395.2
[M+H] ⁺ 395.4
[M+H] ⁺ 7S 0.46
Method 1 LCMS 393.3
[M+H] ⁺ 393.2
[M+H] ⁺ 7T 0.88
Method 2 LCMS 351.2
[M+H] ⁺ 351.6
[M+H] ⁺ 7U 0.45
Method 1 LCMS 379.2
[M+H] ⁺ 379.5
[M+H] ⁺ 7V 0.46
Method 1 LCMS 355.2
[M+H] ⁺ 355.3
[M+H] ⁺ 7W 0.48
Method 1 LCMS 393.2
[M+H] ⁺ 393.4
[M+H] ⁺ 7X 0.86
Method 2 LCMS 303.2
[M+H] ⁺ 303.3
[M+H] ⁺ 7Y 0.42
Method 1 LCMS 321.2
[M+H] ⁺ 321.2
[M+H] ⁺ 7Z 0.80
Method 2 LCMS 341.2
[M+H] ⁺ 341.2
[M+H] ⁺ 7AA 0.49
Method 1 LCMS 361.2
[M+H] ⁺ 361.2
[M+H] ⁺ 7BB 0.53
Method 1 LCMS 375.2
[M+H] ⁺ 375.2
[M+H] ⁺ 7CC 0.51
Method 1 LCMS 371.3
[M+H] ⁺ 371.4
[M+H] ⁺ 7DD 0.49
Method 1 LCMS 321.2
[M+H] ⁺ 321.1
[M+H] ⁺ 7EE 0.63
Method 1 LCMS 415.5
[M+H] ⁺ 415.2
[M+H] ⁺ 7FF 0.44
Method 1 LCMS 351.2
[M+H] ⁺ 351.6
[M+H] ⁺ 7GG 0.44
Method 1 LCMS 340.2
[M+H] ⁺ 340.3
[M+H] ⁺ 7HH 0.43
Method 1 LCMS 355.2
[M+H] ⁺ 355.3
[M+H] ⁺ 7II 0.48
Method 1 LCMS 385.3
[M+H] ⁺ 385.4
[M+H] ⁺ 7JJ 0.50
Method 1 LCMS 395.2
[M+H] ⁺ 395.4
[M+H] ⁺ 7KK 0.51
Method 1 LCMS 413.2
[M+H] ⁺ 413.5
[M+H] ⁺ 7LL 0.45
Method 1 LCMS 381.2
[M+H] ⁺ 381.1
[M+H] ⁺ 7MM 0.44
Method 1 LCMS 363.2
[M+H] ⁺ 363.3
[M+H] ⁺ 7NN 0.50
Method 1 LCMS 403.2
[M+H] ⁺ 403.4
[M+H] ⁺ 7OO 0.52
Method 1 LCMS 373.3
[M+H] ⁺ 373.6
[M+H] ⁺ 7PP 0.43
Method 1 LCMS 385.2
[M+H] ⁺ 385.2
[M+H] ⁺ 7QQ 0.94
Method 2 LCMS 391.2
[M+H] ⁺ 391.2
[M+H] ⁺

Intermediate connection 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

tert -Butyl-( S )-7-(4-(5-fluoro-2-hydroxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylatefluorophenol (intermediate 4A , 619 mg, 1.523 mmol) was dissolved in DCM (3 ml) and TFA (1.0 ml) was added. The reaction mixture was stirred at RT for one hour, additional TFA (1.0 ml) was added and the reaction mixture was stirred for another hour at RT. The reaction mixture was then concentrated and the crude material was dissolved in a 2% aqueous solution TPGS-750-M (6.8 ml) and added THF (0.76 ml), K ₃ PO ₄ (970 mg, 4.57 mmol) and 2-bromo-1,3,4-thiadiazole (503 mg, 3.05 mmol). The reaction mixture was stirred at 60°C for 40 minutes and then cooled to room temperature, diluted with saturated aqueous NaHCO ₃ and extracted with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude material was purified using FCC (0-10% MeOH (10% NH ₄ OH)/DCM) to obtain the title intermediate (78 mg, 0.200 mmol) as a white solid.

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

¹ H NMR (CD ₃ OD) δ 8.66 (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), 3.17-3.05 (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).

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

( 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 to -5°C in an ice-acetone 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 for 30 minutes. at -5°C and then the reaction mixture was concentrated under reduced pressure. EtOAc was added to the residue, 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 in water (8.3 ml) dropwise over 3 minutes. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was then cooled to -10°C and 1 M aqueous HCl was added over 3 hours until pH 2 was reached. The reaction mixture was then poured into EtOAc and increased in basicity using 2 M Na ₂ CO ₃ . The organic layer was separated and dried over magnesium sulfate, filtered and concentrated. The residue was then purified with FCC (0-10% MeOH (1% NH ₄ OH)/DCM) to give the title intermediate (655 mg, 1.325 mmol).

LCMS: Rt: 2.60 min. (LCMS method 4); MS mass/charge 465.4 [M+H] ⁺ .

The following compound in Table 7 was prepared using a similar procedure and appropriate starting materials.

Table 7. 8C Intermediate

Intermediate connection Structure Retention time (min.) and
way Expected
weight Observable
weight 8C 0.94
Method 1 LCMS 483.3
[M+H] ⁺ 483.2
[M+H] ⁺

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

( 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 mixture was stirred at 0°C for 10 minutes, 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 mixture was cooled to 0°C and stirred for 10 minutes. Trifluoromethanesulfonic anhydride (1.17 mL, 1.17 mmol, 1 M in DCM) was then added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, then pyridine (0.21 ml, 2.6 mmol) was added and the reaction mixture was cooled to 0°C and stirred for 10 minutes. Trifluoromethanesulfonic anhydride (1.17 mL, 1.17 mmol, 1 M in DCM) was added at 0° C. and the reaction mixture was heated and stirred at room temperature for 20 minutes. The reaction mixture 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 sat. aq. NaHCO ₃ solution, saline, dried with MgSO ₄ , filtered and evaporated. The residue was purified with FCC (0-10% MeOH/DCM) to give the title intermediate (1.30 g, 2.28 mmol).

LCMS: Rt: 3.01 min. (LCMS method 4); MS mass/charge 521.5 [M+H] ⁺ .

The following compound in Table 8 was prepared using a similar procedure and appropriate starting materials.

Table 8. Intermediate 9B

Intermediate connection Structure Retention time (min.) and
way Expected
weight Observable
weight 9B 1.29
Method 2 LCMS 539.0
[M+H] ⁺ 539.2
[M+H] ⁺

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

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). The vessel was sealed, then evacuated and filled again with nitrogen gas (the process was repeated four times). EtOH (3 ml) was added using a syringe, followed by the addition of a solution of tert-butyl-( S )-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 oven at 80°C for 2 hours. Potassium carbonate (64 mg, 0.46 mmol) in water (1 mL, previously degassed) was then 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 oven at 80°C for 14 hours, then filtered and evaporated under reduced pressure. The residue was purified with FCC (0-100% EtOAc (1% (10% NH ₄ OH in MeOH))/heptane) to give the title intermediate (53 mg, 0.12 mmol).

LCMS: Rt: 0.97 min. (LCMS method 2); MS mass/charge 451.3 [M+H] ⁺ .

The following compounds in Table 9 were prepared using a similar procedure and corresponding starting materials.

Table 9. Intermediates 10B - 10E

Intermediate connection Structure Retention time (min.) and
way Expected
weight Observable
weight 10B 1.12
Method 2 LCMS 440.3
[M+H] ⁺ 440.4
[M+H] ⁺ 10C 1.01
Method 2 LCMS 455.3
[M+H] ⁺ 455.4
[M+H] ⁺ 10D 1.19
Method 2 LCMS 469.4
[M+H] ⁺ 469.3
[M+H] ⁺ 10E 1.00
Method 2 LCMS 451.3
[M+H] ⁺ 451.6
[M+H] ⁺

Intermediate connection 11A. ( S )-7-(4-(2-((2-Oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane- 2-carbonitrile

In a round bottom flask, a solution of ( S )-7-(4-(2-((2-oxaspiro[3.3]heptan-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 mixture 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 saline solution, dried over MgSO ₄ , filtered and concentrated. The residue was purified with FCC (0-100% 10% 7N NH ₃ in MeOH/DCM) to give the title intermediate as a white solid (115 mg, 0.269 mmol).

LCMS: Rt: 0.95 min. (LCMS method 2); MS mass/charge 428.5 [M+H] ⁺ .

The following compounds in Table 10 were prepared in a similar manner using the appropriate starting materials.

Table 10. Intermediates 11B - 11C

Intermediate connection Structure Retention time (min.) and LCMS method Expected mass Observed mass 11B 0.95
Method 2 LCMS 416.2
[M+H] ⁺ 416.2
[M+H] ⁺ 11C 0.87
Method 2 LCMS 388.2
[M+H] ⁺ 388.3
[M+H] ⁺

Intermediate connection 12A. ( S )-7-(4-(2-((2-Oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-N-hydroxy-5-oxa-2-azaspiro[ 3.4]octane-2-carboximidamide

In a 100 ml round bottom flask to a solution of ( S )-7-(4-(2-((2-oxaspiro[3.3]heptan-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 with K ₂ CO ₃ (112 mg, 0.807 mmol) followed by the addition of hydroxylamine hydrochloride ( 33.6 mg, 0.484 mmol). The reaction mixture was stirred at 50°C for 5 hours and then at room temperature for 17 hours. Additional hydroxylamine hydrochloride (6.6 mg, 0.09 mmol) was added and the reaction mixture was stirred at 50°C for 40 minutes and then the reaction mixture was concentrated and the residue was taken up in 10:1 DCM:MeOH, filtered through celite and concentrated. The resulting clear oil was dried under high vacuum overnight to give a yellow solid which was used without further purification (119 mg, 0.259 mmol).

LCMS: Rt: 0.84 min. (LCMS method 2); MS mass/charge 461.4 [M+H] ⁺ .

The following compounds in Table 11 were prepared in a similar manner using the appropriate starting materials.

Table 11. Intermediates 12B - 12C

Intermediate connection Structure Retention time (min.) and LCMS method Expected mass Observed mass 12B 0.84
Method 2 LCMS 449.3
[M+H] ⁺ 449.4
[M+H] ⁺ 12C 0.76 min.
Method 2 LCMS 421.2
[M+H] ⁺ 421.3
[M+H] ⁺

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

( S )-7-(4-(5-Fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7A, 540 mg , 1.49 mmol) was dissolved in a 2% aqueous solution of TPGS-750-M (2.6 ml) and THF (0.3 ml). Ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (329 mg, 1.49 mmol) and tribasic potassium phosphate (949 mg, 4.47 mmol) were then added. The mixture was stirred at room temperature overnight, then 2 M LiOH (2.2 mL, 4.5 mmol) was added and the reaction mixture was stirred at room temperature overnight. MeOH (6 ml) was added followed by 4N. HCl solution to adjust the reaction mixture to pH=2; then stirred at room temperature for 4 hours. The pH of the reaction mixture was then adjusted to >8, the aqueous layer was extracted with DCM, and the combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo . The residue was purified using FCC (0-10% MeOH/DCM) and further purified using preparative HPLC (XBridge 30x50 mm, 5 µm, 15-40% MeCN/H ₂ O (5 mM NH4OH), 75 ml/min .) to obtain the title compound (214 mg, 0.495 mmol).

LCMS: Rt: 1.77 min. (LCMS method 4); MS mass/charge 431.1 [M+H] ⁺ .

^1H NMR (DMSO -d6 ) δ 8.65 (s, _1H ), 7.04 (dd, J=9.8, 2.9 Hz, 1H), 6.98-6.86 (m, 1H ), 6.56 (dd, J=8.9, 4.6 Hz, 1H), 5.30-5.19 (m, 1H), 4.91 (t, J=6.6 Hz, 2H) , 4.59-4.47 (m, 2H), 4.22 (d, J=8.7 Hz, 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

( 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 mixture 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 saline and concentrated. A portion of this material (97 mg, 0.248 mmol) was then dissolved in THF (0.05 mL), 2% aqueous solution of TPGS-750-M (0.45 mL) and ethyl 5-bromo-1,3,4- oxadiazole-2-carboxylate (54 mg, 0.248 mmol) and K ₃ PO ₄ (52.7 mg, 0.248 mmol). The reaction mixture was worked up as in Example 1A and the crude material was purified using FCC (0-7% MeOH/DCM) and preparative HPLC (C18 OBD column 30×50 mm, 5 µm, 75 ml/min, 25- 50% MeCN/H ₂ O (5 mM NH ₄ OH) to give the title compound (43 mg, 0.092 mmol).

LCMS: Rt: 2.05 min. (LCMS method 4); MS mass/charge 459.1 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ: 8.64 (s, 1H), 6.92-7.02 (m, 3H), 4.22 (d, J=8.8 Hz, 1H), 4 ,13 (dd, J=8.6, 2.7 Hz, 2H), 4.02 (d, J=8.3 Hz, 1H), 3.98-3.91 (m, 2H), 3, 90-3.80 (m, 2H), 3.76 (td, J=8.1, 5.4 Hz, 1H), 3.72-3.65 (m, 1H), 3.65-3, 58 (m, 1H), 3.53 (dd, J=8.3, 5.9 Hz, 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).

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

( 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 a 2% aqueous solution of TPGS-750-M (372 μL) and THF (41 μL). Ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (46 mg, 0.21 mmol) and tribasic potassium phosphate (44 mg, 0.21 mmol) were added and the reaction mixture was worked up as in Example 1A. The crude material was purified using FCC (0-7% MeOH/DCM) and preparative HPLC (XBridge 30x50 mm, 5 µm, 25-50% MeCN/H2O (5 mM NH4OH), 75 ml/min.) to obtain the above in the title compound (28 mg, 0.058 mmol).

LCMS: Rt: 1.90 min. (LCMS method 4); MS mass/charge 475.2 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.64 (s, 1H), 7.02-6.92 (m, 3H), 4.22 (d, J=8.8 Hz, 1H), 4, 13 (dd, J=8.3, 3.9 Hz, 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, 7.3 Hz, 1H), 2.12-2.01 ( m, 3H), 1.75-1.66 (m, 2H), 1.65-1.51(m, 2H).

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

( S )-7-(4-(2-((( R )-1,4-Dioxan-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 a 2% aqueous solution of TPGS-750-M (372 μL) and THF (41 μL). Ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (46 mg, 0.21 mmol) and tribasic potassium phosphate (44 mg, 0.21 mmol) were added and the reaction mixture was worked up as in Example 1A. The crude material was purified by FCC (0-7% MeOH/DCM) followed by preparative HPLC (XBridge 30x50 mm, 5 µm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/ min.) to obtain the title compound (36 mg, 0.058 mmol).

LCMS: Rt: 1.91 min. (LCMS method 4); MS mass/charge 445.1 [M+H] ⁺ .

^1H NMR (400 MHz, DMSO _- d6 ) δ 8.65 (s, 1H), 7.07-6.88 (m, 3H), 5.01 (t, J=5.3 Hz, 1H) , 4.22 (d, J=8.7 Hz, 1H), 4.18-4.09 (m, 2H), 4.02 (d, J=8.4 Hz, 1H), 3.93 ( t, J=7.6 Hz, 1H), 3.89-3.71 (m, 4H), 3.67-3.57 (m, 1H), 3.03-2.90 (m, 2H) , 2.80 (t, J=12.7 Hz, 2H), 2.40 (dd, J=12.8, 7.9 Hz, 1H), 2.18 (m, 1H), 2.12- 1.89 (m, 4H), 1.63 (m, 4H).

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-dimethylpropanenitrile

( S )-3-(2-(1-(5-Oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2,2-dimethylpropanenitrile (intermediate 7E , 20 mg, 0.052 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (14 mg, 0.062 mmol) and tribasic potassium phosphate (13 mg, 0.062 mmol) were dissolved in 2% aqueous TPGS solution -750-M (0.7 ml) and THF (0.18 ml). The reaction mixture 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 mixture was stirred at room temperature for 1 hour. 6 M HCl was added to adjust the pH to 4 and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then increased in basicity with sodium bicarbonate solution, extracted with EtOAc and concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge, 30x50 mm, 5 μm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to give the title compound (2.8 mg, 0.0060 mmol).

LCMS: Rt: 2.09 min. (LCMS method 4); MS mass/charge 456.3 [M+H] ⁺ .

¹ H NMR (CD ₃ OD) δ 8.39 (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), 3.12-3.04 ( 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).

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

( S )-7-(4-(2-((( S )-1,4-Dioxan-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 tribasic potassium phosphate (44 mg , 0.21 mmol) was dissolved in a 2% aqueous solution of TPGS-750-M (0.37 ml) and THF (0.041 ml). The reaction mixture was processed similarly to example 1A. The crude material was purified using FCC (0-10% MeOH/DCM) and additionally using preparative HPLC (XBridge 30x50 mm, 5 µm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml /min.) to obtain the title compound (29 mg, 0.059 mmol).

LCMS: Rt: 1.90 min. (LCMS method 4); MS mass/charge 475.1 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.64 (s, 1H), 7.03-6.92 (m, 3H), 4.22 (d, J =8.8 Hz, 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, 7.1 Hz, 1H), 2.13-2.01 (m, 3H), 1.78-1.63 (m, 2H), 1, 63-1.51 (m, 2H).

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

( 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 tribasic potassium phosphate (38 mg, 0. 18 mmol) was dissolved in a 2% aqueous solution of TPGS-750-M (0.32 ml) and THF (0.036 ml). The reaction mixture was worked up as in Example 1A and the crude material was purified by FCC (0-10% MeOH/DCM) and additionally by preparative HPLC (XBridge, 30x50mm, 5 µm, 25-50% MeCN/H ₂ O ( 5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (21 mg, 0.044 mmol).

LCMS: Rt: 1.58 min. (LCMS method 4); MS mass/charge 459.3 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.64 (s, 1H), 7.07-6.90 (m, 3H), 4.53 (m, 1H), 4.22 (d, J =8 ,8 Hz, 1H), 4.15-4.10 (m, 2H), 4.02 (d, J =8.3 Hz, 1H), 3.94 (dd, J =8.3, 6, 8 Hz, 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

( 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 tribasic Potassium phosphate (51 mg, 0.24 mmol) was dissolved in a 2% aqueous solution of TPGS-750-M (0.44 ml) and THF (0.048 ml). The reaction mixture was worked up as in Example 1A and the crude material was purified by FCC (0-10% MeOH/DCM) and additionally by preparative HPLC (XBridge, 30x50mm, 5 µm, 25-50% MeCN/H ₂ O ( 5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (42 mg, 0.092 mmol).

LCMS: Rt: 1.91 min. (LCMS method 4); MS mass/charge 445.1 [M+H] ⁺ .

^1H NMR (400 MHz, DMSO _- d6 ) δ 8.65 (s, 1H), 7.04-6.90 (m, 3H), 5.05-4.98 (m, 1H), 4, 22 (d, J =8.8 Hz, 1H), 4.15-4.09 (m, 2H), 4.02 (d, J =8.5 Hz, 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).

Example 1I. ( 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-(((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 tribasic potassium phosphate (44 mg, 0.21 mmol) were dissolved in a mixture of 2% aqueous solution of TPGS-750-M (0.37 ml) and THF (0.042 ml) and the reaction mixture was processed similarly to example 1A. The residue was purified using FCC (0-10% MeOH/DCM) and additionally using preparative HPLC (XBridge 30×50 mm, 5 µm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (30 mg, 0.064 mmol).

LCMS: Rt: 2.05 min. (LCMS method 4); MS mass/charge 459.5 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.64 (s, 1H), 7.01-6.93 (m, 3H), 4.21 (d, J =8.8 Hz, 1H), 4, 12 (dd, J =8.3, 2.4 Hz, 2H), 4.02 (d, J =8.3 Hz, 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), 3.64-3.58 (m, 1H), 3 .52 (dd, J =8.6, 6.1 Hz, 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, 7.1 Hz, 1H), 2.11-1.96 (m, 4H), 1.75-1.63 (m , 3H), 1.62-1.51 (m, 2H).

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

( 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 ) was dissolved in THF (2.3 ml). The reaction mixture was stirred for 2 hours and then evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with water, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in a mixture of THF (2 ml) and water (1 ml) and LiOH (114 mg, 2.72 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then 6 M aqueous HCl solution (0.76 ml) was added to adjust the pH to 2, and the reaction mixture was stirred at room temperature for 1 hour. Then the basicity of the reaction mixture was increased (pH >8) with a saturated sodium carbonate solution. The residue was diluted with EtOAc, washed with brine and evaporated under reduced pressure. The residue was purified with FCC (0-10% MeOH (10% NH ₄ OH)/DCM) to give the title compound (157 mg, 0.33 mmol).

LCMS: Rt: 2.16 min. (LCMS method 4); MS mass/charge 473.7 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 6.88 (m, 3H), 4.29 (q, J =8.8 Hz, 2H), 4.16 ( q, J =8.6 Hz, 2H), 4.10-4.03 (m, 1H), 3.99 (dd, J =10.8, 3.4 Hz, 2H), 3.83 (d , J =6.0 Hz, 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, 7.4 Hz, 1H), 2.28-1.99 (m, 4H), 1.91-1.59 (m, 6H), 1.51 ( m, 2H).

Example 1K. ( S )-7-(4-(5-Fluoro-2-(3-methoxy-3-methylbutoxy)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-methylbutoxy)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 were dissolved in a mixture of 2% aqueous solution of TPGS-750 -M (0.35 ml) and THF (0.039 ml). The reaction mixture was processed analogously to Example 1A and then purified using preparative HPLC (XBridge, 30x50 mm, 5 μm, 10-30% MeCN/H ₂ O (5 mm NH ₄ OH), 75 ml/min.) to obtain the indicated in the title compound (11 mg, 0.022 mmol).

LCMS: Rt: 2.38 min. (LCMS method 4); MS mass/charge 475.4 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.64 (s, 1H), 7.01-6.9 (m, 3H), 4.21 (d, J =8.8 Hz, 1H), 4, 12 (dd, J =8.6, 2.2 Hz, 2H), 4.05-3.97 (m, 3H), 3.93 (dd, J =8.3, 6.8 Hz, 1H) , 3.61 (t, J =7.8 Hz, 1H), 3.11 (s, 3H), 3.01-2.90 (m, 2H), 2.90-2.75 (m, 2H ), 2.40 (dd, J =12.7, 7.3 Hz, 1H), 2.10-1.98 (m, 3H), 1.91 (t, J =6.8 Hz, 2H) ,1.73-1.51 (m, 4H), 1.17 (s, 6H).

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

Into 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 the addition of tribasic potassium phosphate (36 mg, 0.17 mmol). The reaction mixture was worked up as in Example 1A and the crude material was purified by preparative HPLC (XBridge, 30x50 mm, 5 μm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) with obtaining the title compound (16 mg, 0.036 mmol).

LCMS: Rt: 1.95 min. (LCMS method 4); MS mass/charge 433.2 [M+H] ⁺ .

^1H NMR (400 MHz, DMSO _- d6 ) δ 8.64 (s, 1H), 7.04-6.91 (m, 3H), 4.27-3.89 (m, 7H), 3, 71-3.57 (m, 3H), 3.33 (s, 3H), 3.01-2.74 (m, 4H), 2.40 (dd, J=12.8, 7.3 Hz, 1H), 2.04 (m, 3H), 1.77-1.65 (m, 2H), 1.56 (m, 2H).

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

Into 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) was added to a mixture of 2% aqueous TPGS-750-M (0.454 ml) and THF (0.05 ml) Oxadiazole-2-carboxylate (56 mg, 0.25 mmol) followed by the addition of tribasic potassium phosphate (161 mg, 0.757 mmol). The reaction mixture was worked up as in Example 1A and the crude material was purified by FCC (0-7% MeOH/DCM) and additionally by preparative HPLC (XBridge, 30x50mm, 5 µm, 25-50% MeCN/H ₂ O ( 5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (9.0 mg, 0.018 mmol).

LCMS: Rt: 0.87 min. (LCMS method 4); MS mass/charge 461.5 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.64 (s, 1H), 7.03-6.93 (m, 3H), 4.99-4.85 (m, 2H), 4.41-4 .33 (m, 1H), 4.21 (d, J =8.3 Hz, 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 =7.8 Hz, 1H), 3.02-2.90 ( m, 2H), 2.88-2.75 (m, 2H), 2.40 (dd, J =13.2, 7.3 Hz, 1H), 2.12-1.98 (m, 3H) , 1.77-1.65 (m, 2H), 1.64-1.49 (m, 2H).

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

Into 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 7O, 147 mg, 0.38 mmol) ethyl 5-bromo-1,3,4-oxadiazole-2 was added to a mixture of 2% aqueous solution of TPGS-750-M (0.674 ml) and THF (75 µl) -carboxylate (83 mg, 0.38 mmol) followed by the addition of tribasic potassium phosphate (79 mg, 0.38 mmol). The reaction mixture was processed as in Example 1A and the crude material was purified by FCC (0-10% MeOH/DCM) and additionally by preparative HPLC (XBridge, 30x50mm, 5 µm, 10-30% MeCN/H ₂ O ( 5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (88 mg, 0.19 mmol).

LCMS: Rt: 1.93 min. (LCMS method 4); MS mass/charge 461.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.02-6.77 (m, 3H), 4.36-4.22 (m, 2H), 4.17 (q, J=8.7 Hz, 2H), 4.07 (dd, J=8.7, 6.9 Hz, 1H), 3.76 (d, J=4.7 Hz, 3H), 3 .08 (m, 3H), 2.90 (d, J=11.3 Hz, 1H), 2.55 (dd, J=13.0, 7.4 Hz, 1H), 2.24 (m, 2H), 2.14 (dd, J=13.0, 8.4 Hz, 1H), 1.85 (d, J=10.9 Hz, 2H), 1.80-1.60 (m, 2H ), 1.34 (s, 6H).

Example 1O. ( 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

Into a solution of ( S )-7-(4-(2-((( R )-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate compound 7P, 179 mg, 0.499 mmol) in a mixture of 2% aqueous solution of 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 the addition of tribasic potassium phosphate (106 mg, 0.499 mmol). The reaction mixture was worked up as in Example 1A and the crude material was purified by FCC (0-10% MeOH/DCM) and additionally by preparative HPLC (XBridge, 30x50mm, 5 µm, 25-50% MeCN/H ₂ O ( 5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (58 mg, 0.13 mmol).

LCMS: Rt: 1.87 min. (LCMS method 4); MS mass/charge 427.2 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.64 (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, 2.9 Hz, 2H), 4.02 (d, J =8.3 Hz, 1H), 3.97-3.85 (m, 2H), 3.84-3.72 (m, 3H), 3.62 (t, J =7.8 Hz, 1H ), 3.01-2.91 (m, 2H), 2.87-2.74 (m, 2H), 2.40 (dd, J =12.7, 7.3 Hz, 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).

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

Into 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), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (62 mg, 0.28 mmol) followed by the addition of tribasic potassium phosphate (60 mg, 0.28 mmol). The reaction mixture was worked up as in Example 1A and the crude material was then purified by FCC (0-10% MeOH/DCM) and additionally by preparative HPLC (XBridge, 30x50mm, 5 µm, 15-40% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (27 mg, 0.062 mmol).

LCMS: Rt: 1.74 min. (LCMS method 4); MS mass/charge 413.2 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.65 (s, 1H), 7.24-7.18 (m, 1H), 7.15-7.07 (m, 1H), 6.98-6 .88 (m, 1H), 6.53 (d, J =8.3 Hz, 1H), 5.32-5.22 (m, 1H), 4.93 (t, J =6.6 Hz, 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, 7.6 Hz, 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).

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

Into 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 mixture 2 % aqueous solution of TPGS-750-M (480 µl) and THF (50 µl) was added with ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (59 mg, 0.27 mmol) followed by tribasic phosphate potassium (57 mg, 0.27 mmol). The reaction mixture was processed as in Example 1A and the crude material was purified by FCC (0-10% MeOH/DCM) and additionally by preparative HPLC (XBridge, 30x50mm, 5 µm, 15-40% MeCN/H ₂ O ( 5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (10 mg, 0.026 mmol).

LCMS: Rt: 1.94 min. (LCMS method 4); MS mass/charge 371.0 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.64 (s, 1H), 7.22-7.11 (m, 2H), 6.99-6.83 (m, 2H), 4.22 (d , J =8.8 Hz, 1H), 4.13 (dd, J =8.1, 3.2 Hz, 2H), 4.02 (d, J =8.3 Hz, 1H), 3.93 (dd, J =8.3, 6.8 Hz, 1H), 3.77 (s, 3H), 3.62 (t, J =7.8 Hz, 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, 7.3 Hz, 1H) , 2.12-1.97 (m, 3H), 1.74-1.47 (m, 4H).

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

Into 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 solution of 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 the addition of tribasic potassium phosphate (52 mg, 0.24 mmol). The reaction mixture was worked up as in Example 1A and the crude material was purified by FCC (0-7% MeOH/DCM) and additionally by preparative HPLC (XBridge, 30x50mm, 5 µm, 25-50% MeCN/H ₂ O ( 5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (35 mg, 0.073 mmol).

LCMS: Rt: 2.01 min. (LCMS method 4); MS mass/charge 463.1 [M+H] ⁺ .

^1H NMR (400 MHz, DMSO _- d6 ) δ 8.64 (s, 1H), 7.22 (dd, J =12.1, 9.2 Hz, 1H), 7.12 (dd, J = 12.8, 7.2 Hz, 1H), 5.08-5.01 (m, 1H), 4.21 (d, J =8.7 Hz, 1H), 4.12 (dd, J =8 .5, 2.5 Hz, 2H), 4.02 (d, J =8.4 Hz, 1H), 3.93 (dd, J =8.5, 6.6 Hz, 1H), 3.86 (dd, J =10.3, 4.4 Hz, 1H), 3.83-3.71 (m, 3H), 3.60 (dd, J =8.6, 7.0 Hz, 1H), 3.01-2.91 (m, 2H), 2.82-2.70 (m, 2H), 2.39 (dd, J =12.9, 7.2 Hz, 1H), 2.27- 2.14 (m, 1H), 2.09-1.89 (m, 4H), 1.72-1.48 (m, 4H).

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

Into 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 ) ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (192 mg, 0.87 mmol ) followed by the addition of tribasic potassium phosphate (185 mg, 0.87 mmol). The mixture was processed analogously to Example 1A and the crude material was purified using FCC (0-7% MeOH/DCM) and additionally using preparative HPLC (XBridge, 30x50 mm, 5 μm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (105 mg, 0.27 mmol).

LCMS: Rt: 2.04 min. (LCMS method 4); MS mass/charge 389.2 [M+H] ⁺ .

^1H NMR (DMSO -d6 ) δ 8.64 (s, _1H ), 7.16 (dd, J =8.3, 7.3 Hz, 1H), 6.84 (dd, J =11.2 , 2.4 Hz, 1H), 6.74-6.62 (m, 1H), 4.22 (d, J =8.8 Hz, 1H), 4.16-4.08 (m, 2H) , 4.02 (d, J =8.3 Hz, 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).

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

Into 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) ethyl 5-bromo-1,3,4-oxadiazole was added to a mixture of 2% aqueous TPGS-750-M (0.65 ml) and THF (70 µl) -2-carboxylate (79 mg, 0.36 mmol), followed by the addition of tribasic potassium phosphate (76 mg, 0.36 mmol). The reaction mixture was worked up as in Example 1A and the crude material was purified by FCC (0-10% MeOH/DCM) and additionally by preparative HPLC (XBridge, 30x50mm, 5 µm, 25-50% MeCN/H ₂ O ( 5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (44 mg, 0.094 mmol).

LCMS: Rt: 1.97 min. (LCMS method 4); MS mass/charge 461.4 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.60-8.67 (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), 2.45-2.36 (m, 1H), 2.13-1.96 (m, 3H), 1.75-1.48 (m, 4H), 1.22-1.12 ( m, 6H).

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

(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 tribasic potassium phosphate (38 mg, 0.18 mmol) were suspended in a mixture of 2% aqueous solution of TPGS-750-M (1.6 ml) and THF (0.16 ml). The reaction mixture was processed analogously to Example 1A and the crude material was purified using preparative HPLC (XBridge, 30x50 mm, 5 μm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (6.2 mg, 0.013 mmol).

LCMS: Rt: 1.85 min. (LCMS method 4); MS mass/charge 447.6 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 6.94-6.83 (m, 3H), 4.35-4.24 (m, 2H), 4.17 (q, J =8.7 Hz, 2H), 4.07 (dd, J =8.7, 6.9 Hz, 1H), 3.76 (d, J =4.7 Hz, 3H), 3 ,15-3.04 (m, 3H), 2.90 (d, J =11.3 Hz, 1H), 2.55 (dd, J =13.0, 7.4 Hz, 1H), 2, 24 (m, 2H), 2.14 (dd, J =13.0, 8.4 Hz, 1H), 1.93-1.81 (m, 2H), 1.77-1.62 (m, 2H), 1.34 (s, 6H).

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

(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 tribasic potassium phosphate (77 mg, 0.362 mmol) were dissolved in a mixture of 2% aqueous TPGS solution -750-M (0.65 ml) and THF (0.07 ml). The reaction mixture was worked up as in Example 1A and the residue was purified by FCC (0-10% MeOH/DCM) and additionally by preparative HPLC (XBridge, 30x50 mm, 5 µm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (39 mg, 0.097 mmol).

LCMS: Rt: 1.98 min. (LCMS method 4); MS mass/charge 389.3 [M+H] ⁺ .

^1H NMR (400 MHz, DMSO _- d6 ) δ 8.64 (s, 1H), 7.13-6.82 (m, 3H), 4.22 (d, J =8.6 Hz, 1H) , 4.15-4.09 (m, 2H), 4.02 (d, J =8.4 Hz, 1H), 3.93 (dd, J =8.6, 6.8 Hz, 1H), 3.76 (s, 3H), 3.62 (dd, J =8.5, 7.1 Hz, 1H), 3.04-2.90 (m, 2H), 2.90-2.72 ( m, 2H), 2.39 (dd, J =12.9, 7.3 Hz, 1H), 2.12-1.99 (m, 3H), 1.73-1.51 (m, 4H) .

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

(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 tribasic potassium phosphate (31 mg, 0.15 mmol) were dissolved in a mixture of 2% aqueous solution of TPGS-750-M (0.30 ml) and THF (0.030 ml). The reaction mixture was worked up as in Example 1A and the residue was purified by preparative HPLC (XBridge, 30x50 mm, 5 µm, 25-40% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (17 mg, 0.041 mmol).

LCMS: Rt: 1.52 min. (LCMS method 4); MS mass/charge 419.4 [M+H] ⁺ .

^1H NMR (400 MHz, CD ₂ Cl ₂ ) δ 9.23 (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, 1.2 Hz, 1H), 4.21 (s, 2H), 4.20-4.07 (m , 2H), 4.00 (dd, J =8.5, 6.7 Hz, 1H), 3.73 (t, J =8.0 Hz, 1H), 3.07-2.90 (m, 2H), 2.85-2.68 (m, 1H), 2.54 (m, 1H), 2.40 (dd, J =12.9, 7.1 Hz, 1H), 2.13 (dd , J =12.6, 8.1 Hz, 1H), 1.96 (q, J =11.1, 10.6 Hz, 2H), 1.84 (d, J =13.2 Hz, 2H) , 1.77-1.67 (m, 2H).

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

(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 tribasic potassium phosphate (20 mg, 0.096 mmol) were dissolved in a mixture of 2% aqueous solution of TPGS-750-M (0.30 ml) and THF (0.030 ml). The reaction mixture was processed analogously to example 1A, the crude substance was purified using preparative HPLC (XBridge, 30x50 mm, 5 μm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (13 mg, 0.032 mmol).

LCMS: Rt: 1.78 min. (LCMS method 4); MS mass/charge 408.6 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 8.01 (s, 1H), 7.76 (d, J =7.3 Hz, 1H), 7.49 ( d, J =4.0 Hz, 2H), 7.38-7.22 (m, 2H), 4.36-4.23 (m, 2H), 4.16 (q, J =8.6 Hz , 2H), 4.06 (dd, J =8.7, 6.9 Hz, 1H), 3.76 (dd, J =8.6, 7.4 Hz, 1H), 3.55-3, 40 (m, 1H), 3.09 (m, 2H), 2.88 (dd, J =11.5, 2.3 Hz, 1H), 2.53 (dd, J =13.1, 7, 4 Hz, 1H), 2.30-2.05 (m, 3H), 1.82 (m, 4H).

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

( S )-7-(4-(2-(5-Methyl-1,3,4-oxadiazol-2-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane- 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 tribasic potassium phosphate (5.5 mg , 0.026 mmol) was dissolved in a mixture of 2% aqueous solution of TPGS-750-M (0.60 ml) and THF (0.060 ml). The reaction mixture was worked up as in Example 1A and the crude material 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 obtain the title compound (1 mg, 0.002 mmol).

LCMS: Rt: 1.58 min. (LCMS method 4); MS mass/charge 423.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.81 (d, J =8.2 Hz, 1H), 7.63-7.48 (m, 2H), 7.38 (m, 1H), 4.36-4.24 (m, 2H), 4.18 (t, J =8.7 Hz, 2H), 4.07 (dd, J =8.8, 6.9 Hz, 1H), 3.77 (dd, J =8.7, 7.4 Hz, 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, 7.4 Hz, 1H), 2.33- 2.07 (m, 3H), 1.86 (m, 4H).

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

(S)-2-(1-(2-(1,3,4-Thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenol (8A intermediate connection, 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 mixture was stirred at 60°C overnight and then concentrated under reduced pressure, and the crude material was purified using preparative HPLC (X-bridge C18 OBD, 30×50 mm, 5 μm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (6.2 mg, 0.013 mmol).

LCMS: Rt: 1.91 min. (LCMS method 4); MS mass/charge 461.1 [M+H] ⁺ .

¹ H NMR (CD ₃ OD) δ 8.66 (s, 1H), 6.94 (d, J =4.4 Hz, 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).

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

(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 mixture was stirred at 60°C overnight, concentrated under reduced pressure and purified using preparative HPLC (X-bridge C18 OBD, 30×50 mm, 5 µm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (4.5 mg, 0.0093 mmol).

LCMS: Rt: 2.08 min. (LCMS method 4); MS mass/charge 475.2 [M+H] ⁺ .

¹ H NMR (CD ₃ OD) δ 8.66 (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).

Example 2C. 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 or 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 and Example 2D. 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 or 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

(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 connection 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 mixture was stirred at 60°C overnight, then additional 2-(bromomethyl)oxetane (20 mg, 0.13 mmol) was added and the reaction mixture 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 mixture was heated at 75°C overnight. The reaction mixture was concentrated under reduced pressure and purified using preparative HPLC (XBridge Peptide BEH C18, 5 µm, 19x150 mm, 30-45% MeCN/H₂O (10 mM NH₄OH), 30 ml/min.) to obtain individual diastereoisomers as TFA salts: peak 1 (example 2C, 4.5 mg, 0.0093 mmol) and peak 2 (example 2D, 3.6 mg, 0.0061 mmol ).

Example 2C.

LCMS: Rt: 1.92 min. (LCMS method 4); MS mass/charge 461.2 [M+H] ⁺ .

¹ H NMR (CD ₃ OD) δ 8.66 (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).

2D example.

LCMS: Rt: 2.02 min. (LCMS method 4); MS mass/charge 461.6 [M+H] ⁺ .

¹ H NMR (CD ₃ OD) δ 8.66 (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- 3.73 (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).

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

(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 connection 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 mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure and purified using preparative HPLC (XBridge, 30x50 mm, 5 μm, 15-40% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (9.8 mg, 0.020 mmol) as a white solid.

LCMS: Rt: 1.78 min. (LCMS method 4); MS mass/charge 487.3 [M+H] ⁺ .

¹ H NMR (CD ₃ OD) δ 8.39 (s, 1H), 7.09-7.04 (m, 1H), 7.01-6.95 (m, 1H), 6.95-6, 87 (m, 1H), 5.49 (d, J=3.4 Hz, 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).

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

(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 connection 4F, 20.2 mg, 0.054 mmol) was dissolved in DMF (0.5 ml) and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (8.9 mg, 0.065 mmol) and cesium carbonate (35) were added .2 mg, 0.108 mmol). The resulting reaction mixture was stirred at room temperature for 18 hours. It was then diluted with EtOAc, washed with water and the organic layer was concentrated under reduced pressure. The residue was purified using preparative HPLC (XBridge, 30×50 mm, 5 µm, 15-40% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (15 mg, 0.032 mmol).

LCMS: Rt: 0.87 min. (LCMS method 3); MS mass/charge 471.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.08 (dd, J =9.0, 4.6 Hz, 1H), 6.97 (dd, J =9 .7, 3.1 Hz, 1H), 6.93-6.86 (m, 1H), 5.29 (s, 2H), 4.34-4.23 (m, 2H), 4.16 ( q, J =8.6 Hz, 2H), 4.05 (dd, J =8.6, 7.0 Hz, 1H), 3.75 (dd, J =8.4, 7.6 Hz, 1H ), 3.13-2.94 (m, 3H), 2.87 (d, J =10.8 Hz, 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).

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

( 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, 18.6 mg, 0.050 mmol) was dissolved in DMF (0.5 ml) and then 5-(chloromethyl)-3-methylisoxazole (8.26 mg, 0.060 mmol) and cesium carbonate (32) were added .4 mg, 0.099 mmol). The resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with EtOAc, washed with water and the organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge, 30x50 mm, 5 μm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (13.8 mg, 0.029 mmol).

LCMS: Rt: 1.08 min. (LCMS method 3); MS mass/charge 470.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.03 (dd, J =9.0, 4.6 Hz, 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 =8.8 Hz, 2H) , 4.06 (dd, J =8.6, 7.0 Hz, 1H), 3.75 (dd, J =8.5, 7.6 Hz, 1H), 3.14-3.03 (m , 2H), 2.98 (m, 1H), 2.87 (d, J =10.6 Hz, 1H), 2.53 (dd, J =13.0, 7.4 Hz, 1H), 2 .28 (s, 3H), 2.25-2.08 (m, 3H), 1.84-1.75 (m, 2H), 1.68 (m, 2H).

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

( 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, 18.3 mg, 0.049 mmol) was dissolved in 0.5 ml DMF and 3-(iodomethyl)oxetane (19.36 mg, 0.098 mmol) and cesium carbonate (31.8 mg, 0.098 mmol) were added ). The resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with EtOAc and washed with water and concentrated under reduced pressure. The residue was then purified by preparative HPLC (XBridge, 30x50 mm, 5 μm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (12, 1 mg, 0.027 mmol).

LCMS: Rt: 0.97 min. (LCMS method 3); MS mass/charge 445.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.02-6.78 (m, 3H), 4.88 (dd, J =8.0, 6.1 Hz , 2H), 4.64 (t, J =6.0 Hz, 2H), 4.34-4.23 (m, 2H), 4.17 (dd, J =8.9, 7.4 Hz, 4H), 4.06 (dd, J =8.6, 7.0 Hz, 1H), 3.75 (dd, J =8.4, 7.6 Hz, 1H), 3.47 (m, 1H ), 3.14-2.97 (m, 3H), 2.88 (d, J =10.8 Hz, 1H), 2.53 (dd, J =13.0, 7.4 Hz, 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

( 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, 20.5 mg, 0.055 mmol) was dissolved in 0.5 ml DMF and then 2-(chloromethyl)pyrimidine (8.89 mg, 0.066 mmol) and cesium carbonate (35.7 mg, 0.110 mmol). The resulting reaction mixture was stirred at room temperature for 18 hours and then it was diluted with EtOAc, washed with water and concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge, 30x50 mm, 5 μm, 15-40% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (16 mg, 0.034 mmol).

LCMS: Rt: 0.92 min. (LCMS method 3); MS mass/charge 467.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.81 (d, J =4.9 Hz, 2H), 8.38 (s, 1H), 7.44 (t, J =4.9 Hz, 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 =8.6 Hz, 2H), 4.05 (dd, J =8.6, 7.0 Hz, 1H), 3.80-3.70 (m, 1H), 3.10 ( m, 3H), 2.87 (d, J =10.7 Hz, 1H), 2.53 (dd, J =13.0, 7.4 Hz, 1H), 2.28-2.08 (m , 3H), 1.88 (m, 2H), 1.69 (m, 2H).

Example 2J. ( S )-7-(4-(5-Fluoro-2-((3-fluoroxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl) -5-oxa-2-azaspiro[3.4]octane

( S )-2-(1-(2-(1,3,4-Oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4 α-fluorophenol (intermediate 4F, 17.4 mg, 0.046 mmol) was dissolved in DMF (0.5 ml) and then 3-fluoroxetan-3-yl)methyl-4-methylbenzenesulfonate (commercially available, 13.3 mg, 0.051) was added mmol) and cesium carbonate (30.3 mg, 0.093 mmol). The resulting reaction mixture was stirred at 50°C overnight and then it was diluted with EtOAc, washed with water and concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge, 30x50 mm, 5 μm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to give the title compound (2.7 mg, 0.0058 mmol).

LCMS: Rt: 1.01 min. (LCMS method 3); MS mass/charge 463.7 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.03-6.84 (m, 3H), 4.84-4.72 (m, 4H), 4.39 -4.23 (m, 4H), 4.16 (q, J =8.6 Hz, 2H), 4.06 (dd, J =8.6, 7.0 Hz, 1H), 3.75 ( dd, J =8.4, 7.6 Hz, 1H), 3.13-3.04 (m, 2H), 2.97 (m, 1H), 2.89 (d, J =10.9 Hz , 1H), 2.54 (dd, J =13.0, 7.4 Hz, 1H), 2.27-2.07 (m, 3H), 1.84 (m, 2H), 1.67 ( m, 2H).

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

( 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, 19 mg, 0.051 mmol) was dissolved in acetonitrile (1.0 ml) and 3-(bromomethyl)-3-methyloxetane (16.8 mg, 0.101 mmol) and cesium carbonate (25 mg, 0.076) were added mmol). The reaction mixture was stirred at 80°C overnight. It was then concentrated under reduced pressure and purified by preparative HPLC (XBridge, 30×50 mm, 5 µm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the above title compound (10.7 mg, 0.023 mmol).

LCMS: Rt: 2.00 min. (LCMS method 4); MS mass/charge 459.2 [M+H] ⁺ .

^1H NMR (CD ₃ OD) δ 8.39 (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) , 3.71-3.80 (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) .

Example 2L. ( S )-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

Stage 1. 2-Oxaspiro[3.3]heptan-6-yl-4-methylbenzenesulfonate

Into 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) 4-methylbenzene-1-sulfonyl chloride (877 mg, 4.60 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then washed with 1N. HCl solution, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified with FCC (0→60% EtOAc/heptanes) to give the title intermediate (1.04 g, 3.68 mmol) as a white solid.

LCMS: Rt: 0.87 min. (LCMS method 2); MS mass/charge 269.3 [M+H] ⁺ .

Stage 2. ( S )-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

In MeCN solution (5 ml) (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 connection 4F, 100 mg, 0.267 mmol) and 2-oxaspiro[3.3]heptan-6-yl-4-methylbenzenesulfonate (79 g, 0.294 mmol) Cs was added₂CO₃ (348 mg, 1.07 mmol). The resulting mixture was stirred at 80°C for 18 hours. The crude material 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 material was purified using FCC (0-8% MeOH (1% NH₄OH)/DCM). The isolated material was dissolved in MeCN:water 3:7 and lyophilized to give the title compound (52 mg, 0.105 mmol) as a white solid. The stereochemical configuration of this compound was confirmed by X-ray crystallography.

[α] _D ²⁵ = -11.04° (c = 1.0400% w/v, CH ₃ OH).

LCMS: Rt: 1.96 min. (LCMS method 4); MS mass/charge 471.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 6.90 (dd, J=9.8, 3.0 Hz, 1H), 6.82 (td, J=8 ,5, 3.1 Hz, 1H), 6.70 (dd, J=9.0, 4.6 Hz, 1H), 4.75, (s, 2H), 4.68 (s, 2H), 4.53 (p, J=6.6 Hz, 1H), 4.38-4.23 (m, 2H), 4.16 (q, J=8.6 Hz, 2H), 4.06 (dd , J=8.7, 6.9 Hz, 1H), 3.76 (t, J=8.0 Hz, 1H), 3.17-3.04 (m, 2H), 3.03-2, 85 (m, 2H), 2.85-2.75 (m, 2H), 2.54 (dd, J=13.2, 7.6 Hz, 1H), 2.36-2.09 (m, 5H), 1.87-1.74 (m, 2H), 1.67 (m, 2H).

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

Stage 1. ( R )-(Tetrahydrofuran-2-yl)methyl-4-methylbenzenesulfonate

( 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). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was neutralized with saturated NH ₄ Cl solution and extracted with DCM. The combined DCM layers were dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified with FCC (0-50% EtOAc/heptanes) to give the title intermediate (925 mg, 3.61 mmol) as a colorless oil.

LCMS: Rt: 0.92 min. (LCMS method 1); MS mass/charge 257.1 [M+H] ⁺ .

Stage 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

( 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 mixture was stirred at 75°C for 18 hours. The reaction mixture was concentrated under reduced pressure and purified using preparative HPLC (XBridge, 30x50 mm, 5 μm, 10-30% MeCN/H ₂ O (0.1% formic acid), 75 ml/min.) to obtain the above in the title compound (4.9 mg, 0.0011 mol) as a white solid.

LCMS: Rt: 2.09 min. (LCMS method 4); MS mass/charge 459.4 [M+H] ⁺ .

¹ H NMR (CD ₃ OD) δ 8.39 (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).

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

In DMF solution (1.1 ml) ( 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 cesium carbonate (261 mg, 0.801 mmol) were 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 material was diluted with EtOAc, washed with water and concentrated under reduced pressure. The residue was purified by FCC (0-10% MeOH/DCM) then by preparative HPLC (XBridge, 30x50 mm, 5 µm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml /min.). The two diastereomers were then separated using preparative SFC (ChiralPak IG column, 21×250 mm, 30% IPA, flow rate: 80 g per minute). The product corresponding to peak 1 was isolated and concentrated to give Example 2N (19 mg, 0.039 mmol) and the product corresponding to peak 2 was isolated to give Example 2O (9 mg, 0.019 mmol).

Example 2N.

SFC: Rt: 3.29 min. (Chiralpak IG, 4.6×100 mm, 5 µm, 5→55% IPA with 10 mM NH ₄ OH/CO ₂ , 5 ml/min.). LCMS: Rt: 2.21 min. (LCMS method 4); MS mass/charge 473.3 [M+H] ⁺ .

^1H NMR (400 MHz, DMSO _- d6 ) δ 8.65 (s, 1H), 7.04-6.86 (m, 3H), 5.01 (m, 1H), 4.22 (d, J=8.9 Hz, 1H), 4.13 (dd, J=8.3, 2.7 Hz, 2H), 4.09-3.99 (m, 2H), 3.94 (dd, J =8.5, 6.6 Hz, 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, 7.2 Hz, 1H), 2.13 (dd, J=13.7, 6.7 Hz, 1H), 2.09-1.98 (m, 3H), 1.89 (dd, J=13.8, 1.6 Hz, 1H), 1.76-1.65 (m, 2H) , 1.59 (m, 2H), 1.31 (s, 3H), 1.22 (s, 3H).

Example 2O.

SFC: Rt: 3.41 min. (Chiralpak IG, 4.6×100 mm, 5 µm, 5→55% IPA with 10 mM NH ₄ OH/CO ₂ , 5 ml/min.). LCMS: Rt: 2.23 min. (LCMS method 4); MS mass/charge 473.5 [M+H] ⁺ .

^1H NMR (400 MHz, DMSO _- d6 ) δ 8.65 (s, 1H), 7.12-6.80 (m, 3H), 5.01 (m, 1H), 4.22 (d, J=8.7 Hz, 1H), 4.13 (dd, J=8.5, 4.6 Hz, 2H), 4.08-3.98 (m, 2H), 3.94 (dd, J =8.5, 6.7 Hz, 1H), 3.78 (dt, J=10.1, 1.3 Hz, 1H), 3.65-3.57 (m, 1H), 2.95 ( p, J=7.0 Hz, 2H), 2.92-2.75 (m, 2H), 2.41 (dd, J=12.9, 7.2 Hz, 1H), 2.13 (dd , J=13.6, 6.6 Hz, 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).

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

( S )-2-(1-(2-(1,3,4-Oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4 α-fluorophenol (intermediate 4F, 16 mg, 0.042 mmol) was dissolved in acetonitrile (1.0 ml) and (3-ethyloxetan-3-yl)methyl-4-methylbenzenesulfonate (intermediate 5N, 15 mg, 0.055 mmol) was added and cesium carbonate (21 mg, 0.064 mmol). The reaction mixture was stirred at 80°C for 18 hours and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with DCM and the combined organics were concentrated under reduced pressure. The residue was then purified by preparative HPLC (XBridge, 30x50 mm, 5 μm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (13, 4 mg, 0.027 mmol) as a white solid.

LCMS: Rt: 2.18 min. (LCMS method 4); MS mass/charge 473.5 [M+H] ⁺ .

¹ H NMR (CD ₃ OD) δ 8.39 (s, 1H), 7.03-6.82 (m, 3H), 4.67-4.61 (m, 2H), 4.54-4, 47 (m, 2H), 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 =7.3 Hz, 4H), 1.76-1.59 (m, 2H), 0.98 (t, J =7.6 Hz, 3H ).

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

( S )-2-(1-(2-(1,3,4-Oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4 α-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 it was diluted with EtOAc, washed with water and concentrated under reduced pressure. The residue was purified using FCC (0-10% MeOH/DCM) and further using preparative HPLC (XBridge, 30x50 mm, 5 µm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml /min.). Diastereomers were then separated using SFC (ChiralPak IG column, 21 x 250 mm, 21% MeOH, flow rate: 80 g per minute). Isolate peak 1 to give Example 2Q (8.0 mg, 0.017 mmol) and isolate peak 2 to give Example 2R (7.0 mg, 0.015 mmol)

Example 2Q.

SFC: Rt: 3.14 min. (Chiralpak IA, 4.6×100 mm, 5 µm, 5→55% MeOH with 10 mM NH ₄ OH/CO ₂ , 5 ml/min.). LCMS: Rt: 2.10 min. (LCMS method 4); MS mass/charge 459.5 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.64 (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).

Example 2R.

SFC: Rt: 3.35 min. (Chiralpak IA, 4.6×100 mm, 5 µm, 5→55% MeOH with 10 mM NH ₄ OH/CO ₂ , 5 ml/min.). LCMS: Rt: 2.09 min. (LCMS method 4); MS mass/charge 459.1 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.66-8.62 (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).

Example 2S. ( S )-7-(4-(2-((2-Oxaspiro[3.3]heptan-6-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2 -yl)-5-oxa-2-azaspiro[3.4]octane

(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, 40 mg, 0.11 mmol), cesium carbonate (139 mg, 0.427 mmol) and (2-oxaspiro[3.3]heptan-6-yl)methyl-4-methylbenzenesulfonate (intermediate 5A, 36.2 mg, 0.128 mmol) was dissolved in DMF (10 ml). The resulting mixture was stirred at 80°C for 16 hours. The crude material was diluted with EtOAc, washed with water and the organic layer was concentrated under reduced pressure. The residue was purified using preparative HPLC (XBridge, 30×50 mm, 5 µm, 35-60% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (23 mg, 0.047 mmol).

LCMS: Rt: 2.18 min. (LCMS method 4); MS mass/charge 485.5 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.29 (s, 1H), 6.89-6.64 (m, 3H), 4.66 (s, 2H), 4.54 (s, 2H ), 4.20 (d, J =10.3 Hz, 2H), 4.07 (d, J =8.6 Hz, 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

( 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) was added and cesium carbonate (17 mg, 0.052 mmol). The reaction mixture was stirred at room temperature for 16 hours and then the solvent was concentrated under reduced pressure and the residue was purified using preparative HPLC (XBridge 30x50 mm, 5 μm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH) , 75 ml/min.) to obtain the title compound (4.0 mg, 0.0080 mmol) as a white solid.

LCMS: Rt: 1.93 min. (LCMS method 4); MS mass/charge 501.7 [M+H] ⁺ .

¹ H NMR (CD ₃ OD) δ 8.39 (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), 3.82-3.72 (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).

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

(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, 36 mg, 0.096 mmol) was dissolved in MeCN (1.5 ml) and (3-hydroxyoxetan-3-yl)methyl 4-methylbenzenesulfonate was added (intermediate 5J, 30 mg, 0.12 mmol) and cesium carbonate (47 mg, 0.14 mmol). The reaction mixture was stirred at 70°C for 3 days and then the solvent was removed under reduced pressure. The residue was diluted with DCM and saturated NaHCO solution₃. 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 using preparative HPLC (XBridge, 30×50 mm, 5 µm, 15-40% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (12.4 mg, 0.027 mmol) as a white solid.

LCMS: Rt: 1.54 min. (LCMS method 4); MS mass/charge 461.4 [M+H] ⁺ .

¹ H NMR (CD ₃ OD) δ 8.39 (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-((1 S ,3 r )-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-((1 R ,3 s )-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-((1 S ,3 r )-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-((1 R ,3 s )-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

Stage 1. Methyl-( 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-carboxylate

(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 connection 4F, 50 mg, 0.13 mmol) and methyl 3-(tosyloxy)cyclobutane-1-carboxylate (intermediate 5Q, 102 mg, 0.200 mmol) was dissolved in acetonitrile (2 ml) and cesium carbonate (218 mg, 0.668 mmol) was added. The reaction mixture 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 with FCC (0-5% MeOH/DCM) to give the title intermediate (56 mg, 0.11 mmol).

LCMS: Rt: 0.97 min. (LCMS method 2); MS mass/charge 487.4 [M+H] ⁺ .

Stage 2. 2-((1S,3r)-3-(2-(1-((S)-2-(1,3,4-Oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane- 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

Methyl-( 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-carboxylate (50 mg, 0.078 mmol) was dissolved in THF (2 ml) at -10°C and methylmagnesium chloride (0.057 ml, 0.173 mmol, 3 M THF) was added. The reaction mixture was slowly heated to 0°C and stirred for 1 hour. The reaction mixture 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 using preparative HPLC (X-Bridge, 30x50 mm, 5 μm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain separated diastereomers. The product corresponding to the initial peak is Example 2V (5.0 mg, 0.0099 mmol) and the product corresponding to the next peak is Example 2W (8 mg, 0.016 mmol).

Example 2V.

LCMS: Rt: 2.11 min. (LCMS method 4); MS mass/charge 487.5 [M+H] ⁺ .

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).

Example 2W.

LCMS: Rt: 2.14 min. (LCMS method 4); MS mass/charge 487.4 [M+H] ⁺ .

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).

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

(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 connection 4F, 73 mg, 0.20 mmol), 1-(tetrahydro-2H-pyran-4-yl)ethyl-4-methylbenzenesulfonate (intermediate 5R, 83 mg, 0.29 mmol) was dissolved in acetonitrile (8 ml) and cesium carbonate (127 mg, 0.390 mmol) was added. The reaction mixture was stirred at 80°C for 16 hours and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified using FCC (0-100% EtOAc (0.1% 7N NH₃ in MeOH)/DCM; then 0-3% DCM/MeOH). Diastereomers were then separated using chiral SFC (ChiralPak IF column, 21 x 250 mm, 30% MeOH:IPA 1:1 with 10 mM NH₄OH, flow rate: 80 g per minute). The product corresponding to the original peak was isolated to give Example 2X (17 mg, 0.034 mmol) and the product corresponding to the next peak was isolated to give Example 2Y (17 mg, 0.034 mmol).

Example 2X.

SFC: Rt: 2.78 min. (Chiralpak IF, 3x100 mm, 5 µm, 5→55% MeOH:IPA 1:1 with 10 mM NH ₄ OH/CO ₂ , 2.5 ml/min.).

LCMS: Rt: 2.28 min. (LCMS method 4); MS mass/charge 487.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.06-6.56 (m, 3H), 4.35-4.21 (m, 3H), 4.17 (q, J=8.6 Hz, 2H), 4.11-3.94 (m, 3H), 3.76 (dd, J=8.5, 7.4 Hz, 1H), 3.44 ( m, 2H), 3.21-2.85 (m, 4H), 2.55 (dd, J=12.9, 7.3 Hz, 1H), 2.32-2.07 (m, 3H) , 1.92-1.77 (m, 4H), 1.76-1.42 (m, 5H), 1.21 (d, J=6.0 Hz, 3H).

Example 2Y.

SFC: Rt: 2.93 min. (Chiralpak IF, 3x100 mm, 5 µm, 5→55% MeOH:IPA 1:1 with 10 mM NH ₄ OH/CO ₂ , 2.5 ml/min.).

LCMS: Rt: 2.33 min. (LCMS method 4); MS mass/charge 487.4 [M+H] ⁺ .

1H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.31-6.49 (m, 3H), 4.38-4.22 (m, 3H), 4.17 ( q, J=8.6 Hz, 2H), 4.10-3.92 (m, 3H), 3.76 (dd, J=8.7, 7.4 Hz, 1H), 3.44 (m , 2H), 3.22-2.75 (m, 4H), 2.55 (dd, J=13.1, 7.3 Hz, 1H), 2.38-2.08 (m, 3H), 2.01-1.79 (m, 4H), 1.76-1.43 (m, 5H), 1.22 (d, J=6.0 Hz, 3H).

Example 2Z. (7 S )-7-(4-(2-((3-Oxabicyclo[3.1.0]hexan-6-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazole -2-yl)-5-oxa-2-azaspiro[3.4]octane

(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 connection 4F, 38 mg, 0.10 mmol) and (3-oxabicyclo[3.1.0]hexan-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 mixture was stirred at 80°C for 16 hours and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified using preparative HPLC (X-bridge C18 OBD column, 30x50 mm, 5 µm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (19 mg, 0.040 mmol).

LCMS: Rt: 2.11 min. (LCMS method 4); MS mass/charge 471.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.03-6.29 (m, 3H), 4.36-4.23 (m, 2H), 4.17 (q, J =8.5 Hz, 2H), 4.07 (dd, J =8.7, 6.9 Hz, 1H), 3.96-3.84 (m, 4H), 3.81- 3.64 (m, 3H), 3.17-2.96 (m, 3H), 2.90 (m, 1H), 2.55 (dd, J =13.1, 7.3 Hz, 1H) , 2.31-2.07 (m, 3H), 1.84 (m, 2H), 1.77-1.59 (m, 4H), 1.16 (m, 1H).

Example 2AA. ( S )-7-(4-(2-((2-Oxaspiro[3.3]heptan-6-yl)oxy)-3,5-difluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazole -2-yl)-5-oxa-2-azaspiro[3.4]octane

In a 40 ml bottle in a solution of (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidine -4-yl)-4,6-difluorophenol (intermediate 4C, 0.082 g, 0.209 mmol) in MeCN (2.1 ml) under nitrogen atmosphere, a solution of 2-oxaspiro[3.3]heptan-6-yl-4-methylbenzenesulfonate was added (step 1 from Example 2K,0.062 g, 0.230 mmol) in MeCN (0.5 ml) followed by addition of Cs₂CO₃ (0.272 g, 0.836 mmol) and it was stirred at 80°C for 6 hours. The reaction mixture was then cooled to room temperature and diluted with EtOAc and water. The layers were separated, the aqueous phase was extracted with EtOAc, and the combined organic layers were dried over MgSO₄, filtered and concentrated. The residue was purified using FCC (0-15% MeOH (10% NH₄OH)/EtOAc) to obtain the title compound as a white solid.

LCMS: Rt: 1.20 min. (LCMS method 3); MS mass/charge 489.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 6.89-6.74 (m, 2H), 4.67 (d, J=1.8 Hz, 4H), 4.42-4.24 (m, 3H), 4.17 (q, J=8.6 Hz, 2H), 4.06 (dd, J=8.8, 6.9 Hz, 1H), 3 .77 (dd, J=8.8, 7.3 Hz, 1H), 3.17-3.05 (m, 2H), 3.05-2.86 (m, 2H), 2.69 (m , 2H), 2.55 (dd, J=13.0, 7.4 Hz, 1H), 2.39 (ddd, J=10.2, 7.2, 3.4 Hz, 2H), 2, 31-2.09 (m, 3H), 1.85-1.58 (m, 4H).

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

(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 mixture 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 with magnesium sulfate, filtered and concentrated. The residue was purified using FCC (0-20% MeOH(10% NH₄OH)/EtOAc) and using preparative HPLC (X-bridge C18 OBD column, 30x50 mm, 5 µm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (27 mg, 0.058 mmol) as a white solid.

LCMS: Rt: 1.98 min. (LCMS method 4); MS mass/charge 477.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 6.90-6.77 (m, 2H), 4.35-4.12 (m, 5H), 4.06 (dd, J =8.6, 6.9 Hz, 1H), 3.97 (dt, J =12.0, 4.3 Hz, 2H), 3.76 (dd, J =8.7, 7 ,3 Hz, 1H), 3.48 (m, 2H), 3.16-3.01 (m, 3H), 2.90 (m, 1H), 2.54 (dd, J = 12.9, 7.4 Hz, 1H), 2.27-2.09 (m, 3H), 2.03-1.93 (m, 2H), 1.87-1.58 (m, 6H).

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

(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 mixture was stirred at 80°C for 80 minutes, then cooled at room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with magnesium sulfate, filtered and concentrated. The residue was purified using FCC (0-20% MeOH (10% NH₄OH)/EtOAc) to give the title compound (27 mg, 0.058 mmol) as a white solid.

LCMS: Rt: 1.98 min. (LCMS method 4); MS mass/charge 463.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 6.94-6.75 (m, 2H), 5.03-4.94 (m, 1H), 4.35 -4.23 (m, 2H), 4.17 (q, J =8.6 Hz, 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, 7.4 Hz, 1H), 2.27-2.08 (m, 5H), 1.85-1.56 (m, 4H).

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

(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 mixture was stirred at 80°C for 20 minutes, then cooled at room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with magnesium sulfate, filtered and concentrated. The residue was purified using FCC (0-20% MeOH (10% NH₄OH)/EtOAc) to give the title compound (23 mg, 0.049 mmol) as a white solid.

LCMS: Rt: 1.89 min. (LCMS method 4); MS mass/charge 463.5 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 6.92-6.77 (m, 2H), 4.88 (dd, J =8.0, 6.1 Hz , 2H), 4.63 (t, J =6.0 Hz, 2H), 4.35-4.23 (m, 2H), 4.23-4.12 (m, 4H), 4.06 ( dd, J =8.7, 6.8 Hz, 1H), 3.76 (dd, J =8.7, 7.2 Hz, 1H), 3.44 (m, 1H), 3.17-2 .95 (m, 3H), 2.95-2.86 (m, 1H), 2.54 (dd, J =13.1, 7.4 Hz, 1H), 2.28-2.09 (m , 3H), 1.88-1.62 (m, 4H).

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

(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-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 mixture was stirred at 80°C for 6 hours, then cooled at room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with magnesium sulfate, filtered and concentrated. The residue was purified using FCC (0-20% MeOH (10% NH₄OH)/EtOAc) to give the title compound (15 mg, 0.033 mmol) as a white solid.

LCMS: Rt: 1.87 min. (LCMS method 4); MS mass/charge 449.5 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 6.93-6.75 (m, 2H), 5.15-5.00 (m, 1H), 4.91 (dd, J =7.5, 6.1 Hz, 2H), 4.83-4.77 (m, 2H), 4.35-4.22 (m, 2H), 4.17 (q, J =8.7 Hz, 2H), 4.06 (dd, J =8.8, 6.9 Hz, 1H), 3.77 (dd, J =8.8, 7.3 Hz, 1H), 3 .16-2.95 (m, 3H), 2.95-2.85 (m, 1H), 2.54 (dd, J =13.0, 7.4 Hz, 1H), 2.23 (m , 2H), 2.14 (dd, J =13.0, 8.3 Hz, 1H), 1.86-1.59 (m, 4H).

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

(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), oxetan-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 mixture was stirred at 80°C overnight, cooled to room temperature, filtered and concentrated. The residue was purified using preparative HPLC (X-bridge C18 OBD column, 30×50 mm, 5 µm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.), then using preparative HPLC (X-bridge C18 OBD column, 30x50 mm, 5 µm, 10-30% MeCN/H₂O (0.1% formic acid), 75 mL/min) to give the title compound (6 mg, 0.012 mmol) as the formate salt.

LCMS: Rt: 1.87 min. (LCMS method 4); MS mass/charge 449.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (d, J =6.3 Hz, 1H), 7.13 (dd, J =11.7, 8.9 Hz, 1H), 6, 53 (dd, J =12.2, 6.8 Hz, 1H), 5.26 (m, 1H), 5.02 (t, J =6.8 Hz, 2H), 4.67 (dd, J =7.5, 4.8 Hz, 2H), 4.42-4.00 (m, 5H), 3.86 (dd, J =9.1, 6.7 Hz, 1H), 3.29- 2.78 (m, 4H), 2.61 (dd, J =13.3, 7.5 Hz, 1H), 2.43 (m, 2H), 2.22 (dd, J =13.3, 7.8 Hz, 1H), 1.96-1.51 (m, 4H).

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

( 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 ) was suspended in acetonitrile (2 ml). The reaction mixture was stirred at 80°C overnight, then cooled to room temperature, filtered and concentrated. The residue was purified using preparative HPLC (X-bridge C18 OBD column, 30×50 mm, 5 µm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) and additionally using preparative HPLC (X-bridge C18 OBD column, 30x50 mm, 5 µm, 10-30% MeCN/H ₂ O (0.1% formic acid), 75 ml/min.) to obtain the title compound (14 mg , 0.027 mmol).

LCMS: Rt: 2.11 min. (LCMS method 4); MS mass/charge 477.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.39 (s, 1H), 7.07 (dd, J =11.8, 9.2 Hz, 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, 2H), 3.29-3.14 (m, 2H), 3.01 (m, 2H), 2.59 (dd, J =13.2, 7.4 Hz, 1H), 2.36 (m, 2H), 2.19 (dd, J =13.3, 7.9 Hz, 1H), 2.03 (m, 2H), 1.87 (m, 2H), 1.72 (m, 4H).

Example 2HH. ((1 S ,3 r )-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 ( (1 R ,3 s )-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 ((1 S ,3 r )-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 ( (1 R ,3 s )-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

Methyl-(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-carboxylate (Example 2U, step 1, 29 mg, 0.060 mmol) was dissolved in THF (2 ml) and LiBH ₄ (2.6 mg, 0.12 mmol) was added at 0 °C. The reaction mixture 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 column, 5 µm, 19 x 150 mm, 15-30% MeCN/H ₂ O (0.1% TFA), 25 ml/min) to obtain the product corresponding to peak 1 and Peak 2. The product corresponding to Peak 1 was obtained as the free base on a PL-HCO3 MP resin column (elution with methanol) and concentrated to give Example 2HH (2.0 mg, 0.0043 mmol). The product corresponding to peak 2 was further purified using preparative HPLC (X-bridge C18 OBD column, 30x50 mm, 5 μm, 35-60% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min. ) to give example 2II (2 mg, 0.0043 mmol).

Example 2HH.

LCMS: Rt: 1.88 min. (LCMS method 4); MS mass/charge 459.5 [M+H] ⁺ .

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).

Example 2II.

LCMS: Rt: 1.84 min. (LCMS method 4); MS mass/charge 459.5 [M+H] ⁺ .

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).

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

Stage 1. rubs -Butyl-(S)-7-(4-(2-(2,5-dihydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

rubs-Butyl-(S)-7-(4-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (intermediate connection 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 tribasic potassium phosphate ( 404 mg, 1.90 mmol) was dissolved in a mixture of dioxane (1.4 ml) and water (140 μl). Pd(dppf)Cl₂•CH₂Cl₂ (25 mg, 0.032 mmol) was added 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, and dried over MgSO₄, filtered and evaporated under reduced pressure. The residue was purified with FCC (0-40% EtOAc/heptane) to give the title intermediate (246 mg, 0.558 mmol).

LCMS: Rt: 1.10 min. (LCMS method 2); MS mass/charge 441.2 [M+H] ⁺ .

Stage 2. ( S )-7-(4-(2-(2,5-Dihydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

tert -Butyl-( S )-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 mixture was stirred for 16 hours at room temperature. The reaction mixture was then diluted with DCM and washed with 1 N. 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.

LCMS: Rt: 0.80 min. (LCMS method 2); MS mass/charge 341.1 [M+H] ⁺ .

Stage 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

( 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 tribasic potassium phosphate (350 mg, 1.65 mmol) were dissolved in a mixture of 2% aqueous TPGS solution -750-M (1.0 ml) and THF (0.11 ml). The reaction mixture was stirred at room temperature overnight. Then 4N was added. HCl to adjust pH to 2. The reaction mixture was stirred at room temperature for 3 hours and then increased in basicity with 2 M LiOH to pH > 8. The solution was then extracted with DCM and the combined organic layers were evaporated under reduced pressure. The residue was purified with FCC (0-7% MeOH/DCM) to give the title intermediate (38 mg, 0.089 mmol).

LCMS: Rt: 1.85 min. (LCMS method 4); MS mass/charge 409.7 [M+H] ⁺ .

Stage 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

( 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 mixture was stirred for 16 hours under hydrogen atmosphere. The reaction mixture was then filtered and the crude material was purified using preparative HPLC (X-bridge C18 OBD column, 30x50 mm, 5 μm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min. ). The two diastereomers were then separated by chiral SFC (ChiralPak ID column, 21 x 250 mm, 40% IPA with 10 mM NH ₄ OH, flow rate: 80 g per minute) to give the product corresponding to peak 1 (Example 3A, 32 mg, 0.076 mmol), and the product corresponding to peak 2 (Example 3B, 27 mg, 0.064 mmol).

Example 3A.

SFC: Rt: 3.99 min. (Chiralpak ID, 4.6×100 mm, 5 µm, 5→55% IPA with 10 mM NH ₄ OH/CO ₂ , 5 ml/min.). LCMS: Rt: 1.81 min. (LCMS method 4); MS mass/charge 411.2 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.66-8.63 (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).

Example 3B.

SFC: Rt: 4.65 min. (Chiralpak ID, 4.6×100 mm, 5 µm, 5→55% IPA with 10 mM NH ₄ OH/CO ₂ , 5 ml/min.). LCMS: Rt: 1.82 min. (LCMS method 4); MS mass/charge 411.5 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.64 (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)

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

Stage 1. rubs -Butyl-( S )-7-(4-(2-(3,6-dihydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

rubs-Butyl-(S)-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), Cs₂CO₃ (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 refilled with N gas₂ three times. It was then stirred at 80°C for 4 hours. The reaction mixture was then cooled and extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude material was purified using FCC (0-5% MeOH (10% NH₄OH)/DCM) to give the title intermediate (250 mg, 0.455 mmol).

LCMS: Rt: 1.16 min. (LCMS method 2); MS mass/charge 455.5 [M+H] ⁺ .

Stage 2. rubs -Butyl-( S )-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

tert -Butyl-( S )-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 purged with hydrogen and then the reaction mixture was stirred for 16 hours under a hydrogen atmosphere from a balloon. The solution was filtered and concentrated to give the title intermediate (250 mg, 0.547 mmol).

LCMS: Rt: 0.77 min. (LCMS method 1); MS mass/charge 457.5 [M+H] ⁺ .

Stage 3. ( S )-7-(4-(2-(Tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

tert -Butyl-( S )-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 mixture 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 sat. NaHCO ₃ solution and the DCM layer was dried over MgSO ₄ and concentrated to give the title intermediate (195 mg, 0.547 mmol).

LCMS: Rt: 0.50 min. (LCMS method 1); MS mass/charge 357.3 [M+H] ⁺ .

Stage 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

( 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 (151 mg, 0.711 mmol) were dissolved in a mixture of 2% aqueous solution of TPGS-750-M ( 6.0 ml) and THF (0.6 ml). The reaction mixture was stirred at room temperature overnight, then 2 M LiOH solution (2.73 mL, 5.47 mmol) was added and the reaction mixture was stirred for 2 hours. MeOH and 4N were added. HCl solution to adjust the pH to 2. It was stirred at room temperature for 3 hours, then increased in basicity with 2 M LiOH (pH > 8), extracted 3 times with DCM and the combined organic layers evaporated under reduced pressure. The residue was purified by FCC (0-7% EtOAc/heptane with 1% 7N NH ₄ OH/MeOH), and further by preparative HPLC (XBridge Peptide BEH C18, 5 µm, 19x150 mm, 30-45% MeCN/H ₂ O (5 mM NH ₄ OH), 30 ml/min.) to obtain the title compound (59 mg, 0.14 mmol).

LCMS: Rt: 1.89 min. (LCMS method 4); MS mass/charge 425.5 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.39 (s, 1H), 7.34-6.98 (m, 4H), 4.38-4.25 (m, 2H), 4.17 (q, J =8.6 Hz, 2H), 4.11-3.98 (m, 3H), 3.79 (dd, J =8.8, 7.3 Hz, 1H), 3.60 ( td, J =11.8, 1.9 Hz, 2H), 3.19-3.06 (m,3H), 2.92 (dd, J =11.7, 3.6 Hz, 2H), 2 .56 (dd, J =13.0, 7.5 Hz, 1H), 2.29 (m, 2H), 2.16 (dd, J =13.1, 8.3 Hz, 1H), 1, 91-1.69 (m, 6H), 1.67-1.56 (m, 2H).

3D example. ( 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

Stage 1. rubs -Butyl-( S )-7-(4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2 -carboxylate

rubs-Butyl-(S)-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), K₃P.O.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 filled with nitrogen and this was repeated twice. The reaction mixture was then stirred in a sealed vessel at 80°C for 5 hours. 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).

LCMS: Rt: 1.16 min. (LCMS method 1); MS mass/charge 473.2 [M+H] ⁺ .

Stage 2. rubs -Butyl-( S )-7-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

tert -Butyl-( S )-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 for 16 hours under hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and the solvent was removed to give the title compound (231 mg, 0.487 mmol).

LCMS: Rt: 1.14 min. (LCMS method 2); MS mass/charge 475.6 [M+H] ⁺ .

Stage 3. ( S )-7-(4-(5-Fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

tert -Butyl-( S )-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 for 10 min. TFA (0.75 mL, 9.73 mmol) was added at 0°C and the reaction mixture was warmed to room temperature and stirred for 16 hours. The solution was concentrated and the residue was dissolved in DCM and washed with 1 N. NaOH and brine, dried over MgSO ₄ , filtered and concentrated to give the title intermediate (111 mg, 0.296 mmol).

LCMS: Rt: 0.53 min. (LCMS method 1); MS mass/charge 375.1 [M+H] ⁺ .

Stage 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

( 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) were dissolved in a mixture of 2% aqueous solution TPGS-750-M (0.53 ml) and THF (0.059 ml). The reaction mixture was processed analogously to Example 1A and the crude material was purified using FCC (0-7% MeOH/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 µm, 25-50% MeCN/ H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (60 mg, 0.13 mmol).

LCMS: Rt: 1.33 min. (LCMS method 4); MS mass/charge 443.3 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.67-8.60 (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).

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

Step 1. tert-Butyl-(S)-7-(4-(2-(2,5-dihydrofuran-3-yl)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[ 3.4]octane-2-carboxylate

rubs-Butyl-(S)-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 K₃P.O.₄ (296 mg, 1.393 mmol) was suspended in dioxane (1.0 ml) and water (0.1 ml). Pd(dppf)Cl was added₂•CH₂Cl₂ (18.95 mg, 0.023 mmol) and the vial was evacuated and refilled with nitrogen. This was repeated twice. The contents of the tube were then stirred at 80°C for 5 hours. The reaction mixture was then concentrated and the residue was dissolved in DCM and washed with water and saline. The organic layer was dried over sodium sulfate and concentrated and the residue was purified with FCC (0-40% EtOAc/heptanes) to give the title intermediate (207 mg, 0.451 mmol).

LCMS: Rt: 1.16 min. (LCMS method 2); MS mass/charge 459.3 [M+H] ⁺ .

Stage 2. rubs -Butyl-(7 S )-7-(4-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

tert -Butyl-( S )-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 atmosphere from a 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).

LCMS: Rt: 1.11 min. (LCMS method 2); MS mass/charge 461.6 [M+H] ⁺ .

Stage 3. (7 S )-7-(4-(5-Fluoro-2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

tert -Butyl-( 7S )-7-(4-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2 β-carboxylate (171 mg, 0.371 mmol) was dissolved in DCM (3.7 ml) and cooled to 0°C. The reaction mixture was stirred for 10 minutes and then TFA (0.5 ml, 2.94 mmol) was added and the reaction mixture was stirred for 5 hours at 0°C. The reaction mixture 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).

LCMS: Rt: 0.49 min. (LCMS method 1); MS mass/charge 361.3 [M+H] ⁺ .

Stage 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

( 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) were dissolved in a mixture of 2% aqueous TPGS solution -750-M (0.73 ml) and THF (0.082 ml) and the reaction mixture was processed similarly to example 1A. The crude material was purified using FCC (0-7% MeOH/DCM) and additionally using HPLC (X-bridge C18 OBD, 30x50 mm, 5 µm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH ), 75 ml/min.) to obtain a diastereomeric mixture. The two diastereomers were then separated by SFC (ChiralPak IG, 21x250 mm, co-solvent: 35% IPA with 10 mM NH ₃ , flow rate: 80 g per minute) to give a product corresponding to the original peak of Example 3E (18 mg, 0. 41 mmol) and the product corresponding to the next peak of Example 3F (17 mg, 0.038 mmol).

Example 3E.

SFC: Rt: 3.63 min. (Chiralpak IG, 4.6×100 mm, 5 µm, 5→55% IPA with 10 mM NH ₄ OH/CO ₂ , 5 ml/min.). LCMS: Rt: 1.89 min. (LCMS method 4); MS mass/charge 429.5 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.65 (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).

Example 3F.

SFC Rt: 3.85 min. (Chiralpak IG, 4.6×100 mm, 5 µm, 5→55% IPA with 10 mM NH ₄ OH/CO ₂ , 5 ml/min.). LCMS: Rt: 1.89 min. (LCMS method 4); MS mass/charge 429.3 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.62 (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).

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

Stage 1. rubs -Butyl-( S )-7-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

tert -Butyl-( S )-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 /C (24 mg, 0.034 mmol) were dissolved in EtOH (10 ml). The reaction solution was purged with hydrogen, stirred under a hydrogen atmosphere from a balloon overnight, filtered through a pad of celite and evaporated under reduced pressure. The residue was purified with FCC (0-80% EtOAc/heptane) to give the title compound (45 mg, 0.083 mmol).

LCMS: Rt: 1.20 min. (LCMS method 2); MS mass/charge 471.6 mass/charge [M+H] ⁺ .

Stage 2. ( S )-7-(4-(2-((Tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

tert -Butyl-( S )-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 mixture 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 give the title intermediate (35 mg, 0.094 mmol).

LCMS: Rt: 0.51 min. (LCMS method 1); MS mass/charge 371.4 mass/charge [M+H] ⁺ .

Stage 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

(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 tribasic potassium 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 mixture was worked up as in Example 1A and the crude material was purified by preparative HPLC (XBridge Peptide BEH C18, 5 µm, 19 x 150 mm, 40-55% MeCN/H₂O (5 mM NH₄OH), 30 mL/min) and with FCC (0-15% MeOH/DCM) to give the title compound (13 mg, 0.030 mmol).

LCMS: Rt: 2.07 min. (LCMS method 4); MS mass/charge 439.6 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.30-7.22 (m, 1H), 7.19-7.13 (m, 1H), 7.11 -7.05 (m, 2H), 4.37-4.26 (m, 2H), 4.18 (t, J =8.1 Hz, 2H), 4.07 (dd, J =8.8 , 6.9 Hz, 1H), 3.91 (m, 2H), 3.78 (dd, J =8.8, 7.3 Hz, 1H), 3.35 (dd, J =11.8, 2.0 Hz, 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).

Example 3H. (1 R ,4 s )-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 (1 S ,4 r )-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. (1 R ,4 s )-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 (1 S ,4 r )-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

Stage 1. rubs -Butyl-(6R)-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

To a mixture of tert -butyl-( R )-6-(4-(2-bromophenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate (intermediate 3F, 219 mg, 0.487 mmol), tert -butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)oxy)silane (198 mg, 0.585 mmol) , the adduct of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (17.83 mg, 0.024 mmol) and potassium phosphate (310 mg, 1.462 mmol), dioxane (3 ml) and water (0. 3 ml). The reaction mixture was stirred at room temperature for 16 hours and was then concentrated. The residue was added to water (50 ml) and extracted with EtOAc (x3). Organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was then purified using FCC (0-20% EtOAc (5% 7N NH ₃ in ammonia)/heptanes). The material was then further purified with FCC (0-5% MeOH/DCM) to give the title compound (266 mg, 0.441 mmol) as a clear solid.

LCMS: Rt: 1.78 min. (LCMS method 2); MS mass/charge 581.0 [M+H] ⁺ .

Stage 2. rubs -Butyl-(7S)-7-(4-(4-fluoro-4'-hydroxy-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)piperidine -1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

tert -Butyl-( 7S )-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) was added in THF, 2.114 ml, 2.114 mmol) and the reaction mixture was stirred at 40°C for 16 hours. The reaction mixture was concentrated and the residue was purified with FCC (0-30% EtOAc (8% 7N NH ₃ in ammonia)/heptanes) to give the title compound as a yellow oil (200 mg, 0.411 mmol).

LCMS: Rt: 1.11 min. (LCMS method 2); MS mass/charge 487.6 [M+H] ⁺ .

Stage 3. rubs -Butyl-( S )-7-(4-(5-fluoro-2-(4-hydroxycyclohexyl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

tert -Butyl-(7S)-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 the mixture was stirred under a hydrogen atmosphere for 72 hours. The reaction mixture was concentrated and the crude material was purified with FCC (0-32% EtOAc (8% 7N NH ₃ in MeOH)/heptanes) to give the title compound as a yellow oil (107 mg, 0.197 mmol).

LCMS: Rt: 1.11 min. (LCMS method 2); MS mass/charge 489.5 [M+H] ⁺ .

Stage 4. ( S )-4-(2-(1-(5-Oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenyl)cyclohexan-1-ol

Into DCM solution (750 µl) tert -butyl-( S )-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) was added TFA (422 μl, 5.47 mmol). The reaction mixture was stirred at room temperature for two hours. The reaction mixture was concentrated, diluted with DCM and washed with 1 N. NaOH to give the title compound, which was used without further purification (91 mg, 0.181 mmol).

LCMS: Rt: 0.78 min. (LCMS method 2); MS mass/charge 389.4 [M+H] ⁺ .

Stage 5. (1 R ,4 s )-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 (1 S ,4 r )-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. (1 R ,4 s )-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

In a solution of THF (1 ml) ( 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) ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (48.0 mg, 0.174 mmol) and DIEA (0.056 ml, 0.319 mmol) were added at 0°C. The resulting suspension was stirred at room temperature for 2 hours and was then concentrated and diluted with EtOAc. The crude organic matter was washed with water and saline. The combined organics were then dried over MgSO ₄ , filtered and concentrated. The concentrated reaction mixture was diluted in THF (1 ml) and LiOH (36.5 mg, 0.869 mmol) in water (1 ml) was added and the reaction mixture was stirred for 72 hours. Then 6 n. HCl (0.241 ml, 1.449 mmol) was added to the reaction mixture at -5°C and the solution became clear. It was stirred at room temperature for 2 hours and then solid Na ₂ CO ₃ was added until the solution became basic and then the solution was concentrated in vacuo. The residue was diluted with EtOAc and washed with brine, and the organic layer was dried over magnesium sulfate and concentrated. The crude material was purified with FCC (0-40% EtOAc (10% 7N NH ₃ in MeOH)/heptanes) to give a white solid. The two diastereomers were then separated using preparative HPLC (XBridge C18, 30×50 mm, 10-30% MeCN/H ₂ O (1% formic acid), 75 ml/min.). The product corresponding to the original peak was isolated as an example 3H (27.9 mg, 0.055 mmol) as the formate salt and the product corresponding to the next peak was isolated as an example 3I (1.7 mg, 0.003 mmol) as the formate salt.

Example 3H.

LCMS: Rt: 0.97 min. (LCMS method 3); MS mass/charge 457.5 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.40 (s, 1H), 8.32 (d, J=3.6 Hz, 1H), 7.31 (dd, J=8.6, 6 ,1 Hz, 1H), 6.94 (dd, J=10.9, 2.7 Hz, 1H), 6.89 (td, J=8.5, 2.8 Hz, 1H), 4.41 -4.27 (m, 2H), 4.19 (q, J=8.7 Hz, 2H), 4.13-4.03 (m, 2H), 3.94 (m, 1H), 3, 45 (dt, J=13.6, 6.0 Hz, 1H), 3.28 (d, J=5.9 Hz, 1H), 3.18-3.09 (m, 1H), 3.03 (p, J=7.8 Hz, 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).

Example 3I.

LCMS: Rt: 1.10 min. (LCMS method 3); MS mass/charge 457.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.40 (s, 1H), 8.31 (s, 1H), 7.26 (dd, J=8.6, 6.0 Hz, 1H), 7.00-6.81 (m, 2H), 4.46-4.25 (m, 2H), 4.19 (q, J=8.7 Hz, 2H), 4.15-4.02 ( m, 2H), 3.92 (dd, J=9.3, 6.8 Hz, 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).

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

( 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-bromoxazole (98 mg, 0.66 mmol) were dissolved in dioxane (5.5 ml) and the mixture was purged with nitrogen. Pd ₂ (dba) ₃ (31.7 mg, 0.055 mmol), XantPhos (38 mg, 0.066 mmol) and sodium tert -butoxide (159 mg, 1.66 mmol) were added. The reaction mixture was stirred at 75°C overnight, filtered with a Celite column, washed with EtOAc and concentrated. The residue was purified with FCC (0-10% MeOH (1% NH ₃ )/DCM) to give the title compound (63 mg, 0.14 mmol) as a light yellow solid.

LCMS: Rt: 1.99 min. (LCMS method 4); MS mass/charge 430.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (d, J =1.4 Hz, 1H), 6.96 (dd, J =9.8, 3.2 Hz, 1H), 6, 88-6.78 (m, 2H), 6.49 (dd, J =8.8, 4.4 Hz, 1H), 5.25 (m, 1H), 5.05-4.95 (m, 2H), 4.68 (dd, J =7.4, 4.8 Hz, 2H), 4.25-4.16 (m, 2H), 4.13-4.02 (m, 3H), 3 .80-3.73 (m, 1H), 3.16-3.03 (m, 3H), 2.91 (d, J =11.5 Hz, 1H), 2.53 (dd, J =13 ,0, 7.4 Hz, 1H), 2.32-2.19 (m, 2H), 2.13 (dd, J =12.9, 8.4 Hz, 1H), 1.86 (t, J =10.2 Hz, 2H), 1.81-1.64 (m, 2H).

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

( 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-bromoxazole (39 mg, 0.27 mmol) were dissolved in dioxane (2.2 ml) and the mixture was purged with nitrogen. Pd ₂ (dba) ₃ (12.7 mg, 0.022 mmol), XantPhos (15 mg, 0.027 mmol) and sodium tert -butoxide (64 mg, 0.66 mmol) were added and the reaction mixture was stirred at 75°C overnight . The reaction mixture was filtered through a celite column, washed with EtOAc and concentrated. The residue was purified with FCC (0-10% MeOH (1% NH ₃ )/DCM) to give the title compound (32 mg, 0.064 mmol) as a light yellow solid.

LCMS: Rt: 2.12 min. (LCMS method 4); MS mass/charge 474.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (d, J =1.2 Hz, 1H), 6.94-6.83 (m, 3H), 6.81 (d, J =1 .0 Hz, 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), 3.16-3.06 (m, 2H), 3.06-2.95 (m, 1H), 2, 90 (d, J =11.4 Hz, 1H), 2.53 (dd, J =13.0, 7.4 Hz, 1H), 2.23 (m, 2H), 2.12 (dd, J =13.0, 8.5 Hz, 1H), 1.92-1.80 (m, 2H), 1.78-1.57 (m, 2H).

Example 4C. ( 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-(2-(Oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7Q, 130 mg, 0.38 mmol) and 2-bromoxazole (67 mg, 0.45 mmol) were dissolved in dioxane (3.8 ml) and the mixture was purged with nitrogen. Pd ₂ (dba) ₃ (22 mg, 0.038 mmol), XantPhos (26 mg, 0.045 mmol) and sodium tert -butoxide (109 mg, 1.13 mmol) were added and the reaction mixture was stirred at 75°C overnight. The reaction mixture was filtered through a pad of celite and washed with EtOAc and then concentrated. The residue was purified with FCC (0-10% MeOH (1% NH ₃ )/DCM) to give the title compound (73 mg, 0.17 mmol) as a light yellow solid.

LCMS: Rt: 1.96 min. (LCMS method 4); MS mass/charge 412.7 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (d, J =1.0 Hz, 1H), 7.22 (dd, J =7.4, 1.8 Hz, 1H), 7, 11 (m, 1H), 6.93 (m, 1H), 6.84-6.79 (m, 1H), 6.48 (dd, J =8.3, 1.0 Hz, 1H), 5 .27 (m, 1H), 5.06-4.98 (m, 2H), 4.69 (dd, J =7.3, 4.8 Hz, 2H), 4.26-4.16 (m , 2H), 4.14-4.02 (m, 3H), 3.76 (dd, J =8.6, 7.5 Hz, 1H), 3.16-3.00 (m, 3H), 2.90 (m, 1H), 2.53 (dd, J =12.9, 7.4 Hz, 1H), 2.25 (m, 2H), 2.13 (dd, J =12.9, 8.5 Hz, 1H), 1.91-1.71 (m, 4H).

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

( 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-bromoxazole (42 mg, 0.29 mmol) were dissolved in dioxane (2.4 ml) and the mixture was purged with nitrogen. Pd 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 mixture was stirred at 75°C overnight. The reaction mixture was filtered through a celite column, washed with EtOAc and concentrated. The residue was purified with FCC (0-10% MeOH (1% NH ₃ )/DCM) to give the title compound (13 mg, 0.029 mmol) as a light yellow solid.

LCMS: Rt: 2.14 min. (LCMS method 4); MS mass/charge 444.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (d, J =0.9 Hz, 1H), 6.93 (dd, J =9.8, 2.6 Hz, 1H), 6, 90-6.84 (m, 2H), 6.81 (d, J =1.2 Hz, 1H), 5.01 (m, 1H), 4.20 (q, J =8.7 Hz, 2H ), 4.13-4.01 (m, 3H), 4.01-3.84 (m, 4H), 3.74 (dd, J =8.7, 7.4 Hz, 1H), 3, 08 (m, 2H), 3.03-2.92 (m, 1H), 2.89 (d, J =11.5 Hz, 1H), 2.52 (dd, J =12.9, 7, 4 Hz, 1H), 2.30-2.16 (m, 3H), 2.11 (dd, J =13.1, 8.3 Hz, 2H), 1.87-1.74 (m, 2H ), 1.67 (m, 2H).

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

( 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-bromoxazole (41 mg, 0.28 mmol) were dissolved in dioxane (2.3 ml) and the mixture was purged with nitrogen. Pd 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 mixture was stirred at 75°C overnight. The reaction mixture was filtered through a celite column, washed with EtOAc and concentrated. The residue was purified by FCC (0-10%MeOH (1% NH ₃ )/DCM) and by preparative HPLC (X-Bridge Peptide BEH C18, 5 µm, 19x150 mm, 40-55% MeCN/H ₂ O (10 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (12 mg, 0.026 mmol) as a white powder.

LCMS: Rt: 2.22 min. (LCMS method 4); MS mass/charge 458.7 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (s, 1H), 6.94 (m, 2H), 6.89-6.80 (m, 2H), 4.52 (m, 1H ), 4.20 (q, J =8.7 Hz, 2H), 4.14-4.01 (m, 3H), 3.93 (ddd, J =11.6, 6.1, 3.9 Hz, 2H), 3.79-3.71 (m, 1H), 3.60 (ddd, J =11.7, 8.3, 3.3 Hz, 2H), 3.16-2.98 ( m, 3H), 2.95-2.85 (m, 1H), 2.53 (dd, J =12.9, 7.4 Hz, 1H), 2.22 (m, 2H), 2.12 (dd, J=12.9, 8.4 Hz, 1H), 2.07-1.96 (m, 2H), 1.83 (m, 2H), 1.71 (m, 4H).

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

(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-bromoxazole (39 mg, 0.26 mmol) were dissolved in dioxane (2.2 ml) and the mixture was purged with nitrogen. Added Pd₂(dba)₃ (13 mg, 0.022 mmol), XantPhos (15 mg, 0.026 mmol) and rubs-sodium butoxide (63 mg, 0.65 mmol) and the reaction mixture was stirred at 75°C overnight. The reaction mixture was filtered through a celite column, washed with EtOAc and concentrated. The residue was purified using FCC (0-10% MeOH (1% NH₃)/DCM) to give the title compound (37 mg, 0.083 mmol) as a light yellow solid.

LCMS: Rt: 2.10 min. (LCMS method 4); MS mass/charge 426.5 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (d, J =1.0 Hz, 1H), 7.21-7.11 (m, 2H), 6.94-6.86 (m , 2H), 6.81 (d, J =1.2 Hz, 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, 7.4 Hz, 1H), 2.30-2.18 (m, 3H), 2 .12 (ddd, J =13.0, 7.6, 4.8 Hz, 2H), 1.87-1.66 (m, 4H).

Example 4G. ( S )-7-(4-(2-((2-Oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5- oxa-2-azaspiro[3.4]octane

(S)-7-(4-(2-((2-Oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane ( intermediate connection 7NN, 90 mg, 0.22 mmol) and 2-bromoxazole (40 mg, 0.27 mmol) were dissolved in dioxane (2.2 ml) and the mixture was purged with nitrogen. Added Pd₂(dba)₃ (13 mg, 0.022 mmol), XantPhos (16 mg, 0.028 mmol) and rubs-sodium butoxide (65 mg, 0.67 mmol) and the reaction mixture was stirred at 75°C overnight. The reaction mixture was filtered through a celite column, washed with EtOAc and concentrated. The residue was purified using preparative HPLC (X-bridge C18 OBD column, 30×50 mm, 5 µm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (10 mg, 0.021 mmol) as a white powder.

LCMS: Rt: 2.24 min. (LCMS method 4); MS mass/charge 470.5 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (s, 1H), 6.90 (dd, J =9.8, 3.0 Hz, 1H), 6.87-6.77 (m , 2H), 6.70 (dd, J =9.0, 4.6 Hz, 1H), 4.72 (d, J =30.8 Hz, 4H), 4.53 (p, J =6, 7 Hz, 1H), 4.20 (q, J =8.7 Hz, 2H), 4.13-4.01 (m, 3H), 3.75 (dd, J =8.7, 7.4 Hz, 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, 7.4 Hz, 1H), 2.34-2.26 (m, 2H), 2.21 (m, 2H), 2.11 (dd, J =12.9, 8, 5 Hz, 1H), 1.85-1.75 (m, 2H), 1.75-1.61 (m, 2H).

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

(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-bromoxazole (39 mg, 0.26 mmol) were dissolved in dioxane (2.2 ml) and the mixture was purged with nitrogen. Added Pd₂(dba)₃ (12 mg, 0.022 mmol), XantPhos (15 mg, 0.026 mmol) and rubs-sodium butoxide (63 mg, 0.65 mmol) and the reaction mixture was stirred at 75°C overnight. The reaction mixture was filtered through a celite column, washed with EtOAc and concentrated. The residue was purified using FCC (0-10% MeOH (1% NH₃)/DCM) to give the title compound (18 mg, 0.041 mmol) as a light yellow solid.

LCMS: Rt: 2.08 min. (LCMS method 4); MS mass/charge 426.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (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 =11.4 Hz, 1H), 2.53 (dd, J =13.0, 7.4 Hz, 1H), 2.30-2.17 (m, 3H), 2.12 (ddd, J =13.0, 7.4, 3.8 Hz, 2H), 1.74 (m, 4H).

Example 4I. ( S )-7-(4-(5-Fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

( 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-bromoxazole (39 mg, 0.26 mmol) was dissolved in dioxane (2.2 ml) and the mixture was purged with nitrogen. Pd ₂ (dba) ₃ (12 mg, 0.022 mmol), XantPhos (15 mg, 0.026 mmol) and sodium tert -butoxide (42 mg, 0.44 mmol) were added and the reaction mixture was stirred at 75°C overnight. The reaction mixture was filtered through a celite column, washed with EtOAc and acetonitrile and then concentrated. The residue was purified by preparative HPLC (X-bridge C18 OBD column, 30x50 mm, 5 μm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (45 mg, 0.11 mmol) as a light yellow solid.

LCMS: Rt: 2.27 min. (LCMS method 4); MS mass/charge 388.8 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (s, 1H), 6.93-6.85 (m, 3H), 6.81 (d, J =1.0 Hz, 1H), 4.20 (q, J =8.7 Hz, 2H), 4.12-4.02 (m, 3H), 3.80 (s, 3H), 3.74 (dd, J =8.7, 7.4 Hz, 1H), 3.14-3.04 (m, 2H), 2.98 (tt, J =12.2, 3.7 Hz, 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, 8.5 Hz, 1H), 1.80 (m, 2H), 1.69 (m, 2H).

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

(S)-7-(4-(2-((Tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7OO, 148 mg, 0.40 mmol) and 2-bromoxazole (71 mg, 0.48 mmol) were dissolved in dioxane (5.0 ml) and the mixture was purged with nitrogen. Added Pd₂(dba)₃ (23 mg, 0.040 mmol), XantPhos (28 mg, 0.048 mmol) and rubs-sodium butoxide (115 mg, 1.19 mmol) and the reaction mixture was stirred at 75°C overnight. The reaction mixture was filtered through a Celite column, washed with EtOAc, and concentrated. The residue was purified using preparative HPLC (X-bridge C18 OBD column, 30×50 mm, 5 µm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (68 mg, 0.15 mmol) as a light yellow solid.

LCMS: Rt: 1.04 min. (LCMS method 3); MS mass/charge 440.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.30 (s, 1H), 7.12-6.99 (m, 2H), 6.90-6.76 (m, 2H), 6.72 (d, J =1.0 Hz, 1H), 4.50 (tt, J =7.6, 3.8 Hz, 1H), 4.11 (q, J =8.7 Hz, 2H), 4 .05-3.92 (m, 3H), 3.84 (ddd, J =11.5, 6.2, 3.7 Hz, 2H), 3.70-3.60 (m, 1H), 3 .52 (ddd, J =11.4, 8.1, 3.3 Hz, 2H), 3.09-2.87 (m, 3H), 2.80 (m, 1H), 2.44 (dd , J =12.8, 7.4 Hz, 1H), 2.24-1.86 (m, 5H), 1.83-1.55 (m, 6H).

4K example. ( 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 )-1-(2-(1-(5-Oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylpropan-2-ol (intermediate compound 7U, 45 mg, 0.12 mmol) and 2-bromoxazole (21 mg, 0.14 mmol) were dissolved in dioxane (1.2 ml) and the mixture was purged with nitrogen. Pd 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 mixture was stirred at 75°C in during the night. The reaction mixture was filtered through a celite column, washed with EtOAc and acetonitrile, and the filtrate was concentrated. The residue was purified with FCC (0-10% MeOH (1% NH ₃ )/DCM) to give the title compound (25 mg, 0.053 mmol) as a light yellow solid.

LCMS: Rt: 2.09 min. (LCMS method 4); MS mass/charge 446.6 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (s, 1H), 6.95-6.83 (m, 3H), 6.81 (s, 1H), 4.20 (q, J =8.7 Hz, 2H), 4.12-4.03 (m, 3H), 3.75 (s, 3H), 3.14-3.04 (m, 3H), 2.90 (dd, J =11.4, 4.4 Hz, 1H), 2.53 (dd, J =13.0, 7.4 Hz, 1H), 2.24 (m, 2H), 2.11 (dd, J =13.0, 8.5 Hz, 1H), 1.86 (m, 2H), 1.69 (m, 3H), 1.34 (s, 6H).

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

(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-bromoxazole (32 mg, 0.21 mmol) were dissolved in dioxane (1.8 ml) and the mixture was purged with nitrogen. Added Pd₂(dba)₃ (10 mg, 0.018 mmol), XantPhos (12 mg, 0.021 mmol) and rubs-sodium butoxide (34 mg, 0.36 mmol) and the reaction mixture was stirred at 75°C overnight. The reaction mixture was filtered through a celite column, washed 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 column, 30x50 mm, 5 µm, 35-60% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (25 mg, 0.057 mmol).

LCMS: Rt: 2.20 min. (LCMS method 4); MS mass/charge 432.3 [M+H] ⁺ .

^1H NMR (400 MHz, DMSO -d6 ) δ 7.57 (s, _1H ), 7.03-6.92 (m, 3H), 6.83 (d, J =0.6 Hz, 1H) , 4.13 (d, J =8.5 Hz, 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).

Example 4M. ( S )-7-(4-(2-((2-Oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2 -azaspiro[3.4]octane

(S)-7-(4-(2-((2-Oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7II , 110 mg, 0.29 mmol) and 2-bromoxazole (51 mg, 0.34 mmol) were dissolved in dioxane (2.9 ml) and the mixture was purged with nitrogen. Added Pd₂(dba)₃ (16 mg, 0.029 mmol), XantPhos (20 mg, 0.034 mmol) and rubs-sodium butoxide (82 mg, 0.86 mmol), and the reaction mixture was stirred at 75°C overnight. The reaction mixture was filtered through a celite column, washed with EtOAc and concentrated. The residue was purified using FCC (0-10% MeOH (1% NH₃)/DCM) and using preparative HPLC (X-bridge C18 OBD column, 30×50 mm, 5 µm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (9.5 mg, 0.021 mmol).

LCMS: Rt: 2.18 min. (LCMS method 4); MS mass/charge 452.4 [M+H] ⁺ .

^1H NMR (400 MHz, CD ₃ OD) δ 7.40 (d, J =1.0 Hz, 1H), 7.19-7.06 (m, 2H), 6.88 (dd, J =8 ,1, 6.9 Hz, 1H), 6.81 (d, J =1.0 Hz, 1H), 6.72 (d, J =8.2 Hz, 1H), 4.72 (d, J =31.9 Hz, 4H), 4.62-4.52 (m, 1H), 4.21 (q, J =8.8 Hz, 2H), 4.11 (s, 3H), 3.75 (t, J =8.1 Hz, 1H), 3.15-3.04 (m, 2H), 3.02-2.85 (m, 2H), 2.85-2.77 (m, 2H ), 2.53 (dd, J =12.9, 7.4 Hz, 1H), 2.37-2.26 (m, 2H), 2.26-2.16 (m, 2H), 2, 12 (dd, J =12.9, 8.5 Hz, 1H), 1.76 (m, 4H).

Example 4N. ( S )-7-(4-(2-Methoxyphenyl)piperidin-1-yl)-2-(oxazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

(S)-7-(4-(2-Methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7X, 52 mg, 0.17 mmol) and 2-bromoxazole (31 mg, 0.21 mmol) were dissolved in dioxane (1.7 ml) and the mixture was purged with nitrogen. Added Pd₂(dba)₃ (9.9 mg, 0.017 mmol), XantPhos (12 mg, 0.021 mmol) and sodium rubs-sodium butoxide (31 mg, 0.34 mmol), and the reaction mixture was stirred at 75°C overnight. The reaction mixture was filtered through a celite column, washed with EtOAc and acetonitrile and concentrated. The residue was purified using preparative HPLC (X-bridge C18 OBD column, 30×50 mm, 5 µm, 35-60% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (9.4 mg, 0.024 mmol).

LCMS: Rt: 2.19 min. (LCMS method 4); MS mass/charge 370.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (d, J=1.3 Hz, 1H), 7.21-7.10 (m, 2H), 6.89 (dd, J=14 ,1, 7.7 Hz, 2H), 6.81 (d, J=1.0 Hz, 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=7.7 Hz, 3H), 2.88 (d, J=11 ,9 Hz, 1H), 2.52 (dd, J=13.0, 7.4 Hz, 1H), 2.27-2.17 (m, 2H), 2.12 (dd, J=13, 1, 8.4 Hz, 1H), 1.90-1.66 (m, 4H).

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

(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-bromoxazole (45 mg, 0.30 mmol) were dissolved in dioxane (2.5 ml) and the mixture was purged with nitrogen. Pd was added₂(dba)₃ (15 mg, 0.025 mmol), XantPhos (18 mg, 0.030 mmol) and rubs-sodium butoxide (73 mg, 0.76 mmol), and the reaction mixture was stirred at 75°C overnight. The reaction mixture was filtered through a celite column, washed with EtOAc and concentrated. The residue was purified using FCC (0-10% MeOH (1% NH₃)/DCM) and using preparative HPLC (X-bridge C18 OBD column, 30×50 mm, 5 µm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (20 mg, 0.041 mmol).

LCMS: Rt: 2.15 min. (LCMS method 4); MS mass/charge 462.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (d, J =1.3 Hz, 1H), 7.08 (dd, J =11.9, 9.1 Hz, 1H), 6, 94 (dd, J =12.6, 6.9 Hz, 1H), 6.81 (s, 1H), 4.93-4.87 (m, 2H), 4.63 (t, J =6, 1 Hz, 2H), 4.26-4.11 (m, 4H), 4.11-3.99 (m, 3H), 3.74 (dd, J =8.7, 7.4 Hz, 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, 7.4 Hz, 1H), 2.21 (m, 2H), 2.11 (dd, J =13.0, 8.5 Hz, 1H), 1.82 (m , 2H), 1.66 (m, 2H).

Example 4P. ( S )-7-(4-(4,5-Difluoro-2-((3-fluoroxetan-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-((3-fluoroxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7KK, 100 mg, 0.242 mmol) and 2-bromoxazole (43 mg, 0.29 mmol) were dissolved in dioxane (2.5 ml) and the mixture was purged with nitrogen. Pd ₂ (dba) ₃ (14 mg, 0.024 mmol), XantPhos (17 mg, 0.029 mmol) and sodium tert -butoxide (70 mg, 0.73 mmol) were added and the reaction mixture was stirred at 75°C overnight. The reaction mixture was filtered through a Celite column, washed with EtOAc and the filtrate was concentrated. The residue was purified with FCC (0-10% MeOH (1% NH ₃ )/DCM) to give the title compound (33 mg, 0.069 mmol).

LCMS: Rt: 2.22 min. (LCMS method 4); MS mass/charge 480.1 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (d, J =0.9 Hz, 1H), 7.10 (dd, J =11.8, 9.1 Hz, 1H), 7, 00 (dd, J =12.3, 6.8 Hz, 1H), 6.83-6.80 (m, 1H), 4.84-4.71 (m, 4H), 4.38 (s, 1H), 4.33 (s, 1H), 4.20 (q, J =8.7 Hz, 2H), 4.14-4.00 (m, 3H), 3.74 (dd, J =8 ,7, 7.4 Hz, 1H), 3.07 (p, J =7.0 Hz, 2H), 2.99-2.83 (m, 2H), 2.52 (dd, J =12, 8, 7.4 Hz, 1H), 2.19 (m, 2H), 2.10 (dd, J =12.9, 8.5 Hz, 1H), 1.82 (m, 2H), 1, 65 (m, 2H).

Example 4Q. ( 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 )-7-(4-(4,5-Difluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7LL, 140 mg, 0.368 mmol) and 2-bromoxazole (65 mg, 0.44 mmol) were dissolved in dioxane (3.7 ml) and the mixture was purged with nitrogen. Pd ₂ (dba) ₃ (21 mg, 0.037 mmol), XantPhos (26 mg, 0.044 mmol) and sodium tert -butoxide (106 mg, 1.10 mmol) were added and the reaction mixture was stirred at 75°C overnight. The reaction mixture was filtered through a Celite column, washed with EtOAc and the filtrate was concentrated. The residue was purified with FCC (0-10% MeOH (1% NH ₃ )/DCM) to give the title compound (36 mg, 0.076 mmol).

LCMS: Rt: 2.10 min. (LCMS method 4); MS mass/charge 448.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (s, 1H), 7.12 (dd, J =11.8, 9.1 Hz, 1H), 6.81 (d, J =0 ,9 Hz, 1H), 6.52 (dd, J =12.2, 6.8 Hz, 1H), 5.29-5.21 (m, 1H), 5.01 (dd, J =7, 4, 5.7 Hz, 2H), 4.67 (dd, J =7.6, 4.9 Hz, 2H), 4.26-4.14 (m, 2H), 4.14-3.99 (m, 3H), 3.75 (dd, J =8.7, 7.4 Hz, 1H), 3.16-3.07 (m, 2H), 3.07-2.94 (m, 1H ), 2.90 (dd, J =11.6, 2.6 Hz, 1H), 2.53 (dd, J =13.0, 7.4 Hz, 1H), 2.24 (m, 2H) , 2.12 (dd, J =13.0, 8.4 Hz, 1H), 1.91-1.80 (m, 2H), 1.71 (m, 2H).

Example 4R. ( 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-(2-(Pyrimidin-5-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7FF, 12 mg, 0.034 mmol) and 2-bromoxazole (15 mg, 0.10 mmol) were dissolved in dioxane (3 ml) and the mixture was purged with nitrogen. Pd was added₂(dba)₃ (3.1 mg, 0.0031 mmol), XantPhos (2.4 mg, 0.0041 mmol) and rubs-sodium butoxide (19 mg, 0.17 mmol). The reaction mixture was stirred at 75°C overnight. The reaction mixture was filtered through a pad of silica gel, washed with EtOAc and the filtrate was concentrated. The residue was purified using preparative HPLC (X-Bridge Peptide BEH C18, 5 µm, 19×150 mm, 30-45% MeCN/H₂O (10 mM NH₄OH), 75 ml/min.) to obtain the title compound (4.0 mg, 0.0094 mmol).

LCMS: Rt: 1.15 min. (LCMS method 4); MS mass/charge 418.4 [M+H] ⁺ .

^1H NMR (400 MHz, CD ₃ OD) δ 9.18 (s, 1H), 8.76 (s, 2H), 7.54-7.43 (m, 2H), 7.38 (d, J =1.0 Hz, 1H), 7.36-7.30 (m, 1H), 7.23 (dd, J =7.6, 1.2 Hz, 1H), 6.80 (s, 1H) , 4.18 (q, J =8.8 Hz, 2H), 4.11-3.96 (m, 3H), 3.70 (dd, J =8.9, 7.2 Hz, 1H), 3.07-2.91 (m, 2H), 2.87-2.74 (m, 1H), 2.57-2.40 (m, 2H), 2.13-1.65 (m, 7H ).

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

(S)-7-(4-(4-Fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7MM, 100 mg, 0.276 mmol) and 2-bromoxazole (49 mg, 0.33 mmol) were dissolved in dioxane (2.8 ml) and the mixture was purged with nitrogen. Added Pd₂(dba)₃ (16 mg, 0.028 mmol), XantPhos (19 mg, 0.033 mmol) and rubs-sodium butoxide (80 mg, 0.83 mmol), and the reaction mixture was stirred at 75°C overnight. The reaction mixture was filtered through a pad of celite, washed with EtOAc and the filtrate was concentrated. The residue was purified using FCC (0-10% MeOH (1% NH₃)/DCM) to give the title compound (65 mg, 0.14 mmol) as a light yellow solid.

LCMS: Rt: 2.02 min. (LCMS method 4); MS mass/charge 430.6 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (s, 1H), 7.20 (dd, J =8.5, 6.6 Hz, 1H), 6.82 (d, J =1 ,0 Hz, 1H), 6.67 (m, 1H), 6.32 (dd, J =10.6, 2.6 Hz, 1H), 5.28 (ddd, J =10.8, 5, 9, 4.9 Hz, 1H), 5.12-4.98 (m, 2H), 4.68 (dd, J =7.5, 4.7 Hz, 2H), 4.31-4.13 (m, 2H), 4.13-4.00 (m, 3H), 3.76 (dd, J =8.7, 7.4 Hz, 1H), 3.21-3.07 (m, 2H ), 3.07-2.96 (m, 1H), 2.96-2.85 (m, 1H), 2.53 (dd, J =12.9, 7.4 Hz, 1H), 2, 25 (m, 2H), 2.13 (dd, J =13.0, 8.4 Hz, 1H), 1.92-1.66 (m, 4H).

Example 4T. 2-((1 R ,3 s )-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 or 2-((1 S ,3 r )-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 and example 4U. 2-((1 R ,3 s )-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 or 2-((1 S ,3 r )-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

Stage 1. rubs -Butyl-( S )-7-(4-(5-fluoro-2-(3-(2-hydroxypropan-2-yl)cyclobutoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2 -carboxylate

tert -Butyl-( S )-7-(4-(5-fluoro-2-(3-(methoxycarbonyl)cyclobutoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2 β-carboxylate (intermediate 6X, 130 mg, 0.251 mmol) was dissolved in THF (2.5 ml) and the solution was cooled to 0°C. Methylmagnesium bromide (0.33 ml, 1.0 mmol, 3 M in THF) was added slowly over 5 minutes. The reaction mixture was gradually warmed to room temperature, stirred at room temperature for 6 hours, then cooled to 0°C and neutralized by adding saturated ammonium chloride solution, stirred for 10 minutes and then diluted with additional saturated ammonium chloride solution. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified with FCC (0-10% MeOH (1% NH ₃ )/DCM) to give the title intermediate (100 mg, 0.193 mmol).

LCMS: Rt: 2.81 and 2.84 min. (LCMS method 4); MS mass/charge 519.3 [M+H] ⁺ .

Stage 2. ( S )-2-(3-(2-(1-(5-Oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol

tert -Butyl-(S)-7-(4-(5-fluoro-2-(3-(2-hydroxypropan-2-yl)cyclobutoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro [3.4]octane-2-carboxylate (100 mg, 0.193 mmol) was dissolved in DCM (3 mL) and TFA (0.450 mL, 5.78 mmol) was added. The reaction mixture was stirred for 20 minutes and then the reaction mixture was concentrated and dissolved in DCM and 1N. NaOH. The layers were separated and aq. the layer was extracted with DCM (3x25 ml) and the combined organic layers were washed with brine (1x10 ml), dried over magnesium sulfate, filtered and concentrated. The material was transferred further to the next stage without further purification.

LCMS: Rt: 0.58 and 0.63 (LCMS method 1); MS mass/charge 419.5 [M+H] ⁺ .

Stage 3. 2-((1 R ,3 s )-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 and 2-((1 S ,3 r )-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-(3-(2-(1-(5-Oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)cyclobutyl)propan-2-ol (70 mg, 0.17 mmol) and 2-bromoxazole (30 mg, 0.20 mmol) were dissolved in dioxane (1.7 ml) and the mixture was purged with nitrogen. Pd ₂ (dba) ₃ (9.6 mg, 0.017 mmol), XantPhos (12 mg, 0.020 mmol) and sodium tert -butoxide (48 mg, 0.50 mmol) were added and the reaction mixture was stirred at 75°C for nights. The reaction mixture was filtered through a pad of celite, washed with EtOAc and concentrated. The residue was purified using FCC (0-10% MeOH (1% NH ₄ OH)/DCM). Diastereomers were then separated 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), 30 ml/min.) to obtain the product, the product corresponding to peak 1 of example 4T (5.3 mg, 0.0011 mmol), and the product corresponding to peak 2 of example 4U (9.5 mg, 0.167 mmol), as white powders.

Peak 1, example 4T

LCMS: Rt: 2.33 min. (LCMS method 4); MS mass/charge 486.7 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (s, 1H), 6.90 (dd, J =9.8, 3.2 Hz, 1H), 6.87-6.78 (m , 2H), 6.64 (dd, J =9.0, 4.6 Hz, 1H), 4.68-4.60 (m, 1H), 4.29-4.14 (m, 2H), 4.14-4.02 (m, 3H), 3.83-3.72 (m, 1H), 3.12 (d, J=9.0 Hz, 2H), 3.01 (t, J = 12.0 Hz, 1H), 2.91 (d, J =11.0 Hz, 1H), 2.60-2.36 (m, 4H), 2.26 (q, J =10.7 Hz, 2H), 2.14 (m, 3H), 1.85 (s, 2H), 1.70 (m, 2H), 1.16 (s, 6H).

Peak 2, example 4U

LCMS: Rt: 2.41 min. (LCMS method 4); MS mass/charge 486.5 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (d, J =0.9 Hz, 1H), 6.89 (dd, J =9.8, 3.0 Hz, 1H), 6, 86-6.73 (m, 3H), 4.52-4.42 (m, 1H), 4.26-4.15 (m, 2H), 4.13-4.02 (m, 3H), 3.80-3.71 (m, 1H), 3.10 (q, J =7.0 Hz, 2H), 3.04-2.93 (m, 1H), 2.89 (d, J = 11.3 Hz, 1H), 2.53 (dd, J =12.8, 7.4 Hz, 1H), 2.47-2.34 (m, 2H), 2.22 (m, 2H), 2.12 (dd, J =13.0, 8.5 Hz, 1H), 2.08-1.96 (m, 3H), 1.83 (s, 2H), 1.68 (m, 2H) , 1.12 (s, 6H).

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

In a stirred solution (S)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7L, 3.00 g, 8.41 mmol) and 2-iodoxazole (2.051 g, 10.52 mmol) in THF (3.0 mL) was added with TPGS-750-M (30 mL) followed by tribasic potassium phosphate (10. 72 g, 50.5 mmol). The reaction mixture was stirred at 55°C for 48 hours and then the reaction mixture was cooled to room temperature and diluted with water. The mixture was extracted with DCM and the combined organic layers were washed with water, dried over magnesium sulfate, filtered and concentrated. The residue was purified using FCC (0-10% MeOH (10% NH₄OH)/DCM) to give the title compound as a light yellow foam (2.1 g, 4.96 mmol).

LCMS: Rt: 2.13 min. (LCMS method 4); MS mass/charge 424.4 [M+H] ⁺ .

^1H NMR (400 MHz, DMSO _- d6 ) δ 7.57 (s, 1H), 7.23 (dt, J=7.0, 2.5 Hz, 2H), 7.20-7.10 ( m, 2H), 6.84 (s, 1H), 4.14 (d, J=8.5 Hz, 1H), 4.04 (d, J=8.4 Hz, 2H), 3.99- 3.89 (m, 4H), 3.67-3.58 (m, 1H), 3.48 (m, 2H), 3.10-2.97 (m, 2H), 2.97-2, 93 (m, 1H), 2.80 (m, 2H), 2.38 (dd, J=13.0, 7.3 Hz, 1H), 2.21-1.98 (m, 3H), 1 .74 (dd, J=12.7, 4.3 Hz, 1H), 1.71-1.58 (m, 5H), 1.54 (dd, J=13.2, 3.4 Hz, 2H ).

Example 4W. ( 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-Fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7BB, 90 mg, 0.24 mmol) and 2-iodoxazole (51.5 mg, 0.264 mmol) were dissolved in a mixture of THF (0.3 ml) and TPGS-750-M (9 ml). Tribasic potassium phosphate (306 mg, 1.44 mmol) was added and the reaction mixture was stirred at 55°C for 48 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with DCM. The combined organics were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified using FCC (0-10% MeOH (1% NH₃)/DCM) to give the title compound (20 mg, 0.045 mmol).

LCMS: Rt: 2.20 min. (LCMS method 4); MS mass/charge 442.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.31 (d, J =1.3 Hz, 1H), 7.17 (dd, J =8.6, 6.0 Hz, 1H), 6, 88 (dd, J =10.8, 2.9 Hz, 1H), 6.80 (td, J =8.4, 2.8 Hz, 1H), 6.72 (d, J =1.3 Hz , 1H), 4.19-4.06 (m, 2H), 4.06-3.88 (m, 5H), 3.67 (dd, J =8.8, 7.3 Hz, 1H), 3.50 (td, J =11.8, 1.9 Hz, 2H), 3.00 (m, 3H), 2.81 (d, J =12.2 Hz, 2H), 2.44 (dd , J =12.9, 7.4 Hz, 1H), 2.25-2.10 (m, 2H), 2.04 (dd, J =12.9, 8.4 Hz, 1H), 1, 78-1.59 (m, 6H), 1.58-1.46 (m, 2H).

Example 5A. ( S )-7-(4-(5-Chloro-2-methoxyphenyl)piperidin-1-yl)-2-(1,2,4-thiadiazol-5-yl)-5-oxa-2-azaspiro[3.4]octane

Stage 1. rubs -Butyl-( S )-7-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

(S)-rubs-Butyl-7-(4-(2-methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (intermediate 6C, 109 mg, 0.271 mmol) was dissolved in DMF (2.7 mL) and CBMG (0.142 g, 0.677 mmol) and HCl (4.0 M in dioxane, 0.237 mL, 0.948 mmol) were added under nitrogen. The reaction mixture was stirred at room temperature for 2 hours and then the solution was diluted with water and EtOAc. The basicity of the solution was increased with 1 N. NaOH to pH 13. The aqueous layer was extracted with EtOAc and the combined organics were diluted with heptanes, washed with water and dried over magnesium sulfate, filtered and concentrated. The crude material was taken up in DCM, filtered to remove precipitated solids and purified by flash chromatography (0-10% MeOH (10% NH₄OH)/DCM) to give the title intermediate (18 mg, 0.271 mmol).

LCMS: Rt: 0.82 min. (LCMS method 1); MS mass/charge 437.4 [M+H] ⁺ .

Stage 2. ( S )-7-(4-(5-Chloro-2-methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

( S ) -tert -Butyl-7-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (100 mg, 0.229 mmol ) was dissolved in DCM (1.6 ml) and TFA (0.529 ml, 6.87 mmol) was added. The reaction mixture was stirred for 45 minutes and then concentrated. The residue was dissolved in MeOH (5 ml) and Si-propylsulfonic acid Isolute resin (SCX-2) (1.073 g, 0.687 mmol) was added and the result was stirred for 1 hour. The resin was filtered and washed with MeOH and then the resin was washed with 7N. ammonia in MeOH. 7 n. the ammonia in the MeOH fractions was then concentrated to give the title intermediate (73 mg, 0.217 mmol).

LCMS: Rt: 0.49 min. (LCMS method 1); MS mass/charge 337.5 [M+H] ⁺ .

Stage 3. ( 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-(5-Chloro-2-methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (24 mg, 0.071 mmol) and 5-bromo-1, 2,4-thiadiazole (0.018 g, 0.11 mmol) was dissolved in 2-propanol (0.65 ml) and DIPEA (0.02 ml, 0.11 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen for 10 minutes, and then concentrated and purified using preparative HPLC (X-bridge C18 OBD column, 30x50 mm, 5 μm, 35-60% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (19 mg, 0.045 mmol) as a light yellow solid.

LCMS: Rt: 2.47 min. (LCMS method 4); MS mass/charge 421.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.93 (s, 1H), 7.20-7.07 (m, 2H), 6.90 (d, J =8.5 Hz, 1H), 4.36-4.23 (m, 2H), 4.23-4.11 (m, 2H), 4.08 (dd, J =8.8, 6.9 Hz, 1H), 3.84- 3.74 (m, 3H), 3.16-3.04 (m, 3H), 3.02-2.83 (m, 2H), 2.55 (dd, J = 13.1, 7.5 Hz, 1H), 2.28-2.12 (m, 3H), 1.87-1.61 (m, 4H).

Example 5B. ( S )-7-(4-(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)-5-oxa-2-azaspiro[3.4]octane (intermediate 7X, 60 mg, 0.20 mmol) and 5-bromo-1,2,4-thiadiazole (0.049 g, 0.30 mmol) were dissolved in 2-propanol (2.0 ml). The reaction mixture was stirred at room temperature overnight under nitrogen, concentrated and purified with FCC (0-10% MeOH (1% NH₄OH)/DCM) to give the title compound (34 mg, 0.086 mmol). LCMS: Rt: 2.20 min. (LCMS method 4); MS mass/charge 387.3 [M+H]⁺.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.93 (s, 1H), 7.15 (td, J =7.1, 1.7 Hz, 2H), 6.96-6.85 (m , 2H), 4.38-4.23 (m, 2H), 4.23-4.03 (m, 3H), 3.81 (s, 4H), 3.17-3.05 (m, 2H ), 3.05-2.94 (m, 1H), 2.94 -2.84 (m, 1H), 2.56 (dd, J =13.0, 7.5 Hz, 1H), 2, 31-2.12 (m, 3H), 1.77 (m, 4H).

Example 5C. ( 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)-1-(2-(1-(5-Oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4-fluorophenoxy)-2-methylpropan-2-ol (intermediate 7O, 64 mg, 0.17 mmol) and 5-bromo-1,2,4-thiadiazole (0.042 g, 0.25 mmol) were dissolved in 2-propanol (2.0 ml). The reaction mixture was stirred at room temperature for 2 hours under nitrogen, then heated at 40°C for 3 hours, concentrated and purified using FCC (0-10% MeOH (1% NH₄OH)/DCM) to give the title compound (40 mg, 0.085 mmol).

LCMS: Rt: 2.06 min. (LCMS method 4); MS mass/charge 463.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.93 (s, 1H), 6.96-6.81 (m, 3H), 4.37-4.05 (m, 5H), 3.79 (dd, J =8.8, 7.4 Hz, 1H), 3.75 (s, 2H), 3.17-3.05 (m, 3H), 2.91 (m, 1H), 2, 56 (dd, J =13.1, 7.4 Hz, 1H), 2.30-2.12 (m, 3H), 1.86 (m, 2H), 1.69 (m, 2H), 1 .34 (s, 6H).

Example 5D. ( 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-(5-Fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7N, 65 mg, 0.18 mmol) and 5-bromo-1,2,4-thiadiazole (0.044 g, 0.27 mmol) were dissolved in THF (1.8 ml). The reaction mixture was stirred at room temperature for 90 minutes under nitrogen, concentrated and purified with FCC (0-7% MeOH/DCM) to give the title compound (14 mg, 0.031 mmol).

LCMS: Rt: 1.12 min. (LCMS method 3); MS mass/charge 449.1 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.02 (s, 1H), 6.92-7.04 (m, 3H), 4.26 (d, J =8.8 Hz, 1H), 4, 16 (t, J =7.8 Hz, 2H), 4.03-4.10 (m, 3H), 3.96 (dd, J =8.8, 6.8 Hz, 1H), 3.61 -3.69 (m, 3H), 3.33 (s, 3H), 2.93-3.04 (m, 2H), 2.76-2.91 (m, 2H), 2.39-2 .44 (m, 1H), 1.99-2.14 (m, 3H), 1.66-1.77 (m, 2H), 1.51-1.64 (m, 2H).

Example 5E. ( 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-(4-Fluoro-2-methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7Y, 85 mg, 0.27 mmol) and 5-bromo-1,2,4-thiadiazole (0.066 g, 0.40 mmol) were dissolved in IPA (3.0 ml). The reaction mixture was stirred at room temperature overnight under nitrogen, concentrated and purified with FCC (0-10% MeOH (1% NH₄OH)/DCM) to give the title compound (59 mg, 0.14 mmol).

LCMS: Rt: 2.29 min. (LCMS method 4); MS mass/charge 405.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.93 (s, 1H), 7.14 (dd, J =8.6, 6.6 Hz, 1H), 6.71 (dd, J =11 ,2, 2.5 Hz, 1H), 6.61 (m, 1H), 4.35-4.23 (m, 2H), 4.23-4.12 (m, 2H), 4.08 ( dd, J =8.7, 6.9 Hz, 1H), 3.81 (s, 3H), 3.78 (dd, J =8.8, 7.4 Hz, 1H), 3.13-3 .06 (m, 2H), 2.91 (m, 2H), 2.55 (dd, J =13.0, 7.5 Hz, 1H), 2.27-2.13 (m, 3H), 1.84-1.67 (m, 4H).

Example 5F. ( 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-(2-((5-Methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4 ]octane (intermediate 7PP, 32 mg, 0.083 mmol), 2-bromo-1,3,4-thiadiazole (14 mg, 0.083 mmol) and tribasic potassium phosphate (18 mg, 0.083 mmol) were dissolved in a mixture of 2% aqueous solution TPGS-750-M (150 µl) and THF (20 µl). The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure and purified using FCC (0-5% MeOH/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 µm, 10-30% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (19 mg, 0.040 mmol).

LCMS: Rt: 1.92 min. (LCMS method 4); MS mass/charge 469.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.65 (s, 1H), 7.24-7.11 (m, 2H), 7.05 (d, J =7.3 Hz, 1H), 6.96 (m, 1H), 5.19 (s, 2H), 4.32-4.21 (m, 2H), 4.18-4.09 (m, 2H), 4.06 (dd, J =8.6, 7.1 Hz, 1H), 3.81-3.72 (m, 1H), 3.06 (m, 3H), 2.87 (d, J =10.4 Hz, 1H ), 2.61 (s, 3H), 2.54 (dd, J =13.0, 7.4 Hz, 1H), 2.27-2.11 (m, 3H), 1.89-1, 64 (m, 4H).

Example 5G. ( 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

Into a solution of ( S )-7-(4-(5-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7A, 95 mg, 0.26 mmol) 2-bromo-1,3,4-thiadiazole (43 mg, 0.26 mmol) was added to a 2% aqueous solution of TPGS-750-M (470 μl)/THF (50 μl) followed by the addition of tribasic potassium phosphate (56 mg, 0.26 mmol). The mixture was stirred at room temperature overnight and the crude material was then extracted with DCM (3×25 ml) and the organic layers were combined and evaporated under reduced pressure. The residue was purified using FCC (0-7% MeOH/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 µm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH ), 75 ml/min.) to obtain the title compound (49 mg, 0.11 mmol).

LCMS: Rt: 1.79 min. (LCMS method 4); MS mass/charge 447.3 [M+H] ⁺ .

^1H NMR (400 MHz, DMSO -d6 ) δ 8.80 (s, _1H ), 7.04 (dd, J =9.9, 3.1 Hz, 1H), 6.98-6.87 ( m, 1H), 6.56 (dd, J =9.0, 4.6 Hz, 1H), 5.31-5.17 (m, 1H), 4.91 (t, J =6.6 Hz , 2H), 4.52 (dd, J =7.3, 4.9 Hz, 2H), 4.21 (d, J =8.4 Hz, 1H), 4.16-4.05 (m, 2H), 4.03-3.91 (m, 2H), 3.69-3.57 (m, 1H), 3.07-2.74 (m, 4H), 2.42 (dd, J = 13.0, 7.3 Hz, 1H), 2.10 (dt, J =13.1, 8.1 Hz, 3H), 1.82-1.68 (m, 2H), 1.61 (m , 2H).

Example 5H. ( 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

Into a solution of ( S )-7-(4-(5-fluoro-2-((( R )-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4 ]octane (intermediate 7D, 73 mg, 0.19 mmol) in a mixture of 2% aqueous TPGS-750-M (350 μl)/THF (40 μl) was added 2-bromo-1,3,4-thiadiazole (32 mg, 0.19 mmol) followed by the addition of tribasic potassium phosphate (41 mg, 0.19 mmol). The reaction mixture was processed similarly to Example 5G, and the crude material was purified using FCC (0-7% MeOH/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 μm, 25-50% MeCN/ H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (31 mg, 0.066 mmol).

LCMS: Rt: 1.98 min. (LCMS method 4); MS mass/charge 461.1 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.80 (s, 1H), 7.07-6.91 (m, 3H), 5.01 (br s, 1H), 4.20 (d, J = 8.8 Hz, 1H), 4.10 (dd, J =8.1, 5.1 Hz, 2H), 4.04-3.98 (m, 1H), 3.97-3.91 (m , 1H), 3.90-3.71 (m, 4H), 3.63 (t, J =7.6 Hz, 1H), 3.03-2.92 (m, 2H), 2.85- 2.75 (m, 2H), 2.41 (dd, J =13.0, 7.1 Hz, 1H), 2.25-2.12 (m, 1H), 2.12-1.91 ( m, 4H), 1.74-1.49 (m, 4H).

Example 5I. ( 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

Into a solution of ( S )-7-(4-(5-fluoro-2-((( R )-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4 ]octane (intermediate 7QQ, 85 mg, 0.22 mmol) in a mixture of 2% aqueous TPGS-750-M (390 μl)/THF (45 μl) was added 2-bromo-1,3,4-thiadiazole (36 mg, 0.22 mmol) followed by the addition of tribasic potassium phosphate (46 mg, 0.22 mmol). The reaction mixture was processed similarly to Example 5G, and the crude material was purified using FCC (0-7% MeOH/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 μm, 25-50% MeCN/ H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (36 mg, 0.074 mmol).

LCMS: Rt: 1.16 min. (LCMS method 3); MS mass/charge 475.2 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.80 (s, 1H), 7.02-6.93 (m, 3H), 4.20 (d, J =8.8 Hz, 1H), 4, 14-4.08 (m, 2H), 4.00 (d, J =8.3 Hz, 1H), 3.98-3.91 (m, 2H), 3.90-3.80 (m, 2H), 3.80-3.73 (m, 1H), 3.72-3.67 (m, 1H), 3.66-3.59 (m, 1H), 3.53 (dd, J = 8.3, 5.9 Hz, 1H), 3.03-2.93 (m, 2H), 2.88-2.76 (m, 2H), 2.71-2.61 (m, 1H) , 2.42 (dd, J =13.0, 7.1 Hz, 1H), 2.13-1.97 (m, 4H), 1.74-1.64 (m, 3H), 1.63 -1.53 (m, 2H).

Example 5J. ( 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

Into a solution of ( 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, 60 mg, 0.15 mmol) in a mixture of 2% aqueous TPGS-750-M (280 μl)/THF (30 μl) was added 2-bromo-1,3,4-thiadiazole (25 mg, 0.15 mmol) followed by the addition of tribasic potassium phosphate (33 mg, 0.15 mmol). The reaction mixture was processed similarly to Example 5G and the crude material was purified using FCC (0-7% MeOH/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 µm, 15-40% MeCN/ H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (19 mg, 0.038 mmol).

LCMS: Rt: 2.09 min. (LCMS method 4); MS mass/charge 475.5 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.80 (s, 1H), 7.07-6.90 (m, 3H), 4.60-4.48 (m, 1H), 4.20 (d , J =8.3 Hz, 1H), 4.15-4.06 (m, 2H), 4.04-3.90 (m, 2H), 3.86-3.75 (m, 2H), 3.67-3.57 (m, 1H), 3.55-3.45 (m, 2H), 3.05-2.93 (m, 2H), 2.92-2.77 (m, 2H ), 2.42 (dd, J =12.7, 7.3 Hz, 1H), 2.14-2.01 (m, 3H), 1.99-1.89 (m, 2H), 1, 77-1.64 (m, 2H), 1.64-1.54 (m, 4H).

Example 5K. ( 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

Into a solution of ( S )-7-(4-(2-((( R )-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2- 2-bromo-1,3,4- thiadiazole (33 mg, 0.19 mmol) followed by the addition of tribasic potassium phosphate (42 mg, 0.19 mmol). The reaction mixture was processed similarly to Example 5G, and the crude material was purified using FCC (0-7% MeOH/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 μm, 25-50% MeCN/ H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (35 mg, 0.070 mmol).

LCMS: Rt: 1.94 min. (LCMS method 4); MS mass/charge 491.3 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.80 (s, 1H), 7.02-6.92 (m, 3H), 4.20 (d, J =8.8 Hz, 1H), 4, 11 (t, J =7.3 Hz, 2H), 4.03-3.90 (m, 4H), 3.88-3.81 (m, 2H), 3.77 (dd, J =11, 2, 2.0 Hz, 1H), 3.72-3.59 (m, 3H), 3.53-3.43 (m, 2H), 3.03-2.95 (m, 2H), 2 .88-2.77 (m, 2H), 2.42 (dd, J =12.7, 7.3 Hz, 1H), 2.13-2.02 (m, 3H), 1.75-1 .67 (m, 2H), 1.65-1.51 (m, 2H).

Example 5L. ( 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

Into a solution of ( S )-7-(4-(2-((( S )-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2- 2-bromo-1,3,4- thiadiazole (35 mg, 0.21 mmol) followed by the addition of tribasic potassium phosphate (45 mg, 0.21 mmol). The reaction mixture was processed similarly to Example 5G, and the crude material was purified using FCC (0-7% MeOH/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 μm, 25-50% MeCN/ H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (41 mg, 0.082 mmol).

LCMS: Rt: 1.95 min. (LCMS method 4); MS mass/charge 491.5 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.80 (s, 1H), 7.02-6.92 (m, 3H), 4.20 (d, J =8.8 Hz, 1H), 4, 15-4.08 (m, 2H), 4.04-3.89 (m, 4H), 3.88-3.81 (m, 2H), 3.80-3.74 (m, 1H), 3.72-3.59 (m, 3H), 3.53-3.44 (m, 2H), 3.05-2.94 (m, 2H), 2.89-2.76 (m, 2H ), 2.46-2.38 (m, 1H), 2.14-2.01 (m, 3H), 1.80-1.49 (m, 4H).

Example 5M. ( 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

Into 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, 91 mg, 0.23 mmol) 2-bromo-1,3,4-thiadiazole was added to 2% aqueous TPGS-750-M (415 µl)/THF (45 µl) (38 mg, 0.23 mmol) followed by the addition of tribasic potassium phosphate (49 mg, 0.23 mmol). The reaction mixture was processed similarly to Example 5G, and the crude material was purified using FCC (0-7% MeOH/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 μm, 25-50% MeCN/ H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (29 mg, 0.059 mmol).

LCMS: Rt: 2.09 min. (LCMS method 4); MS mass/charge 479.1 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.80 (s, 1H), 7.22 (dd, J =11.7, 9.3 Hz, 1H), 7.12 (dd, J =13.0 , 7.1 Hz, 1H), 5.08-5.02 (m, 1H), 4.20 (d, J =8.8 Hz, 1H), 4.13-4.07 (m, 2H) , 4.00 (d, J =8.8 Hz, 1H), 3.94 (dd, J =8.3, 6.8 Hz, 1H), 3.90-3.84 (m, 1H), 3.83-3.72 (m, 3H), 3.62 (t, J =7.8 Hz, 1H), 3.02-2.91 (m, 2H), 2.83-2.71 ( m, 2H), 2.45-2.37 (m, 1H), 2.26-2.14 (m, 1H), 2.12-1.99 (m, 3H), 1.98-1, 91 (m, 1H), 1.71-1.49 (m, 4H).

Example 5N. ( S )-7-(4-(5-Fluoro-2-(3-methoxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5- oxa-2-azaspiro[3.4]octane

Into a solution of ( S )-7-(4-(5-fluoro-2-(3-methoxy-3-methylbutoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7M, 74 mg, 0.18 mmol) 2-bromo-1,3,4-thiadiazole (30 mg, 0.18 mmol) followed by the addition of tribasic potassium phosphate (39 mg, 0.18 mmol). The reaction mixture was processed analogously to Example 6B and the crude material was purified using FCC (0-7% MeOH/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 µm, 35-60% MeCN/ H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (39 mg, 0.076 mmol).

LCMS: Rt: 1.34 min. (LCMS method 3); MS mass/charge 491.0 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.82 (s, 1H), 7.02-6.92 (m, 3H), 4.23-4.16 (m, 1H), 4.14-4 .06 (m, 2H), 4.03-3.91 (m, 4H), 3.66-3.59 (m, 1H), 3.13-3.09 (m, 3H), 3.02 -2.91 (m, 2H), 2.92-2.75 (m, 2H), 2.45-2.37 (m, 1H), 2.12-1.98 (m, 3H), 1 .95-1.88 (m, 2H), 1.74-1.49 (m, 4H), 1.20-1.15 (m, 6H).

Example 5O. ( 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

Into a solution of ( S )-7-(4-(5-fluoro-2-((( S )-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4 ]octane (intermediate 7H, 89 mg, 0.24 mmol) in a mixture of 2% aqueous TPGS-750-M (425 μl)/THF (50 μl) was added 2-bromo-1,3,4-thiadiazole (39 mg, 0.24 mmol) followed by the addition of tribasic potassium phosphate (50 mg, 0.24 mmol). The reaction mixture was processed similarly to Example 5G, and the crude material was purified using FCC (0-7% MeOH/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 μm, 25-50% MeCN/ H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (34 mg, 0.072 mmol).

LCMS: Rt: 1.96 min. (LCMS method 4); MS mass/charge 461.6 [M+H] ⁺ .

^1H NMR (400 MHz, DMSO _- d6 ) δ 8.80 (s, 1H), 7.04-6.91 (m, 3H), 5.05-4.98 (m, 1H), 4, 26-4.17 (m, 1H), 4.15-4.07 (m, 2H), 4.01 (d, J =8.5 Hz, 1H), 3.95 (dd, J =8, 6, 6.7 Hz, 1H), 3.90-3.70 (m, 4H), 3.69-3.57 (m, 1H), 3.05-2.91 (m, 2H), 2 .88-2.73 (m, 2H), 2.46-2.37 (m, 1H), 2.25-1.91 (m, 5H), 1.76-1.49 (m, 4H) .

Example 5P. ( 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

Into 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 7O, 143 mg, 0.36 mmol) 2-bromo-1,3,4-thiadiazole (60 mg, 0.36 mmol) followed by the addition of tribasic potassium phosphate (77 mg, 0.36 mmol). The reaction mixture was processed similarly to Example 5G, and the crude material was purified using FCC (0-7% MeOH/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 μm, 25-50% MeCN/ H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (75 mg, 0.15 mmol). LCMS: Rt: 1.91 min. (LCMS method 4); MS mass/charge 477.1 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.80 (s, 1H), 7.02-6.91 (m, 3H), 4.36 (s, 1H), 4.20 (d, J =8 ,3 Hz, 1H), 4.10 (dd, J =8.3, 4.9 Hz, 2H), 4.07-3.98 (m, 3H), 3.94 (dd, J =8, 3, 6.8 Hz, 1H), 3.62 (dd, J =8.3, 7.3 Hz, 1H), 2.97 (quin, J =7.2 Hz, 2H), 2.90- 2.75 (m, 2H), 2.41 (dd, J =13.0, 7.1 Hz, 1H), 2.12-1.98 (m, 3H), 1.84 (t, J = 6.8 Hz, 2H), 1.74-1.50 (m, 4H), 1.17 (s, 6H).

Example 5Q. Formate salt ( 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

In solution (S)-7-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7Q, 21 mg, 0.061 mmol) in a mixture of 2% aqueous TPGS-750-M (275 μl) /THF (30 μl) was added 2-bromo-1,3,4-thiadiazole (10 mg, 0.061 mmol) followed by the addition of tribasic potassium phosphate (19 mg, 0.061 mmol). The reaction mixture was worked up as in Example 6B and the crude material was purified by preparative HPLC (X-bridge column, 30x50mm, 5μm, 30-30% MeCN/H₂O (0.1% formic acid), 75 mL/min) to give the title compound (2 mg, 0.004 mmol) as the formate salt.

LCMS: Rt: 1.79 min. (LCMS method 4); MS mass/charge 429.5 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.68 (s, 1H), 8.32 (s, 1H), 7.22 (dd, J=7.5, 1.7 Hz, 1H), 7.15 (td, J=7.8, 1.7 Hz, 1H), 7.01-6.90 (m, 1H), 6.51 (d, J=8.0 Hz, 1H), 5 .29 (p, J=5.4 Hz, 1H), 5.07-5.00 (m, 2H), 4.70 (dd, J=7.5, 5.0 Hz, 2H), 4, 35 (d, J=8.9 Hz, 1H), 4.28 (d, J=8.9 Hz, 1H), 4.22-4.07 (m, 3H), 3.98 (dd, J =9.6, 6.1 Hz, 1H), 3.68-3.45 (m, 2H), 3.25-3.08 (m, 2H), 2.77-2.60 (m, 3H ), 2.33 (dd, J=13.6, 7.4 Hz, 1H), 2.09-1.78 (m, 4H).

Example 5R. ( S )-7-(4-(2-Methoxyphenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

In solution (S)-7-(4-(2-methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7X, 87 mg, 0.29 mmol) 2-bromo-1,3,4-thiadiazole (48 mg, 0.29 mmol) was added to a 2% aqueous solution of TPGS-750-M (520 μl)/THF (60 μl) followed by the addition of tribasic potassium phosphate (61 mg, 0.29 mmol). The reaction mixture was processed similarly to Example 5G, and the crude material was purified using FCC (0-7% MeOH/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 μm, 25-50% MeCN/ H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (41 mg, 0.10 mmol).

LCMS: Rt: 2.00 min. (LCMS method 4); MS mass/charge 387.3 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.80 (s, 1H), 7.22-7.12 (m, 2H), 7.00-6.84 (m, 2H), 4.21 (d , J=8.8 Hz, 1H), 4.15-4.08 (m, 2H), 4.00 (d, J=8.8 Hz, 1H), 3.94 (dd, J=8, 8, 6.8 Hz, 1H), 3.77 (s, 3H), 3.64 (t, J=7.3 Hz, 1H), 3.04-2.91 (m, 2H), 2, 91-2.73 (m, 2H), 2.44-2.37 (m, 1H), 2.15-2.00 (m, 3H), 1.74-1.53 (m, 4H).

Example 5S. ( 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

In solution (S)-7-(4-(5-fluoro-2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7N, 54 mg, 0.15 mmol) 2-bromo-1,3,4-thiadiazole (24 mg, 0.15 mmol) was added to a 2% aqueous solution of TPGS-750-M (270 μl)/THF (30 μl) followed by the addition of tribasic potassium phosphate (31 mg, 0.15 mmol). The reaction mixture was processed similarly to Example 5G and the crude material was purified using FCC (0-7% MeOH/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 µm, 25-50% MeCN/ H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (24 mg, 0.052 mmol).

LCMS: Rt: 2.03 min. (LCMS method 4); MS mass/charge 449.3 [M+H] ⁺ .

^1H NMR (400 MHz, DMSO _- d6 ) δ 8.80 (s, 1H), 7.02-6.90 (m, 3H), 4.20 (d, J =8.3 Hz, 1H) , 4.13-4.05 (m, 4H), 4.03-3.98 (m, 1H), 3.95 (dd, J =8.5, 6.6 Hz, 1H), 3.68 -3.59 (m, 3H), 3.33 (s, 3H), 3.03-2.93 (m, 2H), 2.92-2.75 (m, 2H), 2.41 (dd , J =12.8, 7.3 Hz, 1H), 2.13-1.99 (m, 3H), 1.77-1.65 (m, 2H), 1.64-1.49 (m , 2H).

Example 5T. ( S )-7-(4-(4-Fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(1,3,4-thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

In solution (S)-7-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7Y, 85 mg, 0.27 mmol) 2-bromo-1,3,4-thiadiazole (44 mg, 0.27 mmol) followed by the addition of tribasic potassium phosphate (56 mg, 0.27 mmol). The reaction mixture was worked up as in Example 5G and the residue was purified using FCC (0-10% MeOH(1% NH₄OH)/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30×50 mm, 5 µm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (26 mg, 0.064 mmol).

LCMS: Rt: 2.10 min. (LCMS method 4); MS mass/charge 405.5 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.66 (s, 1H), 7.14 (dd, J =8.6, 6.6 Hz, 1H), 6.71 (dd, J =11 ,1, 2.7 Hz, 1H), 6.61 (td, J =8.4, 2.5 Hz, 1H), 4.33-4.20 (m, 2H), 4.20-4, 10 (m, 2H), 4.08 (dd, J =8.8, 7.0 Hz, 1H), 3.81 (s, 4H), 3.19-3.06 (m, 2H), 3 .02-2.86 (m, 2H), 2.56 (dd, J =13.1, 7.4 Hz, 1H), 2.33-2.12 (m, 3H), 1.86-1 .67 (m, 4H).

Example 5U. ( 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

In solution (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) 2-bromo-1,3,4-thiadiazole (29 mg, 0.18 mmol) followed by the addition of tribasic potassium phosphate (38 mg, 0.18 mmol). The reaction mixture was worked up analogously to Example 5G and the crude material was purified using FCC (0-10% MeOH (1% NH₄OH)/DCM) to give the title compound (14 mg, 0.030 mmol).

LCMS: Rt: 1.91 min. (LCMS method 4); MS mass/charge 463.6 [M+H] ⁺ .

¹ H (400 MHz, DMSO _- d6 ) δ 8.80 (s, 1H), 7.04-6.90 (m, 3H), 4.36 (s, 1H), 4.20 (d, J =8.6 Hz, 1H), 4.10 (dd, J=8.4, 5.0 Hz, 2H), 4.08-3.98 (m, 3H), 3.94 (dd, J= 8.5, 6.7 Hz, 1H), 3.62 (dd, J=8.5, 7.1 Hz, 1H), 2.97 (p, J=7.4 Hz, 2H), 2, 91-2.75 (m, 2H), 2.41 (dd, J=12.9, 7.2 Hz, 1H), 2.15-1.96 (m, 3H), 1.84 (t, J=6.8 Hz, 2H), 1.68 (m, 2H), 1.56 (m, 2H), 1.17 (s, 6H).

Example 5V. ( 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

In solution (S)-4-(2-(1-(5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-5-fluorophenoxy)-2-methylbutan-2-ol (intermediate 7S , 140 mg, 0.36 mmol) 2-bromo-1,3,4-thiadiazole (59 mg, 0.36 mmol) followed by the addition of tribasic potassium phosphate (76 mg, 0.36 mmol). The reaction mixture was processed similarly to Example 5G and the crude material was purified using FCC (0-7% MeOH/DCM) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 µm, 25-50% MeCN/ H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (61 mg, 0.13 mmol).

LCMS: Rt: 2.04 min. (LCMS method 4); MS mass/charge 477.3 [M+H] ⁺ .

^1H NMR (DMSO -d6 ) δ 8.80 (s, _1H ), 7.15 (dd, J =8.3, 7.3 Hz, 1H), 6.84 (dd, J =11.7 , 2.4 Hz, 1H), 6.73-6.58 (m, 1H), 4.20 (d, J =8.3 Hz, 1H), 4.14-4.04 (m, 4H) , 4.03-3.98 (m, 1H), 3.98-3.91 (m, 1H), 3.62 (t, J =7.6 Hz, 1H), 3.30-3.27 (m, 1H), 3.30-2.91 (m, 2H), 2.86-2.73 (m, 2H), 2.47-2.37 (m, 1H), 2.13-1 .96 (m, 3H), 1.89-1.81 (m, 2H), 1.73-1.50 (m, 4H), 1.21-1.15 (m, 6H).

Example 5W. ( S )-7-(4-(2-((2-Oxaspiro[3.3]heptan-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-(2-((2-Oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4] octane (25 mg, 0.062 mmol) was dissolved in THF (0.62 ml) at -5°C and 2-bromo-1,3,4-thiadiazole (intermediate 7NN, 15 mg, 0.086 mmol) was added. The reaction mixture was stirred at room temperature for 4 days, then concentrated and diluted with a mixture of EtOAc and water. The layers were separated and 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 (0-15% MeOH(10% NH ₄ OH)/EtOAc) and by preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 µm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH), 75 ml/min.) to obtain the title compound (6.7 mg, 0.014 mmol).

LCMS: Rt: 2.06 min. (LCMS method 4); MS mass/charge 487.3.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.66 (s, 1H), 6.91 (dd, 1H), 6.83 (m, 1H), 6.71 (dd, J =8.9 , 4.6 Hz, 1H), 4.75 (s, 2H), 4.68 (s, 2H), 4.53 (p, J =6.6 Hz, 1H), 4.25 (q, 2H ), 4.13 (m, 2H), 4.10-4.05 (m, 1H), 3.77 (dd, J =8.7, 7.3 Hz, 1H), 3.13-3, 06 (m, 2H), 2.93 (m, 2H), 2.84-2.78 (m, 2H), 2.55 (dd, J =13.0, 7.4 Hz, 1H), 2 .29 (m, 2H), 2.24-2.12 (m, 3H), 1.86-1.75 (m, 2H), 1.75-1.60 (m, 2H).

Example 5X. ( 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 )-7-(4-(5-Fluoro-2-((( S )-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (intermediate 7J, 74 mg, 0.19 mmol) was dissolved in 2% aqueous TPGS-750-M (340 μL)/THF (40 μL) and additional 2-bromo-1,3,4-thiadiazole was added (31 mg, 0.19 mmol) followed by the addition of tribasic potassium phosphate (40 mg, 0.19 mmol) and the reaction mixture was worked up as in Example 5G. The residue was purified using FCC (0-7% methanol/dichloromethane) and additionally using preparative HPLC (X-bridge C18 OBD, 30x50 mm, 5 µm, 25-50% MeCN/H ₂ O (5 mM NH ₄ OH ), 75 ml/min.) to obtain the title compound (32 mg, 0.066 mmol).

LCMS: Rt: 2.12 min. (LCMS method 4); MS mass/charge 475.1 [M+H] ⁺ .

^1H NMR (DMSO _- d6 ) δ 8.80 (s, 1H), 7.03-6.92 (m, 3H), 4.20 (d, J=8.8 Hz, 1H), 4, 13-4.07 (m, 2H), 4.00 (d, J=8.8 Hz, 1H), 3.98-3.91 (m, 2H), 3.90-3.80 (m, 2H), 3.79-3.73 (m, 1H), 3.72-3.66 (m, 1H), 3.66-3.59 (m, 1H), 3.53 (dd, J= 8.3, 5.9 Hz, 1H), 3.03-2.93 (m, 2H), 2.88-2.76 (m, 2H), 2.71-2.60 (m, 1H) , 2.46-2.38 (m, 1H), 2.12-1.96 (m, 4H), 1.75-1.63 (m, 3H), 1.63-1.51 (m, 2H).

Example 5Y. ( 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 )-1-(2-(1-(5-Oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol (110 mg, 0.305 mmol) and 5-bromo-1,2,4-thiadiazole (0.076 g, 0.46 mmol) were dissolved in 2-propanol (3.0 ml). The reaction mixture was stirred at room temperature overnight under nitrogen, concentrated and purified twice with FCC (0-10% MeOH (1% NH ₄ OH)/DCM) to give the title compound (67 mg, 0.15 mmol ).

LCMS: Rt: 2.02 min. (LCMS method 4); MS mass/charge 445.7 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.93 (s, 1H), 7.24-7.10 (m, 2H), 6.90 (t, J =7.2 Hz, 2H), 4.36-4.03 (m, 5H), 3.82-3.74 (m, 3H), 3.19-3.04 (m, 3H), 2.91 (m, 1H), 2. 56 (dd, J =13.1, 7.4 Hz, 1H), 2.32-2.11 (m, 3H), 1.87 (m, 2H), 1.74 (m, 2H), 1 .35 (s, 6H).

Example 6A. ( 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

In a nitrogen atmosphere (S)-7-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-N-hydroxy-5-oxa-2-azaspiro[3.4 ]octane-2-carboximidamide (intermediate 12B, 102 mg, 0.228 mmol) was dissolved in diethylphenyl orthoformate (2.3 ml) and 4Å molecular sieves (1 g) were added followed by the monohydrate p-toluenesulfonic acid (131 mg, 0.684 mmol). The reaction mixture was stirred at 80°C under nitrogen overnight, then cooled to room temperature, filtered through Celite, washed with DCM and then concentrated. The residue was purified using FCC (0-10% MeOH (10% NH₄OH)/EtOAc), then using preparative HPLC (X-bridge C18 OBD column, 30x50 mm, 5 µm, 35-60% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (11.5 mg, 0.024 mmol).

LCMS: Rt: 2.24 min. (LCMS method 4); MS mass/charge 459.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.79 (s, 1H), 6.94 (td, J =9.5, 3.9 Hz, 2H), 6.89-6.79 (m , 1H), 4.59-4.46 (m, 1H), 4.21-4.11 (m, 2H), 4.09-3.99 (m, 3H), 3.97-3.90 (m, 2H), 3.75 (t, J =8.1 Hz, 1H), 3.60 (m, 2H), 3.12-2.99 (m, 3H), 2.89 (d, 1H), 2.54 (dd, J =12.8, 7.4 Hz, 1H), 2.28-2.17 (m, 2H), 2.12 (dd, J =13.0, 8, 5 Hz, 1H), 2.06-1.98 (m, 2H), 1.90-1.78 (m, 2H), 1.78-1.64 (m, 4H).

Example 6B. ( 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

(S)-7-(4-(5-Fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-N-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-carboximidamide ( intermediate connection 12C, 24.5 mg, 0.058 mmol) was dissolved in diethylphenyl orthoformate (0.8 ml) and 4Å molecular sieves (0.24 g) were added followed by the monohydrate p-toluenesulfonic acid (34 mg, 0.18 mmol). The reaction mixture was stirred at room temperature overnight, then at 50°C for 5 hours and then at 80°C for 35 minutes. The reaction mixture was cooled at room temperature, filtered through a pad of celite, washed with DCM and then concentrated. The residue was purified using FCC (0-10% MeOH (10% NH₄OH)/EtOAc), then using preparative HPLC (X-bridge C18 OBD column, 30x50 mm, 5 µm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (5.0 mg, 0.012 mmol).

LCMS: Rt: 2.01 min. (LCMS method 4); MS mass/charge 431.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.78 (s, 1H), 6.97 (dd, J =9.7, 3.3 Hz, 1H), 6.83 (td, J =8 ,5, 3.0 Hz, 1H), 6.49 (dd, J =9.0, 4.6 Hz, 1H), 5.24 (m, 1H), 5.05-4.96 (m, 2H), 4.68 (dd, J =7.5, 5.0 Hz, 2H), 4.21-4.12 (m, 2H), 4.09-3.97 (m, 3H), 3 .76 (dd, J =8.7, 7.4 Hz, 1H), 3.16-3.00 (m, 3H), 2.91 (m, 1H), 2.54 (dd, J =12 ,8, 7.4 Hz, 1H), 2.25 (m, 2H), 2.13 (dd, J =12.9, 8.5 Hz, 1H), 1.91-1.83 (m, 2H), 1.80-1.63 (m, 2H).

Example 6C. (S)-7-(4-(2-((2-Oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,2,4-oxadiazole -3-yl)-5-oxa-2-azaspiro[3.4]octane

In a 100 ml round bottom flask (S)-7-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-N-hydroxy-5-oxa-2-azaspiro[ 3.4]octane-2-carboximidamide (intermediate 12A, 119.4 mg, 0.259 mmol) was suspended in diethylphenyl orthoformate (2.6 ml). Next, 4Å molecular sieves (1 g) were added, followed by the addition of monohydrate p-toluenesulfonic acid (149 mg, 0.778 mmol). The reaction mixture was stirred at 60°C under nitrogen atmosphere for 17 hours and then for 5 hours at 80°C. The reaction mixture was cooled to room temperature and filtered through a pad of celite and washed with DCM, then concentrated. The residue was purified using FCC (0-15% MeOH (10% NH₄OH)/EtOAc) and additionally using preparative HPLC (X-bridge C18 OBD column, 30×50 mm, 5 µm, 25-50% MeCN/H₂O (5 mM NH₄OH), 75 ml/min.) to obtain the title compound (29 mg, 0.063 mmol).

LCMS: Rt: 2.16 min. (LCMS method 4); MS mass/charge 471.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.78 (s, 1H), 6.90 (dd, J=9.7, 3.1 Hz, 1H), 6.82 (td, J=8 ,5, 3.0 Hz, 1H), 6.70 (dd, J=8.9, 4.5 Hz, 1H), 4.73 (s, 2H), 4.68 (s, 2H), 4 .53 (m, 1H), 4.26-4.11 (m, 2H), 4.11-3.97 (m, 3H), 3.75 (dd, J=8.7, 7.4 Hz , 1H), 3.18-3.05 (m, 2H), 2.92 (m, 2H), 2.86-2.76 (m, 2H), 2.53 (dd, J=12.8 , 7.4 Hz, 1H), 2.30 (m, 2H), 2.21 (m, 2H), 2.12 (dd, J=12.9, 8.5 Hz, 1H), 1.80 (m, 2H), 1.68 (m, 2H).

Example 7A. ( 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

Stage 1. rubs -Butyl-7-(4-(5-fluoro-2-hydroxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

4-Fluoro-2-(piperidin-4-yl)phenol hydrochloride (see WO 2012/062752 for synthesis, 511 mg, 2.205 mmol) was dissolved in MeOH (15 ml) and tert -butyl-7-oxo-5-oxa was added -2-azaspiro[3.4]octane-2-carboxylate (526 mg, 2.316 mmol) followed by TEA (1.230 mL, 8.82 mmol) and zinc chloride (0.5 M in THF, 6.62 mL, 3. 31 mmol). The resulting solution was stirred at 50°C for 2 hours. The reaction mixture was then cooled to 0°C and sodium cyanoborohydride (277 mg, 4.41 mmol) was added and the reaction mixture was stirred for 16 hours. The reaction mixture was then concentrated and the residue was dissolved in DCM, washed with water and dried over sodium sulfate, filtered and concentrated. The crude material was then purified with FCC (0-8% 7N NH ₃ in MeOH/32% EtOAc/heptanes) to give the title compound (950 mg, 2.197 mmol).

LCMS: Rt: 0.99 min. (LCMS method 2); MS mass/charge 407.3 [M+H] ⁺ .

Stage 2. rubs -Butyl-7-(4-(2-(benzyloxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

tert -Butyl-7-(4-(5-fluoro-2-hydroxyphenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate was dissolved in MeCN (15 ml) and carbonate was added cesium (1432 mg, 4.39 mmol) followed by the addition of benzyl bromide (0.276 ml, 2.307 mmol). The reaction mixture was stirred at room temperature for 4 hours and then the reaction mixture was filtered, washed with DCM and concentrated. The crude material was then purified with FCC (0-6% 7N NH ₃ in MeOH/24% EtOAc/heptanes) to give the title compound (986 mg, 1.985 mmol).

LCMS: Rt: 1.30 min. (LCMS method 2); MS mass/charge 497.2 [M+H] ⁺ .

Step 3. 7-(4-(2-(Benzyloxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

tert -Butyl-7-(4-(2-(benzyloxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate was dissolved in DCM (3 ml) and TFA (3.01 mL, 39.1 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and was then concentrated and diluted with DCM. The organic layer was washed with 1N. NaOH, dried over sodium sulfate, filtered and concentrated and used in the next step without further purification (775 mg, 1.955 mmol).

LCMS: Rt: 2.32 min. (LCMS method 4); MS mass/charge 397.8 [M+H] ⁺ .

Step 4. 7-(4-(2-(Benzyloxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[ 3.4]octane

7-(4-(2-(Benzyloxy)-5-fluorophenyl)piperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane was dissolved in THF (10 ml) and cooled to 0°C. Ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (519 mg, 2.349 mmol) was then added followed by DIPEA (0.82 mL, 4.70 mmol). The reaction mixture was stirred for 2 hours and then the reaction mixture was concentrated and diluted with DCM. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in THF (8 ml) and LiOH (493 mg, 11.74 mmol) in water (3 ml) was added and the reaction mixture was stirred for 16 hours. The reaction mixture was cooled to -5°C and 6 N was added. HCl (3.26 mL, 19.57 mmol) and the reaction mixture was stirred for 2 hours. Sodium carbonate was added to the reaction mixture until pH >12 was reached and the reaction mixture was concentrated. The residue was dissolved in EtOAc and washed with brine and the EtOAc layer was concentrated and the residue was purified with FCC (0-5% MeOH (1% 7N NH ₃ in MeOH)/DCM) to give the title compound (706 mg, 1 .52 mmol).

LCMS: Rt: 1.10 min. (LCMS method 2); MS mass/charge 465.4 [M+H] ⁺ .

Step 5. 2-(1-(2-(1,3,4-Oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4- fluorophenol

7-(4-(2-(Benzyloxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane (706 mg, 1.52 mmol) was dissolved in MeOH (10 ml) and 10% Pd-C (162 mg) was added and the reaction mixture was stirred for 16 hours under hydrogen atmosphere. The reaction mixture was filtered and concentrated and the residue was purified with FCC (0-5% MeOH (1% NH ₃ in MeOH)/DCM) to give the title compound (385 mg, 1.018 mmol).

LCMS: Rt: 0.74 min. (LCMS method 2); MS mass/charge 375.3 [M+H] ⁺ .

Stage 6. ( 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

Into DMF solution (4 ml) 2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl )-4-fluorophenol (230 mg, 0.614 mmol), 2-oxaspiro[3.3]heptan-6-yl-4-methylbenzenesulfonate (intermediate 5M, 181 mg, 0.676 mmol) and Cs ₂ CO ₃ (400 mg, 1.229 mmol) were added ). The resulting reaction mixture was stirred at 90°C for 3 hours and then the crude material was diluted with EtOAc, washed with water and concentrated. The crude material was then purified using FCC (0-5% MeOH (7N NH ₃ in MeOH)/DCM) and further using FCC (0-10% 7 N NH ₃ in MeOH/40% EtOAc/heptanes) with yielding the racemic product (210 mg, 0.437 mmol). A quantity of this material (156 mg, 0.331 mmol) was then subjected to SFC chromatography to separate the two enantiomers (Lux Cellulose-4 (21x250 mm, 45% MeOH (10 mM NH ₄ OH), 80 g/min) to give two enantiomers. Comparison of retention time at SFC of example 2L (Rt: 3.41 min. Lux-Cellulose-4, 3x100 mm, 3 μm, 5→55% MeOH with 10 mM NH ₄ OH/CO ₂ , 2.5 ml /min) demonstrated that the following peak in chiral resolution (Rt: 3.43 min. Lux-Cellulose-4, 3x100 mm, 3 μm, 5→55% MeOH with 10 mM NH ₄ OH/CO ₂ , 2 .5 ml/min) has the same stereochemistry as Example 2L. Based on these data, the product corresponding to the starting peak on chiral resolution is the title example (69 mg, 0.144 mmol).

SFC: Rt: 3.17 min; Lux-Cellulose-4, 3×100 mm, 3 µm, 5→55% MeOH with 10 mM NH ₄ OH/CO ₂ , 2.5 ml/min.

LCMS: Rt: 1.99 min. (LCMS method 4); MS mass/charge 471.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 6.90 (dd, J=9.8, 3.1 Hz, 1H), 6.87-6.79 (m , 1H), 6.71 (dd, J=8.9, 4.5 Hz, 1H), 4.75 (s, 2H), 4.67 (s, 2H), 4.53 (p, J= 6.5 Hz, 1H), 4.35-4.24 (m, 2H), 4.17 (q, J=8.6 Hz, 2H), 4.06 (dd, J=8.8, 6 ,9 Hz, 1H), 3.76 (dd, J=8.8, 7.3 Hz, 1H), 3.15-3.04 (m, 2H), 3.00-2.85 (m, 2H), 2.85-2.76 (m, 2H), 2.54 (dd, J=13.0, 7.4 Hz, 1H), 2.32-2.11 (m, 5H), 1 .80 (m, 2H), 1.68 (m, 2H).

2. Biological activity and selectivity of the new chemical against stable cell lines M1, M2, M3, M4, and M5

The above examples were characterized by measuring intracellular Ca ⁺⁺ ion mobilization due to receptor-mediated signaling events. Intracellular calcium flux levels were captured using a highly sensitive indicator for Ca ⁺⁺ , Calcium Assay Kit (BD Biosciences, cat. no. 640178). The fluorescent activity of all receptors was monitored using a fluorescent imager, FDSS 7000EX (Hamamatsu), for a period of 3 minutes. The change in calcium flux was readily captured upon activation by the muscarinic orthosteric agonist, carbachol.

CHRM4 cell line maintenance

CHO-K1 cells stably expressing the cloned human CHRM4 receptor (M4_CHO cells) were grown and maintained in monolayer culture with F12/HAM (Life Technologies) supplemented with 10% fetal bovine serum, 1X penicillin-streptomycin, and 0.4 mg/ml geneticin in a humidified atmosphere (5% CO ₂ ) at 37°C. Cultures were grown to 80-90% confluency in T150 flasks (Corning) and washed with 1X DPBS, then separated with 0.05% trypsin (Life Technologies). Cells were collected in growth medium, then pelleted (1 krpm, 3 minutes) and cryopreserved using frozen cell culture recovery medium (Gibco Technologies). Cells were stored in liquid nitrogen and thawed one day before analysis.

CHRM1 cell line maintenance

Cloned human receptor M1 (CHRM1) was stably expressed in HEK293 cells and such cells were grown and maintained in monolayer culture with high glucose DMEM (Life Technologies) supplemented with 10% fetal bovine serum, 1X penicillin-streptomycin and 0.5 mg/ml geneticin in a humidified atmosphere (5% CO₂) at 37°C. Cultures were grown to 90% confluence in T150 flasks (Corning) and washed with 1X DPBS and separated with 0.05% trypsin (Life Technologies). Cells were then pelleted (1 krpm, 3 minutes) and frozen using frozen cell culture recovery medium (Gibco Technologies). Cells were stored in liquid nitrogen and thawed one day before analysis.

CHRM2 cell line maintenance

CHO-K1 cells stably expressing the cloned human CHRM2 receptor (M2_CHO cells) were grown and maintained in F12/HAM monolayer culture (Life Technologies) supplemented with 10% fetal bovine serum, 1X penicillin-streptomycin, and 0.4 mg/ml geneticin in humidified atmosphere (5% CO₂) at 37°C. Cultures were grown to 80-90% confluence in T150 flasks (Corning) and washed with 1X DPBS and separated with 0.05% trypsin (Life Technologies). Cells were then pelleted (1 krpm, 3 minutes) and frozen using frozen cell culture recovery medium (Gibco Technologies). Cells were stored in liquid nitrogen and thawed one day before analysis.

Maintenance of CHRM3 and CHRM5 cell lines

CHO-K1 cells stably expressing the cloned human CHRM3 receptor (M3_CHO cells) were grown and maintained in F12/HAM monolayer culture (Life Technologies) supplemented with 10% fetal bovine serum, 1X penicillin-streptomycin, and 0.4 mg/ml geneticin in humidified atmosphere (5% CO₂) at 37°C. Cultures were grown to 80-90% confluence in T150 flasks (Corning) and washed with 1X DPBS and separated with 0.05% trypsin (Life Technologies). Cells were then pelleted (1 krpm, 3 minutes) and frozen using frozen cell culture recovery medium (Gibco Technologies). Cells were stored in liquid nitrogen and thawed one day before analysis. A similar procedure was used for cells stably expressing the cloned human receptor CHRM5 (M5_CHO).

Ca Flux Analysis ⁺⁺ in the CHRM4 cell line

The day before analysis, stably expressing M4_CHO cells were thawed and seeded into HT-treated black 384-well clear-bottom plates (Greiner cat. no. 781091) at 12,000 cells/well using F12/HAM medium supplemented with 10% FBS (Life Technologies) and left overnight in a humidified atmosphere (5% CO₂) at 37°C. The next day, 20 μl of Ca dye was placed on the cells.⁺⁺ (BD Biosciences) using loading buffer (HBSS +Ca/+Mg, 20 mM HEPES, 2.5 mM probenecid) and were placed back into the cell incubator for at least 1 hour. After incubation, the dye was replaced with 45 μl of assay buffer (HBSS-Ca/-Mg, 20 mM HEPES, 2.5 mM probenecid) supplemented with 20 μM ATP (Sigma Aldrich) and left at room temperature in the dark for 60 minutes before running. in a cell imaging device. FDSS 7000EX (Hamamatsu) was used to capture trace Ca⁺⁺ over a period of 3 minutes from cells treated with 11 single doses of the compound in triplicate to obtain dose-response curves in an agonistic manner. All compounds were serially diluted in DMSO then prepared in assay buffer for Ca flux studies⁺⁺. Dose-response curves were obtained from the average of triplicate wells obtained for each data point, and nonlinear regression analysis of the four parameters of the dose-response algorithm was used. Percent activity (PA) was measured relative to EC₁₀₀ carbachol.

Ca Flux Analysis ⁺⁺ in the CHRM1 cell line

The day before analysis, stably M1-expressing HEK293 cells were thawed and seeded in HT-treated black 384-well clear-bottom plates (Greiner cat. no. 781091) at 25,000 cells/well with high-glucose DMEM supplemented with 10% FBS ( Hyclone) penicillin-streptomycin (Life Technologies) and left overnight in a humidified atmosphere (5% CO₂) at 37°C. The next day, 20 μl of Ca dye was placed on the cells.⁺⁺ (BD Biosciences) using loading buffer (HBSS +Ca/+Mg, 20 mM HEPES) and were placed back into the cell incubator for at least 1 hour. The dye was replaced with 45 μl of assay buffer (HBSS-Ca/-Mg, 20 mM HEPES) and left at room temperature before running in the cell imager. Compounds were prepared in assay buffer and 5 μl was added to the cells. FDSS 7000EX (Hamamatsu) was used to detect trace Ca++ for 3 min from cells treated with 11 single doses in triplicate to obtain dose-response curves in an agonistic manner. All compounds were serially diluted in DMSO then prepared in assay buffer for Ca flux studies⁺⁺. Dose-response curves were obtained from the average of triplicate wells obtained for each data point, and nonlinear regression analysis of the four parameters of the dose-response algorithm was used. Percent activity (PA) was measured relative to EC₁₀₀ carbachol.

Ca Flux Analysis ⁺⁺ in the CHRM2 cell line

The day before analysis, stably M2-expressing CHO cells were thawed and seeded into a TC-treated 384-well Greiner plate at a density of 12,000 cells/well and left overnight in a humidified atmosphere (5% CO₂) at 37°C. The next day, Ca dye was placed on the cells.⁺⁺ (BD Biosciences) using loading buffer (HBSS +Ca/+Mg, 20 mM HEPES, 2.5 mM probenecid) and were placed back into the cell incubator for a minimum of 1 hour and a maximum of 2 hours. After incubation, the dye was replaced with assay buffer (HBSS-Ca/-Mg, 20 mM HEPES, 2.5 mM probenecid) supplemented with 20 μM ATP (Sigma Aldrich) and left at room temperature for 60 minutes before running in the imager cells. FDSS 7000EX (Hamamatsu) was used to detect traces of Ca⁺⁺ from cells in response to compound treatment and the data were used to generate dose-response curves in the agonistic mode. All compounds were serially diluted in DMSO then prepared in assay buffer for Ca flux studies⁺⁺. Dose-response curves were obtained from the average of triplicate wells obtained for each data point, and nonlinear regression analysis of the four parameters of the dose-response algorithm was used. Percent activity (PA) was measured relative to EC₁₀₀ carbachol.

Ca Flux Analysis ⁺⁺ in CHRM3 and CHRM5 cell lines

The day before analysis, stably expressing M3_CHO or M5_CHO cells were thawed and seeded into TC-treated black 384-well Greiner plates at 12,000 cells/well in F12/DMEM supplemented with 10% FBS (Hyclone) and left overnight in a humidified atmosphere. (5% CO₂) at 37°C. The next day, Ca dye was placed on the cells.⁺⁺ (BD Biosciences) using loading buffer (HBSS +Ca/+Mg, 20 mM HEPES, 2.5 mM probenecid) and were placed back into the cell incubator for at least 1 hour. After incubation, the dye was replaced with assay buffer (HBSS-Ca/-Mg, 20 mM HEPES, 2.5 mM probenecid) and left at room temperature in the dark until run in the cell imager. FDSS 7000EX (Hamamatsu) was used to detect traces of Ca⁺⁺ from cells treated with 11 single doses corresponding to the response to the compounds, in triplicate to obtain dose-response curves in the agonistic mode. All compounds were serially diluted in DMSO then prepared in assay buffer for Ca flux studies⁺⁺. Dose-response curves were obtained from the average of triplicate wells obtained for each data point, and nonlinear regression analysis of the four parameters of the dose-response algorithm was used. Percent activity (PA) was measured relative to EC₁₀₀ carbachol.

If an example was tested more than once in an assay, then the values reported below represent the geometric mean of the results from each independent experiment.

Table 12. General overview of biological activity

Example M1 FDSS EC50
(µM) M1 FDSS
PA
% M2 FDSS EC50
(µM) M2 FDSS PA
% M3 FDSS EC50
(µM) M3 FDSS PA
% M4 FDSS EC50
(µM) M4 FDSS PA
% M5 FDSS EC50
(µM) M5 FDSS PA
% Example 1A 0.210 92 0.536 32 >25 0 0.008 82 >25 0 Example 1B 0.598 72 0.492 39 >25 0 0.010 84 >25 0 Example 1C 0.576 72 0.503 29 >25 0 0.036 78 >25 0 Example 1D 0.609 69 0.607 50 >25 0 0.021 80 >25 0 Example 1E 0.563 84 0.557 32 >25 0 0.027 78 >25 0 Example 1F 0.368 83 0.390 31 >25 0 0.030 78 >25 0 Example 1G 0.973 77 1.252 35 >25 0 0.031 84 >25 0 Example 1H 0.631 87 0.801 thirty >25 0 0.034 77 >25 0 Example 1I 0.980 54 0.531 32 >25 0 0.035 69 >25 0 Example 1J 4,089 73 0.874 35 >25 0 0.086 79 >25 0 Example 1K 1,589 58 >25 0 >25 0 0.097 58 >25 0 Example 1L 1.323 75 >25 0 >25 0 0.099 74 >25 0 Example 1M 1,366 89 0.752 23 >25 0 0.094 79 >25 0 Example 1N 0.376 82 >25 0 >25 0 0.133 63 >25 0 Example 1O 1,347 69 0.611 36 >25 0 0.026 89 >25 0 Example 1P 0.439 76 1,086 51 >25 0 0.028 94 >25 0 Example 1Q 0.678 81 3,808 16 >25 0 0.052 79 >25 0 Example 1R 0.670 76 0.359 32 >25 0 0.041 77 >25 0 Example 1S 0.634 71 0.656 13 >25 0 0.079 68 >25 0 Example 1T 0.640 74 >25 0 >25 0 0.157 45 >25 0 Example 1U 0.961 75 >25 0 >25 0 0.090 73 >25 0 Example 1V 0.663 76 0.598 35 >25 0 0.035 83 >25 0 Example 1W 0.335 94 0.527 68 >25 0 0.012 89 13.82 20 Example 1X 1.226 99 2,483 25 >25 0 0.112 84 >25 0 Example 1Y 0.579 107 0.874 35 >25 0 0.112 86 >25 0 Example 2A 0.553 103 0.520 46 >25 0 0.024 79 >25 0 Example 2B 1.141 91 0.416 35 >25 0 0.025 71 >25 0 Example 2C 1.148 75 0.321 39 >25 0 0.094 72 >25 0 Example 2D 0.289 72 0.446 50 >25 0 0.020 72 >25 0 Example 2E 0.116 112 0.081 59 >25 0 0.001 85 1.67 23 Example 2F 0.061 103 0.113 67 >25 0 0.001 90 3.65 thirty Example 2G 0.289 89 0.061 55 >25 0 0.003 86 >25 0 Example 2H 0.542 101 0.309 60 >25 0 0.006 88 >25 0 Example 2I 0.098 97 0.109 35 >25 0 0.012 77 >25 0 Example 2J 0.411 103 0.214 62 >25 0 0.012 90 >25 0 Example 2K 1,364 97 0.498 47 >25 0 0.018 82 >25 0 Example 2L 2.221 47 1,068 14 >25 0 0.050 81 >25 0 Example 2M 3,573 7 2,030 20 >25 0 0.145 58 >25 0 Example 2N 5,093 71 4.236 20 >25 0 0.289 65 >25 0 Example 2O 1.117 72 0.581 37 >25 0 0.051 86 >25 0 Example 2P 2,078 71 1,073 36 >25 0 0.085 75 >25 0 Example 2Q 2,020 80 1.159 26 >25 0 0.130 81 >25 0 Example 2R 0.848 56 0.259 42 >25 0 0.025 76 >25 0 Example 2S 5,408 53 2.185 29 >25 0 0.242 68 >25 0 Example 2T 0.063 89 0.041 44 >25 0 0.002 89 0.73 0 Example 2U 0.223 81 0.275 51 >25 0 0.012 86 >25 0 Example 2V 1,648 31 1,080 28 >25 0 0.094 75 >25 0 Example 2W 3,441 66 3,080 29 >25 0 0.087 70 >25 0 Example 2X 11.29 42 11.19 23 >25 0 1,781 40 >25 0 Example 2Y 10.79 51 3.327 35 >25 0 0.554 76 9.46 13 Example 2Z 5,064 eleven 0.760 24 >25 0 0.108 51 >25 0 Example 2AA 6,657 thirty 7,976 22 >25 0 0.210 16 >25 0 Example 2BB 7,000 65 4.845 27 >25 0 0.946 91 >25 0 Example 2CC 2,176 85 2,069 37 >25 0 0.168 79 >25 0 Example 2DD 1.118 67 6,757 23 >25 0 0.155 64 >25 0 Example 2EE 2,343 95 2.945 50 >25 0 0.086 74 >25 0 Example 2FF 0.264 70 0.312 28 >25 0 0.026 66 >25 0 Example 2GG 2,900 64 >25 0 >25 0 0.087 58 >25 0 Example 2HH 2,569 96 6,565 25 >25 0 0.124 85 >25 0 Example 2II 4,052 107 4,294 23 >25 0 0.124 81 >25 0 Example 3A 1.112 85 1,570 35 >25 0 0.083 91 >25 0 Example 3B 1.118 82 1,498 31 >25 0 0.069 86 >25 0 Example 3C 3,889 78 4.824 34 >25 0 0.184 85 >25 0 3D example 1.406 75 1.917 48 >25 0 0.063 84 >25 0 Example 3E 0.695 86 0.404 60 >25 0 0.028 86 >25 0 Example 3F 0.595 86 0.406 49 >25 0 0.023 80 >25 0 3G example 7,241 44 3.656 16 >25 0 0.185 82 >25 0 Example 3H 2,412 84 2.465 thirty 10.70 20 0.010 83.2 >25 0 Example 3I 3,307 76 3.857 32 >25 0 0.038 91.2 >25 0 Example 4A 0.234 84 0.432 21 >25 0 0.004 80 >25 0 Example 4B 0.424 117 >25 32 >25 0 0.004 77 >25 0 Example 4C 0.382 79 0.433 38 >25 0 0.007 80 >25 0 Example 4D 0.741 95 >25 17 >25 0 0.007 77 >25 0 Example 4E 0.979 75 >25 0 >25 0 0.012 81 >25 0 Example 4F 0.540 90 3,259 17 >25 0 0.015 80 >25 0 4G example 1.756 62 13.11 58 >25 0 0.017 68 >25 0 Example 4H 0.745 63 >25 20 >25 0 0.017 69 >25 0 Example 4I 0.227 82 >25 0 >25 0 0.019 73 >25 0 Example 4J 1.668 72 >25 0 >25 0 0.030 82 >25 0 4K example 0.444 60 >25 0 >25 0 0.025 66 >25 0 Example 4L 0.336 66 >25 0 >25 0 0.027 52 >25 0 Example 4M 2,806 49 >25 0 >25 0 0.086 82 >25 0 Example 4N 0.384 64 >25 0 >25 0 0.093 74 >25 0 Example 4O 0.364 63 12.68 31 >25 0 0.007 58 >25 0 Example 4P 0.334 89 10.47 28 >25 0 0.005 63 >25 0 Example 4Q 0.294 71 1.882 13 >25 0 0.011 60 >25 0 Example 4R 0.128 95 0.203 12 >25 0 0.003 70 >25 0 Example 4S 0.624 89 >25 31 >25 0 0.021 74 >25 0 Example 4T 0.909 63 17.67 43 >25 0 0.025 63 >25 0 Example 4U 2.239 55 15.16 38 >25 0 0.042 62 >25 0 Example 4V 1,992 72 10.69 14 >25 0 0.046 82 >25 0 Example 4W 1,094 74 5,161 21 >25 0 0.021 75 >25 0 Example 5A 0.630 70 >25 26 >25 0 0.074 60 >25 0 Example 5B 1,567 22 >25 0 >25 0 0.087 59 >25 0 Example 5C 1.601 60 >25 0 >25 0 0.110 66 >25 4 Example 5D 1.146 60 >25 0 >25 0 0.128 46 >25 0 Example 5E 2,579 29 >25 0 >25 0 0.345 39 13.02 0 Example 5F 0.011 106 0.073 51 11.77 15 <0.0004 90 2.53 35 5G example 0.311 88 0.657 35 >25 0 0.013 76 >25 0 Example 5H 0.432 67 0.443 40 >25 0 0.015 99 >25 0 Example 5I 0.775 69 0.545 43 >25 0 0.020 71 >25 0 Example 5J 1.201 6 4,746 46 >25 0 0.029 92 >25 0 Example 5K 0.434 96 0.453 32 >25 0 0.031 87 6.64 0 Example 5L 0.370 88 0.456 32 >25 0 0.038 79 >25 0 Example 5M 0.786 66 0.415 34 >25 0 0.058 73 >25 0 Example 5N 2,969 68 >25 38 >25 0 0.068 61 12.45 21 Example 5O 0.789 78 1.174 33 >25 0 0.071 74 >25 0 Example 5P 0.413 91 9,699 25 >25 0 0.086 58 >25 0 Example 5Q 0.864 86 >25 0 >25 0 0.092 83 >25 0 Example 5R 0.904 52 1.236 18 >25 0 0.096 73 >25 0 Example 5S 0.761 87 4,598 23 >25 0 0.197 69 >25 0 Example 5T 1,789 57 19.99 35 >25 0 0.208 61 >25 0 Example 5U 2.445 75 0.483 17 >25 0 0.238 67 >25 0 Example 5V 0.786 79 >25 0 >25 0 0.250 40 >25 0 Example 5W 3,591 68 20.70 thirty >25 0 0.104 85 >25 0 Example 5X 2,343 75 1.417 43 >25 0 0.058 71 >25 0 Example 5Y 1,989 47 >25 0 >25 0 0.109 64 >25 0 Example 6A 0.887 53 0.623 18 >25 0 0.012 74 >25 0 Example 6B 0.490 88 0.390 38 >25 0 0.008 79 >25 0 Example 6C 2,420 65 1.505 18 >25 0 0.044 74 >25 0 Example 7A >25 0 >25 0 >25 0 1.41 42 >25 0

Testing New Compounds in the Amphetamine-Induced Mouse Hyperlocomotion Assay

The purpose of this study is to determine the effect of a test compound on hyperactivity in mice induced by the stimulant d-amphetamine. Clinically effective muscarinic antipsychotics such as xanomeline are active in this assay and are therefore considered a suitable test for new M4 agonists. The studies described in this report were conducted in a manner approved by the Novartis Biomedical Research Institute, including the Animal Care and Use Committee. Treatment groups were randomized and chamber-and-run compensated. Locomotor activity was assessed under open field test conditions (40 cm x 40 cm). Each chamber was surrounded by light-proof curtains and illuminated with LED light. Mice were acclimatized to the housing for a minimum of 60 minutes and exposed to test drug (vehicle, dose 1, dose 2, dose 3, PO) immediately before being introduced into the chamber for the habituation phase (1-30 minutes). After the habituation phase, mice were administered either d-amphetamine (2.0 mg/kg) or saline (IP), plus xanomeline as a positive control (1.0 mg/kg, SC) if they had not previously received a test PO injection drug. The injection volume for all injection samples was 10 mL/kg. Measurements were obtained by infrared interruption using Accuscan hardware and Superflex 5.6 software. Locomotor activity was monitored during an additional 2-hour test phase (31–150 minutes) after amphetamine injections. Animals were returned to their housing cage and living area after receiving a test report.

Data analysis

All statistical analyzes were performed using Graphpad Prism 7.04. AUC values were calculated by summing the distance traveled during each 10-min beam segments and compared by t test or one-way ANOVA. Comparison of the AUC30-150 t test for the d-amphetamine-vehicle injected group with that of the vehicle-vehicle injected group determined whether d-amphetamine produced effective stimulation of activity. A conventional one-way ANOVA was performed to compare each test compound-treated group with the d-amphetamine-vehicle-treated group using Dunnett's multiple comparison test. Since d-amphetamine is primarily active during the first hour of the test phase, such tests are performed in the first half (31-90 minutes). P-value <0.05 was considered statistically significant. Data for Example 1A and Example 2L are shown in Figure 1. Data for Example 3C and Example 3D are shown in Figure 2. Data for Example 4A and Example 5G are shown in Figure 3.

Overall, the experimental data presented herein indicate that the disclosed compounds are potent and highly selective M4 receptor agonists (see Table 12) and are effective in vivo as demonstrated by their effectiveness in reducing hyperactivity induced by the stimulant d-amphetamine. in mice in a dose-dependent manner (see Figs. 1-3).

Claims (208)

1. Compound according to formula (I) (I) or a pharmaceutically acceptable salt thereof, where R ¹ represents halogen or hydrogen; R ² represents halogen or hydrogen; R ³ represents optionally substituted C _1-3 alkyl, wherein said alkyl is optionally substituted with tetrahydropyranyl, an optionally substituted 5-6 membered heteroaryl selected from the group consisting of pyrimidinyl, 1,3,4-oxadiazolyl and oxazolyl, wherein said heteroaryl is optionally substituted with one C _1-3 alkyl, an optionally substituted 4-6 membered heterocycloalkyl selected from the group consisting of tetrahydrofuranyl and tetrahydropyranyl, wherein said heterocycloalkyl is optionally substituted with one -OH, optionally substituted 4-6 membered cycloalkyl, wherein said cycloalkyl is optionally substituted with one -OH; or -OR ⁴ ; R ⁴ represents optionally substituted C _1-5 alkyl, wherein said alkyl is optionally substituted with one or two R ⁶ , an optionally substituted 3-9 membered heterocycloalkyl selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxanyl and 2-oxaspiro[3.3]heptanyl, wherein said heterocycloalkyl is optionally substituted with one or two R ⁶ , or optionally substituted 4-6 membered cycloalkyl, wherein said cycloalkyl is optionally substituted with one, two or three R ⁶ ; R ⁵ represents halogen or hydrogen; each R ⁶ independently represents halogen, -OH, -OCH ₃ , -C(CH ₃ ) ₂ OH, -CH ₂ OH, cyano, optionally substituted C ₁ -C ₄ alkyl, wherein said alkyl is optionally substituted -OH, optionally substituted 4-7 membered heterocycloalkyl selected from the group consisting of tetrahydrofuranyl, 1,4-dioxanyl, tetrahydropyranyl, oxetanyl, 2-oxaspiro[3.3]heptanyl and 3-oxabicyclo[3.1.0]hexanyl, wherein said heterocycloalkyl is optional substituted with one or two substituents independently selected from the group consisting of halogen, -OH, -OCH ₃ and C _1-3 alkyl, or an optionally substituted 5-6 membered heteroaryl selected from the group consisting of 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, isoxazolyl, pyrimidinyl and 1,2,4-oxadiazolyl, wherein said heteroaryl is optionally substituted with one C _1-3 alkyl; And R ⁷ is a 5-membered heteroaryl selected from the group consisting of 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, oxazolyl, 1,2,4-thiadiazolyl and 1,2,4-oxadiazolyl. 2. Compound according to claim 1 of formula (Ia) (Ia) or a pharmaceutically acceptable salt or stereoisomer thereof. 3. Compound according to claim 1 of formula (Ib) (Ib) or a pharmaceutically acceptable salt or stereoisomer thereof. 4. Connection according to any one of paragraphs. 1-3, where R ¹ is selected from the group consisting of H, chlorine and fluorine. 5. Connection according to any one of paragraphs. 1-4, where R ¹ represents fluorine. 6. Connection according to any one of paragraphs. 1-5, where R ² represents H or fluorine. 7. Connection according to any one of paragraphs. 1-6, where R ⁵ represents H or fluorine. 8. Connection according to any one of paragraphs. 1-3, where R ¹ , R ² and R ⁵ represent H. 9. Connection according to any one of paragraphs. 1-3, where R ² and R ⁵ represent H. 10. Connection according to any one of paragraphs. 1-9, where R ³ is selected from the group consisting of: , , , , , , And . 11. Connection according to any one of paragraphs. 1-9, where R ³ represents -OR ⁴ . 12. Connection according to any one of paragraphs. 1-11, where R ⁴ is 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. 13. Connection according to any one of paragraphs. 1-11, where R ⁴ is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And . 14. Connection according to any one of paragraphs. 1-11, where R ⁴ represents C ₁ -C ₅ alkyl and R ⁶ independently represents cyano-, -OH, -OCH ₃ , , , , , , , , , , , , , , , , , , , And . 15. Connection according to any one of paragraphs. 1-14, where R ⁷ is selected from the group consisting of: , , , And . 16. A compound according to claim 1, 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; 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-oxadiazol-2-carboxylate; (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-dimethylpropanenitrile; (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-methylbutoxy)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; trifluoroacetate (S)-7-(4-(5-fluoro-2-(((R)-oxetan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,4-thiadiazole -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-thiadiazole -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-thiadiazole -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-thiadiazole -2-yl)-5-oxa-2-azaspiro[3.4]octane; (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-fluoroxetan-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]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazole -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]heptan-6-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazole -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]octane- 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]octane- 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]octane- 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]octane- 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]heptan-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]octane-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]octane-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]octane-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]octane-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)cyclohexan-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)cyclohexan-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]heptan-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]heptan-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-fluoroxetan-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]octane-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]octane-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]octane-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]octane-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-methylbutoxy)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; formate salt (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; (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]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-thiadiazole -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-oxadiazole -3-yl)-5-oxa-2-azaspiro[3.4]octane. 17. The connection according to claim 16, where the connection is selected from the group consisting of: (S)-7-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazole -2-yl)-5-oxa-2-azaspiro[3.4]octane, having the following structure: ; (R)-7-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(1,3,4-oxadiazole -2-yl)-5-oxa-2-azaspiro[3.4]octane, having 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 having the following structure: ; And (S)-2-(oxazol-2-yl)-7-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-5-oxa-2-azaspiro[ 3.4]octane having the following structure: , or a pharmaceutically acceptable salt thereof. 18. The compound according to claim 16, where the compound is (S)-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, having the following structure: , or a pharmaceutically acceptable salt thereof. 19. The compound according to claim 16, where 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, having the following structure: , or a pharmaceutically acceptable salt thereof. 20. The compound according to claim 16, where 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, having the following structure: , or a pharmaceutically acceptable salt thereof. 21. The compound according to claim 16, where 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, having the following structure: , or a pharmaceutically acceptable salt thereof. 22. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of paragraphs. 1-21 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for the treatment of psychosis associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease or frontotemporal dementia. 23. Use of a therapeutically effective amount of a compound according to any one of claims. 1-21 or a pharmaceutically acceptable salt thereof for the treatment of psychosis associated with schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychotic features, Alzheimer's disease or frontotemporal dementia. 24. Use according to claim 23, wherein psychosis is associated with Alzheimer's disease.