Emopamil binding protein inhibitors and uses thereof

Abstract

Compounds of formula (I): [Formula 1] JPEG2025506667000433.jpg4162, or a pharma- ceutically acceptable salt thereof, which is useful for inhibiting EBP and for treating various EBP-mediated conditions or diseases, such as multiple sclerosis, is provided.

Description

[Technical field]

[0001] Related Applications This application claims the benefit under 35 U.S.C. §119(e) of the filing date of U.S. Provisional Application No. 63 / 309,923, filed February 14, 2022. The entire contents of the aforementioned application are expressly incorporated herein by reference.

[0002] The present disclosure relates to inhibitors of emopamil binding protein (EBP) and pharma- ceutically acceptable salts thereof, compositions of these compounds, processes for their preparation, their use in the treatment of disease, their use optionally in combination with a pharma- ceutically acceptable carrier for the manufacture of a pharmaceutical preparation, the use of the pharmaceutical preparation in the treatment of disease, and methods of treating disease comprising administering an EBP inhibitor to a warm-blooded animal, particularly a human. [Background technology]

[0003] Emopamil-binding protein (EBP) is a Δ8-Δ7 sterol isomerase enzyme that isomerizes the double bond in the sterol molecule, moving it from position 8-9 to position 7-8. Specifically, EBP converts either zymostenol to lathosterol or zymosterol to dehydrolatosterol during cholesterol biosynthesis (Silve et al., 1996, J Biol Chem. 271(37), 22434-22440). Accumulation of 8-9 unsaturated sterols has been shown to activate oligodendrogenesis and remyelination (Hubler et al., 2019, Nature 560(7718), 372-376).

[0004] Myelin is a lipid-based molecule that forms a protective layer (myelin sheath) around nerve cell axons, insulating them. Demyelinating diseases, or myelin-related diseases, occur when these myelin sheaths are damaged, degraded, or reduced in thickness. Loss of myelin sheaths can disrupt electronic signals from the brain, which can lead to nerve damage, vision loss, numbness, muscle weakness, cognitive decline, loss of motor function, and other similar symptoms. In some myelin-related diseases, such as multiple sclerosis, the subject's immune system targets and destroys its own myelin sheath. The ability to repair and regenerate myelin sheaths is the key to treating these myelin-related diseases. Inhibition of EBP is a potential target for activating remyelination because of its function to convert 8-9 sterols, as its inhibition leads to an increase in these 8-9 sterol starting materials (Theodoropoulous et al, 2020, J. Am. Chem. Soc., 142, (13), 6128-6138).

[0005] In addition to its role in remyelination, EBP has also been shown to be a key enzyme in certain colorectal cancers due to the reduction of essential lipids such as cholesterol (Theodoropoulous et al., 2020, J. Am. Chem. Soc., 142, (13), 6128-6138).

[0006] Thus, there is a need for EBP inhibitors as potential therapeutic agents for the treatment of diseases or disorders that respond to EBP inhibition. Summary of the Invention

[0007] The present disclosure provides compounds that are EBP inhibitors. In a first aspect, the present disclosure provides a compound having formula I: [ka] or a pharma- ceutically acceptable salt thereof, X is O, CH 2 or a bond, with the proviso that when X is a bond, p and q are 1; p is 0 or 1, with the proviso that if p is 0, then q is 1; q is 0 or 1, with the proviso that if q is 0, then p is 1; R 1 and R 2 are independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 cycloalkenyl, 6- to 10-membered bicyclic heterocycle, and 4- to 6-membered monocyclic heterocyclyl, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, 6- to 10-membered bicyclic heterocycle, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more R 4 where R 1 and R 2 At least one of them is not H, Or, R 1 and R 2 together with the N atom to which they are attached form a 4- to 7-membered monocyclic heterocycle or a 6- to 10-membered bicyclic heterocycle, each of which may be joined by one or more R 4 Optionally replaced by Each R 4 are, independently, OR 4a , Haro, C 1-3 Alkyl, C 3-8 cycloalkyl, and 4- to 6-membered monocyclic heterocyclyl; R 4a H and C 1-3 alkyl, wherein C 1-3 The alkyl is optionally substituted with one or more halo; R 3 is phenyl, a 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, or a 6- to 10-membered bicyclic heterocycle, wherein the phenyl, the 5- or 6-membered monocyclic heteroaryl, the 9- or 10-membered bicyclic heteroaryl, and the 6- to 10-membered bicyclic heterocycle are each optionally selected from one or more R 5 is replaced by Each R 5is independently 1-3 Alkyl, C 3-6 Cycloalkyl, OR 5a , cyano, halo, and 5- or 6-membered monocyclic heteroaryl, where C 1-3 Alkyl, C 3-6 Cycloalkyl and heteroaryl are each independently one or more R 5b Optionally replaced by R 5a , H, C 1-3 Alkyl, and C 3-6 cycloalkyl, where C 1-3 The alkyl is optionally substituted with one or more halo; R 5b OR 5a , C 1-3 selected from alkyl, cyano, and halo; R 6 is, for each occurrence, independently, a halo or C 1-3 Alkyl or two R 6 Together -C 1-3 Forming an alkylene n is 0, 1, or 2; m is 0, 1, or 2.

[0008] In some embodiments, the compound of formula (I) is not any of the compounds listed in Table I below.

[0009] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharmaceutical carrier.

[0010] In yet another aspect, the present disclosure provides a method for treating a disease or disorder responsive to inhibition of EBP in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method for treating multiple sclerosis. In some embodiments, the present disclosure provides a method for promoting myelination in a subject having a myelin-related disorder.

[0011] Another aspect of the present disclosure relates to the use of at least one compound as described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder that responds to the inhibition of EBP.Also provided is a compound as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder that responds to the inhibition of EBP. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present disclosure provides compounds and pharmaceutical compositions thereof that may be useful in the treatment of diseases or disorders through the mediation of EBP function / activity, such as multiple sclerosis or other myelin-related disorders, in some embodiments, the compounds of the present disclosure are EBP inhibitors.

[0013] Compounds and Compositions In a first aspect, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables in formula (I) are as defined in the first embodiment above. In some embodiments, the compound of formula (I) is not any of the compounds listed in Table I below.

[0014] In a first embodiment, the present disclosure provides a compound having formula I: [ka] or a pharma- ceutically acceptable salt thereof, X is O, CH 2 or a bond, with the proviso that when X is a bond, p and q are 1; p is 0 or 1, with the proviso that if p is 0, then q is 1; q is 0 or 1, with the proviso that if q is 0, then p is 1; R 1 and R 2 are independently H, C1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 cycloalkenyl, and 4-6 membered monocyclic heterocyclyl, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl and 4- to 6-membered monocyclic heterocyclyl each optionally include one or more R 4 where R 1 and R 2 At least one of them is not H, Or, R 1 and R 2 together with the N atom to which they are attached form a 4- to 7-membered monocyclic heterocycle or a 6- to 10-membered bicyclic heterocycle, each of which may be joined by one or more R 4 Optionally replaced by R 4 OR 4a , Haro, C 1-3 Alkyl, or C 3-8 cycloalkyl; R 4a H and C 1-3 alkyl, wherein C 1-3 The alkyl is optionally substituted with one or more halo; R 3 is phenyl, a 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, or a 6- to 10-membered bicyclic heterocycle, wherein the phenyl, the 5- or 6-membered monocyclic heteroaryl, the 9- or 10-membered bicyclic heteroaryl, and the 6- to 10-membered bicyclic heterocycle each optionally contain one or more substituents R 5 is replaced by R 5 is C 1-3 Alkyl, C 3-6 Cycloalkyl, OR 5a , cyano, halo, and 5- or 6-membered monocyclic heteroaryl, where C 1-3 Alkyl, C 3-6 Cycloalkyl and heteroaryl are each independently one or more R 5b Optionally replaced by R 5a , H, C 1-3 Alkyl, and C 3-6 cycloalkyl, where C 1-3 The alkyl is optionally substituted with one or more halo; R 5b OR 5a , C 1-3 selected from alkyl, cyano, and halo; R 6 is, for each occurrence, independently, a halo or C 1-3 Alkyl or two R 6 Together -C 1-3 Forming an alkylene n is 0, 1, or 2; m is 0, 1, or 2.

[0015] In some embodiments, the compound of formula (I) described in the first aspect or first embodiment is not any of the compounds listed in Table I below.

[0016] In a second embodiment, for a compound of formula (I), or a pharma- ceutically acceptable salt thereof, (i) when X is O, R 1 and R 2 together with the N atom to which they are attached form unsubstituted morpholine, unsubstituted pyrrolidine, or unsubstituted N-methylpiperazine, and R 3 each optionally contains one or more substituents R 5 or phenyl, or at least two R 5 Group OR 5a One R 5 (ii) when X is O, R 1 and R 2 Both are C 1-6 is alkyl, R 1 and R 2 Represented by C 1-6 At least one of the alkyl groups is OR. 4a, Halo, and C 3-8 one or more R selected from cycloalkyl 4 and (iii) when X is a bond, R 1 and R 2 Both are C 1-6 is alkyl, R 1 and R 2 Represented by C 1-6 At least one of the alkyl groups is selected from one or more R 4 or (iv) when p is 0, q is 1 and X is O. In a second alternative embodiment, for compounds of formula (I), or a pharma- ceutically acceptable salt thereof, (i) when X is O, R 1 and R 2 together with the N atom to which they are attached form unsubstituted morpholine, unsubstituted pyrrolidine, or unsubstituted N-methylpiperazine, and R 3 each optionally contains one or more substituents R 5 or phenyl, or at least two R 5 Group OR 5a One R 5 (ii) when X is O, R 1 and R 2 Both are C 1-6 is alkyl, R 1 and R 2 Represented by C 1-6 At least one of the alkyl groups is OR. 4a , Haro, C 3-8 one or more R selected from cycloalkyl and 4- to 6-membered monocyclic heterocyclyl; 4 and (iii) when X is a bond, R 1 and R 2 Both are C 1-6 is alkyl, R 1 and R 2 Represented by C 1-6 At least one of the alkyl groups is selected from one or more R 4or (iv) when p is 0, q is 1 and X is O.

[0017] In a third embodiment, the compound of the present disclosure has formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables in formula (II) are as defined in the first aspect, or the first or second embodiment above.

[0018] In a fourth embodiment, the compound of the present disclosure has formula (IIA) or (IIB): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables in formula (IIA) and (IIB) are as defined in the first aspect, or the first or second embodiment above.

[0019] In a fifth embodiment, the compound of the present disclosure has formula (III) or (IV): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables in formula (III) or (IV) are as defined in the first aspect, or the first or second embodiment above.

[0020] In a sixth embodiment, the compound of the present disclosure has formula (IIIA), (IIIB), (IVA), or (IVB): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables in formula (IIIA), (IIIB), (IVA), or (IVB) are as defined in the first aspect, or the first or second embodiment above.

[0021] In a seventh embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 3 is phenyl, a 5- or 6-membered monocyclic heteroaryl, a 9-10 membered bicyclic heteroaryl, or an 8-10 membered bicyclic heterocycle, wherein the phenyl, the 5- or 6-membered monocyclic heteroaryl, the 9-10 membered bicyclic heteroaryl, and the 8-10 membered bicyclic heterocycle are each optionally selected from one to three R 5 and the remaining variables are as described in the first aspect, or the first or second embodiment.

[0022] In an eighth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 3 is pyridyl, phenyl, thiazolyl, pyrazolyl, pyrazinyl, imidazopyridinyl, quinolinyl, tetrahydropyranopyrazolyl, thiophenyl, benzothiophenyl, furanyl, indazolyl, indolizinyl, or benzofuranyl, each of which is optionally selected from one to three R 5 and the remaining variables are as described in the first aspect, or the first or second embodiment. In an alternative eighth embodiment, for a compound of formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 3 is selected from the group consisting of pyridyl, pyrimidinyl, phenyl, thiazolyl, pyrazolyl, pyrazinyl, triazolyl, imidazopyridinyl, quinolinyl, tetrahydropyranopyrazolyl, thiophenyl, benzothiophenyl, furanyl, indazolyl, indolizinyl, pyrazolo[1,5-a]pyridinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, and benzofuranyl, each of which is optionally selected from one to three R 5and the remaining variables are as described in the first aspect, or the first or second embodiment.

[0023] In a ninth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 3 is pyridyl, phenyl, pyrazolyl, thiophenyl, thiazolyl, quinolinyl, tetrahydropyranopyrazolyl, or benzofuranyl, each of which is optionally selected from one to three R 5 and the remaining variables are as described in the first aspect, or the first or second embodiment.

[0024] In a tenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 3 teeth, [ka] Each of these has 1 to 3 R 5 and the remaining variables are as described in the first aspect, or the first or second embodiment. In an alternative tenth embodiment, for a compound of formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 3 is the following formula: [ka] Each of the above formulas is expressed by 1 to 3 R 5 and the remaining variables are as described in the first aspect, or the first or second embodiment.

[0025] In an eleventh embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 3 teeth, [ka] Each of these has 1 to 3 R 5 and the remaining variables are as described in the first aspect, or the first or second embodiment.

[0026] In a twelfth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 3 teeth, [ka] and the remaining variables are as described in the first aspect, or the first or second embodiment. In an alternative twelfth embodiment, for a compound of formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 3 is the following formula: [ka] [ka] and the remaining variables are as described in the first aspect, or the first or second embodiment.

[0027] In a thirteenth embodiment, for a compound of formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 3 teeth, [ka] and the remaining variables are as described in the first aspect, or the first or second embodiment.

[0028] In a fourteenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 5 is, for each occurrence, independently, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5- or 6-membered monocyclic heteroaryl, OR 5a and halo, where C 1-4 Alkyl is one to three R 5b and 5- or 6-membered monocyclic heteroaryl is C 1-3 Optionally substituted with alkyl, R 5a , H, C 1-3 Alkyl or C 3-6 cycloalkyl, where C 1-3 The alkyl is optionally substituted with 1 to 3 halo, R 5b is independently selected for each occurrence from halo and -OR 5a and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment, or any alternative embodiment described herein.

[0029] In a fifteenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 5 is, for each occurrence, independently, -CH 3 , -C(CH 3 ) 3 , -CH 2 CH 3 , -CH 2 CN, -CF 3 , -CH2 OCH 3 , -OCH 3 , -OCHF 2 , -OCF 3 , -OCH 2 CH 3 , -OH, -F, -Cl, cyclopropyl, cyclopropyloxy, 4-methyloxazol-2-yl, and -CN, and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment, or any alternative embodiment described herein. In an alternative fifteenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R is selected from: 5 is, for each occurrence, independently, -CH 3 , -CHF 2 , -C(CH 3 ) 3 , -CH 2 CH 3 , -CH 2 CN, -CF 3 , -CH 2 OCH 3 , -OCH 3 , -OCHF 2 , -OCF 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OH, -F, -Cl, cyclopropyl, cyclopropyloxy, 4-methyloxazol-2-yl, and -CN, and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment, or any alternative embodiment described herein.

[0030] In a sixteenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 1and R 2 together with the N atom to which they are attached form a 4- to 6-membered monocyclic heterocycle or a 6- to 10-membered bicyclic heterocycle, each of which may contain one or two R 4 and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or any alternative embodiment described herein.

[0031] In a seventeenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 together with the N atoms to which they are attached, [ka] and each of these has one or two R 4 and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or any alternative embodiment described herein. In an alternative seventeenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 together with the nitrogen atom to which they are attached form the following formula: [ka] Each of the above formulas may be formed by one or two R 4and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or any alternative embodiment described herein.

[0032] In an eighteenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 together with the N atoms to which they are attached, [ka] and each of these has one or two R 4 and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or any alternative embodiment described herein.

[0033] In a nineteenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 together with the N atoms to which they are attached, [ka] and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or any alternative embodiment described herein. In an alternative nineteenth embodiment, for a compound of formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R1 and R 2 together with the nitrogen atom to which they are attached form the following formula: [ka] and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or any alternative embodiment described herein.

[0034] In a twentieth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 together with the N atoms to which they are attached, [ka] and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or any alternative embodiment described herein.

[0035] In a twenty-first embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 4 For each occurrence, independently, halo, C 1-3 Alkyl and -OR 4a Selected from R 4a is H or C 1-3 is alkyl, and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth or twentieth embodiment, or any alternative embodiment described herein.

[0036] In a twenty-second embodiment, for a compound of formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 4 is, for each occurrence, independently, -OCH 3 , -F, -OH, and -CH 3 and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth or twentieth embodiment, or any alternative embodiment described herein.

[0037] In a twenty-third embodiment, for a compound of formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 1 is H or 1 to 3 R 4 Optionally replaced by C 1-3 is alkyl, R 2 is C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkenyl, or 4-6 membered monocyclic heterocyclyl, where C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl and 4- to 6-membered monocyclic heterocyclyl are each optionally represented by C 1-3 Alkyl, C 1-3and 1 or 2 substituents independently selected from alkoxy, and halo, and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or any alternative embodiment described herein. In an alternative twenty-third embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 1 is H or 1 to 3 R 4 Optionally replaced by C 1-3 is alkyl, R 2 is C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkenyl, 6- to 10-membered bicyclic heterocyclyl, or 4- to 6-membered monocyclic heterocyclyl, where C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 6- to 10-membered bicyclic heterocyclyl, and 4- to 6-membered monocyclic heterocyclyl are each optionally represented by C 1-3 Alkyl, C 1-3 and substituted with 1 or 2 substituents independently selected from alkoxy, halo, and 4-6 membered monocyclic heterocyclyl, and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or any alternative embodiment described herein.

[0038] In a twenty-fourth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 1 is H or 1 to 3 R 4 Optionally replaced by C 1-3 is alkyl, R 2 is C 1-3 Alkoxy-substituted C1-3 Alkyl, C optionally substituted with 1 to 2 halo 3-6 Cycloalkyl, or one or two C 1-3 and R is a 4-6 membered monocyclic heterocyclyl optionally substituted with alkyl, and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or any alternative embodiment described herein. In an alternative twenty-fourth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, ... 1 is H or 1 to 3 R 4 Optionally replaced by C 1-3 is alkyl, R 2 is C 1-3 C substituted with alkoxy or 4-6 membered monocyclic heterocyclyl 1-3 Alkyl, C optionally substituted with 1 to 2 halo 3-6 Cycloalkyl, 6-10 membered bicyclic heterocyclyl, or one or two C 1-3 and 4-6 membered monocyclic heterocyclyl optionally substituted with alkyl, and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or any alternative embodiment described herein.

[0039] In a twenty-fifth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 1 is H or methyl, R 2is 2-methoxyethyl, 4,4-difluorocyclohexyl, 4-fluorocyclohex-3-en-1-yl, 2,2-difluoroethyl, 4-methylpiperidinyl, tetrahydro-2H-pyran-4-yl, 3-methyloxetan-3-yl, oxatan-3-ylmethyl, tetrahydrofuran-3-yl, and 2-oxaspiro[3.3]heptan-6-yl, and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or any alternative embodiment described herein. In an alternative twenty-fifth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R is 2-methoxyethyl, 4,4-difluorocyclohexyl, 4-fluorocyclohex-3-en-1-yl, 2,2-difluoroethyl, 4-methylpiperidinyl, tetrahydro-2H-pyran-4-yl, 3-methyloxetan-3-yl, oxatan-3-ylmethyl, tetrahydrofuran-3-yl, and 2-oxaspiro[3.3]heptan-6-yl. 1 is H or methyl, R 2 is 2-methoxyethyl, -CH 2 -tetrahydropyranyl, 4,4-difluorocyclohexyl, 4-fluorocyclohex-3-en-1-yl, 2,2-difluoroethyl, 4-methylpiperidinyl, tetrahydro-2H-pyran-4-yl, oxetan-3-yl, 3-methyloxetan-3-yl, tetrahydrofuran-3-yl, 3-methyltetrahydrofuran-3-yl, and 2-oxaspiro[3.3]heptan-6-yl, and the remaining variables are as described in the first aspect, or the first, second, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or any alternative embodiment described herein.

[0040] In a twenty-sixth embodiment, the compound of the present disclosure has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein X is O or CH 2 and R 1 is H or 1 to 3 R 4Optionally replaced by C 1-3 is alkyl, R 2 is C 1-3 Alkoxy-substituted C 1-3 Alkyl, C optionally substituted with 1 to 2 halo 3-6 Cycloalkyl, or one or two C 1-3 is a 4-6 membered monocyclic heterocyclyl optionally substituted with alkyl; Or, R 1 and R 2 together with the N atom to which they are attached form a 4- to 6-membered monocyclic heterocycle, a 7- to 9-membered bicyclic heterocycle, each of which may contain one or two R 4 Optionally replaced by R 4 For each occurrence, independently, C 1-3 Alkoxy, OH, halo, and C 1-3 alkyl, R 3 is phenyl, a 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, or a 9- or 10-membered bicyclic heterocycle, wherein the phenyl, the 5- or 6-membered monocyclic heteroaryl, the 9- or 10-membered bicyclic heteroaryl, and the 9- or 10-membered bicyclic heterocycle are each optionally selected from one to three R 5 is replaced by R 5 Cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, OR 5a , and halo, where C 1-4 Alkyl is one to three R 5b Optionally replaced by R 5a C optionally substituted with 1 to 3 halo 1-3 It is an alkyl.

[0041] In some embodiments, for the compound of the twenty-sixth embodiment, or a pharma- ceutically acceptable salt thereof, (i) when X is O, R 1 and R 2together with the N atom to which they are attached form unsubstituted morpholine, unsubstituted pyrrolidine, or unsubstituted N-methylpiperazine, and R 3 each optionally contains one or more substituents R 5 or phenyl, or at least two R 5 Group OR 5a One R 5 (ii) when X is O, R 1 and R 2 Both are C 1-6 is alkyl, R 1 and R 2 Represented by C 1-6 At least one of the alkyl groups is OR. 4a , Halo, and C 3-8 one or more R selected from cycloalkyl 4 and (iii) when X is a bond, R 1 and R 2 Both are C 1-6 is alkyl, R 1 and R 2 Represented by C 1-6 At least one of the alkyl groups is selected from one or more R 4 or (iv) when p is 0, q is 1 and X is O.

[0042] In an alternative twenty-sixth embodiment, the compound of the present disclosure has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein X is O or CH 2 and R 1 is H or 1 to 3 R 4 Optionally replaced by C 1-3 is alkyl, R 2 is C 1-3C substituted with alkoxy or 4-6 membered monocyclic heterocyclyl 1-3 Alkyl, C optionally substituted with 1 to 2 halo 3-6 Cycloalkyl, 6-10 membered bicyclic heterocyclyl, or one or two C 1-3 is a 4-6 membered monocyclic heterocyclyl optionally substituted with alkyl; Or, R 1 and R 2 together with the N atom to which they are attached form a 4- to 6-membered monocyclic heterocycle, a 7- to 9-membered bicyclic heterocycle, each of which may contain one or two R 4 Optionally replaced by R 4 For each occurrence, independently, C 1-3 Alkoxy, OH, halo, and C 1-3 alkyl, R 3 is phenyl, a 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, or a 9- or 10-membered bicyclic heterocycle, wherein the phenyl, the 5- or 6-membered monocyclic heteroaryl, the 9- or 10-membered bicyclic heteroaryl, and the 9- or 10-membered bicyclic heterocycle are each optionally selected from one to three R 5 is replaced by R 5 Cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, OR 5a , and halo, where C 1-4 Alkyl is one to three R 5b Optionally replaced by R 5a C optionally substituted with 1 to 3 halo 1-3 It is an alkyl.

[0043] In a twenty-seventh embodiment, for the compound of the twenty-sixth embodiment, or a pharma- ceutically acceptable salt thereof, R 1 is H or 1 to 3 R 4 Optionally replaced by C 1-3 is alkyl, R 2is C 1-3 Alkoxy-substituted C 1-3 Alkyl, or halo and C 1-3 is a 4-6 membered monocyclic heterocyclyl optionally substituted with 1 or 2 substituents independently selected from alkyl; Or, R 1 and R 2 together with the N atom to which they are attached form the following formula: [ka] Each of these groups is represented by one or two R 4 Optionally replaced by R 3 teeth, [ka] Each of these has 1 to 3 R 5 and the remaining variables are as described in the twenty-sixth embodiment.

[0044] In an alternative twenty-seventh embodiment, for the compound of the twenty-sixth embodiment, or a pharma- ceutically acceptable salt thereof, R 1 is H or 1 to 3 R 4 Optionally replaced by C 1-3 is alkyl, R 2 is C 1-3 C substituted with alkoxy or 4-6 membered monocyclic heterocyclyl 1-3 Alkyl, 6-10 membered bicyclic heterocyclyl, or halo and C 1-3 is a 4-6 membered monocyclic heterocyclyl optionally substituted with 1 or 2 substituents independently selected from alkyl; Or, R 1 and R 2 together with the N atom to which they are attached form the following formula: [ka] Each of these groups is represented by one or two R 4 Optionally replaced by R 3 teeth, [ka] Each of these has 1 to 3 R 5 and the remaining variables are as described in the twenty-sixth embodiment.

[0045] In a twenty-eighth embodiment, for the compound of the twenty-sixth embodiment, or a pharma- ceutically acceptable salt thereof, R 3 teeth, [ka] and R 1 and R 2 together with the nitrogen atom to which they are attached, [ka] and the remaining variables are as described in the twenty-sixth or twenty-seventh embodiment, or any alternative embodiment described herein.

[0046] In an alternative twenty-eighth embodiment, for the compound of the twenty-sixth embodiment, or a pharma- ceutically acceptable salt thereof, R 3 teeth, [ka] and (1)R 1 is H or CH 3 and R 2 is 2-methoxyethyl, oxatan-3-ylmethyl, 3-methyltetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, -CH 2 -tetrahydropyranyl, or 2-oxaspiro[3.3]heptan-6-yl, or (2)R 1 and R2 together with the nitrogen atom to which they are attached, [ka] and the remaining variables are as described in the twenty-sixth or twenty-seventh embodiment, or any alternative embodiment described herein.

[0047] In a 29th embodiment, for the compound of the 26th embodiment, or a pharma- ceutically acceptable salt thereof, R 4 For each occurrence, independently, halo, C 1-3 Alkyl and -OR 4a Selected from R 4a is H or C 1-3 alkyl, and the remaining variables are as described in the twenty-sixth, twenty-seventh, or twenty-eighth embodiment, or any alternative embodiment described herein.

[0048] In a 30th embodiment, for the compound of the 26th embodiment, or a pharma- ceutically acceptable salt thereof, R 4 is, for each occurrence, independently, -OCH 3 , F, -OH, or -CH 3 and the remaining variables are as described in the twenty-sixth, twenty-seventh, or twenty-eighth embodiment, or any alternative embodiment described herein.

[0049] In a thirty-first embodiment, for the compound of the twenty-sixth embodiment, or a pharma- ceutically acceptable salt thereof, R 5 is, for each occurrence, independently, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, OR 5a and halo, where C 1-4 Alkyl is one to three R 5b Optionally replaced by R 5a , H, C 3-6 C optionally substituted with cycloalkyl or 1 to 3 halo 1-3 is alkyl, R5b For each occurrence, independently, halo and C 1-3 alkoxy, and the remaining variables are as described in the twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, or thirtieth embodiment, or any alternative embodiment described herein. In some embodiments, R 5 C substituted with 1 to 3 halo 1-3 It is an alkyl.

[0050] In a thirty-second embodiment, for the compound of the twenty-sixth embodiment, or a pharma- ceutically acceptable salt thereof, R 5 is, for each occurrence, independently, -CH 3 , -CF 3 , -OCH 3 , -OCHF 2 , -OCF 3 , -OH, -CN, F, Cl, -CH 2 OCH 3 , cyclopropyl, and cyclopropyloxy, and the remaining variables are as described in the twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, or thirtieth embodiment, or any alternative embodiment described herein.

[0051] In a thirty-third embodiment, the compound of the present disclosure has formula (V): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables in formula (V) are as defined in the first aspect, or the first or second embodiment above.

[0052] In a thirty-fourth embodiment, the compound of the present disclosure has formula (VA) or (VB): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables in formula (VA) or (VB) are as defined in the first aspect, or the first or second embodiment above.

[0053] In a thirty-fifth embodiment, for compounds of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, X is CH 2 and the remaining variables are as described in the first aspect, or the first or second embodiment.

[0054] In a thirty-sixth embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 3 is phenyl or 5- or 6-membered monocyclic heteroaryl, each of which optionally contains 1 to 2 substituents R 5 and the remaining variables are as described in the first aspect, or the first, second, or thirty-fifth embodiment.

[0055] In a thirty-seventh embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 3 is pyridyl, phenyl, or pyrazolyl, and the remaining variables are as described in the first aspect, or the first, second, or thirty-fifth embodiment.

[0056] In a thirty-eighth embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 3 teeth, [ka] Each of these has one to two R 5 and the remaining variables are as described in the first aspect, or the first, second, or thirty-fifth embodiment.

[0057] In a thirty-ninth embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 3 teeth, [ka] and the remaining variables are as described in the first aspect, or the first, second, or thirty-fifth embodiment.

[0058] In a fortieth embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 5 is, for each occurrence, independently, cyano, C 1-4 Alkyl, OR 5a and halo, where C 1-4 Alkyl is one to three R 5b Optionally replaced by R 5a C optionally substituted with 1 to 3 halo 1-3 is alkyl, R 5b is, at each occurrence, halo, and the remaining variables are as described in the first aspect, or the first, second, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment. In an alternative fortieth embodiment, for compounds of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 5 is, for each occurrence, independently, cyano, C 1-4 Alkyl, OR 5a , C 3-4 cycloalkyl, and halo, where C 1-4 Alkyl is one to three R 5b Optionally replaced by R 5a C optionally substituted with 1 to 3 halo 1-3 is alkyl, R 5b is, at each occurrence, halo, and the remaining variables are as described in the first aspect, or the first, second, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment.

[0059] In a forty-first embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 5 is, for each occurrence, independently, -CH 3 , -CH 2 CH 3 , -CF 3, -OCH 3 , -OCHF 2 , -OCF 3 , -F, and -CN, and the remaining variables are as described in the first aspect, or the first, second, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment. In an alternative forty-first embodiment, for compounds of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 5 is, for each occurrence, independently, -CH 3 , -CHF 2 , -CH 2 CH 3 , -CF 3 , -OCH 3 , -OCHF 2 , -OCF 3 , -F, -Cl, cyclopropyl, and -CN, and the remaining variables are as described in the first aspect, or the first, second, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment.

[0060] In a forty-second embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 Both are C 1-6 When it is an alkyl group, the C 1-6 At least one of the alkyl groups is selected from at least one R 4 and the remaining variables are as described in the first aspect, or the first, second, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, or forty-first embodiment, or any alternative embodiment described herein.

[0061] In a forty-third embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 1 is H or C 1-3 is alkyl, R 2 is C 1-3 C optionally substituted with alkoxy 1-3and the remaining variables are as described in the first aspect, or the first, second, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, or forty-first embodiment, or any alternative embodiment described herein. In an alternative forty-third embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R is alkyl. 1 is H or C 1-3 is alkyl, R 2 is C 1-3 C optionally substituted with alkoxy or 4-6 membered heterocyclyl 1-3 is alkyl, and the remaining variables are as described in the first aspect, or the first, second, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, or forty-first embodiment, or any alternative embodiment described herein.

[0062] In a forty-fourth embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 1 -CH 3 and R 2 -CH 2 OCH 3 and the remaining variables are as described in the first aspect, or the first, second, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, or forty-first embodiment, or any alternative embodiment described herein. In an alternative forty-fourth embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 1 -CH 3 and R 2 -CH 2 CH 2 OCH 3 or tetrahydropyranyl, and the remaining variables are as described in the first aspect, or the first, second, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, or forty-first embodiment, or any alternative embodiment described herein.

[0063] In a forty-fifth embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 together with the N atom to which they are attached form a 4- to 6-membered monocyclic heterocycle or a 6- or 7-membered bicyclic heterocycle, each of which may contain one or two R 4 and the remaining variables are as described in the first aspect, or the first, second, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, or forty-first embodiment, or any alternative embodiment described herein.

[0064] In a forty-sixth embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 together with the N atoms to which they are attached, [ka] and the remaining variables are as described in the first aspect, or the first, second, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, or forty-first embodiment, or any alternative embodiment described herein. In an alternative forty-sixth embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 together with the N atoms to which they are attached, [ka] and the remaining variables are as described in the first aspect, or the first, second, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, or forty-first embodiment, or any alternative embodiment described herein.

[0065] In a forty-seventh embodiment, the compound of the present disclosure has formula (VI): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables in formula (VI) are as defined in the first aspect, or the first or second embodiment above.

[0066] In a forty-eighth embodiment, the compound of the present disclosure has formula (VIA) or (VIB): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables in formula (VIA) or (VIB) are as defined in the first aspect, or the first or second embodiment above.

[0067] In a forty-ninth embodiment, for compounds of formula (VIA) or (VIB), or a pharma- ceutically acceptable salt thereof, X is O, and the remaining variables are as described in the first aspect, or the first or second embodiment.

[0068] In a 50th embodiment, for a compound of formula (VIA) or (VIB), or a pharma- ceutically acceptable salt thereof, R 3 is 1 to 2 R 4 and the remaining variables are as described in the first aspect, or the first, second, or forty-ninth embodiment.

[0069] In a fifty-first embodiment, for compounds of formula (VIA) or (VIB), or pharma- ceutically acceptable salts thereof, R 3 teeth, [ka] and the remaining variables are as described in the first aspect, or the first, second, or forty-ninth embodiment.

[0070] In a fifty-second embodiment, for compounds of formula (VIA) or (VIB), or pharma- ceutically acceptable salts thereof, R 1 and R 2 together with the nitrogen atom to which they are attached, [ka] and the remaining variables are as described in the first aspect, or the first, second, forty-ninth, fiftieth, or fifty-first embodiment.

[0071] In a fifty-third embodiment, the compound of the present disclosure has formula (VII): [ka] or a pharma- ceutically acceptable salt thereof, wherein X is O, CH 2 , or a bond, R 1 is H and R 2 is a 4- to 6-membered monocyclic heterocyclyl or a 6- to 10-membered bicyclic heterocyclyl; or R 1 and R 2 together with the N atom to which they are attached form a 4- to 7-membered monocyclic heterocycle or a 6- to 10-membered bicyclic heterocycle; R 3 is phenyl or 5- or 6-membered monocyclic heteroaryl, each of which is selected from one or two R 5 Optionally replaced by Each R 5 is independently 1-3 Alkyl, C 1-3 Haloalkyl, C 3-4 Cycloalkyl, OR 5a , cyano, and halo; and R 5a is C 1-3 It is haloalkyl.

[0072] In a fifty-fourth embodiment, the compound of the present disclosure has formula (III) or (IV): [ka] or a pharma- ceutically acceptable salt thereof, and the remainder of the variables are as described in the 53rd embodiment.

[0073] In a fifty-fifth embodiment, the compound of the present disclosure has formula (IIIA), (IIIB), (IVA), or (IVB): [ka] or a pharma- ceutically acceptable salt thereof, and the remainder of the variables are as described in the 53rd embodiment.

[0074] In a fifty-sixth embodiment, for a compound of formula (VII), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 3 is phenyl, pyrazolyl, or pyridinyl, each of which may be selected from one or two R 5 and the remaining variables are as described in the 53rd, 54th, or 55th embodiment.

[0075] In a fifty-seventh embodiment, for a compound of formula (VII), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 3 is the following formula: [ka] Each of the above formulas is expressed by one to two R 5 and the remaining variables are as described in the 56th embodiment.

[0076] In a fifty-eighth embodiment, for a compound of formula (VII), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, R 3is the following formula: [ka] and the remainder of the variables are as described in the 56th embodiment.

[0077] In a fifty-ninth embodiment, for a compound of formula (VII), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof: (1)R 2 is the following formula: [ka] or (2)R 1 and R 2 together with the N atom to which they are attached form the following formula: [ka] and the remainder of the variables are as described in the 53rd, 54th, 55th, 56th, 57th, or 58th embodiment.

[0078] In a sixtieth embodiment, for a compound of formula (VII), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharma- ceutically acceptable salt thereof, each R 5 are independently -CH 3 , -CF 3 , -F, -CN, and -OCHF 2 and the remaining variables are as described in the 53rd, 54th, 55th, 56th, 57th, 58th or 59th embodiment.

[0079] In a sixty-first embodiment, the compound of the present disclosure has formula (VIII): [ka] and the remainder of the variables are as described in the 53rd embodiment.

[0080] In a sixty-second embodiment, the compound of the present disclosure has formula (VIIIA) or (VIIIB): [ka] and the remainder of the variables are as described in the 53rd or 61st embodiment.

[0081] In a sixty-third embodiment, for compounds of formula (VII), (VIII), (VIIIA), (VIIIB), or a pharma- ceutically acceptable salt thereof, R 3 is pyrazolyl or pyridinyl, each of which may contain one or two R 5 and the remaining variables are as described in the 53rd, 61st, or 62nd embodiment.

[0082] In a sixty-fourth embodiment, for compounds of formula (VII), (VIII), (VIIIA), (VIIIB), or a pharma- ceutically acceptable salt thereof, R 3 is the following formula: [ka] Each of the above formulas is expressed by one to two R 5 and the remaining variables are as described in the 53rd, 61st, 62nd, or 63rd embodiment.

[0083] In a sixty-fifth embodiment, for compounds of formula (VII), (VIII), (VIIIA), (VIIIB), or a pharma- ceutically acceptable salt thereof, R 3 is the following formula: [ka] and the remainder of the variables are as described in the 53rd, 61st, 62nd, 63rd, or 64th embodiment.

[0084] In a sixty-sixth embodiment, for compounds of formula (VII), (VIII), (VIIIA), (VIIIB), or a pharma- ceutically acceptable salt thereof: (1)R 2 is the following formula: [ka] or (2)R 1 and R 2 together with the N atom to which they are attached form the following formula: [ka] and the remainder of the variables are as described in the 53rd, 61st, 62nd, 63rd, 64th, or 65th embodiment.

[0085] In a sixty-seventh embodiment, for compounds of formula (VII), (VIII), (VIIIA), (VIIIB), or a pharma- ceutically acceptable salt thereof, each R 5 are independently -CH 3 , -CF 3 and cyclopropyl, and the remaining variables are as described in the 53rd, 61st, 62nd, 63rd, 64th, 65th, or 66th embodiment.

[0086] In a sixty-eighth embodiment, the present disclosure provides a compound described herein (e.g., a compound of any one of Examples 1-144), or a pharma- ceutically acceptable salt thereof.

[0087] In a sixty-ninth embodiment, the present disclosure provides a compound selected from the group consisting of: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] or a pharma- ceutically acceptable salt thereof.

[0088] In some embodiments, the compounds of Table I, or pharma- ceutically acceptable salts thereof, are excluded from the compounds of the present disclosure (eg, compounds of Formula (I)). [Table 2-1] [Table 2-2]

[0089] In a seventieth embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (eg, according to any one of the preceding embodiments), or a pharma- ceutically acceptable salt thereof.

[0090] In a seventy-first embodiment, the present disclosure provides a method of treating a disease or disorder mediated by EBP, comprising administering to a subject an effective amount of a compound of the present disclosure (e.g., a compound of formula (I) according to any one of embodiments 1-69), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the fifty-fifth embodiment.

[0091] In a seventy-second embodiment, the present disclosure provides a compound of the present disclosure (e.g., a compound of formula (I) according to any one of embodiments 1-69), or a pharma- ceutically acceptable salt thereof, for use in treating a disease or disorder mediated by EBP.

[0092] In a seventy-third embodiment, the present disclosure provides the use of a compound of the present disclosure (e.g., a compound of formula (I) according to any one of embodiments 1 to 69), or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder mediated by EBP.

[0093] In some embodiments, a compound that can be used in the methods and uses disclosed herein is any one of the compounds in Table I, or a pharma- ceutically acceptable salt thereof.

[0094] The compounds and intermediates described herein may be isolated and used as the compounds themselves. Alternatively, if moieties capable of forming salts are present, the compounds or intermediates may be isolated and used as their corresponding salts. As used herein, the term "salt" or "salts" refers to acid addition or base addition salts of the compounds described herein. "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds described herein and are typically not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto.

[0095] Pharmaceutically acceptable acid addition salts include, for example, acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, malate, malonate ... Salts may be formed using inorganic or organic acids, such as leate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

[0096] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0097] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0098] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0099] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table, in certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly suitable salts including ammonium, potassium, sodium, calcium, and magnesium salts.

[0100] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0101] Salts can be synthesized by conventional chemical methods from compounds that contain a basic or acidic site. In general, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. In general, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable where feasible. Additional lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985), and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0102] Isotopically labeled compounds of formula (I) may generally be prepared by conventional techniques known to those of skill in the art, or by processes analogous to those described in the accompanying examples and preparations, substituting an appropriate isotopically labeled reagent for the unlabeled reagent previously used. In one embodiment, the present disclosure provides a deuterated compound described herein, or a pharma- ceutically acceptable salt thereof.

[0103] Pharmaceutically acceptable solvates according to the invention include those in which the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -Acetone, and d 6 -Contains DMSO.

[0104] Those skilled in the art will recognize that the compounds of the present invention may contain chiral centers and therefore may exist in different stereoisomeric forms.As used herein, the term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present disclosure.It is understood that a substituent may be bonded at a chiral center of a carbon atom.Therefore, the present disclosure includes the enantiomers, diastereomers, or racemates of the compounds.

[0105] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of one another. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The terms "racemic" or "rac" are used to designate racemic mixtures where appropriate. In specifying the stereochemistry of the compounds of the invention, single stereoisomers in which the relative and absolute configurations of the two chiral centers are known are specified using the conventional RS system (e.g., (1S,2S)). "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. If the compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds of unknown absolute configuration may be designated (+) or (-) depending on the way (dextrorotatory or levorotatory) they rotate plane polarized light at the wavelength of the sodium D line. Alternatively, resolved compounds may be defined by their respective retention times relative to the corresponding enantiomer / diastereomer via chiral HPLC.

[0106] Some of the compounds described herein contain one or more asymmetric centers or axes and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-.

[0107] Unless otherwise specified, the compounds of the present disclosure are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R) and (S) stereoisomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques (e.g., separated on chiral SFC or HPLC chromatography columns such as CHIRALPAK® and CHIRALCEL® available from DAICEL Corp., using a suitable solvent or solvent mixture to achieve good separation). When the compound contains a double bond, the substituent may be in the E or Z configuration. When the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0108] How to use The compounds disclosed herein have EBP inhibitory activity.As used herein, "EBP inhibitory activity" refers to the ability of a compound or composition to induce detectable reduction in EBP activity in vivo or in vitro (e.g., at least 10% reduction in EBP activity as measured by a given assay, such as the bioassay described in the examples and known in the art).

[0109] In certain embodiments, the disclosure provides a method of treating a disease or disorder responsive to inhibition of EBP activity (herein referred to as an "EBP-mediated disease or disorder" or an "EBP-mediated disease or disorder") in a subject in need of such treatment. The method includes administering to the subject a compound described herein (e.g., a compound described in any one of the first to sixth embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0110] In certain embodiments, the disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to sixth embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an EBP-mediated disorder or disease in a subject in need thereof.

[0111] In certain embodiments, the disclosure provides a compound described herein (e.g., a compound described in any one of the first to sixth embodiments) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for use in treating an EBP-mediated disorder or disease in a subject in need thereof.

[0112] In certain embodiments, the EBP-mediated disorder is colon cancer.

[0113] In certain embodiments, the present disclosure provides a method for treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a compound described herein (e.g., a compound described in any one of embodiments 1-69) or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0114] In certain embodiments, the disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to sixth embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an autoimmune disease in a subject in need thereof.

[0115] In certain embodiments, the disclosure provides a compound described herein (e.g., a compound described in any one of the first to sixth embodiments) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for use in treating an autoimmune disease in a subject in need thereof.

[0116] In certain embodiments, the autoimmune disease is multiple sclerosis (MS). The compounds of the present disclosure can be used to treat all stages of MS, including relapsing multiple sclerosis (or relapsing form(s) of multiple sclerosis), relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, and clinically isolated syndrome (hereinafter "CIS").

[0117] Relapsing multiple sclerosis (or relapsing form(s) of multiple sclerosis) includes clinically isolated syndromes, relapsing-remitting multiple sclerosis and active secondary-progressive multiple sclerosis.

[0118] Relapsing-remitting multiple sclerosis is a stage of MS characterized by unpredictable relapses followed by relatively quiet (remission) periods of months to years without new signs of disease activity. Deficits occurring during attacks may resolve or remain problematic, the latter occurring in approximately 40% of attacks and being more common the longer the patient has had the disease. This accounts for the initial course in 80% of individuals with multiple sclerosis.

[0119] Secondary progressive multiple sclerosis occurs in approximately 65% ​​of patients with initial relapsing-remitting multiple sclerosis and eventually results in progressive neurological decline during acute attacks without clear periods of remission. Occasional relapses and mild remissions may occur. The most common time from disease onset to conversion from relapsing-remitting to secondary progressive multiple sclerosis is 19 years.

[0120] Primary progressive multiple sclerosis is characterized by the same symptoms as secondary progressive multiple sclerosis, i.e., progressive neurological deterioration during acute attacks without prior relapsing-remitting periods and with no distinct periods of remission.

[0121] CIS is the first episode of neurological symptoms caused by inflammation and demyelination of the central nervous system. By definition, the episode, which must last at least 24 hours, is characteristic of multiple sclerosis, but does not yet meet the criteria for a diagnosis of MS, as a person who experiences CIS may or may not develop MS. If CIS is accompanied by lesions on brain MRI (magnetic resonance imaging) similar to those seen in MS, the person is more likely to have a second episode of neurological symptoms and a diagnosis of relapsing-remitting MS. If CIS is not accompanied by MS-like lesions on brain MRI, the person is much less likely to develop MS.

[0122] In certain embodiments, the disclosure provides a method of promoting myelination in a subject having a myelin-related disease or disorder in a subject in need of treatment, the method comprising administering to the subject a compound described herein (e.g., a compound described in any one of the first to sixth embodiments) or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0123] In certain embodiments, the disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to sixth embodiments) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for promoting myelination in a subject having a myelin-related disease or disorder in a subject in need of treatment.

[0124] In certain embodiments, the disclosure provides a compound described herein (e.g., a compound described in any one of the first to sixth embodiments) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for use in promoting myelination in a subject having a myelin-related disease or disorder in a subject in need of treatment.

[0125] In certain embodiments, the myelin-related disease or disorder is multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, childhood leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), acute disseminated encephalomyelitis (ADEM), central pontine myelitis (CPM), adrenoleukodystrophy, Alexander's disease, Pelizaeus-Merzbacher disease (PMD), vanishing white matter disease, Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, external musculoskeletal syndrome, pulmonary edema ... The present invention is directed to a method for treating or preventing autism, comprising administering to a patient a therapeutically effective amount of ...

[0126] In certain embodiments, the present disclosure provides a method for treating cancer in a subject in need of such treatment, comprising administering to the subject a compound described herein (e.g., a compound described in any one of embodiments 1-69) or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0127] In certain embodiments, the disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to sixth embodiments) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer in a subject in need thereof.

[0128] In certain embodiments, the disclosure provides a compound described herein (e.g., a compound described in any one of the first to sixth embodiments) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof.

[0129] In certain embodiments, the cancer is colon cancer.

[0130] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the subject is a mammal, hi certain embodiments, the subject is a primate, hi certain embodiments, the subject is a human.

[0131] As used herein, "effective amount" and "therapeutically effective amount" may be used interchangeably. Means an amount effective to treat or reduce the severity of one or more of the diseases, disorders, or conditions described herein. In some embodiments, an effective dose may be from 10 μg to 500 mg.

[0132] The compounds and compositions according to the disclosed methods may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the above-listed diseases, disorders, or conditions.

[0133] In certain embodiments, the disclosure relates to the aforementioned method, wherein the compound is administered parenterally. In certain embodiments, the disclosure relates to the aforementioned method, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectally, intrathecally, topically, or intranasally. In certain embodiments, the disclosure relates to the aforementioned method, wherein the compound is administered systemically.

[0134] The compounds of the present invention can be used as pharmaceutical compositions (e.g., a compound of the present invention and at least one pharma- ceutically acceptable carrier). As used herein, the term "pharma- ceutically acceptable carrier" includes solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, salts, preservatives, drug stabilizers, buffers (e.g., maleic acid, tartaric acid, butyric acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.), and the like, and combinations thereof, which are generally recognized as safe (GRAS), as understood by those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except in the event that any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated. For purposes of this disclosure, solvates and hydrates are considered to be pharmaceutical compositions that include a compound of the present invention and a solvent (i.e., a solvate) or water (i.e., a hydrate).

[0135] The formulations can be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., the compound of the present invention, or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds of the present invention are typically formulated into pharmaceutical dosage forms to provide an easily controllable drug dosage and to provide the patient with an elegant and easily handled product.

[0136] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending on the method used to administer the drug. Generally, the article for distribution includes a container having disposed therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-evident assembly to prevent unintentional access to the contents of the package. In addition, a label is disposed on the container that describes the contents of the container. The label may also include appropriate warnings.

[0137] Pharmaceutical compositions containing the compounds of the present disclosure will generally be formulated for parenteral or oral administration or for use as suppositories.

[0138] For example, oral pharmaceutical compositions of the present disclosure may be configured in a solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or in a liquid form (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical processes, such as sterilization, and / or may contain conventional inert diluents, lubricants, or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, and the like.

[0139] Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient together with a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol, also in the case of tablets; c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone, optionally d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures, and / or e) Absorbents, colouring agents, flavouring agents and sweeteners.

[0140] Tablets may be film coated or enteric coated according to methods known in the art.

[0141] Compositions suitable for oral administration include the compounds of the present disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide pharma-ceutically elegant and palatable preparations. Tablets may contain the active ingredient in a mixture with non-toxic, pharma-ceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin, or acacia; and lubricants, for example, magnesium stearate, stearic acid, or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be utilized.Formulations for oral use can be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0142] Parenteral compositions (e.g., intravenous (IV) preparations) are aqueous, isotonic solutions or suspensions. Parenteral compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizing agents, wetting agents or emulsifying agents, dissolution promoters, salts for controlling osmotic pressure, and / or buffers. In addition, they may contain other therapeutically valuable substances. The compositions are generally prepared according to conventional mixing, granulating, or coating methods, respectively, and contain about 0.1-75% or about 1-50% of the active ingredient.

[0143] The compounds of the present disclosure or pharmaceutical compositions thereof for use in subjects (e.g., humans) are usually administered orally or parenterally in therapeutic doses. When administered intravenously by infusion, the dosage may depend on the infusion rate at which the IV formulation is administered. In general, the therapeutically effective dosage of the compounds, pharmaceutical compositions, or combinations thereof depends on the species, weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity. A physician, pharmacist, clinician, or veterinarian who is skilled in the art can easily determine the effective amount of each of the active ingredients required to prevent, treat, or inhibit the progression of the disorder or disease.

[0144] The above-mentioned administration properties are demonstrable in in vivo and in vitro tests, preferably using mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues and preparations thereof. The compounds of the invention can be applied in vitro in the form of solutions, for example aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, for example in suspension or aqueous solution. The dosage in vitro can range from about 10-3 molar to 10-9 molar.

[0145] definition As used herein, "patient," "subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. The term includes mammals, such as humans. Typically, the animal is a mammal. A subject also refers to, for example, a primate (e.g., a human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a primate. Preferably, the subject is a human.

[0146] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0147] As used herein, the terms "treat", "treating" or "treatment" of any disease, condition, or disorder refer to the management and care of a patient with the goal of combating the disease, condition, or disorder, and include the administration of a compound of the present invention to obtain a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partially or completely reducing the extent of the disease, condition, or disorder; ameliorating or improving clinical symptoms, complications, or indicators associated with the disease, condition, or disorder; or delaying, inhibiting, or reducing the likelihood of progression of the disease, condition, or disorder; or eliminating the disease, condition, or disorder. In certain embodiments, the effect may be preventing the onset of symptoms or complications of the disease, condition, or disorder.

[0148] As used herein, the term "cancer" has its commonly accepted meaning in the art. The term can refer broadly to abnormal cell growth.

[0149] As used herein, the term "autoimmune disease" has its commonly accepted meaning in the art. The term may refer broadly to diseases in which the host's immune system targets or attacks the host's normal or healthy tissues.

[0150] As used herein, the term "myelination" has its commonly accepted meaning in the art. The term can refer broadly to the process by which myelin is produced.

[0151] As used herein, the terms "myelin-related disease or disorder," "demyelinating disease," or "demyelinating disorder" have their commonly accepted meanings in the art. These terms may refer broadly to diseases or disorders involving damage to myelin.

[0152] As used herein, a subject is "in need of" a treatment if such a subject (preferably a human) would benefit biologically, medically, or in quality of life from such treatment.

[0153] As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In general, the term "optionally substituted" refers to replacing a hydrogen radical in a given structure with a radical of a specified substituent. Specific substituents are described in the definitions and descriptions of the compounds and examples thereof. Unless otherwise stated, an optionally substituted group may have a substituent at each substitutable position of the group, and when two or more positions in any given structure can be substituted with two or more substituents selected from a specified group, the substituents may be the same or different at all positions.

[0154] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. 1-4 The term "alkyl" refers to an alkyl having 1 to 4 carbon atoms. 1-3 Alkyl" and "C1-2 The term "alkyl" should be construed accordingly. 1-4 Representative examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl. Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy has the same definition as above. When indicated as "optionally substituted," the alkane group or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally 1 to 3 substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[0155] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e., --O--C 1-4 An alkyl group (wherein 1-4 Alkyl is as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like. Preferably, an alkoxy group has about 1-4 carbons, more preferably about 1-2 carbons. 1-2 The term "alkoxy" should be construed accordingly.

[0156] As used herein, "C 1-4 Alkoxy C 1-4 The term "alkyl" means that at least one of the hydrogen atoms is C 1-4 C, as defined herein, which is replaced by alkoxy. 1-4 Refers to an alkyl group. 1-4 Alkoxy C 1-4 The alkyl group is linked through the alkyl group to the remainder of the molecule described herein.

[0157] The number of carbon atoms in a group is indicated herein by the prefix "C x-xx " where x and xx are integers. For example, "C 1-3"Alkyl" is an alkyl group having 1 to 3 carbon atoms.

[0158] "Halogen" or "halo" can be fluorine, chlorine, bromine, or iodine.

[0159] As used herein, "halo-substituted C 1-4 Alkyl" or "C 1-4 The term "haloalkyl" refers to a C alkyl group, as defined herein, in which at least one of the hydrogen atoms is replaced by a halo atom. 1-4 Refers to an alkyl group. 1-4 The haloalkyl group is a monohalo-C 1-4 Alkyl, dihalo-C 1-4 Alkyl, or perhalo-C 1-4 Polyhalo-C containing alkyl 1-4 It can be alkyl. 1-4 The alkyl may have one iodo, bromo, chloro or fluoro in the alkyl group. Dihalo-C 1-4 Alkyl groups and polyhalo-C 1-4 The alkyl group may have two or more of the same halo atoms or a combination of different halo groups within the alkyl group. Typically, polyhalo-C 1-4 The alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. 1-4 Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. 1-4 An alkyl group is a C group in which all hydrogen atoms have been replaced by halo atoms. 1-4 Refers to an alkyl group.

[0160] The term "aryl" refers to an aromatic carbocyclic monocyclic or two fused ring system containing from 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0161] The term "heteroaryl" refers to a 5-12 membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. In some cases, the nitrogen atom in a heteroaryl may be quaternized. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic compound". Heteroaryl groups may be monocyclic or bicyclic. Monocyclic heteroaryls include, for example, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, furanyl, oxadiazolyl, thiophenyl, and the like. Bicyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include pyrazolopyridinyl, pyrazolopyridinyl, benzotriazolyl, imidazopyridinyl, and indolyl.

[0162] The term "carbocyclic ring" or "carbocyclyl" refers to a 4-12 membered saturated or partially unsaturated hydrocarbon ring, which may exist as a monocyclic, bicyclic (including fused, helical, or bridged carbocyclic rings), or helical ring. Bicyclic carbocyclyl groups include, for example, unsaturated carbocyclic radicals fused to another unsaturated carbocyclic radical, a cycloalkyl, or an aryl, such as 2,3-dihydroindenyl, decahydronaphthalenyl, and 1,2,3,4-tetrahydronaphthalenyl. Unless otherwise specified, carbocyclic rings generally contain 4 to 10 ring members.

[0163] "C 3-6 The term "cycloalkyl" refers to fully saturated carbocyclic rings (eg, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0164] The term "heterocycle" or "heterocyclyl" refers to a 4-12 membered saturated or partially unsaturated heterocycle containing 1-4 heteroatoms independently selected from N, O, and S. Heterocyclyl groups can be monocyclic or bicyclic (e.g., bridged, fused, or spiro bicyclic rings). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, but are not limited to, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and piperidinyl. Bicyclic heterocyclyl groups include, for example, an unsaturated heterocyclic radical fused to another unsaturated heterocyclic radical, a cycloalkyl, aryl, or heteroaryl ring, such as tetrahydro-3H-[1,2,3]triazolo[4,5-c]pyridinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 5-oxabicyclo[2.1.1]hexanyl, and 9-azabicyclo[3.3.1]nonanyl. In some embodiments, the heterocyclyl group is a 4-6 membered monocyclic heterocyclyl group. In some embodiments, the heterocyclyl group is a 4-6 membered monocyclic saturated heterocyclyl group. In some embodiments, the heterocyclyl group is an 8-10 membered bicyclic heterocyclyl group. In some embodiments, the heterocyclyl group is an 8-10 membered bicyclic saturated heterocyclyl group.

[0165] As used herein, the term "spiral" ring refers to a bicyclic ring system in which both rings share one common atom. Examples of spiral rings include 2-oxa-6-azaspiro[3.3]heptanyl, and the like.

[0166] The term "fused" ring refers to two ring systems that share two adjacent ring atoms. A fused heterocycle has at least one ring system that contains a ring atom that is a heteroatom selected from O, N, and S (e.g., 3-oxabicyclo[3.1.0]hexane).

[0167] As used herein, the term "bridged" refers to a 5- to 10-membered cyclic moiety connected at two non-adjacent ring atoms (eg, 5-oxabicyclo[2.1.1]hexane).

[0168] The phrase "pharmacologically acceptable" indicates that a substance, composition, or dosage form must be chemically and / or toxicologically compatible with other ingredients included in the formulation and / or with the mammal being treated therewith.

[0169] Unless otherwise specified, the term "compounds of the disclosure" refers to compounds of formula (I) and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitutions). Salts, particularly pharmaceutically acceptable salts, are also included where moieties capable of forming salts are present.

[0170] As used herein, the terms "a," "an," "the," and similar terms used within the context of the present invention (particularly within the context of the claims) should be construed to include both the singular and the plural, unless otherwise specified herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended merely to better elucidate the invention and does not limit the scope of the invention as otherwise claimed.

[0171] It is also possible that the intermediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via rearrangement of some of the bond electrons.

[0172] In one embodiment, the disclosure relates to a compound of formula (I) as defined herein in free form. In another embodiment, the disclosure relates to a compound of formula (I) as defined herein in salt form. In another embodiment, the disclosure relates to a compound of formula (I) as defined herein in acid addition salt form. In a further embodiment, the disclosure relates to a compound of formula (I) as defined herein in pharma- ceutically acceptable salt form. In yet a further embodiment, the disclosure relates to a compound of formula (I) as defined herein in pharma- ceutically acceptable acid addition salt form. In yet a further embodiment, the disclosure relates to any one of the compounds of the examples in free form. In yet a further embodiment, the disclosure relates to any one of the compounds of the examples in salt form. In yet a further embodiment, the disclosure relates to any one of the compounds of the examples in acid addition salt form. In yet a further embodiment, the disclosure relates to any one of the compounds of the examples in pharma- ceutically acceptable salt form. In yet another embodiment, the disclosure relates to any one of the compounds of the examples in pharma- ceutically acceptable acid addition salt form.

[0173] The compounds of the present disclosure can be synthesized by synthetic routes, including processes similar to those well known in the chemical arts, particularly in light of the description contained herein.Starting materials are generally available from commercial sources such as Sigma-Aldrich, or can be easily prepared using methods well known to those skilled in the art (for example, by the methods generally described in Louis F.Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organanischen Chemie, 4, Aufl.ed.Springer-Verlag, Berlin, (including dietary supplements) (also available via Beilstein online database)).

[0174] For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds and key intermediates of the present disclosure. For more detailed descriptions of the individual reaction steps, see the Examples section below. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions. EXAMPLES

[0175] Short description: PE=petroleum ether EtOAc = EA = ethyl acetate ESI = electrospray ionization MeOH = methanol EtOH = ethanol DCE = 1,2-dichloroethane DCM = dichloromethane CHCl 3 = Chloroform HCl = Hydrochloric Acid H 2 O=water IPA = Isopropyl alcohol LCMS = Liquid Chromatography Mass Spectrometry HFIP = hexafluoro-2-propanol HPLC = High Pressure Liquid Chromatography THF = tetrahydrofuran MeCN = ACN = Acetonitrile MgSO 4 = Magnesium sulfate DMSO = dimethyl sulfoxide AcOH = acetic acid TFA = trifluoroacetic acid DIPEA = diisopropylethylamine N 2 = Nitrogen NH 4 HCO 3 = Ammonium bicarbonate t-BuOH = tert-butanol NH 4 Cl = Ammonium chloride NaH = sodium hydride Na 2 SO 4 = Sodium sulfate K 2 CO 3 = Potassium carbonate NaHCO 3 = Sodium bicarbonate NaBH(OAc) 3 =STAB=Sodium triacetoxyborohydride SiO 2 = Silicon dioxide or silica PDA = Photodiode array detection

[0176] General method LCMS instrument specifications: Agilent Technologies 1200 Series LC / MSD Systems: DAD ELSD Alltech 3300 and Agilent LC MSD G6130A, G6120B mass spectrometers. · Agilent Technologies 1260 Infinity LC / MSD system: DAD￥ELSD Alltech 3300 and Agilent LC￥MSD G6120B mass spectrometer. Agilent Technologies 1260 Infinity II LC / MSD System: DAD ELSD G7102A 1290 Infinity II and Agilent LC MSD G6120B Mass Spectrometer. ·Agilent 1260 Series LC / MSD Systems: DAD￥ELSD and Agilent LC￥MSD (G6120B) mass spectrometer. ·UHPLC Agilent 1290 Series LC / MSD System: DAD￥ELSD and Agilent LC￥MSD (G6125B) Mass Spectrometer.

[0177] HPLC analysis method specifications: Columns: Agilent Poroshell 120 SB-C18 4.6×30mm 2.7μm and UHPLC Guard Infinity Lab Poroshell 120 SB-C18 4.6×5mm 2.7μm Column temperature: 60℃ ·Injection volume 0.5μL Modifier: Formic acid at a concentration of 0.1% (v / v) Method: 99% water / 1% MeCN (initial conditions), hold initial conditions for 0.1 min, linear gradient to 0% water / 100% MeCN at 1.5 min, hold 0% water / 100% MeCN until 1.73 min, linear gradient to 99% water / 1% MeCN at 1.74 min. Flow rate 3.0 mL / min. UV scan: 207~223nm, 246~262nm, 272~288nm

[0178] QC analysis LC / MS method conditions: Ammonium hydroxide (basic pH) conditions MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters ACQUITY UPLC BEH C18 2.1 x 50 mm, 1.7 μm, part number 186002350 Modifier: Ammonium hydroxide at a concentration of 0.2% (v / v) Method: 95% water / 5% MeCN (initial condition), linear gradient to 5% water / 95% MeCN in 3.75 min, hold at 5% water / 95% MeCN until 4 min. Flow rate 0.8 mL / min.

[0179] Trifluoroacetic acid (acidic pH) conditions MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters ACQUITY UPLC BEH C18 2.1 x 50 mm, 1.7 μm, part number 186002350 Modifier: Trifluoroacetic acid at a concentration of 0.1% (v / v) Method: 95% water / 5% MeCN (initial condition), linear gradient to 5% water / 95% MeCN in 3.75 min, hold at 5% water / 95% MeCN until 4 min. Flow rate 0.8 mL / min.

[0180] General preparative HPLC conditions: Ammonium hydroxide (basic pH) conditions Flow rate: 30mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters XSELECT CSH C18 PREP 19 x 100 mm, 5 μm, part number 186005421 Modifier: Ammonium hydroxide at a concentration of 0.2% (v / v) Method: A% water / B% MeCN (initial condition), linear gradient to A% water / B% MeCN in 8 min, increasing to 5% water / 95% MeCN in 8.5 min, holding at 5% water / 95% MeCN until 10 min. Flow rate: 50mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters XSELECT CSH C18 PREP 30 x 100 mm, 5 μm, part number 186005425 Modifier: NH at a concentration of 0.2% (v / v) 4 OH Method: A% water / B% MeCN (initial condition), linear gradient to A% water / B% MeCN in 8 min, increasing to 5% water / 95% MeCN in 8.5 min, holding at 5% water / 95% MeCN until 10 min. Flow rate: 60mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters XSELECT CSH C18 PREP 30 x 50 mm, 5 μm, part number 186005423 Modifier: NH at a concentration of 0.2% (v / v) 4 OH Method: A% water / B% MeCN (initial condition), linear gradient to A% water / B% MeCN in 8 min, increasing to 5% water / 95% MeCN in 8.5 min, holding at 5% water / 95% MeCN until 10 min.

[0181] Trifluoroacetic acid (acidic pH) conditions Flow rate: 30mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters Sunfire OBD C18 PREP 19 x 100 mm, 5 μm, part number 186002567 Modifier: Trifluoroacetic acid at a concentration of 0.1% (v / v) Method: A% water / B% MeCN (initial condition), linear gradient to A% water / B% MeCN in 8 min, increasing to 5% water / 95% MeCN in 8.5 min, holding at 5% water / 95% MeCN until 10 min. Flow rate: 50mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters Sunfire OBD C18 PREP 30 x 100 mm, 5 μm, part number 186002572 Modifier: Trifluoroacetic acid at a concentration of 0.1% (v / v) Method: A% water / B% MeCN (initial condition), linear gradient to A% water / B% MeCN in 8 min, increasing to 5% water / 95% MeCN in 8.5 min, holding at 5% water / 95% MeCN until 10 min. Flow rate: 60mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters Sunfire OBD C18 PREP 30 x 50 mm, 5 μm, part number 186002570 Modifier: Trifluoroacetic acid at a concentration of 0.1% (v / v) Method: A% water / B% MeCN (initial condition), linear gradient to A% water / B% MeCN in 8 min, increasing to 5% water / 95% MeCN in 8.5 min, holding at 5% water / 95% MeCN until 10 min.

[0182] Preparation of intermediates Intermediate A: 3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride [ka]

[0183] Synthesis of tert-butyl 1,3-morpholino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate A reaction vessel was charged with tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (2 g, 7.8 mmol), morpholine (1.0 mL, 11.8 mmol) and NaBH(OAc) in DCE (20 mL). 3 (3.3 g, 15.7 mmol) was added and the resulting solution was stirred at room temperature for 24 hours. The reaction mixture was evaporated and diluted with 2M K 2 CO 3 It was diluted with water (50 mL) and DCM (50 mL) and the layers were separated. The organic layer was evaporated under reduced pressure and the crude tert-butyl 3-morpholino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate was used in the next step without further purification. LCMS m / z=327.1 [M+H] + .

[0184] Synthesis of 2.3-morpholino-1-oxa-8-azaspiro[4.5]decane A reaction vessel was charged with tert-butyl 3-morpholino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (2.4 g, 7.4 mmol) in dioxane (10 mL) and 10% HCl in dioxane (10.4 g, 29.4 mmol) and the resulting solution was stirred at 50° C. for 24 h. The reaction mixture was filtered and the precipitate was washed with EtOAc and dried at 70° C. to give 3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride (2 g), which was used without further purification. LCMS m / z=227.2 [M+H] + .

[0185] Examples 1 to 5 The title compound was prepared in a single step library at approximately 50 mg target product scale using the following protocol. [ka] The appropriate sulfonyl chloride (1.1 equiv.) was added to a solution of 3-(morpholin-4-yl)-1-oxa-8-azaspiro[4.5]decane dihydrochloride (1.0 equiv.) and DIPEA (4.5 equiv. + 1.1 equiv. for each acid equivalent for the sulfonyl chloride building block salt) in dry MeCN (1.2 mL) and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo and the residue was dissolved in DMSO (0.8 mL) and purified by preparative HPLC (column: YMC Actus Trial C18 20×100 5 mm, method: water-MeOH-NH as mobile phase). 3 0.1%) to give the pure product. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0186] Example 6: 7-((4-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-7-azaspiro[3.5]nonan-2-amine [ka]

[0187] 1. Synthesis of 7-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one [ka] To a vial containing 7-azaspiro[3.5]nonan-2-one hydrochloride (184 mg, 1.1 mmol) in anhydrous DCM (4 mL) was added DIPEA (0.6 mL, 3.4 mmol) dropwise at <5 °C. After 5 min, 4-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (351 mg, 1.4 mmol) was added. The reaction was brought to room temperature, stirred for 30 min, quenched by slow addition of 1 M aqueous NaOH and stirred for an additional 10 min. The biphasic mixture was loaded directly onto silica gel and purified by column chromatography (20-70% EtOAc in heptane) to give 7-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one as a white solid (285 mg, 75%), which was used in the next step without further purification. LCMS m / z=363.2(M+H) + . 1 H-NMR (500 MHz, DCM-d 2 ) δ(ppm): 9.06 (s, 1H), 7.67 (s, 1H), 3.28 - 3.25 (m, 4H), 2.80 (s, 4H), 2.72 (s, 3H), 1.86 - 1.83 (m, 4H).

[0188] 2. Synthesis of 7-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-7-azaspiro[3.5]nonan-2-amine [ka] To a vial containing 7-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (85 mg, 0.2 mmol) in anhydrous DCM (6 mL) was added tetrahydropyran-4-amine (24 mg, 0.2 mmol) followed by AcOH (30 μL, 0.5 mmol) dropwise at room temperature. After 15 min, NaBH(OAc) 3 (199 mg, 0.94 mmol) was added. After 6 h, the reaction mixture was diluted with saturated NH 4 It was quenched with aqueous Cl, stirred for 10 min, and extracted with DCM (3x). The organic layer was washed with anhydrous MgSO 4 After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (0-100% 3:1 EtOAc:EtOH in heptane with 2% aqueous ammonia) to give 7-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-7-azaspiro[3.5]nonan-2-amine as a colorless film (30 mg, 28%). LCMS m / z=448.2 (M+H). + . 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm): 9.05 (s, 1H), 7.65 (s, 1H), 3.98 - 3.90 (m, 2H), 3.45 - 3.38 (m, 3H), 3.25 - 3.20 (m, 2H), 3.17 - 3.13 (m, 2H), 2.67 (s, 3H), 2.65 - 2.62 (m, 1H), 2.20 - 2.15 (m, 2H), 1.9 - 1.8 (broad m, 1H), 1.75 - 1.70 (m, 4H), 1.74 - 1.60 (m, 2H), 1.52 - 1.48 (m, 2H), 1.42 - 1.35 (m, 2H).

[0189] Example 7: (R)- or (S)-8-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane [ka]

[0190] 1. Synthesis of (R)-tert-butyl 3-morpholino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate and (S)-tert-butyl 3-morpholino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate [ka] NaBH(OAc) 3 (13.3 g, 211.5 mmol) was added portionwise to a solution of tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (18 g, 70.5 mmol) and morpholine (18.2 mL, 211.5 mmol) in MeOH (450 mL) and acetic acid (1.21 mL, 21.2 mmol), and the reaction mixture was cooled to 5° C. with N 2 The mixture was stirred at 20° C. for 12 h under reduced pressure. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (0% to 60% in PE, EtOAc) to give tert-butyl 3-morpholino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (20 g, 87%). This was purified by preparative SFC (column: ChiralPak AD-3 150×4.6 mm ID, 3 μm, mobile phase: A:CO 2 Further purification with B: ethanol (0.05% DEA), gradient: 5% to 40% B in 4.5 min, then 5% B in 1.5 min, flow rate: 2.5 mL / min, column temperature: 40 °C, pressure 100 bar) gave the first eluting peak, E1 (5.1 g, 22%) as a white solid. LCMS m / z=327.2 [M+H] + . v (400 MHz, CDCl3 ) δ (ppm): 4.00 (dd, J = 6.8, 8.4 Hz, 1H), 3.74 - 3.66 (m, 5H), 3.56 (s, 2H), 3.35 - 3.24 (m, 2H), 2.96 (d, J = 7.6 Hz, 1H), 2.54 - 2.43 (m, 2H), 2.42 - 2.32 (m, 2H), 1.96 (dd, J = 7.6, 12.0 Hz, 1H), 1.66 - 1.58 (m, 4H), 1.53 - 1.46 (m, 1H), 1.44 (s, 9H). Also obtained was the second eluting peak, E2 (6.2 g, 27%) as a white solid. LCMS m / z=327.2[M+H] + . 1 H-NMR: (400 MHz, CDCl 3 ) δ (ppm): 4.00 (dd, J = 6.8, 8.4 Hz, 1H), 3.75 - 3.67 (m, 5H), 3.63 - 3.51 (m, 2H), 3.36 - 3.25 (m, 2H), 2.96 (d, J = 7.6 Hz, 1H), 2.54 - 2.44 (m, 2H), 2.43 - 2.34 (m, 2H), 1.96 (dd, J = 7.6, 12.0 Hz, 1H), 1.65 - 1.59 (m, 4H), 1.53 - 1.47 (m, 1H), 1.44 (s, 9H).

[0191] 2. Synthesis of (R)- or (S)-3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride [ka] To a solution of (R)- or (S)-tert-butyl 3-morpholino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (326 mg, 1.0 mmol) in EtOAc (2 mL) was added HCl in EtOAc (1 M, 3.0 mL) and the reaction was stirred at room temperature overnight. The resulting white suspension was filtered and purified by filtration using Et 2Washing with O gave (R)- or (S)-3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride as a white solid. LCMS m / z=227.1 [M+H] + .

[0192] 3. Synthesis of (R)- or (S)-8-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane [ka] To a mixture of (R)- or (S)-3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride (41 mg, 0.1 mmol) and 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride (31 mg, 0.1 mmol) in DCM (2 mL) was added DIPEA (85 mL, 0.5 mmol). The reaction mixture was stirred at room temperature for 2 h. The organic phase was washed with saturated NaHCO 3 and washed with water and MgSO 4 The crude residue was purified by silica gel column chromatography (50-100% EtOAc in heptane) to give (R)- or (S)-8-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane (28 mg, 52%) as a colorless oil. LCMS m / z=439.2 (M+H). + . 1 H-NMR (400 MHz, CD 3 OD): δ (ppm): 7.11 (s, 1H), 4.14 (s, 3H), 3.98 (dd, J = 8.7, 6.9 Hz, 1H), 3.67 (t, J = 4.8 Hz, 5H), 3.58 - 3.46 (m, 2H), 2.99 (s, 3H), 2.57 - 2.32 (m, 4H), 2.09 - 2.01 (m, 1H), 1.86 - 1.75 (m, 3H), 1.73 - 1.60 (m, 2H).

[0193] Synthesis of Intermediate B: 3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane [ka]

[0194] Synthesis of tert-butyl 1.3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate 2-Oxa-6-azaspiro[3.3]heptane hydrochloride (186 mg, 1.9 mmol) was added to a solution of tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (400 mg, 1.6 mmol) in DCM (40 mL) and the reaction was stirred at room temperature for 15 min. Acetic acid (180 μL, 3.1 mmol) was added dropwise followed after 30 min by NaBH(OAc) 3 (1.3 g, 6.3 mmol) was added dropwise. The reaction mixture was stirred at room temperature until the disappearance of the starting material. Brine (20 mL) and DCM (40 mL) were added, the layers were separated, and the organic layer was washed with water (20 mL) and brine (20 mL) and diluted with Na 2 SO 4 Drying at 40° C., filtration and evaporation under reduced pressure gave tert-butyl 3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate. LCMS m / z=339.1 [M+H] + .

[0195] Synthesis of 2.3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane To a solution of tert-butyl 3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (400 mg, 1.2 mmol) in DCM (5 mL) was added TFA (270 μL, 3.6 mmol) and 1,1,1,3,3,3-hexafluoropropan-2-ol (10 mL, 95.0 mmol) and the mixture was stirred at 25° C. for 1 h. DIPEA (0.5 mL, 2.9 mmol) was added and the resulting mixture was concentrated under reduced pressure to give 3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane (450 mg) as a colorless oil, which was used in the next step without further purification. LCMS m / z=239.1 [M+H] + .

[0196] Intermediate C: Synthesis of 6-(8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka]

[0197] Synthesis of tert-butyl 1.3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate To a solution of tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (950 mg, 3.8 mmol) and 2-oxa-6-azaspiro[3.3]heptane (1.1 g, 3.8 mmol) in MeOH (20 mL) was added sodium cyanoborohydride (707 mg, 11.3 mmol) and the mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 μm; conditions: water (NH 4 HCO 3)-MeCN; Start B: 36; End B: 66; Gradient time (min): 10; Flow rate (mL / min): 25) to give tert-butyl 3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.0 g, 81%) as a pale yellow oil. LCMS m / z=337.2 [M+H] + .

[0198] Synthesis of 2.6-(8-azaspiro[4.5]decan-3-yl)-2-oxa-6-azaspiro[3.3]heptane To a solution of tert-butyl 3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decane-8-carboxylate (600 mg, 1.8 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (12 mL, 114.0 mmol), TFA (410 μL, 5.4 mmol) was added and the mixture was stirred at 25° C. for 1 h. DIPEA (3 mL, 17.3 mmol) was added and the resulting mixture was concentrated under reduced pressure to give 6-(8-azaspiro[4.5]decan-3-yl)-2-oxa-6-azaspiro[3.3]heptane (650 mg) as a colorless oil, which was used in the next step without further purification. LCMS m / z=237.2 [M+H] + .

[0199] Examples 8 to 13 The title compound was prepared in a single step library at approximately 60 mg target product scale using the following protocol. [ka] The appropriate sulfonyl chloride (1.0 equiv.) was added to a solution of 3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane (1.0 equiv.) or 6-(8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane (1.0 equiv.) and DIPEA (2.0 equiv.) in dry DCM (10 mL) and the reaction mixture was stirred at room temperature for 30 min. The solids were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC with the appropriate gradient (column: Welch Xtimate C18 150×25 mm×5 μm; conditions: water (10 mM NH 4 HCO 3 )-MeCN) to give the desired product. [Table 4-1] [Table 4-2] [Table 4-3]

[0200] Example 14: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]decane [ka]

[0201] Synthesis of tert-butyl 1.3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate [ka] Piperidine hydrochloride (160 mg, 1.9 mmol) was added to a solution of tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (400 mg, 1.6 mmol) in DCM (40 mL) and the reaction was stirred at room temperature for 15 min. Acetic acid (180 μL, 3.1 mmol) was added dropwise and the solution was stirred for an additional 30 min and NaBH(OAc) 3 (1.3 g, 6.3 mmol) was added and the reaction was stirred at room temperature for 6 h. The reaction was diluted with saturated NH 4 It was quenched with aqueous Cl and diluted with DCM. The organics were washed with water and brine, then concentrated in vacuo to give the desired product (450 mg, 70%), which was not further purified. LCMS m / z=325.2 [M+H] + .

[0202] Synthesis of 2.8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]decane [ka]

[0203] Step A: TFA (180 μL, 2.3 mmol) was added to a solution of tert-butyl 3-(1-piperidyl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (340 mg, 1.1 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (10 mL, 95 mmol) at 0° C. and the solution was allowed to warm to room temperature over 90 min. The reaction mixture was concentrated in vacuo and then diluted with DMF (8 mL). The material was purified by HPLC using a 10 g hyperSep SCX column (2N NH in MeOH). 3 The mixture was filtered through a column (eluted with ethyl acetate) and the solvent was removed in vacuo to give 3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]decane, which was used without further purification.

[0204] Step B: 3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]decane (85 mg, 0.4 mmol) was dissolved in DMF (2 mL), DIPEA (660 μL, 3.8 mmol) and 4-(difluoromethoxy)benzenesulfonyl chloride (92 mg, 0.4 mmol) were added and the reaction was stirred for 30 min. The reaction was quenched with water and the mixture was extracted with EtOAc (3×). The combined organics were washed with saturated NaHCO 3 Wash with aqueous solution (twice), then with anhydrous Na 2 SO 4 The crude material was purified by silica gel chromatography (0-65% EtOAc to 3:1 EtOAc:EtOH) to give 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]decane (27 mg, 16%). LCMS m / z=431.2 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.80 - 7.70 (m, 2H), 7.30 - 7.20 (m, 2H), 6.62 (t, J = 7.3 Hz, 1H), 3.92 (dd, J = 6.8, 8.5 Hz, 1H), 3.62 (t, J = 8.4 Hz, 1H), 3.47 (tdd, J = 2.0, 4.1, 11.5 Hz, 2H), 2.88 (quin, J = 8.0 Hz, 1H), 2.72 (dq, J = 4.0, 11.1 Hz, 2H), 2.50 - 2.20 (m, 4H), 1.94 (dd, J = 7.8, 12.3 Hz, 1H), 1.80 - 1.50 (m, 9H), 1.50-1.40 (m, 2H).

[0205] Examples 15a and 15b: (R)-4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile and (S)-4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile [ka]

[0206] Synthesis of 1.4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile [ka] DIPEA (335 μL, 1.9 mmol) was added to 3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride (Intermediate A, 75 mg, 0.3 mmol) in anhydrous DMF (1.5 mL). After 5 min, 5-cyano-2-methyl-benzenesulfonyl chloride (71.5 mg, 0.3 mmol) was added and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water, the aqueous layer was separated and extracted with EtOAc (3 times). The combined organics were washed with saturated NaHCO 3 Wash with aqueous solution (2 times), Na 2 SO 4 The crude material was purified by silica gel chromatography (0-65% EtOAc to 3:1 EtOAc:EtOH) to give 4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile (27 mg, 16%).

[0207] Isolation of 2.4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile [ka] 4-Methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile was purified by SFC (LUX Cellulose-2LC 30 × 250 mm, 5 μm column, method: CO 2Further purification by elution with 30% MeOH in 100 mL / min (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) afforded two enantiomers of arbitrarily assigned stereochemistry: Peak 1, (R)-4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile: LCMS m / z=406.2[M+H] + .R f =4.01 min, ee=98.86% Peak 2, (S)-4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile, the stereochemistry of which was arbitrarily assigned. LCMS m / z=406.2 [M+H] + .R f =4.31 min, ee=90.62%

[0208] Example 16: 4-Fluoro-3-((3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile [ka] 4-Fluoro-3-((3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]decane-8-yl)sulfonyl)benzonitrile was obtained from 2,6-difluoro-4-methyl-benzenesulfonyl chloride and 3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride (Intermediate A) according to the procedure described in Example 16, Step 1 (15 mg, 35%). LCMS m / z=417.2 [M+H] + 1H-NMR (400 MHz, CDCl 3) δ (ppm): 6.82 (d, J = 9.8 Hz, 2H), 4.13 (q, J = 7.0 Hz, 1H), 3.95 (dd, J = 6.9, 8.4 Hz, 1H), 3.70 (t, J = 4.6 Hz, 4H), 3.68 - 3.58 (m, 2H), 3.02 - 2.88 (m, 2H), 2.54 - 2.29 (m, 7H), 1.95 (dd, J = 7.7, 12.4 Hz, 1H), 1.85 - 1.58 (m, 6H).

[0209] Example 17: 8-((2-methyl-4-(trifluoromethyl)phenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane [ka] 8-((2-Methyl-4-(trifluoromethyl)phenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane was obtained from 2-methyl-4-(trifluoromethyl)benzenesulfonyl chloride and 3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride (Intermediate A) according to the procedure described in Example 16, Step 1 (26 mg, 46%). LCMS m / z=449.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.10 - 7.90 (m, 1H), 7.58 (br s, 2H), 3.98 (dd, J = 6.8, 8.3 Hz, 1H), 3.80 - 3.60 (m, 5H), 3.60 - 3.50 (m, 2H), 3.20 - 2.90 (m, 3H), 2.70 (s, 3H), 2.60 - 2.30 (m, 4H), 1.90 - 1.60 (m, 6H).

[0210] Example 18: 8-((2-fluoro-5-methylphenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane [ka] 8-((2-Fluoro-5-methylphenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane was obtained from 3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride (intermediate A) and 2-fluoro-5-methyl-benzenesulfonyl chloride according to the procedure described in Example 16, step 1 (41 mg, 61%). LCMS m / z=399.2 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.62 (dd, J = 1.6, 6.7 Hz, 1H), 7.50 - 7.30 (m, 1H), 7.09 (dd, J = 8.5, 9.8 Hz, 1H), 3.95 (dd, J = 6.8, 8.5 Hz, 1H), 3.80 - 3.40 (m, 6H), 3.20 - 2.80 (m, 4H), 2.60 - 2.30 (m, 7H), 1.90 - 1.60 (m, 6H).

[0211] Example 19: 8-((2,5-difluorophenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane [ka] 8-((2,5-difluorophenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane was obtained from 2,5-difluorobenzenesulfonyl chloride and 3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride (Intermediate A) according to the procedure described in Example 16, Step 1 (41 mg, 61%). LCMS m / z=403.1 [M+H] + . 1 H-NMR (400 MH Z , CDCl 3) δ (ppm): 7.56 (ddd, J = 3.1, 5.0, 7.7 Hz, 1H), 7.30 - 7.10 (m, 2H), 3.96 (dd, J = 6.8, 8.5 Hz, 1H), 3.80 - 3.50 (m, 6H), 3.10 - 2.90 (m, 4H), 2.60 - 2.30 (m, 4H), 2.00 - 1.60 (m, 6H).

[0212] Example 20: 8-((6-Methoxy-2-methylpyridin-3-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane [ka] 8-((6-Methoxy-2-methylpyridin-3-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane was obtained from 6-methoxy-2-methyl-pyridine-3-sulfonyl chloride and 3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride (Intermediate A) according to the procedure described in Example 16, Step 1 (42 mg, 61%). LCMS m / z=412.2 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.00 (d, J = 8.8 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 4.00 - 3.90 (m, 3H), 3.80 - 3.60 (m, 6H), 3.50 - 3.40 (m, 2H), 3.10 - 2.90 (m, 3H), 2.75 (s, 3H), 2.60 - 2.30 (m, 4H), 2.00 - 1.60 (m, 6H).

[0213] Example 21: 4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka]

[0214] Synthesis of 1.2-morpholino-8-azaspiro[4.5]decane-8-carboxylate [ka] Morpholine (2 mL, 22.9 mmol) was added dropwise to a solution of tert-butyl 3-oxo-8-azaspiro[4.5]decane-8-carboxylate (2.75 g, 10.9 mmol) in anhydrous DCM (40 mL) and acetic acid (0.67 mL, 11.7 mmol) at 0° C. After 15 min, NaBH(OAc) 3 (7.0 g, 33 mmol) was added portionwise. Once the addition was complete, the reaction was allowed to warm to room temperature and stirred for 5 h. The reaction was quenched with 2M aqueous NaOH and the mixture was stirred at room temperature for 20 min. The phases were separated and the aqueous phase was extracted with DCM (3x). The combined organic extracts were washed with MgSO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave 2-morpholino-8-azaspiro[4.5]decane-8-carboxylate. LCMS m / z=325.2 (M+H). + .

[0215] Synthesis of 2.4-(8-azaspiro[4.5]decan-2-yl)morpholine hydrochloride [ka] 1M HCl in EtOAc (35 mL) was added dropwise to a solution of tert-butyl 2-morpholino-8-azaspiro[4.5]decane-8-carboxylate (3.5 g, 10.8 mmol) in MeOH (25 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 7 days. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and filtered to give 4-(8-azaspiro[4.5]decan-2-yl)morpholine hydrochloride as a white solid (2.79 g, 99%). LCMS m / z=225.1 (M+H). + . 1 H-NMR (500 MHz, CD 3OD) δ (ppm): 4.06 (br d, J = 12.8 Hz, 2H), 3.83 (br t, J = 11.3 Hz, 2H), 3.71 (quin, J = 8.7 Hz, 1H), 3.52 (br t, J = 12.2 Hz, 2H), 3.22 - 3.10 (m, 6H), 2.30 - 2.22 (m, 2H), 2.00 - 1.88 (m, 2H), 1.88 - 1.78 (m, 2H), 1.77 - 1.67 (m, 4H).

[0216] 3. Synthesis of 4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka] To a solution of 4-(8-azaspiro[4.5]decan-2-yl)morpholine hydrochloride (81 mg, 0.3 mmol) in anhydrous THF (1 mL) was added DIPEA (320 μL, 1.8 mmol) and DMAP (4 mg, 0.04 mmol) dropwise at less than 5° C. After 5 min, 2,5-dimethylpyrazole-3-sulfonyl chloride (88.3 mg, 0.5 mmol) was added to the cold solution and the reaction was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was quenched with 2 M aqueous NaOH and the mixture was stirred at room temperature for 10 min. The biphasic mixture was loaded onto a silica gel column and purified by chromatography (15-95% 3:1 EtOAc:EtOH in heptane) to give 4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine (80 mg, 64%). LCMS m / z = 383.1 (M+H). + . 1 H-NMR (500 MHz, DMSO-d 6) δ (ppm): 6.59 (s, 1H), 3.92 (s, 3H), 3.53 (br t, J = 4.3 Hz, 4H), 3.08 - 3.03 (m, 4H), 2.49 - 2.44 (m, 1H), 2.38 - 2.28 (m, 4H), 2.18 (s, 3H), 1.80 - 1.74 (m, 1H), 1.71 - 1.65 (m, 1H), 1.58 - 1.52 (m, 1H), 1.51 - 1.44 (m, 4H), 1.43 - 1.33 (m, 2H), 1.19 - 1.14 (m, 1H).

[0217] Examples 22a and 22b: (R)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine and (S)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka]

[0218] 1. Synthesis of (R)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine and (S)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka] 4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine (Example 22, 74 mg, 0.2 mmol) was dissolved in CO 2 Purification on a Lux Cellulose-4 30×250 mm, 5 μm column eluting with 40% MeOH in water (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) afforded two enantiomers of arbitrarily assigned stereochemistry: Peak 1, (R)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine (t R = 2.35 min to give enantiomer 1) as a colorless film (25 mg, 32%). LCMS m / z = 383.2 [M+H] + . 1 H-NMR (500 MHz, DMSO-d 6 ) δ (ppm): 6.59 (s, 1H), 3.92 (s, 3H), 3.53 (br s, 4H), 3.09 - 3.02 (m, 4H), 2.39 - 2.27 (m, 4H), 2.18 (s, 3H), 1.80 - 1.73 (m, 1H), 1.71 - 1.66 (m, 1H), 1.65 - 1.27 (m, 8H), 1.20 - 1.12 (m, 1H). Peak 2, (S)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine (t R = 2.68 min to give enantiomer 2) as a colorless film (25 mg, 33%). LCMS m / z = 383.3 [M+H] + . 1 H-NMR (500 MHz, DMSO-d 6 ) δ (ppm): 6.59 (s, 1H), 3.92 (s, 3H), 3.53 (br s, 4H), 3.05 (br s, 4H), 2.37 - 2.26 (m, 4H), 2.18 (s, 3H), 1.80 - 1.73 (m, 1H), 1.71 - 1.65 (m, 1H), 1.59 - 1.30 (m, 8H), 1.19 - 1.13 (m, 1H).

[0219] Example 23: 4-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka] To a solution of 4-(8-azaspiro[4.5]decan-2-yl)morpholine hydrochloride (130 mg, 0.5 mmol) in DCM (3 mL) was added DIPEA (260 μL, 1.5 mmol) and 4-(difluoromethoxy)benzenesulfonyl chloride (133 mg, 0.6 mmol) at 0° C., and the mixture was stirred at 20° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: Boston Prime C18 150×30 mm×5 μm, method: water (0.05% NH 4 Purification by OH v / v)-MeCN start B34 end B64, flow rate (mL / min) 30) gave 4-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine (98 mg, 46%) as a yellow gum. LCMS m / z=431.2 (M+H). + . 1 H-NMR (400MHz, DMSO-d 6 ) 7.80 (d, J = 8.8 Hz, 2H), 7.62 - 7.21 (m, 3H), 3.51 (br t, J = 4.4 Hz, 4H), 2.96 - 2.80 (m, 4H), 2.35 - 2.23 (m, 5H), 1.78 - 1.03 (m, 10H).

[0220] Example 24: 2-Methyl-3-((2-morpholino-8-azaspiro[4.5]decan-8-yl)sulfonyl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole [ka]

[0221] 1. Synthesis of 2-methyl-3-((2-morpholino-8-azaspiro[4.5]decan-8-yl)sulfonyl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole [ka] To a solution of 4-(8-azaspiro[4.5]decan-2-yl)morpholine hydrochloride (Example 22, Step 2, 70 mg, 0.3 mmol) in anhydrous THF (1 mL) was added DIPEA (300 μL, 1.7 mmol) dropwise below 5° C. After 5 min, 2-methyl-6,7-dihydro-4H-rapino[4,3-c]pyrazole-3-sulfonyl chloride (89 mg, 0.4 mmol) was added and the reaction was allowed to warm to room temperature and stirred for 30 min. The heterogeneous reaction mixture was quenched with 2 M aqueous NaOH and the mixture was stirred at room temperature for 10 min. The biphasic mixture was loaded onto a silica gel column and purified (20-80% 3:1 EtOAc:EtOH in heptane) to give 2-methyl-3-((2-morpholino-8-azaspiro[4.5]decan-8-yl)sulfonyl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole (17 mg, 14%). LCMS m / z=425.3 (M+H). + . 1 H-NMR (500 MHz, DMSO-d 6 ) δ (ppm): 4.63 (s, 2H), 3.94 (s, 3H), 3.84 (t, J = 5.8 Hz, 2H), 3.53 (br t, J = 4.0 Hz, 4H), 3.08 (br t, J = 5.5 Hz, 4H), 2.67 (t, J = 5.8 Hz, 2H), 2.48 - 2.44 (m, 1H), 2.37 - 2.27 (m, 4H), 1.81 - 1.73 (m, 1H), 1.69 (dd, J = 7.3, 12.8 Hz, 1H), 1.57 - 1.50 (m, 1H), 1.50 - 1.44 (m, 4H), 1.43 - 1.35 (m, 2H), 1.19 - 1.14 (m, 1H).

[0222] Example 25: 4-(8-((3,5-dimethylpyridin-2-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka]

[0223] 1. Synthesis of 4-(8-((3,5-dimethylpyridin-2-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka] To a solution of 4-(8-azaspiro[4.5]decan-2-yl)morpholine hydrochloride (Example 22, Step 2, 154 mg, 0.6 mmol) in anhydrous THF (1.5 mL) and MeOH (0.2 mL) was added DIPEA (300 μL, 1.7 mmol) dropwise at room temperature. The resulting mixture was stirred for 10 min and evaporated under reduced pressure. 2-Methyl-2-butanol (1.5 mL), 3,5-dimethylpyridine-2-sulfonyl fluoride (567 mg, 0.3 mmol) were added, followed by Ca(NTf 2 ) 2 (195 mg, 0.3 mmol) was added batchwise. The resulting mixture was heated at 60° C. for 19 h. The reaction mixture was brought to room temperature, quenched with 2 M aqueous NaOH, and the resulting heterogeneous mixture was loaded onto a silica gel column and purified by column chromatography (25-85% 3:1 EtOAc:EtOH in heptane). The product was purified using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with mobile phases water (A) and MeCN (B) and 5-60% B (0.2% NH 4 Further purification by preparative HPLC with a gradient of OH (final v / v % modifier) ​​at a flow rate of 80 mL / min afforded 4-(8-((3,5-dimethylpyridin-2-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine as a white solid (30 mg, 24%). LCMS m / z=394.4 (M+H). + . 1 H-NMR (500 MHz, DMSO-d 6) δ (ppm): 8.33 (s, 1H), 7.73 (s, 1H), 3.56 (br s, 4H), 3.42 - 3.36 (m, 4H), 2.56 - 2.52 (m, 1H), 2.50 (s, 3H), 2.41 - 2.30 (m, 7H), 1.86 - 1.79 (m, 1H), 1.79 - 1.73 (m, 1H), 1.57 - 1.43 (m, 7H), 1.27 - 1.21 (m, 1H).

[0224] Example 26: 4-(8-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka]

[0225] 1. Synthesis of 4-(8-((3-bromo-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka] 4-(8-((3-Bromo-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine was obtained from 4-(8-azaspiro[4.5]decan-2-yl)morpholine hydrochloride and 5-bromo-2-methyl-pyrazole-3-sulfonyl chloride according to the procedure described in example 23, step 1 (582 mg, 84%). 1 H-NMR (500 MHz, DCM-d 2) δ (ppm): 6.66 (s, 1H), 4.04 (s, 3H), 3.62 (t, J = 4.6 Hz, 4H), 3.16 - 3.09 (m, 4H), 2.55 - 2.50 (m, 1H), 2.42 - 2.35 (m, 4H), 1.88 - 1.82 (m, 1H), 1.75 - 1.70 (m, 1H), 1.68 - 1.63 (m, 1H), 1.61 - 1.56 (m, 2H), 1.55 - 1.50 (m, 2H), 1.49 - 1.38 (m, 2H), 1.26 - 1.21 (m, 1H).

[0226] 2. Synthesis of 4-(8-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka] A vial containing 4-(8-((3-bromo-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine (152 mg, 0.3 mmol), t-Butyl BrettPhos (50 mg, 0.1 mmol), t-Butyl BrettPhos PdG3 (43 mg, 0.01 mmol), and sodium tert-butoxide (176 mg, 1.8 mmol) in anhydrous dioxane (3 mL) was evacuated and flushed with N 2 The mixture was backfilled with 100 mL of MeOH. Degassed MeOH (400 μL, 9.9 mmol) was added dropwise and the resulting mixture was heated at 55° C. for 24 h. The reaction was cooled to room temperature, diluted with water and extracted with DCM (×3). The combined organic layers were washed with anhydrous MgSO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (30-90% 3:1 EtOAc:EtOH in heptane). The resulting product was purified using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with mobile phases water (A) and MeCN (B) and 5-50% B (0.2% NH 4Further purification by HPLC with a gradient of 0.1% OH (final v / v % modifier) ​​at a flow rate of 60 mL / min gave 4-(8-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine as a colorless film (6 mg, 4%). LCMS m / z=399.3 [M+H] + . 1 H-NMR (500 MHz, DCM-d 2 ) δ (ppm): 6.04 (s, 1H), 3.91 (s, 3H), 3.85 (s, 3H), 3.73 - 3.54 (m, 4H), 3.15 - 3.07 (m, 4H), 2.76 - 2.55 (m, 1H), 2.54 - 2.22 (m, 4H), 1.90 - 1.83 (m, 1H), 1.76 - 1.71 (m, 1H), 1.68 - 1.64 (m, 1H), 1.61 - 1.52 (m, 5H), 1.46 - 1.40 (m, 1H), 1.35 - 1.20 (m, 1H).

[0227] Example 27: (1R,4R)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka]

[0228] 1. Synthesis of tert-butyl 2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-8-azaspiro[4.5]decane-8-carboxylate [ka] To a solution of tert-butyl 3-oxo-8-azaspiro[4.5]decane-8-carboxylate (247 mg, 1.0 mmol) in anhydrous DCM (3 mL) and acetic acid (200 μL, 3.5 mmol) was added a solution of (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (295 mg, 2.2 mmol) and DIPEA (430 μL, 2.5 mmol) in anhydrous DCM (3 mL). After 15 min, NaBH(OAc) 3 (857 mg, 4.0 mmol) was added portionwise and the reaction mixture was stirred at room temperature for 20 h. The reaction was quenched with 2 M aqueous NaOH and the mixture was stirred at room temperature for 20 min. The biphasic mixture was extracted with DCM (3 times) and the combined organic extracts were washed with anhydrous MgSO 4 Drying at 40° C., filtration and evaporation under reduced pressure afforded tert-butyl 2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-8-azaspiro[4.5]decane-8-carboxylate (307 mg, 94%) which was used without further purification. LCMS m / z=337.3 (M+H). + .

[0229] 2. Synthesis of (1R,4R)-5-(8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride [ka] A solution of tert-butyl 2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-8-azaspiro[4.5]decane-8-carboxylate (307 mg, 0.9 mmol) in MeOH (0.5 mL) was cooled in an ice-water bath and 1M HCl in EtOAc (1M, 3.5 mL) was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to room temperature and stirred for 5 days. The reaction mixture was concentrated under reduced pressure to provide (1R,4R)-5-(8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride, which was used in the next step without further purification. LCMS m / z=237.1 (M+H). + .

[0230] 3. Synthesis of (1R,4R)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka] To a solution of (1R,4R)-5-(8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (124 mg, 0.5 mmol) in anhydrous THF (2 mL) was added DIPEA (500 μL, 2.9 mmol) dropwise at <5 °C. After 5 min, 4-(difluoromethoxy)benzenesulfonyl chloride (120 μL, 0.8 mmol) was added and the reaction was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was quenched with 2 M aqueous NaOH and the resulting biphasic mixture was stirred at room temperature for 10 min. The biphasic mixture was loaded onto silica gel and purified by column chromatography (15-85% 3:1 EtOAc:EtOH in heptane). The product was purified using a Waters XSelect CSH C18, 5 μm, 50 mm × 100 mm column with mobile phases water (A) and MeCN (B) and 5-70% B (0.2% NH 4 Further purification by HPLC with a gradient of 0.1% OH (final v / v % modifier) ​​at a flow rate of 80 mL / min gave (1R,4R)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane as a beige solid (67 mg, 30%). LCMS m / z=443.3 [M+H] + . 1 H-NMR (600MHz, DMSO-d 6)d= 7.80 (d, J = 9.4 Hz, 2H), 7.61 - 7.22 (m, 3H), 3.80 - 3.78 (m, 1H), 2.96 - 2.84 (m, 5H), 2.76 - 2.71 (m, 1H), 2.28 (br dd, J = 5.1, 9.4 Hz, 1H), 1.63 (br d, J = 8.7 Hz, 2H), 1.58 - 1.53 (m, 2H), 1.52 - 1.46 (m, 6H), 1.42 - 1.35 (m, 3H), 1.28 (br dd, J = 4.4, 8.0 Hz, 1H), 1.15 - 1.11 (m, 1H).

[0231] Example 28: 8-((4,6-dimethylpyridin-3-yl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane [ka]

[0232] Synthesis of tert-butyl 1.3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate [ka] TEA (601 μL, 4.3 mmol) was added slowly to a solution of tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (500 mg, 2.0 mmol) and 2-oxa-7-azaspiro[4.4]nonane (299 mg, 2.4 mmol) in DCM (15 mL) at room temperature. After 15 min, acetic acid (280 μL, 4.90 mmol) was added slowly, followed after another 30 min by NaBH(OAc). 3 (1.7 g, 7.8 mmol) was added. Stirring was continued at room temperature for 1 day and saturated NH 4 Aqueous Cl was added. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine and anhydrous Na 2 SO4 The mixture was dried at 77° C., filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-100% 1:3 EtOH:EtOAc in heptane) to give tert-butyl 3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (197 mg, 27%). LCMS m / z=367.2 [M+H] + .

[0233] Synthesis of 2.3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane hydrochloride [ka] 3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane-8-tert-butyl carboxylate (197 mg, 0.5 mmol) was dissolved in EtOAc (4 mL). 4M HCl in dioxane (670 μL, 2.7 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane hydrochloride (215 mg). LCMS m / z=267.1 [M+H] + .

[0234] Synthesis of 3.8-((4,6-dimethylpyridin-3-yl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane [ka] To a solution of 3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane hydrochloride (36 mg, 0.1 mmol) in THF (1 mL) was added DMA (83 μL), DMAP (1 mg, 0.01 mmol), and 4,6-dimethylpyridine-3-sulfonyl chloride (29 mg, 0.1 mmol) at room temperature. DCM (1 mL), DMF (0.5 mL), and DIPEA (80 μL, 0.5 mmol) were added and the reaction was stirred for 15 min. The reaction mixture was diluted with saturated NH 4 The mixture was quenched by adding aqueous Cl and brine. The mixture was extracted with EtOAc (2x) and the combined organic extracts were separated and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire Prep C18, 5μm, OBD 30x100mm, Method: (A) 95% water / / (B) 5% MeCN with 0.1% TFA to 70% (A) / 30% (B) over 7.5min (Flow rate: 50mL / min)) to give 8-((4,6-dimethylpyridin-3-yl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]trifluoroacetate decane (7.9mg, 14%) as a clear oil. LCMS m / z=436.2[M+H] + .

[0235] Example 29: 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane [ka]

[0236] Synthesis of 1,8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane [ka] DIPEA (120 μL, 0.7 mmol) followed by DMAP (1 mg, 0.01 mmol) was added to a solution of 3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane hydrochloride (Example 28, Step 2, 36 mg, 0.11 mmol) in THF (1 mL). 1,3-Dimethyl-1H-pyrazole-5-sulfonyl chloride (28 mg, 0.1 mmol) was added and the reaction was stirred at room temperature for 1 day. The reaction was diluted with saturated NH 4 The mixture was diluted with Cl and brine and extracted with EtOAc (2x). The combined organic extracts were concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire Prep C18, 5μm, OBD 30x100mm, Method: (A) 95% water / / (B) 5% MeCN with 0.1% TFA to 50% (A) / 50% (B) over 7.5min (Flow rate: 50mL / min)) to give 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]trifluoroacetate decane (7.4mg, 13%) as a yellow oil. LCMS m / z=425.3[M+H] + .

[0237] Examples 30a, 30b, 30c, 30d: (S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((R)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane, (S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((S)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro [4.5]decane, (R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((R)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane, and (R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((S)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane [ka]

[0238] Synthesis of 1,8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane [ka] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane was obtained from 3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane hydrochloride (example 28, step 2) and 4-(difluoromethoxy)benzenesulfonyl chloride according to the same reaction as described in example 28, step 3.

[0239] Isolation of 2.8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane [ka] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane was purified using a chiral SFC (CHIRALPAK AD-H 30×250 mm, 5 um, method: CO 2 Purification by elution with 30% EtOH and 0.1% DEA (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) afforded the following enantiomers of arbitrarily assigned stereochemistry: Peak 1, Enantiomer 1 (4.1 mg, 3%), R f =4.82 min, LCMS m / z=473.2[M+H] + Peak 2, enantiomer 2 (4.4 mg, 3%), Rf =5.43 min, LCMS m / z=473.2[M+H] + . 1 H-NMR (400 MHz, CD 3 OD) δ (ppm):7.85 - 7.78 (m, 2H), 7.38 - 7.32 (m, 2H), 7.21 - 6.80 (m, 1H), 3.90 - 3.76 (m, 3H), 3.64 - 3.51 (m, 3H), 3.41 - 3.33 (m, 2H), 2.95 (quin, J = 7.47 Hz, 1H), 2.80 - 2.67 (m, 2H), 2.65 - 2.55 (m, 3H), 2.46 (d, J = 9.54 Hz, 1H), 2.01 - 1.88 (m, 3H), 1.87 - 1.76 (m, 4H), 1.76 - 1.61 (m, 3H). Peak 3, enantiomer 3 (1.2 mg, 1%), R f =6.27 min, LCMS m / z=473.2[M+H] + Peak 4, enantiomer 4 (1.3 mg, 1%), R f =6.50 min, LCMS m / z=473.2[M+H] +

[0240] Example 31: 4-(8-((7-fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka]

[0241] Synthesis of 1,7-fluoroquinoline-6-sulfonyl fluoride [ka] A microwave vial was charged with 6-bromo-7-fluoroquinoline (45 mg, 0.2 mmol), DABSO (48 mg, 0.2 mmol), and Pd(amphos)Cl. 2(7 mg, 0.01 mmol). A solution of N,N-dicyclohexylmethylamine (130 μL, 0.6 mmol) in anhydrous IPA (1.0 mL, 0.2 M) was added under inert atmosphere, the vial was sealed, and N 2 The mixture was aerated at 40° C. for 5 min and heated under microwave irradiation at 110° C. for 1 h. The reaction mixture was brought to room temperature, NFSI (95 mg, 0.3 mmol) was added and the resulting mixture was stirred for 3 h. The reaction mixture was diluted with EtOAc, washed with water (3 mL) and extracted with EtOAc (5 mL, 2 times). The combined organic phase was washed with anhydrous MgSO 4 Drying at 40° C. and concentration in vacuo afforded 7-fluoroquinoline-6-sulfonyl fluoride, which was used in the next step without further purification. LCMS m / z=230.0 [M+H] +

[0242] 2. Synthesis of 4-(8-((7-fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka] A solution of 7-fluoroquinoline-6-sulfonyl fluoride (23 mg, 0.1 mmol) and 4-(8-azaspiro[4.5]decan-2-yl)morpholine (22 mg, 0.1 mmol) in THF (1.0 mL) was added to the solution of Ca(NTf 2 ) 2 (66 mg, 0.1 mmol) and DABCO (17 mg, 0.2 mmol) were added and the heterogeneous reaction solution was heated at 60 °C for 16 h. The reaction mixture was brought to room temperature, quenched with water and extracted with EtOAc (2 mL, 3 times). The combined organic phase was washed with anhydrous MgSO 4 The residue was purified on a Waters XSelect CSH Prep C18 column (5 μm, OBD 19×100 mm, purification gradient: 5-60%, purification modifier: ammonium hydroxide) to give 4-(8-((7-fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine (3.2 mg, yield: 7%). LCMS m / z=434.0 (M+H). + .Rf =1.72 minutes.

[0243] Example 32: 4-(8-((5-cyclopropoxypyridin-2-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka]

[0244] Synthesis of 1,5-cyclopropoxypyridine-2-sulfonyl fluoride [ka] 5-Cyclopropoxypyridine-2-sulfonyl fluoride was obtained from 2-bromo-5-cyclopropoxypyridine following a procedure similar to that described in Example 31, step 1. LCMS m / z=218.0 (M+H). +

[0245] 2. Synthesis of 4-(8-((5-cyclopropoxypyridin-2-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka] 4-(8-((5-cyclopropoxypyridin-2-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine was obtained from 5-cyclopropoxypyridine-2-sulfonyl fluoride and 4-(8-azaspiro[4.5]decan-2-yl)morpholine according to the procedure described in Example 31, step 2 (11 mg, 27%). LCMS m / z=422.0 [M+H] + .R f =1.80 minutes.

[0246] Example 33: 4-(8-((3-fluoro-2-methoxypyridin-4-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka]

[0247] Synthesis of 1.3-fluoro-2-methoxypyridine-4-sulfonyl fluoride [ka] A solution of lithium 3-fluoro-2-methoxypyridine-4-sulfinate (39 mg, 0.2 mmol) and Selectfluor (92 mg, 0.3 mmol) in water (1.0 mL) was stirred at 60° C. for 16 h. The reaction mixture was extracted with EtOAc (2 mL, 3 times). The combined organic phase was washed with anhydrous MgSO 4 Drying at 40° C. and concentration in vacuo afforded 3-fluoro-2-methoxypyridine-4-sulfonyl fluoride, which was used in the next step without further purification (assuming 100% yield). LCMS m / z=210.0 [M+H] +

[0248] 2. Synthesis of 4-(8-((3-fluoro-2-methoxypyridin-4-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine [ka] A solution of 3-fluoro-2-methoxypyridine-4-sulfonyl fluoride (21 mg, 0.1 mmol) and 4-(8-azaspiro[4.5]decan-2-yl)morpholine (34 mg, 0.2 mmol) in 2-methyl-2-butanol (0.5 mL) was added with Ca(NTf 2 ) 2 (90 mg, 0.2 mmol) was added and the resulting heterogeneous reaction mixture was heated at 60 °C for 16 h. After cooling to room temperature, the reaction was quenched with water and extracted with EtOAc (2 mL, 3 times). The combined organic phase was washed with anhydrous MgSO 4The residue was purified by preparative HPLC using a Waters SunFire Prep C18 column (5 μm, OBD 30×100 mm, purification gradient: 5-55%, purification modifier: TFA) to give 4-(8-((3-fluoro-2-methoxypyridin-4-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)morpholine (11 mg, yield: 6%). LCMS m / z=414.0 (M+H). + .R f =1.93 minutes

[0249] Example 34: 4-(7-((1-ethyl-3-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine [ka]

[0250] Synthesis of tert-butyl 1.2-morpholino-7-azaspiro[3.5]nonane-7-carboxylate [ka] tert-Butyl 2-morpholino-7-azaspiro[3.5]nonane-7-carboxylate was obtained from morpholine and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate following a similar reaction as described in Example 21, step 1 (2.9 g, 96%). LCMS m / z=311.2 [M+H] +

[0251] Synthesis of 2.4-(7-azaspiro[3.5]nonan-2-yl)morpholine hydrochloride [ka] 4-(7-Azaspiro[3.5]nonan-2-yl)morpholine hydrochloride was obtained as a pale yellow solid from tert-butyl 2-morpholino-7-azaspiro[3.5]nonane-7-carboxylate according to the procedure described in Example 21, step 2 (2.1 g, 93%).1 H-NMR (500 MHz, CD 3 OD) δ (ppm): 4.11 - 4.02 (m, 2H), 3.89 - 3.74 (m, 3H), 3.46 - 3.37 (m, 2H), 3.21 - 3.16 (m, 2H), 3.15 - 3.09 (m, 2H), 2.97 (dt, J = LCMS m / z=211.2(M+H) + .

[0252] 3. Synthesis of 4-(7-((1-ethyl-3-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine [ka] DIPEA (320 μL, 1.8 mmol) was added dropwise to a solution of 4-(7-azaspiro[3.5]nonan-2-yl)morpholine hydrochloride (78 mg, 0.3 mmol) in DCM (1 mL) at less than 5 °C. After 5 min, 2-ethyl-5-methyl-pyrazole-3-sulfonyl chloride (81 mg, 0.4 mmol) was added and the reaction mixture was allowed to warm to room temperature and stir for 30 min. The reaction mixture was quenched with 1 M aqueous NaOH and stirred at room temperature for 10 min. The biphasic mixture was loaded directly onto a silica gel column and purified (20-80% 3:1 EtOAc:EtOH in heptane) to give 4-(7-((1-ethyl-3-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine as a colorless film (65 mg, 51%). LCMS m / z=383.3(M+H) + . 1 H-NMR (500 MHz, DMSO-d 6) δ (ppm): 6.56 (s, 1H), 4.28 (q, J = 7.3 Hz, 2H), 3.54 (br t, J = 4.3 Hz, 4H), 3.08 - 3.04 (m, 2H), 2.98 - 2.94 (m, 2H), 2.65 - 2.61 (m, 1H), 2.26 - 2.12 (m, 7H), 1.90 - 1.84 (m, 2H), 1.64 - 1.60 (m, 2H), 1.55 - 1.47 (m, 4H), 1.35 - 1.31 (m, 3H).

[0253] Example 35: 4-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine [ka] 4-(7-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine was obtained from 4-(7-azaspiro[3.5]nonan-2-yl)morpholine hydrochloride (example 34, step 2) and 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride following a similar reaction as described in example 23 (92 mg, 58%). LCMS m / z=434.2 (M+H). + . 1 H-NMR (500 MHz, DMSO-d 6 ) δ (ppm): 8.41 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 3.53 (br t, J = 4.0 Hz, 4H), 3.17 - 3.15 (m, 2H), 3.09 - 3.05 (m, 2H), 2.81 (s, 3H), 2.65 - 2.58 (m, 1H), 2.30 - 2.08 (m, 4H), 1.89 (ddd, J = 2.4, 7.8, 9.9 Hz, 2H), 1.63 - 1.59 (m, 2H), 1.54 - 1.47 (m, 4H).

[0254] Example 36: 4-(7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine [ka]

[0255] 1. Synthesis of 4-(7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine [ka] To a solution of 4-(7-azaspiro[3.5]nonan-2-yl)morpholine hydrochloride (Example 34, Step 2, 69 mg, 0.3 mmol) in anhydrous DMF (4 mL) was added DIPEA (244 μL, 1.4 mmol). After 5 min, 2-methoxy-5-methyl-pyridine-3-sulfonyl chloride (62 mg, 0.3 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction was quenched with water and the mixture was extracted with EtOAc (3×). The combined organics were washed with saturated NaHCO 3 Wash with aqueous solution (twice) and anhydrous Na 2 SO 4 The crude material was purified by silica gel chromatography (0-25% EtOAc to 3:1 EtOAc:EtOH) to give 4-(7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine as a yellow oil. LCMS m / z=396.2 (M+H). + . 1 H-NMR (400 MHz, CDCl 3) δ (ppm):8.09 (dd, J = 0.8, 2.3 Hz, 1H), 8.00 - 7.90 (m, 1H), 4.01 (s, 3H), 3.70 (t, J = 4.6 Hz, 4H), 3.30 - 3.20 (m, 2H), 3.20 - 3.10 (m, 2H), 2.80 - 2.60 (m, 1H), 2.29 (s, 7H), 2.00 - 1.90 (m, 2H), 1.70 - 1.50 (m, 6H).

[0256] Example 37: 4-(7-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine [ka] 4-(7-((3-Cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine was obtained as a yellow oil from 4-(7-azaspiro[3.5]nonan-2-yl)morpholine hydrochloride and 5-cyclopropyl-2-methyl-pyrazole-3-sulfonyl chloride according to the procedure described in Example 36. LCMS m / z=395.3 (M+H). + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm):6.33 (s, 1H), 3.98 (s, 3H), 3.69 (t, 4H, J = 4.6 Hz), 3.20 - 3.10 (m, 2H), 3.10 - 3.00 (m, 2H), 2.66 (quin, 1H, J = 7.8 Hz), 2.29 (br s, 4H), 2.00 - 1.80 (m, 3H), 1.70 - 1.50 (m, 6H), 1.00 - 0.80 (m, 2H), 0.80 - 0.60 (m, 2H).

[0257] Example 38: 4-(8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclobutan]-3'-yl)morpholine [ka]

[0258] Synthesis of tert-butyl 3'-morpholino-8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclobutane]-8-carboxylate [ka] 3'-morpholino-8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclobutane]-8-carboxylate tert-butyl was obtained from morpholine and 3'-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclobutane]-8-carboxylate tert-butyl according to the procedure described in Example 27, step 1 (986 mg, crude). LCMS m / z=337.2 [M+H] + .

[0259] 2. Synthesis of 4-(8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclobutan]-3'-yl)morpholine [ka] A solution of tert-butyl 3'-morpholinospiro[8-azabicyclo[3.2.1]octane-3,1'-cyclobutane]-8-carboxylate (986 mg, 2.9 mmol) in MeOH (3 mL) was cooled in an ice-water bath and 4 M HCl in dioxane (2.2 mL) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 20 h. The yellow solution was concentrated under reduced pressure and the yellow residue was triturated with EtOAc containing a few drops of MeOH. The heterogeneous mixture was filtered to give 4-(8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclobutane]-3'-yl)morpholine hydrochloride as a white solid (602 mg, crude) which was used in the next step without purification. LCMS m / z=237.2 (M+H) + . 1 H-NMR (500 MHz, CD 3 OD) δ (ppm): 4.14 - 3.96 (m, 4H), 3.94 - 3.78 (m, 3H), 3.41 - 3.34 (m, 2H), 3.01 - 2.90 (m, 2H), 2.82 (ddd, J = 4.9, 7.6, 11.9 Hz, 1H), 2.59 - 2.52 (m, 1H), 2.38 - 2.32 (m, 1H), 2.29 - 2.18 (m, 3H), 2.17 - 2.06 (m, 3H), 2.05 - 1.94 (m, 3H).

[0260] 3. Synthesis of 4-(8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclobutan]-3'-yl)morpholine [ka] To a solution of 4-spiro(8-azabicyclo[3.2.1]octan-3,3'-cyclobutan)-1'-ylmorpholine hydrochloride (61 mg, 0.2 mmol) in anhydrous DCM (0.5 mL) was added DIPEA (171 mg, 1.3 mmol) dropwise below 5 °C. After 5 min, 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (82 mg, 0.3 mmol) was added and the reaction was allowed to warm to room temperature and stirred for 30 min. The reaction was quenched with 1 M aqueous NaOH and the mixture was stirred at room temperature for 20 min. The biphasic mixture was extracted with DCM (3 times) and the combined organic extracts were washed with anhydrous MgSO 4 The crude material was purified by elution with mobile phases water (A) and MeCN (B) and 5-60% B (0.2% NH 4 Purification by HPLC with a gradient of 0.1% OH (final v / v % modifier) ​​at a flow rate of 60 mL / min gave 4-(8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclobutan]-3'-yl)morpholine as a colorless film (7.9 mg, 7%). LCMS m / z=460.3 (M+H). + . 1 H-NMR (500 MHz, DCM-d 2 ) d = 8.41 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 4.22 - 4.18 (m, 1H), 4.13 - 4.09 (m, 1H), 3.61 (t, J = 4.6 Hz, 4H), 2.89 (s, 3H), 2.68 - 2.62 (m, 1H), 2.43 - 2.38 (m, 1H), 2.21 (br d, J = 2.4 Hz, 4H), 2.02 - 1.93 (m, 4H), 1.84 - 1.75 (m, 6H), 1.68 - 1.63 (m 1H).

[0261] Example 39: 7-((4-(difluoromethoxy)phenyl)sulfonyl)-3-morpholino-1-oxa-7-azaspiro[3.5]nonane [ka]

[0262] Synthesis of tert-butyl 1,3-morpholino-1-oxa-7-azaspiro[3.5]nonane-7-carboxylate [ka] To a solution of tert-butyl 3-oxo-1-oxa-7-azaspiro[3.5]nonane-7-carboxylate (483 mg, 2.0 mmol) in DCM (15 mL) was added acetic acid (70 μL, 1.2 mmol) and morpholine (500 μL, 5.7 mmol) dropwise at room temperature. After 15 min, NaBH(OAc) 3 (1.76 g, 8.29 mmol) was added batchwise and the reaction was stirred at room temperature for 20 h. The reaction was diluted with saturated NH 4 The mixture was quenched with aqueous Cl and then extracted with DCM (3x). The combined organics were washed with brine and anhydrous MgSO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave tert-butyl 3-morpholino-1-oxa-7-azaspiro[3.5]nonane-7-carboxylate (625 mg, crude), which was used in the next step without purification. LCMS m / z=313.1 (M+H)+.

[0263] Synthesis of 2.3-morpholino-1-oxa-7-azaspiro[3.5]nonane trifluoroacetic acid [ka] To a solution of tert-butyl 3-morpholino-1-oxa-7-azaspiro[3.5]nonane-7-carboxylate (625 mg, 2.0 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (5 mL, 48 mmol) was added TFA (500 μL, 6.5 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The volatiles were removed under reduced pressure to give 3-morpholino-1-oxa-7-azaspiro[3.5]nonane trifluoroacetate as a brown film, which was used in the next step without purification. LCMS m / z=213.1 (M+H)+.

[0264] Synthesis of 3.7-((4-(difluoromethoxy)phenyl)sulfonyl)-3-morpholino-1-oxa-7-azaspiro[3.5]nonane [ka] To a solution of 3-morpholino-1-oxa-7-azaspiro[3.5]nonane trifluoroacetate (130 mg, 0.4 mmol) in anhydrous THF (2 mL) was added DIPEA (500 μL, 2.9 mmol) and DMAP (6 mg, 0.05 mmol) dropwise at less than 5° C. The resulting solution was stirred for 5 min, after which 4-(difluoromethoxy)benzenesulfonyl chloride (137 mg, 0.6 mmol) was added. The reaction mixture was allowed to come to room temperature and stirred for 30 min. The reaction was quenched with 1 M aqueous NaOH, the mixture was stirred for 10 min, and then the biphasic mixture was extracted with EtOAc (3×). The combined organics were washed with saturated NaHCO 3 Wash with aqueous solution (twice) and anhydrous Na 2 SO 4 The mixture was dried at 77° C., filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (25-100% EtOAc in heptane) to give 7-((4-(difluoromethoxy)phenyl)sulfonyl)-3-morpholino-1-oxa-7-azaspiro[3.5]nonane as a colorless film, which was triturated with MeOH to give a white solid (10 mg, 6%). LCMS m / z=419.1 (M+H). + . 1H-NMR (500MHz, DMSO-d6) δ (ppm): 7.82 - 7.79 (m, 2H), 7.58 - 7.27 (m, 3H), 4.21 - 4.14 (m, 2H), 3.61 - 3.48 (m, 6H), 2.97 (t, J = 7.6 Hz, 1H), 2.37 - 2.18 (m, 3H), 2.18 - 2.04 (m, 4H), 1.85 (br dd, J = 1.8, 13.4 Hz, 1H), 1.73 - 1.62 (m, 2H).

[0265] Examples 40 to 43 Synthesis of 1.8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one [ka] To a vial containing 8-azaspiro[4.5]nonan-3-one hydrochloride (605 mg, 3.2 mmol) in anhydrous DCM (20 mL) was added DIPEA (2.2 mL, 12.4 mmol) dropwise below 5° C. After 5 min, 2-methoxy-5-methyl-pyridine-3-sulfonyl chloride (825 mg, 3.7 mmol) was added to the cold solution and the reaction was allowed to warm to room temperature. After 30 min, the homogeneous reaction mixture was quenched with 1 M aqueous NaOH and the mixture was stirred at room temperature for 10 min. The phases were separated and the aqueous layer was washed with DCM (10 mL×2). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give an orange oil which was purified by silica gel column chromatography (10-55% EtOAc in heptane) to give 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one (830 mg, 77%). LCMS m / z=338.9[M+H] + .

[0266] The title compound was prepared in a single step library at approximately 85 mg target product scale using the following protocol. [ka] DIPEA (2.0 equiv.) was added to a solution of the appropriate amine (1.5 equiv.) in DCM (1 mL). After 15 min, this solution was added to 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one (1.0 equiv.) in DCM (1 mL). After stirring for an additional 15 min at room temperature, acetic acid (4.0 equiv.) was added followed by NaBH(OAc). 3 (8.0 equiv.) was added dropwise and the reaction mixture was stirred at room temperature overnight. 4 Aqueous Cl (5 mL) and DCM (5 mL) were added, the aqueous phase was separated and extracted with DCM (3×5 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), separated and added to Na 2 SO 4 The residue was purified by preparative HPLC (flow rate: 30 mL / min, column: Waters XSelect CSH C18 PREP 19×100 mm, 5 μm, modifier: NH 4 OH, Method: Linear gradient to A% water / B% MeCN over 8 min) to give the respective products. [Table 5-1] [Table 5-2]

[0267] Example 44: 4-Fluoro-3-((3-((2-methoxyethyl)amino)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile [ka]

[0268] Synthesis of 1.1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride [ka] tert-Butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.5 g, 2.0 mmol) was dissolved in 1 M HCl / EtOAc solution (9.8 mL, 9.8 mmol) at 0° C. and the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered to give 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride as a white solid (300 mg, 99%).

[0269] Synthesis of 2.4-fluoro-3-((3-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile [ka] DIPEA (1.1 mL, 6.5 mmol) was added to 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride (250 mg, 1.3 mmol) in anhydrous DMF (2 mL). After 5 min, 5-cyano-2-fluoro-benzenesulfonyl chloride (287 mg, 1.3 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction was quenched with water and the mixture was extracted with EtOAc (3 times). The combined organics were washed with saturated NaHCO 3 Wash with aqueous solution (twice), then with anhydrous Na 2 SO 4 The crude material was purified by silica gel chromatography (0-75% hexane to EtOAc) to give 4-fluoro-3-((3-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile (300 mg, 68%). LCMS m / z=339.0 [M+H] + . 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 8.20 (dd, J = 2.0, 6.3 Hz, 1H), 7.90 (ddd, J = 2.3, 4.5, 8.6 Hz, 1H), 7.39 (t, J = 8.9 Hz, 1H), 3.97 (s, 2H), 3.70 - 3.60 (m, 2H), 3.20 - 3.10 (m, 2H), 2.39 (s, 2H), 2.00 - 1.80 (m, 4H).

[0270] Synthesis of 3.4-fluoro-3-((3-((2-methoxyethyl)amino)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile [ka] 2-Methoxyethanamine hydrochloride (119 mg, 1.1 mmol) was added to a solution of 4-fluoro-3-((3-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile (300 mg, 0.9 mmol) in DCM (25 mL) and the solution was stirred at room temperature for 15 min. Acetic acid (100 μL, 1.8 mmol) was added dropwise and the reaction was stirred for 30 min and then NaBH(OAc) 3 (752 mg, 3.6 mmol) was added and the reaction was stirred at room temperature for 3 h. The reaction was diluted with saturated NH 4 The mixture was quenched with aqueous Cl and diluted with DCM. The organics were washed with water and brine, then concentrated in vacuo. The crude product was purified by silica gel chromatography (0-100% EtOAc to 3:1 EtOAc:EtOH (with 2% NH 3 OH) to give 4-fluoro-3-((3-((2-methoxyethyl)amino)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile (210 mg, 59%). LCMS m / z=398.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 8.18 (dd, 1H, J = 2.0, 6.3 Hz), 7.87 (ddd, 1H, J = 2.1, 4.4, 8.5 Hz), 7.35 (t, 1H, J = 8.8 Hz), 3.93 (dd, 1H, J = 6.0, 9.0 Hz), 3.70 - 3.60 (m, 3H), 3.50 - 3.40 (m, 3H), 3.36 (s, 3H), 3.10 - 2.90 (m, 2H), 2.80 - 2.60 (m, 2H), 2.10 - 2.00 (m, 1H), 2.00 - 1.60 (m, 5H).

[0271] Example 45: 3-((3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)-4-fluorobenzonitrile [ka] 3-((3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)-4-fluorobenzonitrile was obtained from (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 4-fluoro-3-((3-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile according to the procedure described in Example 44, step 3 (100 mg, 35%). LCMS m / z=422.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 8.20 - 8.10 (m, 1H), 7.86 (ddd, J = 1.8, 4.2, 8.3 Hz, 1H), 7.40 - 7.30 (m, 1H), 4.37 (br s, 1H), 4.00 (br d, 1H, J = 7.8 Hz), 3.90 - 3.70 (m, 1H), 3.70 - 3.50 (m, 4H), 3.42 (br d, J = 19.1 Hz, 1H), 3.31 (dt, J=3.0, 6.4 Hz, 1H), 3.10 - 2.70 (m, 3H), 2.60 - 2.30 (m, 1H), 2.10 - 1.60 (m, 8H).

[0272] Example 46: 3-((3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)-4-fluorobenzonitrile [ka] 3-((3-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)-4-fluorobenzonitrile was obtained from 2-oxa-6-azaspiro[3.3]heptane hydrochloride and 4-fluoro-3-((3-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile according to the procedure described in Example 44, step 3 (77 mg, 82%). LCMS m / z=422.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.16 (dd, J = 2.0, 6.3 Hz, 1H), 7.86 (ddd, J = 1.9, 4.3, 8.4 Hz, 1H), 7.34 (t, J = 8.8 Hz, 1H), 4.72 (s, 4H), 3.80 - 3.50 (m, 5H), 3.40 - 3.20 (m, 4H), 3.00 - 2.80 (m, 3H), 1.90-1.40 (m, 5H).

[0273] Example 47: 4-Fluoro-3-((3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile [ka] 4-Fluoro-3-((3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile was obtained from 4-fluoro-3-((3-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile and piperidine hydrochloride according to the procedure described in Example 44, step 3 (41 mg, 45%). LCMS m / z=408.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.17 (dd, J = 2.1, 6.1 Hz, 1H), 7.87 (ddd, J = 2.0, 4.3, 8.5 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 3.96 (dd, J = 7.0, 8.3 Hz, 1H), 3.70 - 3.50 (m, 3H), 3.10 - 2.80 (m, 4H), 2.50 - 2.20 (m, 4H), 2.10 - 1.90 (m, 2H), 1.90 - 1.50 (m, 9H).

[0274] Example 48: 3-((3-((4,4-difluorocyclohexyl)amino)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)-4-fluorobenzonitrile [ka] 3-((3-((4,4-difluorocyclohexyl)amino)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)-4-fluorobenzonitrile was obtained from 4,4-difluorocyclohexanamine hydrochloride and 4-fluoro-3-((3-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile according to the procedure described in example 44, step 3 (61 mg, 44%). LCMS m / z=458.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm):8.19 (td, J = 2.4, 6.1 Hz, 1H), 7.88 (ddd, J = 2.0, 4.2, 8.3 Hz, 1H), 7.36 (dt, J = 1.6, 8.8 Hz, 1H), 4.00 - 3.80 (m, 1H), 3.70 - 3.60 (m, 2H), 3.60 - 3.40 (m, 1H), 3.20 - 2.90 (m, 2H), 2.30 - 1.60 (m, 14H), 1.60 - 1.40 (m, 2H).

[0275] Example 49: 8-((2-chloro-4-methylphenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane [ka]

[0276] Synthesis of 1,8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one [ka] DIPEA (2.3 mL, 13.0 mmol) was added to a vial containing 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride (500 mg, 2.6 mmol) in anhydrous DMF (3 mL), the solution was stirred for 5 min, and then 2-chloro-4-methyl-benzenesulfonyl chloride was added (587 mg, 2.6 mmol). The reaction was stirred at room temperature for 1 h, then the reaction was quenched with water and the mixture was extracted with EtOAc (3 times). The combined organics were washed with saturated NaHCO 3 The organic layer was separated and then washed with anhydrous Na 2 SO 4 The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give 8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one. LCMS m / z=344.0[M+H] + .

[0277] Synthesis of 2.8-((2-chloro-4-methylphenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane [ka] 2-Oxa-6-azaspiro[3.3]heptane (29 mg, 0.3 mmol) was added to a solution of 8-(2-chloro-4-methyl-phenyl)sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-one (100 mg, 0.3 mmol) in DCM (10 mL) and the solution was stirred at room temperature for 15 min. Acetic acid (40 μL, 0.6 mmol) was added dropwise, followed by NaBH(OAc). 3 (247 mg, 1.16 mmol) was added dropwise and the reaction was stirred at room temperature for 3 h. The reaction was diluted with saturated NH 4 The mixture was quenched with aqueous Cl and diluted with DCM. The organic solution was washed with water and brine, then concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0-100% EtOAc to 3:1 EtOAc:EtOH (with 2% NH 3OH) to give 8-((2-chloro-4-methylphenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane (70 mg, 56%). LCMS m / z=427.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.89 (d, J = 8.3 Hz, 1H), 7.40 - 7.30 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.71 (s, 4H), 3.70 (dd, J = 5.5, 9.3 Hz, 1H), 3.60 - 3.40 (m, 3H), 3.40 - 3.20 (m, 4H), 3.20 - 3.00 (m, 2H), 3.00 - 2.80 (m, 1H), 2.39 (s, 3H), 1.90 - 1.40 (m, 6H).

[0278] Example 50: 1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)-3-methylazetidin-3-ol [ka] 1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)-3-methylazetidin-3-ol was obtained from 3-methylazetidin-3-ol and 8-(2-chloro-4-methyl-phenyl)sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-one according to the procedure described in Example 49, step 2 (120 mg, 99%). LCMS m / z=415.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 7.90 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 0.8 Hz, 1H), 7.20 - 7.10 (m, 1H), 3.75 (dd, J = 5.5, 9.3 Hz, 1H), 3.70 - 3.40 (m, 3H), 3.30 - 3.20 (m, 2H), 3.20 - 2.90 (m, 5H), 2.40 (s, 3H), 2.00 - 1.50 (m, 6H), 1.47 (s, 3H).

[0279] Example 51: 8-((2-chloro-4-methylphenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-1-oxa-8-azaspiro[4.5]decan-3-amine [ka] 8-((2-chloro-4-methylphenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-1-oxa-8-azaspiro[4.5]decan-3-amine was obtained from tetrahydropyran-4-amine and 8-(2-chloro-4-methyl-phenyl)sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-one according to the procedure described in Example 49, step 2 (199 mg, 84%). LCMS m / z=429.2 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.83 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.20-7.10 (m, 1H), 3.88 (br dd, J = 5.6, 8.2 Hz, 3H), 3.60-3.40 (m, 4H), 3.31 (br t, J = 11.7 Hz, 2H), 3.20-3.00 (m, 2H), 2.70-2.50 (m, 1H), 2.33 (s, 3H), 2.10-1.80 (m, 1H), 1.70-1.20 (m, 10H).

[0280] Example 52: 1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)azetidin-3-ol [ka] 1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)azetidin-3-ol was obtained from azetidin-3-ol hydrochloride and 8-(2-chloro-4-methyl-phenyl)sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-one according to the procedure described in example 49, step 2 (110 mg, 94%). LCMS m / z = 401.2 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.00 - 7.70 (m, 1H), 7.40-7.30 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H), 4.60 - 4.30 (m, 1H), 3.80 - 3.70 (m, 1H), 3.60 - 3.50 (m, 5H), 3.30 - 3.10 (m, 2H), 3.10 - 3.00 (m, 1H), 2.90 - 2.70 (m, 2H), 2.40 (s, 3H), 2.00 - 1.50 (m, 6H).

[0281] Examples 53a and 53b: (R)-1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)azetidin-3-ol and (S)-1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)azetidin-3-ol [ka] 1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)azetidin-3-ol (Example 52) was purified using a CHIRALPAK AD-H 30×250 mm, 5 μm column, Method: CO 2 Separation in 40% MeOH and 0.1% DEA (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) afforded two enantiomers of arbitrarily assigned stereochemistry: Peak 1, Enantiomer 1, (R)-1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)azetidin-3-ol: LCMS m / z=401.2 [M+H] + .R f = 2.57 min, ee = 100%. Peak 2, Enantiomer 2, (S)-1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)azetidin-3-ol: LCMS m / z=401.2 [M+H] + .R f = 3.10 min, ee = 100%.

[0282] Example 54: 8-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane [ka]

[0283] Synthesis of 1.8-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one [ka] DIPEA (800 μL, 4.6 mmol) was added to a vial containing 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride (800 μL, 0.9 mmol) in anhydrous DMF (2 mL). After 5 min, 2-methyl-4-(trifluoromethoxy)benzenesulfonyl chloride (254 mg, 0.9 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction was quenched with water and the mixture was extracted with EtOAc (3 times). The combined organics were washed with saturated NaHCO 3 The organic layer was washed with anhydrous Na 2 SO 4 The crude material was purified by silica gel column (0-40% hexane-EtOAc) to give 8-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one (358 mg, 98%). LCMS m / z=394.1 [M+H] + .

[0284] Synthesis of 2.8-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane [ka] Morpholine hydrochloride (38 mg, 0.3 mmol) was added to a solution of 8-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one (100 mg, 0.3 mmol) in DCM (8 mL) and the solution was stirred at room temperature for 15 min. Acetic acid (30 μL, 0.5 mmol) was added dropwise, followed by NaBH(OAc). 3 (216 mg, 1.0 mmol) was added dropwise and the reaction was stirred at room temperature for 3 h. The reaction was diluted with saturated NH 4 Quench with aqueous Cl and saturated NaHCO 3 The organics were washed with water and brine, the solvent was removed in vacuo, and the crude product was purified by column chromatography on a silica gel column (0-100% EtOAc to 3:1 EtOAc:EtOH (and 2% NH 3Purification by HPLC with 50% NaOH gave 8-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane (118 mg, 75%). LCMS m / z=465.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.00 - 7.80 (m, 1H), 7.15 (br d, J = 0.8 Hz, 2H), 3.97 (dd, J = 6.8, 8.5 Hz, 1H,), 3.80 - 3.60 (m, 5H), 3.60 - 3.40 (m, 2H), 3.20 - 2.90 (m, 3H), 2.64 (s, 3H), 2.60 - 2.30 (m, 4H), 1.97 (dd, J = 7.8, 12.3 Hz, 1H), 1.80 - 1.50 (m, 5H).

[0285] Example 55: 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane [ka]

[0286] Synthesis of 1.8-((2-cyclopropylthiazol-5-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one [ka] DIPEA (1.9 mL, 11.2 mmol) was added to a vial containing 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride (428 mg, 2.2 mmol) in DMF (4 mL). After 5 min, 2-cyclopropylthiazole-5-sulfonyl chloride (500 mg, 2.24 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water and the mixture was extracted with EtOAc (3 times). The combined organics were washed with saturated NaHCO 3The organic layer was separated and washed with anhydrous Na 2 SO 4 The crude material was purified by silica gel column (0-25% EtOAc to 3:1 EtOAc:EtOH) to give 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one as a yellow solid (630 mg, 82%). LCMS m / z=343.0 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94 (s, 1H), 3.97 (s, 2H), 3.60 - 3.50 (m, 2H), 2.93 (dt, J = 3.5, 11.2 Hz, 2H), 2.40 - 2.20 (m, 3H), 2.00 - 1.80 (m, 4H), 1.40 - 1.10 (m, 4H).

[0287] Synthesis of 2.8-((2-cyclopropylthiazol-5-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane [ka] 3-Methoxyazetidine hydrochloride (42 mg, 0.3 mmol) was added to a solution of 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one (116 mg, 0.3 mmol) in DCM (10 mL) and the solution was stirred at room temperature for 15 min. Acetic acid (40 μL, 0.7 mmol) was added dropwise, followed by NaBH(OAc). 3 (278 mg, 1.4 mmol) was added dropwise and the reaction was stirred at room temperature for 3 h. The reaction was diluted with saturated NH 4 It was quenched with aqueous Cl and diluted with DCM. The organics were washed with water and brine and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (0-100% EtOAc to 3:1 EtOAc:EtOH (and 2% NH 3Purification by HPLC with 50% NaOH gave 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane (140 mg, 95%). LCMS m / z=414.2 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.88 (s, 1H), 3.72 (dd, J = 5.4, 9.2 Hz, 1H), 3.58 (dd, J = 3.8, 9.0 Hz, 1H), 3.47 (td, J = 3.0, 7.5 Hz, 2H), 3.20 - 3.10 (m, 4H), 3.10 - 3.00 (m, 1H), 3.00 - 2.90 (m, 2H), 2.80 - 2.70 (m, 2H), 2.40 - 2.20 (m, 1H), 1.80 - 1.40 (m, 8H), 1.30 - 1.10 (m, 4H).

[0288] Example 56: 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane [ka]

[0289] Synthesis of 1.8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one [ka] DIPEA (1.6 mL, 9.4 mmol) was added to a vial containing 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride (360 mg, 1.9 mmol) in DMF (4 mL). After 5 min, 5-cyclopropyl-2-methyl-pyrazole-3-sulfonyl chloride (415 mg, 1.9 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction was quenched with water and the mixture was extracted with EtOAc (3 times). The combined organics were washed with saturated NaHCO 3 The organic layer was separated and then washed with Na 2 SO 4 The crude material was purified by silica gel column (0-25% EtOAc to 3:1 EtOAc:EtOH) to give 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one (610 mg, 95%). LCMS m / z=340.1 [M+H] + .

[0290] Synthesis of 2.8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane [ka] 2-Oxa-6-azaspiro[3.3]heptane (25 mg, 0.3 mmol) was added to a solution of 8-(5-cyclopropyl-2-methyl-pyrazol-3-yl)sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-one (84 mg, 0.3 mmol) in DCM (15 mL) and the solution was stirred at room temperature for 15 min. Acetic acid (30 mg, 0.5 mmol) was added dropwise, followed by NaBH(OAc). 3 (210 mg, 1.0 mmol) was added dropwise and the reaction was stirred at room temperature for 3 h. The reaction was diluted with saturated NH 4It was quenched with aqueous Cl and diluted with DCM. The organics were washed with water and brine and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (0-100% EtOAc to 3:1 EtOAc:EtOH (and 2% NH 3 OH) to give 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane (100 mg, 96%). LCMS m / z=423.2[M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm):6.25 (s, 1H), 4.70 - 4.60 (m, 4H), 3.92 (s, 3H), 3.62 (dd, J = 5.3, 9.3 Hz, 1H), 3.50 - 3.40 (m, 3H), 3.30 - 3.10 (m, 4H), 2.90 - 2.70 (m, 3H), 1.90 - 1.70 (m, 2H), 1.70 - 1.50 (m, 4H), 1.44 (dd, J = 3.8, 13.1 Hz, 1H), 0.90 - 0.80 (m, 2H), 0.70 - 0.60 (m, 2H).

[0291] Examples 57a and 57b: (R)-8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane and (S)-8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane [ka] 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane (Example 56) was purified using a CHIRALPAK IA 30×250 mm, 5 μm column, method: CO 2 Separation in 30% MeOH and without modifier (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) afforded two enantiomers of arbitrarily assigned stereochemistry: Peak 1, Enantiomer 1, (R)-8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane: LCMS m / z=423.2[M+H] + .R f =2.09 min, ee=100% Peak 2, enantiomer 2, (S)-8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane: LCMS m / z=423.2[M+H] + .R f =2.25 min, ee=82.84%

[0292] Example 58: 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane [ka] 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane was obtained from 3-methoxyazetidine and 8-(5-cyclopropyl-2-methyl-pyrazol-3-yl)sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-one according to the procedure described in Example 56, step 2 (78 mg, 77%). LCMS m / z=411.2 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 6.32 (s, 1H), 4.10 - 3.90 (m, 4H), 3.90 - 3.70 (m, 1H), 3.70 - 3.40 (m, 5H), 3.24 (s, 3H), 3.10 - 2.70 (m, 5H), 2.00 - 1.50 (m, 7H), 1.10 - 0.80 (m, 2H), 0.80 - 0.60 (m, 2H).

[0293] Example 59: 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decan-3-amine [ka] 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decan-3-amine was obtained from 2-methoxyethanamine and 8-(5-cyclopropyl-2-methyl-pyrazol-3-yl)sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-one according to the procedure described in Example 56, step 2 (80 mg, 73%). LCMS m / z=399.2 [M+H] + . 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 6.32 (s, 1H), 3.98 (s, 3H), 3.91 (dd, J = 6.0, 9.0 Hz, 1H), 3.70 - 3.40 (m, 6H), 3.33 (s, 3H), 2.93 (dq, J = 3.5, 11.5 Hz, 2H), 2.80 - 2.60 (m, 2H), 2.10 - 1.50 (m, 9H), 1.00 - 0.80 (m, 2H), 0.80 - 0.70 (m, 2H).

[0294] Example 60: 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-1-oxa-8-azaspiro[4.5]decan-3-amine [ka]

[0295] Synthesis of 1.8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-1-oxa-8-azaspiro[4.5]decan-3-amine [ka] 8-(5-Cyclopropyl-2-methyl-pyrazol-3-yl)sulfonyl-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (70 mg, 0.2 mmol) was dissolved in MeCN (3 mL) and K 2 CO 3 (49 mg, 0.4 mmol) was added and the mixture was stirred for 30 min. Methyl iodide (10 μL, 0.2 mmol) was added and the reaction was stirred overnight. The reaction was diluted with EtOAc and washed with water (3 times). The organic phase was concentrated in vacuo and the residue was purified by silica gel column (0-100% EtOAc to 3:1 EtOAc:EtOH (with 2% NH 3OH) to give 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-1-oxa-8-azaspiro[4.5]decan-3-amine (72 mg, 37%). LCMS m / z=413.3 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 6.26 (s, 1H), 4.00 - 3.80 (m, 4H), 3.80 - 3.50 (m, 2H), 3.50 - 3.30 (m, 4H), 3.28 (s, 3H), 3.00 - 2.70 (m, 2H), 2.60 - 2.40 (m, 2H), 2.19 (s, 3H), 1.90 - 1.50 (m, 7H), 0.90 - 0.80 (m, 2H), 0.70 - 0.60 (m, 2H).

[0296] Example 61: 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane [ka]

[0297] Synthesis of 1.8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one [ka] 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one was obtained from 5-chloro-2-methoxy-pyridine-3-sulfonyl chloride and 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride according to the procedure described in Example 56, step 1 (120 mg, 40%). LCMS m / z=361.1 [M+H] + . 1 H-NMR (400 MHz, CDCl3 ) δ (ppm): 8.26 (d, J = 2.5 Hz, 1H), 8.14 (d, J = 2.5 Hz, 1H), 4.05 (s, 3H), 3.98 (s, 2H), 3.66 (td, J = 3.5, 12.7 Hz, 2H), 3.30 - 3.00 (m, 2H), 2.37 (s, 2H), 2.00 - 1.70 (m, 4H).

[0298] Synthesis of 2.8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane [ka] 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane was obtained from 3-methoxyazetidine and 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one following a similar synthesis as described in Example 56, step 2 (40 mg, 60%). LCMS m / z=432.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.30 - 8.20 (m, 1H), 8.20 - 8.10 (m, 1H), 4.20 - 4.00 (m, 4H), 3.76 (br dd, J = 5.3, 9.3 Hz, 1H), 3.70 - 3.50 (m, 5H), 3.26 (s, 3H), 3.20 - 3.00 (m, 3H), 2.87 (td, J = 6.4, 19.3 Hz, 2H), 2.00 - 1.50 (m, 6H).

[0299] Example 62: 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane [ka] 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane was obtained from 2-oxa-6-azaspiro[3.3]heptane and 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one following a similar synthesis as described in Example 56, step 2 (80 mg, 97%). LCMS m / z=444.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.16 (d, J = 2.5 Hz, 1H), 8.04 (d, J = 2.5 Hz, 1H), 4.70 - 4.60 (m, 4H), 3.95 (s, 3H), 3.63 (dd, J = 5.3, 9.3 Hz, 1H), 3.60 - 3.40 (m, 3H), 3.40 - 3.20 (m, 4H), 3.10 - 2.90 (m, 2H), 2.90 - 2.70 (m, 1H), 1.90 - 1.50 (m, 5H), 1.43 (dd, J = 3.9, 12.9 Hz, 1H).

[0300] Examples 63a and 63b: (R)-8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane and (S)-8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane [ka] 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane (Example 62) was purified using a CHIRALPAK AD-H 30×250 mm, 5 μm column, Method: CO 2 Separation in 25% MeOH and 0.1% DEA (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) afforded two enantiomers of arbitrarily assigned stereochemistry: Peak 1, Enantiomer 1, (R)-8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane: LCMS m / z=444.1 [M+H] + .R f =2.12 min, ee=100% Peak 2, enantiomer 2, (S)-8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane: LCMS m / z=444.1 [M+H] + .R f = 2.33 min, ee = 96.9%.

[0301] Example 64: 3-((3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)-4-fluorobenzonitrile [ka]

[0302] Synthesis of 1,4-chloro-3-((3-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile [ka] 4-Chloro-3-((3-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile was obtained from 2-chloro-5-cyanobenzenesulfonyl chloride and 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride according to the procedure described in Example 56, step 1 (210 mg, 57%). LCMS m / z=355.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.38 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 2.0, 8.3 Hz, 1H), 7.70 - 7.60 (m, 1H), 4.01 (s, 2H), 3.80 - 3.60 (m, 2H), 3.40 - 3.20 (m, 2H), 2.40 (s, 2H), 2.00 - 1.80 (m, 4H).

[0303] Synthesis of 2.3-((3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)-4-chlorobenzonitrile [ka] 3-((3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)-4-chlorobenzonitrile was obtained from 2-oxa-6-azaspiro[3.3]heptane and 4-chloro-3-((3-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile following a similar synthesis as described in example 56, step 2 (68 mg, 79%). LCMS m / z=438.2 [M+H] + . 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 8.32 (d, J = 1.8 Hz, 1H), 7.74 (dd, J = 2.0, 8.0 Hz, 1H), 7.70 - 7.50 (m, 1H), 4.80 - 4.60 (m, 4H), 3.71 (dd, J = 5.4, 9.4 Hz, 1H), 3.70 - 3.50 (m, 3H), 3.40 - 3.20 (m, 4H), 3.20 - 3.00 (m, 2H), 3.00 - 2.90 (m, 1H), 1.94 (br d, J = 13.8 Hz, 1H), 1.80 - 1.60 (m, 4H), 1.52 (dd, J = 3.8, 13.1Hz, 1H).

[0304] Example 65: 8-((2-Methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decan-3-amine [ka]

[0305] Synthesis of 1.8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one [ka] 8-((2-Methoxy-5-methylpyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one was obtained from 2-methoxy-5-methyl-pyridine-3-sulfonyl chloride and 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride according to the procedure described in Example 56, step 1 (260 mg, 73%). LCMS m / z=341.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 8.11 (d, J = 2.3 Hz, 1H), 7.97 (d, J = 2.5 Hz, 1H), 4.02 (s, 3H), 3.96 (s, 2H), 3.61 (td, J = 3.8, 12.7 Hz, 2H), 3.30 - 3.10 (m, 2H), 2.35 (s, 2H), 2.30 (s, 3H), 1.90 - 1.70 (m, 4H).

[0306] Synthesis of 2.8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decane-3-amine [ka] 8-((2-Methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decan-3-amine was obtained from 2-methoxyethanamine and 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one following a similar synthesis as described in Example 56, step 2 (85 mg, 72%). LCMS m / z=400.2 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.09 (dd, J = 0.8, 2.5 Hz, 1H), 7.96 (d, J = 2.5 Hz, 1H), 4.01 (s, 3H), 3.92 (dd, J = 5.8, 9.0 Hz, 1H), 3.70 - 3.50 (m, 5H), 3.41 (qd, J = 5.8, 7.5 Hz, 1H), 3.35 (s, 3H), 3.10 - 3.00 (m, 2H), 2.80 - 2.70 (m, 2H), 2.29 (s, 3H), 2.02 (dd, J = 7.5, 12.8 Hz, 1H), 1.90 - 1.60 (m, 5H), 1.56 (dd, J = 5.9, 12.9 Hz, 1H).

[0307] Example 66: 8-((2-Methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-(methyl-d3)-1-oxa-8-azaspiro[4.5]decan-3-amine [ka]

[0308] Synthesis of 1.8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-(methyl-d3)-1-oxa-8-azaspiro[4.5]decan-3-amine [ka] 8-((2-Methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (Example 65, 13 mg, 0.3 mmol) was dissolved in MeCN (3 mL) and K 2 CO 3 (9 mg, 0.7 mmol) was added and the reaction was stirred for 30 min. Trideuterio(iodo)methane (5 mg, 0.03 mmol) was added and the reaction was stirred overnight. The reaction was diluted with EtOAc and washed with water (3 times). The organic solution was concentrated in vacuo and the crude product was purified by silica gel column chromatography (0-100% EtOAc to 3:1 EtOAc:EtOH (with 2% NH 3 OH) to give 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-(methyl-d3)-1-oxa-8-azaspiro[4.5]decan-3-amine. LCMS m / z=417.3[M+H] + . 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 8.03 (dd, J = 0.9, 2.4 Hz, 1H), 7.90 - 7.80 (m, 1H), 4.00 - 3.90 (m, 3H), 3.89 (br dd, J = 7.3, 9.0 Hz, 1H), 3.60 - 3.40 (m, 4H), 3.30 - 3.20 (m, 3H), 3.10 - 2.90 (m, 2H), 2.23 (s, 3H), 1.80 - 1.40 (m, 10H).

[0309] Example 67: 8-((2-Methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-1-oxa-8-azaspiro[4.5]decan-3-amine [ka] 8-((2-Methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-1-oxa-8-azaspiro[4.5]decan-3-amine was obtained from 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (Example 65) and methyl iodide according to the procedure described in Example 66 (27 mg, 60%). LCMS m / z=414.2 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.12 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 2.5 Hz, 1H), 4.10 - 4.00 (m, 3H), 3.97 (dd, J = 7.0, 9.0 Hz, 1H), 3.70 - 3.50 (m, 4H), 3.37 (s, 3H), 3.20 - 3.00 (m, 2H), 2.40 - 2.30 (m, 6H), 1.99 (br dd, J = 8.3, 12.3 Hz, 1H), 1.90 - 1.50 (m, 9H).

[0310] Examples 68a and 68b: (R)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane and (S)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka]

[0311] Synthesis of 1.8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one [ka] A solution of 8-azaspiro[4.5]decan-3-one hydrochloride (2.5 g, 13.1 mmol) in anhydrous DCM (50 mL) was cooled to below 5° C. in an ice bath, then DIPEA (9 mL, 51.7 mmol) and DMAP (123 mg, 1.0 mmol) were added. After 5 min, 2,5-dimethylpyrazole-3-sulfonyl chloride (3.4 g, 17.5 mmol) in anhydrous DCM (50 mL) was added. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with aqueous solution of MgSO, stirred for 10 min, and extracted with DCM (3x). The combined organic layers were washed with anhydrous MgSO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column eluted with (15-80% EtOAc in heptane) to give 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one as a white solid (3.49 g, 81%). LCMS m / z=312.1 (M+H). + . 1 H-NMR (500 MHz, DCM-d 2) δ (ppm): 6.46 (s, 1H), 4.01 (s, 3H), 3.37 - 3.32 (m, 2H), 2.95 (ddd, J = 4.0, 8.4, 12.1 Hz, 2H), 2.27 - 2.23 (m, 5H), 2.06 (s, 2H), 1.83 (t, J = 7.9 Hz, 2H), 1.71 - 1.63 (m, 4H).

[0312] 2. Synthesis of 6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] A solution of 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one (3.5 g, 11.1 mmol) in anhydrous DCM (40 mL) was cooled to below 5° C. After 10 min, acetic acid (400 μL, 7.0 mmol) and a solution of 2-oxa-6-azaspiro[3.3]heptane (2.3 g, 23.2 mmol) in anhydrous DCM (10 mL) were added dropwise successively below 5° C. After 20 min, NaBH(OAc) 3 (8.6 g, 40.5 mmol) was added batchwise and the mixture was allowed to warm to room temperature and stirred for 2.5 h. The reaction was diluted with saturated NaHCO 3 After 20 min, the biphasic mixture was extracted with DCM (x3). The combined organic extracts were washed with anhydrous MgSO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (40-90% 3:1 EtOAc:EtOH in heptane) to give 6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane as a colorless oil (3.1 g, 67%). LCMS m / z=395.3 (M+H). + . 1 H-NMR (500 MHz, DMSO-d 6) δ (ppm): 6.58 (s, 1H), 4.55 (s, 4H), 3.92 (s, 3H), 3.20 - 3.10 (m, 4H), 3.06 - 2.99 (m, 4H), 2.62 - 2.54 (m, 1H), 2.18 (s, 3H), 1.58 - 1.51 (m, 3H), 1.46 - 1.39 (m, 4H), 1.35 - 1.26 (m, 2H), 1.07 (dd, J = 5.2, 13.1 Hz, 1H).

[0313] 3. Synthesis of (R)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane and (S)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] 6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane (3.1 g, 7.86 mmol) was purified using a LUX Cellulose 30×250 mm, 5 μm column with CO 2 Purification using 40% MeOH in 100 mL / min (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) afforded two enantiomers of arbitrarily assigned stereochemistry: Peak 1, enantiomer 1, (R)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane (t R The product (containing E1=1.86 min) was a colorless film (1.18 g, 36%). LCMS m / z=395.3[M+H] + . 1 H-NMR (400 MHz, DMSO-d 6) δ (ppm): 6.58 (s, 1H), 4.55 (s, 4H), 3.95 - 3.89 (m, 3H), 3.19 - 3.11 (m, 4H), 3.07 - 2.99 (m, 4H), 2.61 - 2.53 (m, 1H), 2.18 (s, 3H), 1.60 - 1.50 (m, 3H), 1.48 - 1.38 (m, 4H), 1.37 - 1.26 (m, 2H), 1.12 - 1.03 (m, 1H). Peak 2, enantiomer 2, (S)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane (t R The product (containing E2=2.24 min) was a colorless film (1.24 g, 38%). LCMS m / z=395.3[M+H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 6.58 (s, 1H), 4.55 (s, 4H), 3.92 (s, 3H), 3.16 - 3.11 (m, 4H), 3.07 - 2.99 (m, 4H), 2.61 - 2.53 (m, 1H), 2.18 (s, 3H), 1.58 - 1.50 (m, 3H), 1.47 - 1.38 (m, 4H), 1.36 - 1.25 (m, 2H), 1.11 - 1.04 (m, 1H).

[0314] Example 69: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(6-oxa-2-azaspiro[3.4]octan-2-yl)-1-oxa-8-azaspiro[4.5]decane [ka]

[0315] Synthesis of 1,8-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one [ka] To a vial containing 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride (1.0 g, 5.2 mmol) in THF (24 mL) was added DIPEA (3.6 mL, 20.9 mmol) dropwise, followed by DMAP (64 mg, 0.5 mmol). After 5 min, 4-(difluoromethoxy)benzenesulfonyl chloride (1.0 mL, 6.3 mmol) was added and the reaction was stirred at room temperature for 1 day. The reaction was diluted with saturated NaHCO 3 The mixture was quenched with ethyl acetate, extracted with EtOAc (3x), the organic layer separated and washed with brine. The combined organic phase was washed with anhydrous Na 2 SO 4 The residue was purified using silica gel chromatography (0-75% EtOAc in heptane) to give 8-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one (1.69 g, 90%). LCMS m / z=362.0 [M+H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 7.90 - 7.74 (m, 2H) 7.64 - 7.22 (m, 3H) 3.88 (s, 2H) 3.36 - 3.22 (m, 2H) 2.76 - 2.61 (m, 2H) 2.38 (s, 2H) 1.89 - 1.68 (m, 4H).

[0316] Synthesis of 2.8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(6-oxa-2-azaspiro[3.4]octan-2-yl)-1-oxa-8-azaspiro[4.5]decane [ka] A solution of 8-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one (45 mg, 0.1 mmol) in DCM (1.5 mL) followed by TEA (40 μL, 0.3 mmol) was added to 6-oxa-2-azaspiro[3.4]octane (17 mg, 0.2 mmol) and the solution was stirred for 15 min. Acetic acid (18 μL, 0.3 mmol) was added and the solution was stirred for 30 min, then NaBH(OAc) 3 (106 mg, 0.5 mmol) was added. The reaction mixture was stirred at room temperature for 1 day and saturated NH 4 The mixture was quenched with Cl solution (2 mL) and extracted with EtOAc (2x). The combined organic solution was concentrated under reduced pressure and the crude residue was purified by preparative HPLC (Waters SunFire Prep C18, 5 μm, OBD 30x100 mm, Method: (A) 95% water / / (B) 5% MeCN with 0.1% TFA to 50% (A) / 50% (B) over 7.5 min (Flow rate: 50 mL / min)) to give 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(6-oxa-2-azaspiro[3.4]octan-2-yl)-1-oxa-8-azaspiro[4.5]decane as a clear oil (13.1 mg, 18%). LCMS m / z=458.8[M+H] + . 1 H-NMR (500 MHz, DMSO-d 6 ) δ (ppm): 7.86-7.76 (m, 2H), 7.60-7.28 (m, 3H), 4.16-4.02 (m, 5H), 3.85-3.60 (m, 4H), 3.33-3.19 (m, 2H), 2.66-2.53 (m, 3H), 2.19-2.13 (m, 2H), 2.12-2.05 (m, 2H), 1.83-1.75 (m, 2H), 1.71 (br d, J = 13.43 Hz, 1H), 1.61-1.48 (m, 2H).

[0317] Example 70: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane [ka]

[0318] Synthesis of 1,8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane [ka] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane was prepared from 8-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one and 2-oxa-7-azaspiro[4.4]nonane according to the procedure described in Example 69, step 2. The crude product was purified by preparative HPLC (Waters XSelect CSH Prep C18, 5 μm, OBD 30×100 mm, Method: (A) 95% (water) / / (B) 5% (MeCN) with 0.2% NH 4 OH to 35%(A) / 65%(B) over 7.5 min (flow rate: 50 mL / min) to give 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane as a clear oil (0.5 mg, 1%). LCMS m / z=472.8[M+H] + , R f =0.52 minutes.

[0319] Example 71: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-1-oxa-8-azaspiro[4.5]decane [ka]

[0320] Synthesis of 1.8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-1-oxa-8-azaspiro[4.5]decane [ka] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-1-oxa-8-azaspiro[4.5]decane was obtained from 8-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one and (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole according to the procedure described in Example 69, step 2. The crude product was purified by preparative HPLC (Waters XSelect CSH Prep C18, 5 μm, OBD 30×100 mm, method: (A) 95% (water) / / (B) 5% (MeCN) with 0.2% NH 4 OH to 40%(A) / 60%(B) over 7.5 min (flow rate: 50 mL / min) to give 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)-1-oxa-8-azaspiro[4.5]decane as a clear oil (14.9 mg, 26%). LCMS m / z=458.8[M+H] + , R f =1.91 minutes.

[0321] Examples 72a, 72b, 72c, and 72d: (S)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-((R)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane, (S)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-((S)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-aza Pyro[4.5]decane, (R)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-((R)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane and (S)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-((S)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane [ka]

[0322] Synthesis of 1,8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one [ka] To a vial containing 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride (397 mg, 2.1 mmol) in anhydrous DMF (7.5 mL) was added DIPEA (1.8 mL, 10.4 mmol). After 5 min, 1,3-dimethyl-1H-pyrazole-5-sulfonyl chloride (403 mg, 2.1 mmol) was added and the reaction was stirred at room temperature for 2.5 h. Saturated NaHCO 3 The reaction was quenched by the addition of ethyl acetate, extracted with EtOAc, and washed with brine. The organic layer was washed with anhydrous Na 2 SO 4The mixture was dried at 70° C., filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc in heptane) to give 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one (572.3 mg, 88%). LCMS m / z=314.0 [M+H] + . 1 H-NMR (400 MHz, CD 3 OD) δ (ppm): 6.57 (s, 1H) 4.00 (s, 3H) 3.96 (s, 2H) 3.55 - 3.47 (m, 2H) 3.08 (td, J = 11.6, 3.3 Hz, 2H) 2.41 (s, 2H) 2.25 (s, 3H) 1.98 - 1.91 (m, 2H) 1.89 - 1.80 (m, 2H).

[0323] Synthesis of 2.8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane [ka] Hunig's base (110 μL, 0.6 mmol) was added slowly to a solution of 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one (200 mg, 0.6 mmol) and 2-oxa-7-azaspiro[4.4]nonane (146 mg, 1.2 mmol) in DCM (4 mL). After 15 min, acetic acid (110 μL, 1.9 mmol) was added and the solution was stirred for 30 min. NaBH(OAc) 3 (541 mg, 2.6 mmol) was added and the reaction was stirred at room temperature for 1 day. The reaction was diluted with saturated NaHCO 3 The solution was quenched with ethyl acetate, extracted with EtOAc, washed with brine, and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (2% NH 4Purification with 0% to 100% 1:3 EtOH:EtOAc) gave 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane.

[0324] Isolation of 3.8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane 8-((1,3-Dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane was purified using a chiral SFC (CHIRALPAK AD-H 30×250 mm, 5 um, method: CO 2 Further purification with 20% EtOH and 0.1% DEA (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) afforded four enantiomers of arbitrarily assigned stereochemistry: Peak 1, enantiomer 1, (S)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-((R)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane (35.1 mg, 12%): R f =2.97min, LCMS m / z=425.3[M+H] + . 1 H-NMR (400 MHz, CD 3OD) δ (ppm): 6.54 (s, 1H) 3.99 (s, 3H) 3.92 (dd, J = 8.8, 6.5 Hz, 1H) 3.88 - 3.78 (m, 2H) 3.67 - 3.61 (m, 2H) 3.54 (d, J = 8.0 Hz, 1H) 3.49 - 3.41 (m, 2H) 3.03 - 2.92 (m, 3H) 2.71 - 2.49 (m, 4H) 2.25 (s, 3H) 2.05 - 1.87 (m, 3H) 1.86 - 1.73 (m, 5H) 1.72 - 1.63 (m, 2H). Peak 2, enantiomer 2, (S)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-((S)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane (33.2 mg, 11%): R f =3.26 min, LCMS m / z=425.3[M+H] + . Peak 3, enantiomer 3, (R)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-((R)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane (18.2 mg, 6%): R f =3.42 min, LCMS m / z=425.3[M+H] + . Peak 4, enantiomer 4, (S)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-((S)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane (24 mg, 8%): R f =3.76min, LCMS m / z=425.3[M+H] + .

[0325] Example 73: 4-(7-((4-(difluoromethoxy)phenyl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine [ka]

[0326] Synthesis of 1.7-((4-(difluoromethoxy)phenyl)sulfonyl)-7-azaspiro[3.5]nonan-2-one [ka] To a vial containing 7-azaspiro[3.5]nonan-2-one hydrochloride (522 mg, 3.0 mmol) in anhydrous THF (10 mL) was added DIPEA (1.2 g, 9.2 mmol) dropwise at less than 5 °C. After 5 min, 4-(difluoromethoxy)benzenesulfonyl chloride (1.1 g, 4.4 mmol) was added to the cold solution. The reaction was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was quenched with 1 M aqueous NaOH and stirred for 10 min. The biphasic mixture was loaded onto a silica gel column and purified (10-50% EtOAc in heptane) to give 7-((4-(difluoromethoxy)phenyl)sulfonyl)-7-azaspiro[3.5]nonan-2-one as a white solid (977 mg, 95%), which was used in the next step without further purification. LCMS m / z=346.1(M+H) + . 1 H-NMR (500 MHz, DMSO-d 6 ) δ (ppm): 7.84 - 7.79 (m, 2H), 7.60 - 7.27 (m, 3H), 2.96 - 2.89 (m, 4H), 2.72 (s, 4H), 1.78 - 1.70 (m, 4H).

[0327] 2. Synthesis of 4-(7-((4-(difluoromethoxy)phenyl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine [ka] To a vial containing 7-((4-(difluoromethoxy)phenyl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (84 mg, 0.2 mmol) in anhydrous DCM (2 mL) was added AcOH (10 μL, 0.2 mmol) and then morpholine (50 μL, 0.6 mmol) dropwise at room temperature. After 15 min, NaBH(OAc) 3 (212 mg, 1.0 mmol) was added portionwise to the reaction mixture. After 6.5 h, the reaction was quenched with 1 M aqueous NaOH, stirred for 20 min, and extracted with DCM (3x). The combined organic layers were washed with anhydrous MgSO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (10-70% 3:1 EtOAc:EtOH in heptane) to give 4-(7-((4-(difluoromethoxy)phenyl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine as a colorless film (72 mg, 67%). LCMS m / z=417.2 (M+H). + . 1 H-NMR (500 MHz, DCM-d 2 ) δ (ppm): 7.77 - 7.73 (m, 2H), 7.26 (d, J = 8.5 Hz, 2H), 6.66 (t, J = 72.9 Hz, 1H), 4.25 - 3.83 (m, 1H), 3.71 - 3.57 (m, 3H), 3.41 - 3.03 (m, 1H), 3.03 - 2.76 (m, 5H), 2.74 - 2.40 (m, 2H), 2.34 - 2.17 (m, 3H), 1.93 - 1.82 (m, 2H), 1.74 - 1.64 (m, 3H), 1.63 - 1.58 (m, 1H).

[0328] Example 74: 4-(7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine [ka] 4-(7-((1,3-Dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine was prepared according to the two-step procedure described for Example 73 starting from 7-azaspiro[3.5]nonan-2-one hydrochloride and 1,3-dimethyl-1H-pyrazole-5-sulfonyl chloride to give 7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one as a white solid (201 mg, 67%). LCMS m / z=298.0 (M+H). + . 1 H-NMR (500 MHz, CD 3 OD) δ (ppm): 6.56 (s, 1H), 4.00 (s, 3H), 3.22 - 3.19 (m, 4H), 2.81 (s, 4H), 2.24 (s, 3H), 1.87 - 1.84 (m, 4H). Step 2: Reaction of this compound with morpholine gave 4-(7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine as a pink oil (56 mg, 43%). LCMS m / z=369.3 (M+H). + . 1 H-NMR (600MHz, DMSO-d 6 ) d = 6.57 (s, 1H), 3.91 (s, 3H), 3.54 (br s, 1H), 3.35 - 3.31 (m, 1H), 3.05 (br t, J = 5.1 Hz, 2H), 3.00 - 2.94 (m, 2H), 2.18 (s, 6H), 1.87 (br t, J = 9.4 Hz, 3H), 1.64 - 1.59 (m, 3H), 1.56 - 1.47 (m, 6H).

[0329] Example 75: 6-(7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka]

[0330] Synthesis of 1.7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one [ka] To a vial containing 7-azaspiro[3.5]nonan-2-one hydrochloride (375 mg, 2.1 mmol) in anhydrous THF (5 mL) was added DIPEA (890 mg, 6.9 mmol) dropwise at <5 °C. After 5 min, 6-methoxy-2-methyl-pyridine-3-sulfonyl chloride (571 mg, 2.6 mmol) was added. The reaction was brought to room temperature, stirred for 30 min, quenched by slow addition of 1 M aqueous NaOH and stirred for an additional 10 min. The biphasic mixture was loaded directly onto silica gel and purified by column chromatography (10-50% EtOAc in heptane) to give 7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one as a white solid (595 mg, 86%), which was used in the next step without further purification. LCMS m / z=325.0(M+H) + . 1 H-NMR (500 MHz, DCM-d 2 ) δ (ppm): 8.04 (d, J = 9.2 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 3.99 (s, 3H), 3.16 - 3.13 (m, 4H), 2.77 (s, 4H), 2.76 (s, 3H), 1.82 - 1.79 (m, 4H).

[0331] 2. Synthesis of 6-(7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] To a vial containing 7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (76 mg, 0.2 mmol) in anhydrous DCM (2 mL) was added 2-oxa-6-azaspiro[3.3]heptane (47 mg, 0.5 mmol) followed by AcOH (10 μL, 0.2 mmol) dropwise at room temperature. After 15 min, NaBH(OAc) 3 (156 mg, 0.7 mmol) was added. After 1.5 h, the reaction mixture was quenched with 1M aqueous NaOH, stirred for 10 min, and extracted with DCM (3x). The organic layer was washed with anhydrous MgSO 4 After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (25-100% 3:1 EtOAc:EtOH in heptane) to give 6-(7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane as a colorless film (26 mg, 26%). LCMS m / z=408.3 (M+H). + . 1 H-NMR (500 MHz, DCM-d 2 ) δ (ppm): 7.96 (d, J = 8.5 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 4.64 (s, 4H), 3.96 (s, 3H), 3.19 (s, 4H), 3.05 - 3.02 (m, 2H), 3.00 - 2.97 (m, 2H), 2.91 (quin, J = 7.3 Hz, 1H), 2.70 (s, 3H), 1.80 - 1.75 (m, 2H), 1.59 (q, J = 5.7 Hz, 4H), 1.48 - 1.44 (m, 2H).

[0332] Example 76: 6-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] 6-(7-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane was prepared following the two-step procedure described for Example 75 starting from 7-azaspiro[3.5]nonan-2-one hydrochloride and 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride to give 7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (2.2 g, 82%). LCMS m / z=363.2 (M+H). + . 1 H-NMR (500 MHz, DCM-d 2 ) δ (ppm): 8.36 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 3.27 - 3.23 (m, 4H), 2.89 (s, 3H), 2.80 (s, 4H), 1.86 - 1.82 (m, 4H). Step 2: Reaction of this compound with 2-oxa-6-azaspiro[3.3]heptane afforded the title compound as a white solid (1.73 g, 60%). LCMS m / z=446.2 (M+H). + . 1 H-NMR (500 MHz, DMSO-d 6 ) δ (ppm): 8.40 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 4.55 (s, 4H), 3.14 (s, 4H), 3.12 - 3.09 (m, 2H), 3.08 - 3.04 (m, 2H), 2.92 (quin, J = 7.3 Hz, 1H), 2.80 (s, 3H), 1.76 - 1.71 (m, 2H), 1.56 - 1.52 (m, 4H), 1.45 - 1.40 (m, 2H).

[0333] Example 77: 6-(7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] 6-(7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane was prepared according to the two-step procedure described for Example 75 starting from 7-azaspiro[3.5]nonan-2-one hydrochloride and 6-chloro-2-methylpyridine-3-sulfonyl chloride to give 7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one as a white solid (274 mg, 81%). LCMS m / z=329.0 (M+H). + . 1 H-NMR (500 MHz, CD 3 OD) δ (ppm): 8.20 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 3.27 - 3.23 (m, 4H), 2.84 - 2.81 (m, 4H), 2.81 - 2.78 (m, 3H), 1.87 - 1.82 (m, 4H). Step 2: Reaction of this compound with 2-oxa-6-azaspiro[3.3]heptane afforded the title compound as a white solid (32.5 mg, 35%). LCMS m / z=412.2 (M+H). + . 1 H-NMR (500 MHz, DMSO-d 6 ) δ (ppm): 8.14 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 4.55 (s, 4H), 3.14 (s, 4H), 3.06 - 3.02 (m, 2H), 3.01 - 2.97 (m, 2H), 2.96 - 2.88 (m, 1H), 2.70 (s, 3H), 1.76 - 1.69 (m, 2H), 1.56 - 1.50 (m, 4H), 1.45 - 1.39 (m, 2H).

[0334] Example 78: 6-(7-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] 6-(7-((4-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane was prepared according to the two-step procedure described for Example 75 starting from 7-azaspiro[3.5]nonan-2-one hydrochloride and 4-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride to give 7-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one as a white solid (285 mg, 75%). LCMS m / z=363.2 (M+H). + . 1 H-NMR (500 MHz, DCM-d 2 ) δ (ppm): 9.06 (s, 1H), 7.67 (s, 1H), 3.28 - 3.25 (m, 4H), 2.80 (s, 4H), 2.72 (s, 3H), 1.86 - 1.83 (m, 4H). Step 2: Reaction of this compound with 2-oxa-6-azaspiro[3.3]heptane afforded the title compound as a colorless film (11.8 mg, 8%). LCMS m / z=446.2 (M+H). + . 1 H-NMR (500 MHz, DMSO-d 6 ) δ (ppm): 8.99 (s, 1H), 8.10 (s, 1H), 4.56 (s, 4H), 3.32 - 3.30 (m, 1H), 3.18 - 3.10 (m, 5H), 3.09 - 3.04 (m, 2H), 3.00 - 2.86 (m, 1H), 2.67 (s, 3H), 1.77 - 1.70 (m, 2H), 1.57 - 1.50 (m, 4H), 1.46 - 1.36 (m, 2H).

[0335] Example 79: 6-(7-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] 6-(7-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane was prepared according to the two-step procedure described for Example 75 starting from 7-azaspiro[3.5]nonan-2-one hydrochloride and 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride (307 mg, 1.2 mmol) to give 7-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one as a white solid (206 mg, 58%). 1 H-NMR (500 MHz, DCM-d 2 ) δ (ppm): 6.95 (s, 1H), 4.15 (s, 3H), 3.25 - 3.21 (m, 4H), 2.80 (s, 4H), 1.89 - 1.86 (m, 4H). Step 2: Reaction of this compound with 2-oxa-6-azaspiro[3.3]heptane afforded the title compound as a colorless film (12 mg, 9%). LCMS m / z=435.3 (M+H). + . 1 H-NMR (500 MHz, DMSO-d 6) δ (ppm): 7.39 - 7.37 (m, 1H), 4.56 (s, 4H), 4.12 - 4.09 (m, 4H), 3.16 - 3.14 (m, 4H), 3.11 (br dd, J = 4.6, 5.5 Hz, 2H), 3.09 - 3.04 (m, 2H), 1.76 - 1.72 (m, 2H), 1.59 - 1.56 (m, 4H), 1.45 - 1.41 (m, 2H).

[0336] Example 80: 6-(7-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] 6-(7-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane was prepared according to the two-step procedure described for Example 75 starting from 7-azaspiro[3.5]nonan-2-one hydrochloride and 5-cyclopropyl-2-methyl-pyrazole-3-sulfonyl chloride to give 7-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one as a white solid (195 mg, 87%). LCMS m / z=324.1 [M+H] + . 1 H-NMR (500 MHz, DCM-d 2 ) δ (ppm): 6.35 (s, 1H), 3.97 (s, 3H), 3.16 - 3.12 (m, 4H), 2.77 (s, 4H), 1.91 - 1.86 (m, 1H), 1.86 - 1.83 (m, 4H), 0.94 - 0.90 (m, 2H), 0.73 - 0.69 (m, 2H). Step 2: Reaction of this compound with 2-oxa-6-azaspiro[3.3]heptane afforded the title compound as a colorless film (31 mg, 23%). LCMS m / z=407.3 (M+H). + . v (500 MHz, DMSO-d 6 ) δ (ppm): 6.51 (s, 1H), 4.56 (s, 1H), 3.89 (s, 3H), 3.32 - 3.29 (m, 3H), 3.22 - 3.10 (m, 4H), 3.01 - 2.97 (m, 2H), 2.95 - 2.88 (m, 3H), 1.91 - 1.86 (m, 1H), 1.74 - 1.68 (m, 2H), 1.58 - 1.53 (m, 4H), 1.45 - 1.39 (m, 2H), 0.89 - 0.85 (m, 2H), 0.70 - 0.67 (m, 2H).

[0337] Example 81: (1R,4R)-5-(7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka]

[0338] 1. Synthesis of (1R,4R)-5-(7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka] To a vial containing (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (78 mg, 0.6 mmol) in anhydrous DCM (1 mL) was added DIPEA (100 μL, 0.6 mmol) dropwise at room temperature. After 15 min, AcOH (50 μL, 0.9 mmol) and 7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (Example 75, Step 1) (87 mg, 0.3 mmol) were added dropwise. After 30 min, NaBH(OAc) 3 (200 mg, 1.0 mmol) was added portionwise to the reaction mixture and the resulting mixture was stirred for 2.5 h. The reaction was quenched with 1 M aqueous sodium NaOH and stirred for an additional 10 min, then extracted with DCM (3 times). The combined organic layers were washed with anhydrous MgSO 4 The residue was loaded onto silica gel and purified by column chromatography (25-100% 3:1 EtOAc:EtOH in heptane) to give (1R,4R)-5-(7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane as a colorless film (78 mg, 68%). LCMS m / z=408.3 (M+H). + . 1 H-NMR (500 MHz, DMSO-d 6) δ (ppm): 7.99 (d, J = 9.2 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 4.30 (br s, 1H), 3.92 (s, 3H), 3.73 - 3.65 (m, 1H), 3.48 - 3.41 (m, 1H), 3.37 - 3.32 (m, 1H), 3.16 - 3.08 (m, 1H), 3.02 - 2.96 (m, 2H), 2.95 - 2.90 (m, 2H), 2.66 (s, 3H), 2.64 - 2.56 (m, 1H), 2.38 - 2.31 (m, 1H), 1.92 - 1.85 (m, 1H), 1.84 - 1.77 (m, 1H), 1.66 - 1.61 (m, 1H), 1.60 - 1.56 (m, 2H), 1.56 - 1.52 (m, 2H), 1.52 - 1.43 (m, 3H).

[0339] Example 82: (1R,4R)-5-(7-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka] (1R,4R)-5-(7-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane was prepared from (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 7-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (Example 79, step 1) using the method described for Example 81 to give the title compound (32 mg, 26%). LCMS m / z=435.2 (M+H). + . 1 H-NMR (500 MHz, DMSO-d 6) δ (ppm): 7.38 (s, 1H), 4.30 (s, 1H), 4.10 (s, 3H), 3.69 (d, J = 6.7 Hz, 1H), 3.44 (br d, J = 7.3 Hz, 1H), 3.37 - 3.34 (m, 1H), 3.18 - 3.12 (m, 3H), 3.10 - 3.05 (m, 2H), 2.62 - 2.58 (m, 1H), 2.37 - 2.34 (m, 1H), 1.95 - 1.91 (m, 1H), 1.88 - 1.83 (m, 1H), 1.65 - 1.57 (m, 5H), 1.54 - 1.47 (m, 3H).

[0340] Example 83: 7-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-7-azaspiro[3.5]nonan-2-amine [ka] 7-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-7-azaspiro[3.5]nonan-2-amine was prepared from tetrahydropyran-4-amine and 7-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (Example 79, step 1) using the method described for Example 81 to give the title compound. LCMS m / z=437.1 [M+H] + . 1 H-NMR (CDCl 3, 500 MHz) δ (ppm): 6.88 (s, 1H), 4.12 (s, 3H), 3.92 (br d, J = 11.3 Hz, 2H), 3.40 - 3.20 (m, 3H), 3.20 - 3.10 (m, 2H), 3.10 - 3.00 (m, 2H), 2.70 - 2.60 (m, 1H), 2.16 (br t, J = 9.8 Hz, 2H), 1.80 - 1.60 (m, 7H), 1.48 (br t, J = 10.1 Hz, 2H), 1.40 - 1.30 (m, 2H).

[0341] Example 84: 1-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-4-methylpiperidin-4-ol [ka]

[0342] 1. Synthesis of 1-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-4-methylpiperidin-4-ol [ka] To a vial containing 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one (75 mg, 242 umol) in DCM (2 mL) was carefully added dropwise AcOH (0.02 mL, 349 umol) followed by 4-methylpiperidin-4-ol (57 mg, 491 umol) at 23° C. After 15 min, NaBH(OAc) 3 (203 mg, 960 umol) was carefully added in portions to the reaction mixture. 3Upon complete addition, the reaction was stirred at 23° C. and monitored by LCMS. After 6.5 h, the reaction was carefully quenched by slow addition of 1M aqueous NaOH. The mixture was stirred at 23° C. for 20 min, then the biphasic mixture was extracted with DCM (3×). The organic extracts were pooled and then diluted with MgSO 4 The mixture was dried at 37° C. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (40-100% 3:1 EtOAc:ethanol in heptane). Fractions containing the product were pooled and then concentrated under reduced pressure to give a colorless film, which was dissolved in DMSO and a few drops of water and then filtered. The homogeneous solution was subjected to mass directed reversed phase HPLC purification. Liquid chromatography was performed using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with mobile phase H 2 O (A) and MeCN (B) with 5-65% B (0.2% NH 4 A gradient of 1000 mL / min (final v / v % modifier) ​​was performed at a flow rate of 50 mL / min. Fractions containing the desired product were pooled and then concentrated under reduced pressure to give a yellow oil as 1-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-4-methylpiperidin-4-ol (34 mg, 32%). LCMS m / z=411.3 (M+H). + . 1 H NMR (600MHz, DMSO-d 6 )δ(ppm) = 6.58 (s, 1H), 3.92 (s, 3H), 3.10 - 3.01 (m, 3H), 2.49 - 2.25 (m, 2H), 2.18 (s, 3H), 1.79 (br d, J=6.5 Hz, 1H), 1.75 - 1.69 (m, 1H), 1.57 - 1.53 (m, 1H), 1.50 - 1.33 (m, 14H), 1.19 (br d, J=10.9 Hz, 1H), 1.07 (s, 4H).

[0343] Examples 85a and 85b: (R)-3-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-5-fluorobenzonitrile or (S)-3-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-5-fluorobenzonitrile [ka]

[0344] Synthesis of 1.3-fluoro-5-((2-oxo-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile [ka] To a flask containing 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride (3 g, 16 mmol) in DCM (60 mL) was added DIPEA (8.5 mL, 48.8 mmol) dropwise. After 5 min, 3-cyano-5-fluoro-benzenesulfonyl chloride (4.13 g, 18.8 mmol) was added and the reaction was stirred at room temperature for 30 min. The reaction was cooled to room temperature with saturated NaHCO 3 The mixture was quenched with ethyl acetate and then extracted with DCM (3x). The organic layers were pooled and then washed with brine. The combined organic phase was dried (Na 2 SO 4 ), filtered and evaporated. The residue was purified using silica gel chromatography (0-75% EtOAc in heptane) to give 3-fluoro-5-((2-oxo-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile (4.9 g, 91%). 1 H NMR (500 MHz, DCM-d 2) δ (ppm) = 7.87 (s, 1H), 7.74 - 7.70 (m, 1H), 7.66 - 7.61 (m, 1H), 3.34 - 3.27 (m, 2H), 2.89 - 2.81 (m, 2H), 2.22 (t, J = 7.9 Hz, 2H), 2.02 - 1.99 (m, 2H), 1.79 (t, J = 7.9 Hz, 2H), 1.73 - 1.64 (m, 4H).

[0345] 2. Synthesis of (R)-3-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-5-fluorobenzonitrile and (S)-3-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-5-fluorobenzonitrile [ka] A flask containing 3-fluoro-5-((2-oxo-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile (4.9 g, 14.6 mmol) in DCM (50 mL) was cooled in an ice-water bath to below 5° C., and then AcOH (0.8 mL, 14 mmol) and 2-oxa-6-azaspiro[3.3]heptane (3.0 g, 30 mmol) were carefully added dropwise below 5° C. After 15 min, NaBH(OAc) 3 (10.5 g, 49.4 mmol) was carefully added in portions to the cold reaction mixture. Once the addition was complete, the reaction was allowed to warm to 23 °C and monitored by LCMS. After 1 h, the reaction was carefully quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23 °C for 20 min, then the biphasic mixture was extracted with DCM (3 times). The organic extracts were pooled and then MgSO 4The mixture was dried at 37° C. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (35-95% 3:1 EtOAc:ethanol in heptane). The desired fractions were pooled and then concentrated under reduced pressure to give a white solid as (R)-3-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-5-fluorobenzonitrile and (S)-3-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-5-fluorobenzonitrile (4.6 g, 71%), which was subjected to chiral SFC purification. LCMS m / z=420.4 (M+H) + . 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm) = 8.27 (br d, J = 8.2 Hz, 1H), 8.06 (s, 1H), 7.97 - 7.94 (m, 1H), 4.53 (s, 4H), 3.11 (br s, 4H), 2.99 - 2.91 (m, 4H), 2.59 - 2.52 (m, 1H), 1.55 - 1.49 (m, 3H), 1.43 - 1.33 (m, 4H), 1.31 - 1.23 (m, 2H), 1.01 (dd, J = 5.0, 13.3 Hz, 1H).

[0346] 3. Synthesis of (R)-3-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-5-fluorobenzonitrile or (S)-3-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-5-fluorobenzonitrile [ka] (R)-3-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-5-fluorobenzonitrile and (S)-3-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-5-fluorobenzonitrile (4.6 g, 10.9 mmol) were dissolved in methanol (12 mL) and DCM (8 mL) and purified on a Lux Cellulose-4 LC 30×250 mm, 5 um column using 40% methanol (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) to give the following compounds, which were concentrated to dryness and then lyophilized: Peak 1 or Example 85a was arbitrarily assigned as (R)-3-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-5-fluorobenzonitrile (2.1 g, 45%), a white solid. LCMS m / z=420.3 (M+H). + . 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm) = 8.30 - 8.25 (m, 1H), 8.07 (s, 1H), 7.98 - 7.94 (m, 1H), 4.53 (s, 4H), 3.13 - 3.09 (m, 4H), 3.00 - 2.92 (m, 4H), 2.58 - 2.53 (m, 1H), 1.54 - 1.48 (m, 3H), 1.43 - 1.34 (m, 4H), 1.30 - 1.23 (m, 2H), 1.01 (dd, J = 5.2, 13.1 Hz, 1H). Peak 2 or Example 85b was a white solid arbitrarily assigned as (S)-3-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-5-fluorobenzonitrile (2.1 g, 45% yield).

[0347] Examples 86a and 86b: (1R,4R)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane and (1R,4R)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka]

[0348] Synthesis of 1.8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-one [ka] To a flask containing 8-azaspiro[4.5]decan-3-one hydrochloride (2.8 g, 15 mmol) in DCM (30 mL) was carefully added dropwise DIPEA (10.5 mL, 60 mmol) below 5° C. After 15 min, 4-(difluoromethoxy)benzenesulfonyl chloride (4.3 g, 17.6 mmol) was carefully added to the cold solution. Once the sulfonyl chloride addition was complete, the reaction was allowed to warm to 23° C. and monitored by LCMS. After 30 min, the reaction was diluted with saturated NaHCO 3 The mixture was carefully quenched by slow addition of aqueous solution of 1,2-dichloromethane. The mixture was stirred at 23° C. for 20 min, then the biphasic mixture was extracted with DCM (×3). The organic extracts were pooled and then MgSO 4 The mixture was dried at rt. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (25-75% EtOAc in heptane). The desired fractions were pooled and then concentrated under reduced pressure to give a white solid as 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-one (4.9 g, 92%). LCMS m / z=360.1 (M+H). + . 1 H NMR (500 MHz, DCM-d 2) δ (ppm) = 7.79 - 7.75 (m, 2H), 7.28 (d, J = 8.5 Hz, 2H), 6.67 (t, J = 72.9 Hz, 1H), 3.30 - 3.22 (m, 2H), 2.75 (ddd, J = 3.4, 8.8, 12.0 Hz, 2H), 2.21 (t, J = 7.9 Hz, 2H), 1.98 (s, 2H), 1.77 (t, J = 8.1 Hz, 2H), 1.72 - 1.61 (m, 4H).

[0349] 2. Synthesis of (1R,4R)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane and (1R,4R)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka] To a flask containing 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-one (4.9 g, 13.6 mmol) in DCM (40 mL) was carefully added dropwise AcOH (3 mL, 52 mmol) followed by a solution of (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (3.69 g, 27 mmol) and DIPEA (7.5 mL, 43 mmol) in DCM (20 mL) at 23° C. After 15 min, NaBH(OAc) 3 (12 g, 57 mmol) was carefully added in portions to the reaction mixture. 3 Upon complete addition, the reaction was stirred at 23 °C and monitored by LCMS. After 3 h, the reaction was carefully quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23 °C for 45 min, then the biphasic mixture was extracted with DCM (3 times). The organic extracts were pooled and then MgSO 4The mixture was dried at 37° C. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (20-80% 3:1 EtOAc:ethanol in heptane). The desired fractions were pooled and then concentrated under reduced pressure to give a sticky white wax as (1R,4R)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane and (1R,4R)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (5 g, 83%), which was subjected to chiral SFC purification. LCMS m / z=443.2 (M+H) + . 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm) = 7.83 - 7.78 (m, 2H), 7.59 - 7.28 (m, 3H), 4.25 (s, 1H), 3.81 - 3.78 (m, 1H), 3.45 - 3.40 (m, 2H), 2.97 - 2.82 (m, 5H), 2.73 (ddd, J = 1.5, 9.8, 15.0 Hz, 1H), 2.27 (dd, J = 4.3, 9.8 Hz, 1H), 1.75 - 1.60 (m, 2H), 1.58 - 1.45 (m, 6H), 1.42 - 1.34 (m, 2H), 1.30 - 1.22 (m, 1H), 1.16 - 1.09 (m, 1H).

[0350] 3. Synthesis of (1R,4R)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane or (1R,4R)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka] (1R,4R)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane and (1R,4R)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (5 g, 11 mmol) were dissolved in methanol (50 mL) and then CO 2 Purification on a Lux Cellulose-4 30×250 mm, 5 um column using 45% methanol in water (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) gave the following compounds, which were concentrated to dryness and then lyophilized: Peak 1 or Example 86a (R f (E1=2.31 min.) was arbitrarily assigned as (1R,4R)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (1.9 g, 36%) as an off-white solid. LCMS m / z=443.2 (M+H). + . 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm) = 7.80 (d, J = 8.9 Hz, 2H), 7.59 - 7.27 (m, 3H), 4.25 (br s, 1H), 3.79 (br d, J = 7.0 Hz, 1H), 3.45 - 3.37 (m, 2H), 2.99 - 2.90 (m, 2H), 2.85 (br s, 3H), 2.75 (br d, J = 9.2 Hz, 1H), 2.36 - 2.23 (m, 1H), 1.78 - 1.69 (m, 1H), 1.68 - 1.60 (m, 1H), 1.59 - 1.44 (m, 6H), 1.42 - 1.33 (m, 2H), 1.31 - 1.24 (m, 1H), 1.18 - 1.09 (m, 1H). Peak 2 or Example 86b (Rf (E2=3.98 min) was arbitrarily assigned as (1R,4R)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (2.4 g, 46%) as an off-white solid. LCMS m / z=443.2 (M+H). + . 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm) = 7.80 (d, J = 8.9 Hz, 2H), 7.60 - 7.28 (m, 3H), 4.25 (br s, 1H), 3.79 (br d, J = 7.3 Hz, 1H), 3.47 - 3.37 (m, 2H), 2.96 - 2.82 (m, 5H), 2.76 - 2.68 (m, 1H), 2.30 - 2.23 (m, 1H), 1.68 - 1.59 (m, 2H), 1.59 - 1.46 (m, 6H), 1.42 - 1.34 (m, 2H), 1.30 - 1.23 (m, 1H), 1.15 - 1.09 (m, 1H).

[0351] Example 87: (1S,4S)-5-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka]

[0352] 1. Synthesis of (1S,4S)-5-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (1S,4S)-5-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane can be synthesized similarly to the method used to make Example 21, but starting from (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride. (1S,4S)-5-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (33 mg, 20%). LCMS m / z=395.3 (M+H) + . 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm) = 6.59 (s, 1H), 4.27 (br s, 1H), 3.92 (s, 3H), 3.82 (d, J = 7.9 Hz, 1H), 3.45 (br d, J = 7.3 Hz, 2H), 3.08 - 3.02 (m, 4H), 2.94 - 2.86 (m, 1H), 2.81 - 2.74 (m, 1H), 2.36 - 2.27 (m, 1H), 2.18 (s, 3H), 1.70 - 1.62 (m, 2H), 1.59 - 1.44 (m, 7H), 1.44 - 1.34 (m, 2H), 1.23 - 1.16 (m, 1H).

[0353] Example 88: (1R,4R)-5-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka]

[0354] 1. Synthesis of (1R,4R)-5-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (1R,4R)-5-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane can be synthesized similarly to the method used to make Example 21, but starting from (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride. (1R,4R)-5-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (49 mg, 26%). LCMS m / z=395.3 (M+H) + . 1 H NMR (600MHz, DMSO-d 6 ) δ (ppm) = 6.58 (s, 1H), 3.92 (s, 3H), 3.82 (d, J=8.0 Hz, 1H), 3.09 - 3.03 (m, 3H), 2.93 - 2.88 (m, 1H), 2.77 (dd, J=9.4, 15.3 Hz, 1H), 2.31 (d, J=10.2 Hz, 1H), 2.18 (s, 3H), 1.68 - 1.63 (m, 3H), 1.59 - 1.52 (m, 4H), 1.52 - 1.47 (m, 5H), 1.46 - 1.33 (m, 3H), 1.22 - 1.19 (m, 1H).

[0355] Example 89: (1S,4S)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka]

[0356] 1. Synthesis of (1S,4S)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (1S,4S)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane can be synthesized similarly to the method used to make Example 21, but starting from 4-(difluoromethoxy)benzenesulfonyl chloride. (1S,4S)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (87 mg, 44%). LCMS m / z=443.3 (M+H). + . 1 H NMR (600MHz, DMSO-d 6 ) δ (ppm)= 7.80 (d, J=8.7 Hz, 2H), 7.58 - 7.27 (m, 3H), 3.81 - 3.78 (m, 1H), 2.96 - 2.84 (m, 5H), 2.73 (dd, J=9.8, 17.1 Hz, 1H), 2.29 - 2.26 (m, 1H), 1.63 (br d, J=9.4 Hz, 2H), 1.58 - 1.53 (m, 2H), 1.52 - 1.46 (m, 6H), 1.42 - 1.35 (m, 3H), 1.28 (br dd, J=4.0, 7.6 Hz, 1H), 1.15 - 1.11 (m, 1H).

[0357] Examples 90a and 90b: (1S,4S)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane or (1S,4S)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka]

[0358] 1. Synthesis of (1S,4S)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane or (1S,4S)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka] (1S,4S)-5-(-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (80 mg, 181 umol) was dissolved in methanol (8 mL) and then cooled to 5° C. 2 Purification on a CHIRALPAK AD-H 30×250 mm, 5 um column using 45% methanol and 0.1% DEA in water (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) gave the following compounds, which were concentrated to dryness and then lyophilized: Peak 1 or Example 90a (R f (E1=2.43 min. including 1S,4S)-5-[(3R)-8-[4-(difluoromethoxy)phenyl]sulfonyl-8-azaspiro[4.5]decan-3-yl]-2-oxa-5-azabicyclo[2.2.1]heptane (26 mg, 31%) was arbitrarily assigned as a white solid. LCMS m / z=443.3 (M+H). + . 1 H NMR (500 MHz, DMSO-d 6) δ (ppm) = 7.80 (d, J = 8.9 Hz, 2H), 7.59 - 7.29 (m, 3H), 4.25 (br s, 1H), 3.79 (br d, J = 7.3 Hz, 1H), 3.41 (br d, J = 11.9 Hz, 2H), 2.97 - 2.90 (m, 2H), 2.88 - 2.80 (m, 3H), 2.77 - 2.73 (m, 1H), 2.30 - 2.23 (m, 1H), 1.76 - 1.69 (m, 1H), 1.65 - 1.61 (m, 1H), 1.57 - 1.45 (m, 6H), 1.41 - 1.34 (m, 2H), 1.31 - 1.25 (m, 1H), 1.18 - 1.11 (m, 1H). Peak 2 or Example 90b (R f (E2=2.62 min) was arbitrarily assigned as (1S,4S)-5-[(3S)-8-[4-(difluoromethoxy)phenyl]sulfonyl-8-azaspiro[4.5]decan-3-yl]-2-oxa-5-azabicyclo[2.2.1]heptane (34 mg, 40%), a white solid. LCMS m / z=443.2 (M+H). + . 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm) = 7.80 (d, J = 8.9 Hz, 2H), 7.60 - 7.28 (m, 3H), 4.25 (s, 1H), 3.79 (d, J = 7.6 Hz, 1H), 3.42 (br d, J = 5.8 Hz, 2H), 2.94 - 2.83 (m, 5H), 2.72 (br d, J = 9.8 Hz, 1H), 2.29 - 2.23 (m, 1H), 1.66 - 1.60 (m, 2H), 1.57 - 1.46 (m, 6H), 1.41 - 1.32 (m, 2H), 1.31 - 1.25 (m, 1H), 1.14 - 1.11 (m, 1H).

[0359] Example 91: 7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-7-azaspiro[3.5]nonan-2-amine [ka]

[0360] Synthesis of 1.7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one [ka] To a vial containing 7-azaspiro[3.5]nonan-2-one hydrochloride (177 mg, 1.01 mmol) in THF (2 mL), DIPEA (0.54 mL, 3.1 mmol) was carefully added dropwise below 5 °C. After 5 min, 2,5-dimethylpyrazole-3-sulfonyl chloride (222 mg, 1.14 mmol) was carefully added to the cold solution. Once the sulfonyl chloride addition was complete, the reaction was allowed to warm to 23 °C and monitored by LCMS. After 30 min, the reaction mixture was carefully quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23 °C for 10 min, then the biphasic mixture was loaded onto a silica gel column and purified (15-800% EtOAc in heptane). Fractions containing the product were pooled and then concentrated under reduced pressure to give a white solid as 7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (201 mg, 67%), which was used without further purification. LCMS m / z=298.0 (M+H). + . 1 H NMR (500 MHz, methanol-d 4 ) δ (ppm) = 6.56 (s, 1H), 4.00 (s, 3H), 3.22 - 3.19 (m, 4H), 2.81 (s, 4H), 2.24 (s, 3H), 1.87 - 1.84 (m, 4H).

[0361] Synthesis of 2.7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-7-azaspiro[3.5]nonan-2-amine [ka] To a vial containing 7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (100 mg, 336 umol) in DCM (2 mL) was carefully added dropwise AcOH (0.02 mL, 349 umol) followed by 2-methoxy-N-methyl-ethanamine (57 mg, 644 umol) at 23° C. After 15 min, NaBH(OAc) 3 (279 mg, 1.32 mmol) was carefully added in portions to the reaction mixture. 3 Upon complete addition, the reaction was stirred at 23 °C and monitored by LCMS. After 2 h, the reaction was carefully quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23 °C for 20 min, then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then diluted with MgSO 4 The mixture was dried at 37° C. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (20-90% 3:1 EtOAc:ethanol in heptane). Fractions containing the product were pooled and then concentrated under reduced pressure to give a colorless film, which was dissolved in DMSO and a few drops of water and then filtered. The homogeneous solution was subjected to mass directed reversed phase HPLC purification. Liquid chromatography was performed using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with mobile phase H 2 O (A) and MeCN (B) with 5-60% B (0.2% NH 4 A gradient of 0.1% OH final v / v % modifier was performed at a flow rate of 60 mL / min. Fractions containing the desired product were pooled and then concentrated under reduced pressure to give a clear oil as 7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-7-azaspiro[3.5]nonan-2-amine (39 mg, 30% yield). LCMS m / z=371.3 (M+H).+ . 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm) = 6.59 (s, 1H), 3.92 (s, 3H), 3.75 - 3.32 (m, 5H), 3.24 (br s, 2H), 3.07 - 3.03 (m, 2H), 2.99 - 2.94 (m, 2H), 2.80 - 2.61 (m, 1H), 2.47 - 2.21 (m, 2H), 2.18 (s, 3H), 2.13 - 1.83 (m, 4H), 1.63 - 1.59 (m, 2H), 1.59 - 1.53 (m, 2H), 1.50 - 1.34 (m, 1H).

[0362] Example 92: 6-(7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka]

[0363] 1. Synthesis of 6-(7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] To a vial containing 7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (91 mg, 306 umol) in DCM (1.5 mL) was carefully added dropwise AcOH (0.02 mL, 349 umol) followed by 2-oxa-6-azaspiro[3.3]heptane (62 mg, 623 umol) at 23° C. After 15 min, NaBH(OAc) 3 (238 mg, 1.12 mmol) was carefully added in portions to the reaction mixture. 3Upon complete addition, the reaction was stirred at 23 °C and monitored by LCMS. After 2 h, the reaction was carefully quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23 °C for 20 min, then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then diluted with MgSO 4 The mixture was dried at 40° C. After filtration and concentration under reduced pressure, the residue was dissolved in DMSO and a few drops of water, then filtered. The homogenous solution was subjected to mass directed reversed phase HPLC purification. Liquid chromatography was performed using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with mobile phase H 2 O (A) and MeCN (B) with 5-40% B (0.2% NH 4 A gradient of 1000 mg / ml of OH (final v / v % modifier) ​​was performed at a flow rate of 60 mL / min. Fractions containing the desired product were pooled and then concentrated under reduced pressure to give a colorless film as 6-(7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane (13 mg, 11%). LCMS m / z=381.3 (M+H). + . 1 H NMR (500 MHz, methanol-d 4 ) δ (ppm) = 6.53 (s, 1H), 4.71 (s, 4H), 3.98 (s, 3H), 3.35 - 3.33 (m, 4H), 3.14 - 3.10 (m, 2H), 3.10 - 3.03 (m, 3H), 2.24 (s, 3H), 1.91 - 1.85 (m, 2H), 1.71 - 1.66 (m, 2H), 1.64 - 1.60 (m, 2H), 1.56 - 1.50 (m, 2H).

[0364] Example 93: 6-(7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka]

[0365] Synthesis of 1.7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one [ka] To a vial containing 7-azaspiro[3.5]nonan-2-one hydrochloride (183 mg, 1.04 mmol) in DCM (4 mL), DIPEA (0.73 mL, 4.2 mmol) was carefully added dropwise below 5 °C. After 5 min, 2-methoxy-5-methyl-pyridine-3-sulfonyl chloride (243 mg, 1.10 mmol) was carefully added to the cold solution. Once the sulfonyl chloride solution was added, the reaction was warmed to 23 °C and monitored by LCMS. After 30 min, the reaction was carefully quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23 °C for 20 min, then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then MgSO 4 The mixture was dried at 77° C. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (15-65% EtOAc in heptane). The desired fractions were pooled and then concentrated under reduced pressure to give a white solid as 7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (337 mg, 99%), which was used without further purification. LCMS m / z=325.1 (M+H). + . 1 H NMR (400 MHz, DCM-d 2 ) δ (ppm)= 8.16 - 8.12 (m, 1H), 8.04 - 7.99 (m, 1H), 4.04 (s, 3H), 3.29 - 3.22 (m, 4H), 2.76 (s, 4H), 2.31 (s, 3H), 1.82 - 1.77 (m, 4H).

[0366] 2. Synthesis of 6-(7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] To a vial containing 7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (62 mg, 192 umol) in DCM (2 mL) was carefully added dropwise AcOH (0.01 mL, 201 umol) followed by 2-oxa-6-azaspiro[3.3]heptane (40 mg, 406 umol) at 23° C. After 15 min, NaBH(OAc) 3 (163 mg, 771 umol) was carefully added in portions to the reaction mixture. 3 Upon complete addition, the reaction was stirred at 23 °C and monitored by LCMS. After 19 h, the reaction was quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23 °C for 20 min, then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then diluted with MgSO 4 The mixture was dried at 40° C. After filtration and concentration under reduced pressure, the residue was dissolved in DMSO and a few drops of water, then filtered. The homogenous solution was subjected to mass directed reversed phase HPLC purification. Liquid chromatography was performed using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with mobile phase H 2 O (A) and MeCN (B) with 5-50% B (0.2% NH 4 A gradient of 0.1% OH final v / v % modifier) ​​was performed at a flow rate of 60 mL / min. Fractions containing the desired product were pooled and then concentrated under reduced pressure to give a colorless film as 6-(7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane (8 mg, 10%). LCMS m / z=408.3 (M+H). + . 1 H NMR (400 MHz, DCM-d 2) δ (ppm) = 8.10 (dd, J = 0.8, 2.3 Hz, 1H), 7.97 - 7.90 (m, 1H), 4.65 (s, 4H), 4.03 - 3.96 (m, 3H), 3.25 (s, 4H), 3.18 - 3.13 (m, 2H), 3.11 - 3.03 (m, 2H), 2.96 (quin, J = 7.4 Hz, 1H), 2.29 (s, 3H), 1.85 - 1.76 (m, 2H), 1.63 - 1.54 (m, 4H), 1.54 - 1.45 (m, 2H).

[0367] Example 94: (1R,4R)-5-(7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka]

[0368] Synthesis of 1.7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one [ka] To a vial containing 7-azaspiro[3.5]nonan-2-one hydrochloride (180 mg, 1.02 mmol) in DCM (4 mL), DIPEA (0.7 mL, 4.02 mmol) was carefully added dropwise below 5 °C. After 5 min, 6-chloro-2-methyl-pyridine-3-sulfonyl chloride (300 mg, 1.33 mmol) was carefully added to the cold solution. Once the sulfonyl chloride solution was added, the reaction was warmed to 23 °C and monitored by LCMS. After 30 min, the reaction was carefully quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23 °C for 20 min, then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then MgSO 4The mixture was dried at 77° C. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (25-80% EtOAc in heptane). The desired fractions were pooled and then concentrated under reduced pressure to give a white solid as 7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (274 mg, 81%), which was used without further purification. LCMS m / z=329.0 (M+H). + . 1 H NMR (500 MHz, methanol-d 4 ) δ (ppm) = 8.20 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 3.27 - 3.23 (m, 4H), 2.84 - 2.81 (m, 4H), 2.81 - 2.78 (m, 3H), 1.87 - 1.82 (m, 4H).

[0369] 2. Synthesis of (1R,4R)-5-(7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka] To a vial containing 7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (80 mg, 244 umol) in DCM (2 mL) was carefully added dropwise AcOH (0.08 mL, 1.40 mmol) followed by a solution of (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (67 mg, 497 umol) and DIPEA (0.15 mL, 861 umol) in DCM at 23° C. After 15 min, NaBH(OAc) 3 (222 mg, 1.05 mmol) was carefully added in portions to the reaction mixture. 3Upon complete addition, the reaction was stirred at 23 °C and monitored by LCMS. After 2 h, the reaction was carefully quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23 °C for 20 min, then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then diluted with MgSO 4 The mixture was dried at 40° C. After filtration and concentration under reduced pressure, the residue was dissolved in DMSO and a few drops of water, then filtered. The homogenous solution was subjected to mass directed reversed phase HPLC purification. Liquid chromatography was performed using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with mobile phase H 2 O (A) and MeCN (B) with 5-60% B (0.2% NH 4 A gradient of 0.1% OH final v / v % modifier) ​​was performed at a flow rate of 60 mL / min. Fractions containing the desired product were pooled and then concentrated under reduced pressure to give a colorless film as (1R,4R)-5-(7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (25 mg, 23%). LCMS m / z=412.2 (M+H). + . 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm) = 8.15 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 4.30 (s, 1H), 3.68 (d, J = 7.3 Hz, 1H), 3.43 (dd, J = 1.7, 7.2 Hz, 1H), 3.34 (s, 1H), 3.18 - 3.11 (m, 1H), 3.10 - 3.05 (m, 2H), 3.03 - 2.98 (m, 2H), 2.71 (s, 3H), 2.59 (dd, J = 1.4, 9.9 Hz, 1H), 2.34 (d, J = 10.1 Hz, 1H), 1.94 - 1.88 (m, 1H), 1.87 - 1.80 (m, 1H), 1.65 - 1.61 (m, 1H), 1.60 - 1.52 (m, 4H), 1.52 - 1.45 (m, 3H).

[0370] Example 95: 1-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)azetidin-3-ol [ka]

[0371] Synthesis of 1.7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one [ka] To a vial containing 7-azaspiro[3.5]nonan-2-one hydrochloride (531 mg, 3.02 mmol) in DCM (10 mL) was carefully added dropwise at room temperature DIPEA (2 mL, 11.51 mmol). After 10 min, 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (789 mg, 3.04 mmol) was carefully added to the mixture. Once the sulfonyl chloride addition was complete, the reaction was maintained at 23° C. and monitored by LCMS. After 1 h, the reaction mixture was diluted with saturated NaHCO 3 The mixture was carefully quenched by slowly adding aqueous solution of 1,2-dichloromethane (HCl), ... 4 The mixture was dried at 50° C. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (5-60% EtOAc in heptane). The desired fractions were pooled and then concentrated under reduced pressure to give a white solid as 7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (925 mg, 84%), which was used without further purification. LCMS m / z=363.0 (M+H). + . 1 H NMR (500 MHz, DMSO-d 6) δ (ppm) = 8.45 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 3.25 - 3.17 (m, 4H), 2.83 (s, 3H), 2.80 (s, 4H), 1.79 - 1.73 (m, 4H).

[0372] 2. Synthesis of 1-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)azetidin-3-ol [ka] A vial containing azetidin-3-ol hydrochloride (66 mg, 601 umol) in methanol (2 mL) was cooled in an ice-water bath, then DIPEA (0.2 mL, 1.15 mmol) was carefully added to the starting free base material. After 20 min, 7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (102 mg, 282 umol) and AcOH (0.08 mL, 1.40 mmol) were carefully added to the cooled mixture. After 15 min, NaBH(OAc) 3 (345 mg, 1.63 mmol) was carefully added in portions to the cooled reaction solution. 3 Upon complete addition, the reaction was kept below 5° C. and monitored by LCMS. After 1.5 h, the reaction was diluted with saturated NaHCO 3 The mixture was carefully quenched by slowly adding aqueous solution of 1,2-dichloromethane (DCM) to the reaction mixture. The mixture was stirred at 23° C. for 30 min, and then the mixture was extracted three times with DCM. The organic extracts were pooled and then diluted with MgSO 4 The mixture was dried at 37° C. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (40-100% 3:1 EtOAc:ethanol in heptane). The desired fractions were pooled and then concentrated under reduced pressure to give a colorless film, which was dissolved in DMSO and a few drops of water and then filtered. The homogeneous solution was subjected to mass directed reversed phase HPLC purification. Liquid chromatography was performed using a Waters XSelect CSH C18, 5 μm, 30 mm×100 mm column with mobile phase H2 O (A) and MeCN (B) with 5-50% B (0.2% NH 4 A gradient of 1000 mL / min (final v / v % modifier) ​​was performed at a flow rate of 30 mL / min. The desired fractions were pooled and then concentrated under reduced pressure to give a colorless film as 1-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)azetidin-3-ol (8 mg, 6%). LCMS m / z=420.1 (M+H). + . 1 H NMR (500 MHz, DCM-d 2 ) δ (ppm) = 8.41 - 8.35 (m, 1H), 7.75 - 7.69 (m, 1H), 4.64 - 4.27 (m, 1H), 3.75 - 3.37 (m, 2H), 3.23 - 3.10 (m, 4H), 2.90 (s, 3H), 2.12 - 1.75 (m, 4H), 1.72 - 1.68 (m, 2H), 1.61 - 1.43 (m, 6H).

[0373] Example 96: 3-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-7-azaspiro[3.5]nonan-7-yl)sulfonyl)-5-fluorobenzonitrile [ka]

[0374] Synthesis of 1.3-fluoro-5-((2-oxo-7-azaspiro[3.5]nonan-7-yl)sulfonyl)benzonitrile [ka] To a vial containing 7-azaspiro[3.5]nonan-2-one hydrochloride (188 mg, 1.07 mmol) in DCM (4 mL), DIPEA (0.6 mL, 3.44 mmol) was carefully added dropwise below 5 °C. After 5 min, 3-cyano-5-fluoro-benzenesulfonyl chloride (341 mg, 1.55 mmol) was carefully added to the cold solution. Once the sulfonyl chloride addition was complete, the reaction was allowed to warm to 23 °C and monitored by LCMS. After 30 min, the reaction was carefully quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23 °C for 20 min, then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then diluted with MgSO 4 The mixture was dried at rt. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (20-80% EtOAc in heptane). The desired fractions were pooled and then concentrated under reduced pressure to give a white solid as 3-fluoro-5-((2-oxo-7-azaspiro[3.5]nonan-7-yl)sulfonyl)benzonitrile (267 mg, 78%), which was used without further purification. 1 H NMR (500 MHz, DCM-d 2 ) δ (ppm) = 7.87 (s, 1H), 7.74 - 7.70 (m, 1H), 7.65 - 7.61 (m, 1H), 3.10 - 3.07 (m, 4H), 2.74 (s, 4H), 1.88 - 1.85 (m, 4H).

[0375] Synthesis of 2.3-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-7-azaspiro[3.5]nonan-7-yl)sulfonyl)-5-fluorobenzonitrile [ka] To a vial containing 3-fluoro-5-((2-oxo-7-azaspiro[3.5]nonan-7-yl)sulfonyl)benzonitrile (111 mg, 345 umol) in DCM (2 mL) was carefully added dropwise AcOH (0.02 mL, 349 umol) followed by 2-oxa-6-azaspiro[3.3]heptane (72 mg, 728 umol) at 23° C. After 15 min, NaBH(OAc) 3 (278 mg, 1.31 mmol) was carefully added in portions to the reaction mixture. 3 Upon complete addition, the reaction was stirred at 23 °C and monitored by LCMS. After 1 h, the reaction was carefully quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23 °C for 20 min, then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then diluted with MgSO 4 The mixture was dried at 40° C. After filtration and concentration under reduced pressure, the residue was dissolved in DMSO and a few drops of water, then filtered. The homogenous solution was subjected to mass directed reversed phase HPLC purification. Liquid chromatography was performed using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with mobile phase H 2 O (A) and MeCN (B) with 5-55% B (0.2% NH 4 A gradient of 0.1% OH final v / v % modifier was performed at a flow rate of 60 mL / min. Fractions containing the desired product were pooled and then concentrated under reduced pressure to give a white solid as 3-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-7-azaspiro[3.5]nonan-7-yl)sulfonyl)-5-fluorobenzonitrile (32 mg, 22%). LCMS m / z=406.2 (M+H). + . 1 H NMR (500 MHz, DMSO-d 6) δ (ppm) = 8.27 (br d, J = 8.5 Hz, 1H), 8.06 (s, 1H), 7.95 (dd, J = 1.5, 7.9 Hz, 1H), 4.54 (s, 4H), 3.12 (s, 4H), 2.95 - 2.86 (m, 5H), 1.69 - 1.63 (m, 2H), 1.53 (br t, J = 4.3 Hz, 4H), 1.39 - 1.33 (m, 2H).

[0376] Example 97: 3-((2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-5-fluorobenzonitrile [ka]

[0377] 1. Synthesis of 3-((2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-5-fluorobenzonitrile [ka] To a vial containing 3-fluoro-5-[(3-oxo-8-azaspiro[4.5]decan-8-yl)sulfonyl]benzonitrile (99 mg, 294 umol) in DCM (5 mL) was carefully added dropwise AcOH (0.08 mL, 1.4 mmol) followed by a solution of (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (92 mg, 681 umol) and DIPEA (0.2 mL, 1.15 mmol) in DCM at 23° C. After 15 min, NaBH(OAc) 3 (311 mg, 1.47 mmol) was carefully added in portions to the reaction mixture. 3Upon complete addition, the reaction was stirred at 23 °C and monitored by LCMS. After 1 h, the reaction was carefully quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23 °C for 20 min, then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then diluted with MgSO 4 The mixture was dried at rt. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (45-100% 3:1 EtOAc:ethanol in heptane). The desired fractions were pooled and then concentrated under reduced pressure to give a colorless film as 3-((2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-5-fluorobenzonitrile (49 mg, 38%). LCMS m / z=420.3 (M+H). + . 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm) = 8.27 (br d, J = 8.2 Hz, 1H), 8.08 (s, 1H), 7.97 (br d, J = 7.6 Hz, 1H), 4.25 (br s, 1H), 3.80 (br d, J = 7.0 Hz, 1H), 3.46 - 3.40 (m, 2H), 3.03 - 2.93 (m, 4H), 2.92 - 2.83 (m, 1H), 2.79 - 2.69 (m, 1H), 2.28 (br d, J = 9.5 Hz, 1H), 1.76 - 1.61 (m, 2H), 1.55 - 1.25 (m, 9H), 1.19 - 1.11 (m, 1H).

[0378] Example 98: 3-Fluoro-5-((3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile [ka]

[0379] Synthesis of 1.3-fluoro-5-((3-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile [ka] To a vial containing 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride (139 mg, 897 umol) in DCM (3 mL), DIPEA (0.7 mL, 4.02 mmol) was carefully added dropwise below 5° C. After 5 min, 3-cyano-5-fluoro-benzenesulfonyl chloride (293 mg, 1.33 mmol) was carefully added to the cold solution. Once the sulfonyl chloride addition was complete, the reaction was allowed to warm to 23° C. and monitored by LCMS. After 30 min, the reaction was carefully quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23° C. for 20 min, then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then diluted with MgSO 4 The mixture was dried at rt. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (20-80% EtOAc in heptane). The desired fractions were pooled and then concentrated under reduced pressure to give a sticky white foam as 3-fluoro-5-((3-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile (169 mg, 56%), which was used without further purification. 1 H NMR (500 MHz, DCM-d 2 ) δ (ppm) = 7.88 (s, 1H), 7.73 (td, J = 1.8, 7.6 Hz, 1H), 7.63 (dd, J = 1.2, 7.6 Hz, 1H), 3.90 (s, 2H), 3.57 - 3.53 (m, 2H), 2.86 (dt, J = 3.4, 11.4 Hz, 2H), 2.34 (s, 2H), 1.93 - 1.84 (m, 4H).

[0380] 2. Synthesis of 3-fluoro-5-((3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile [ka] To a vial containing 3-fluoro-5-((3-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile (81 mg, 239 umol) in DCM (3 mL) was carefully added dropwise AcOH (0.02 mL, 349 umol) followed by tetrahydropyran-4-ylmethanamine (60 mg, 521 umol) at 23° C. After 15 min, NaBH(OAc) 3 (200 mg, 943 umol) was carefully added in portions to the reaction mixture. 3 Upon complete addition, the reaction was stirred at 23 °C and monitored by LCMS. After 18 h, the reaction was carefully quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23 °C for 20 min, then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then diluted with MgSO 4 The mixture was dried at rt. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (35-90% 3:1 EtOAc:ethanol in heptane). The desired fractions were pooled and then concentrated under reduced pressure to give a colorless film as 3-fluoro-5-((3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile (42 mg, 38%). LCMS m / z=438.3 (M+H). + . 1 H NMR (500 MHz, DMSO-d 6) δ (ppm) = 8.27 (br d, J = 8.5 Hz, 1H), 8.10 (s, 1H), 7.98 (br d, J = 7.6 Hz, 1H), 3.80 (br dd, J = 3.4, 11.3 Hz, 2H), 3.74 (dd, J = 6.1, 8.5 Hz, 1H), 3.39 - 3.35 (m, 1H), 3.31 - 3.15 (m, 6H), 2.78 - 2.69 (m, 2H), 2.34 - 2.24 (m, 2H), 1.88 (s, 1H), 1.80 - 1.75 (m, 1H), 1.72 - 1.64 (m, 1H), 1.59 - 1.49 (m, 5H), 1.44 (dd, J = 5.6, 12.7 Hz, 1H), 1.07 (br s, 2H).

[0381] Example 99: 1-(8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)azetidin-3-ol [ka]

[0382] Synthesis of 1.8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one [ka] To a flask containing 8-azaspiro[4.5]decan-3-one hydrochloride (1.0 g, 5.3 mmol) in DCM (35 mL), DIPEA (3.6 mL, 21 mmol) was carefully added dropwise below 5° C. After 5 min, 6-methoxy-2-methyl-pyridine-3-sulfonyl chloride (1.4 g, 6.1 mmol) was carefully added to the cold solution. Once the sulfonyl chloride addition was complete, the reaction was allowed to warm to 23° C. and monitored by LCMS. After 30 min, the reaction mixture was carefully quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23° C. for 10 min, then the phases of the biphasic mixture were separated. The aqueous phase was washed with DCM (10 mL×2) and the combined organic phases were washed with Na 2 SO 4 The crude product was loaded onto a silica gel column and purified (10-55% EtOAc in heptane). The desired fractions were pooled and then concentrated under reduced pressure to give a white solid as 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one (1.7 g, 97%). LCMS m / z=338.9 (M+H). + .

[0383] 2. Synthesis of 1-(8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)azetidin-3-ol [ka] A vial containing azetidin-3-ol hydrochloride (24 mg, 323 umol) in methanol (2 mL) was cooled in an ice-water bath, then DIPEA (0.15 mL, 652 umol) was carefully added to the starting free base material. After 20 min, 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one (73 mg, 215 umol) and AcOH (0.05 mL, 862 umol) were carefully added to the cooled mixture. After 15 min, NaBH(OAc) 3 (365 mg, 1.73 mmol) was carefully added in portions to the cooled reaction solution. 3Upon complete addition, the reaction was kept below 5° C. and monitored by LCMS. After 18 h, the reaction was carefully quenched by slow addition of 1 M aqueous NaOH. The mixture was stirred at 23° C. for 20 min, then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then diluted with MgSO 4 The mixture was dried at 40° C. After filtration and concentration under reduced pressure, the residue was dissolved in DMSO and a few drops of water, then filtered. The homogenous solution was subjected to mass directed reversed phase HPLC purification. Liquid chromatography was performed using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with mobile phase H 2 O (A) and MeCN (B) with 5-65% B (0.2% NH 4 A gradient of 1000 mL of OH (final v / v % modifier) ​​was performed at a flow rate of 60 mL / min. Fractions containing the desired product were pooled and then concentrated under reduced pressure to give a white solid as 1-(8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)azetidin-3-ol (56 mg, 66%). LCMS m / z=396.2 (M+H). + . 1 H NMR (600 MHz, DMSO-d 6 ) δ (ppm)= 7.96 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 3.88 (s, 3H), 3.21 - 3.15 (m, 2H), 3.08 - 2.98 (m, 2H), 2.97 - 2.89 (m, 2H), 2.63 (s, 3H), 2.46 (td, J = 1.8, 3.6 Hz, 3H), 1.72 - 1.55 (m, 2H), 1.51 - 1.40 (m, 4H), 1.40 - 1.31 (m, 5H), 1.12 - 1.07 (m, 1H).

[0384] Example 100: 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-8-azaspiro[4.5]decan-2-amine [ka]

[0385] Synthesis of 1.8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-8-azaspiro[4.5]decane-2-amine [ka] 8-((6-Methoxy-2-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-8-azaspiro[4.5]decane-2-amine was prepared in a similar manner to Example 99, step 2 using 2-methoxy-N-methylethan-1-amine (0.03 mL, 323 umol) to give a colorless film as 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-8-azaspiro[4.5]decane-2-amine (50 mg, 57%). LCMS m / z=412.3 (M+H). + . 1 H NMR (600 MHz, DMSO-d 6 ) δ (ppm) = 8.01 (d, J = 9.1 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 3.50 - 3.30 (m, 4H), 3.25 (s, 3H), 3.10 - 2.99 (m, 5H), 2.67 (s, 3H), 2.54 (s, 2H), 2.43 - 2.32 (m, 2H), 1.90 - 1.75 (m, 2H), 1.59 - 1.52 (m, 2H), 1.51 - 1.34 (m, 7H), 1.32 - 1.23 (m, 1H).

[0386] Example 101: 6-(8-((5-(trifluoromethyl)furan-3-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka]

[0387] Synthesis of benzyl 1.2-oxo-8-azaspiro[4.5]decane-8-carboxylate [ka] To a flask containing 8-azaspiro[4.5]decan-3-one hydrochloride (10 g, 53 mmol) suspended in DCM (200 mL) under argon, TEA (8.4 mL, 61 mmol) was added dropwise to the reaction mixture with stirring at 0° C., followed by benzyl chloroformate (8.3 mL, 58 mmol). The mixture was stirred at room temperature under an argon atmosphere, and the reaction mixture was then washed with brine (2×50 mL) and sodium chloride. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The yellow oil was identified as benzyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate (14 g, 88%) which was used without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 7.41 - 7.34 (m, 5H), 5.14 (s, 2H), 3.77 - 3.64 (m, 1H), 3.35 - 3.25 (m, 2H), 2.31 (br t, J = 7.9 Hz, 2H), 2.18 (s, 2H), 1.88 (br t, J = 7.9 Hz, 2H), 1.55 (br s, 4H).

[0388] Synthesis of benzyl 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decane-8-carboxylate [ka] To a solution of benzyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate (14 g, 49 mmol) and 2-oxa-6-azaspiro[3.3]heptane oxalate (11 g, 59 mmol) in DCE (250 mL) was added AcOH (2.8 mL, 49 mmol) and STAB (21 g, 97 mmol). The resulting mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated under reduced pressure and then diluted with NaHCO 3 The solution was carefully adjusted to pH 8-9. After extraction with ethyl acetate (100 mL x 3), the combined organic layers were washed with water (50 mL) and then with brine (50 mL). 2 SO 4 After drying at 40° C., filtering and concentrating in vacuo, the yellow oil was identified as benzyl 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decane-8-carboxylate (11 g, 59%), which was used without further purification. LCMS m / z=371.2 (M+H). + .

[0389] 3. Synthesis of 6-(8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] To a solution of benzyl 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decane-8-carboxylate (11 g, 30 mmol) in MeOH (200 mL) was added 10% Pd / C (16 g, 15 mmol). The reaction mixture was stirred at room temperature under hydrogen atmosphere. After 4 h, nitrogen was bubbled into the reaction mixture, which was then carefully filtered through a plug of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (Interchim, SiO2 (40 g), EtOAc / methanol with 0-95% methanol, flow rate = 60 mL / min, Rt = 24 min) to give a white solid as 6-(8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane (6 g, 51%). LCMS m / z=237.2(M+H) + .

[0390] 4. Synthesis of 6-(8-((5-(trifluoromethyl)furan-3-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] 4-Bromo-2-(trifluoromethyl)furan (0.25 g, 1.2 mmol) was suspended in DMSO (2 mL) under argon and then sodium formate (87 mg, 1.3 mmol), disodium (sulfinoxy)sulfinate (782 mg, 2.33 mmol), 1,10-phenanthroline (31 mg, 174 umol), triphenylphosphine (305 mg, 1.2 mmol), and Pd(PPh 3 ) 4 (134 mg, 116 umol) was added. The mixture was heated at 60° C. After 14 h, the reaction mixture was cooled to room temperature and NFSI (550 mg, 1.74 mmol) was added. After 14 h, the suspension was diluted with water (5 mL) and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL) and then Na 2 SO 4 After filtration and concentration under reduced pressure, the crude sulfonyl fluoride was dissolved in THF (2 mL). 6-(8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane (60 mg, 1.2 mmol), Ca(NTf 2 ) 2 (1.05 g, 1.74 mmol) and DABCO (0.26 mL, 2.33 mmol) were added and the mixture was then stirred at 60° C. under an argon atmosphere. After 14 h, the reaction was diluted with water (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 ml) and then with Na 2 SO 4 After filtration and concentration under reduced pressure, the residue was analyzed by HPLC (column: XBridge BEH C18 5um 130A, 35-35-55% 0-1-6 min H 2 O / ACN / 0.1% NH4 OH, flow rate: 30 ml / min) to give 6-(8-((5-(trifluoromethyl)furan-3-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane (1.3 mg, 0.26%). LCMS m / z=435.0 (M+H). + .LCMS R f =2.75 minutes.

[0391] Example 102: 6-(8-((7-fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka]

[0392] 1. Synthesis of 6-(8-((7-fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] Example 102 was prepared in a similar manner to Example 101, step 4 starting from 6-bromo-7-fluoro-quinoline to give 6-(8-((7-fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane (28 mg, 29%). LCMS m / z=446.2 (M+H). + .LCMS Rf(2 minutes)=0.86.

[0393] Examples 103 to 111 The title compound was prepared in a single step library at approximately 25 mg target product scale using the following protocol. [ka] The appropriate sulfonyl chloride (1.1 equiv.) was added to a solution of 6-(8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane (1.0 equiv.) and DIPEA (4.5 equiv. + 1.1 equiv. for each acid equivalent for the sulfonyl chloride building block salt) in dry MeCN (0.7 mL) and the reaction mixture was stirred at room temperature for 24 h. The solvent was evaporated in vacuum and the residue was dissolved in DMSO (0.2 mL) and purified by preparative HPLC (Column: YMC Actus Trial C18 20×100 mm 5 um, Method: water-MeOH-NH as mobile phase). 3 0.1%) to give the pure product. [Table 6-1] [Table 6-2] [Table 6-3]

[0394] Examples 112 to 114 The title compound was prepared in a single step library at approximately 60 mg target product scale using the following protocol. [ka] The appropriate sulfonyl fluoride (1.0 equiv.) was dissolved in 6-(8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane (1.0 equiv.), Ca(NTf 2 ) 2 (1.1 equiv.) and DABCO (1.5 equiv.). The reaction mixture was stirred at 60° C. for 16 h. The solvent was evaporated in vacuo and the residue was dissolved in DMSO (0.5 mL) and purified by preparative HPLC (Column: YMC Actus Trial C18 20×100 mm, 5 um, Method: water-MeOH-NH as mobile phase). 3 0.1%) to give the pure product. [Table 7]

[0395] Example 114 The title compound was prepared in a single step library at approximately 60 mg target product scale using the following protocol. [ka] The appropriate sulfonyl chloride (1.1 equiv.) was added to a solution of 3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane (1.0 equiv.) as the bis(trifluoroacetate) salt and DIPEA (6.0 equiv.) in dry ACN (1.2 mL) and the reaction mixture was stirred at room temperature for 24 h. The solids were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in DMSO (0.5 mL) and then purified by preparative HPLC (Waters SunFire C18 19×100, 5 mm column, gradient mixture H as mobile phase). 2 O-MeOH-TFA 0.1%, or YMC Actus Trial C18 20×100mm, 5um column, gradient mixture H as mobile phase 2 Purification with O-MeOH-ammonia 0.1%) with an appropriate gradient gave the desired product. [Table 8]

[0396] Example 115 The title compound was prepared in a single step library at approximately 60 mg target product scale using the following protocol. [ka] The appropriate sulfonyl fluoride (1.0 equiv.) was reacted with 3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane (1.6 equiv.) as the bis(trifluoroacetate) salt in dry THF, Ca(NTf 2 ) 2(1.2 equiv.), and DABCO (5 equiv.). The reaction mixture was stirred at 60° C. for 16 h. The solvent was evaporated in vacuo and the residue was dissolved in DMSO (0.5 mL) and purified by preparative HPLC (Column: YMC Actus Trial C18 20×100 mm, 5 um, Method: water-MeOH-NH as mobile phase). 3 0.1%) to give the pure product. [Table 9]

[0397] Example 116: 8-((2,4-dimethylphenyl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decan-3-amine [ka]

[0398] Synthesis of 1,8-((2,4-dimethylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one [ka] The synthesis was carried out in a similar manner as described in step 1 of example 56 using 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride and 2,4-dimethylbenzenesulfonyl chloride (260 mg, 73%). LCMS m / z=324.0 [M+H] + , 1 H NMR (chloroform-d, 400 MHz) δ (ppm) 7.80 (d, 1H, J=8.5 Hz), 7.1-7.2 (m, 2H), 3.98 (s, 2H), 3.3-3.6 (m, 2H), 3.0-3.2 (m, 2H), 2.60 (s, 3H), 2.38 (d, 5H, J=10.5 Hz), 1.8-1.9 (m, 4H).

[0399] Synthesis of 2.8-((2,4-dimethylphenyl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decane-3-amine [ka] 8-((2,4-dimethylphenyl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decan-3-amine was obtained from 2-methoxyethanamine and 8-((2,4-dimethylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one following a similar synthesis as described in example 56, step 2 (100 mg, 84%). LCMS m / z=382.2 [M+H] + , 1 H NMR (chloroform-d, 400 MHz) δ (ppm) 7.75 (d, 1H, J=8.8 Hz), 7.0-7.2 (m, 2H), 3.92 (dd, 1H, J=6.0, 9.0 Hz), 3.70 (q, 1H, J=7.0 Hz), 3.57 (dd, 1H, J=5.5, 9.0 Hz), 3.4-3.5 (m, 5H), 3.34 (s, 3H), 3.0-3.1 (m, 2H), 2.6-2.8 (m, 2H), 2.57 (s, 3H), 2.36 (s, 3H), 2.0-2.1 (m, 2H), 1.7-1.9 (m, 2H), 1.55 (dd, 1H, J=6.0, 12.8 Hz).

[0400] Example 117: 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane [ka] 8-((2-Methoxy-5-methylpyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane was obtained from 2-oxa-6-azaspiro[3.3]heptane and 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one following a similar synthesis as described in Example 56, step 2 (150 mg, 80%). LCMS m / z=424.2 [M+H] + , 1 H NMR (chloroform-d, 400 MHz) δ (ppm) 8.05 (dd, 1H, J=0.8, 2.3 Hz), 7.90 (d, 1H, J=2.5 Hz), 4.6-4.7 (m, 4H), 3.96 (s, 3H), 3.6-3.7 (m, 1H), 3.4-3.5 (m, 3H), 3.2-3.3 (m, 4H), 2.9-3.1 (m, 2H), 2.86 (tdd, 1H, J=3.9, 5.3, 7.3 Hz), 2.25 (s, 3H), 1.84 (br d, 1H, J=13.6 Hz), 1.5-1.7 (m, 4H), 1.45 (dd, 1H, J=4.0, 13.1 Hz).

[0401] Example 118: Rac-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane [ka]

[0402] 1. Synthesis of Rac-8-((2,4-dimethylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one [ka] The synthesis was carried out in a similar manner as described in step 1 of example 56 using 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride and 2,3,5-difluorobenzenesulfonyl chloride (92 mg, 74%). LCMS m / z=332.0 [M+H] + , 1 H NMR (chloroform-d, 400 MHz) δ (ppm) 7.3-7.3 (m, 2H), 7.09 (tt, 1H, J=2.4, 8.4 Hz), 3.95 (s, 2H), 3.5-3.7 (m, 2H), 2.88 (dt, 2H, J=3.9, 11.2 Hz), 2.37 (s, 2H), 1.8-2.0 (m, 4H).

[0403] 2. Synthesis of Rac-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane The synthesis was carried out in a similar manner as described in step 2 of example 56 using Rac-8-((2,4-dimethylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one and 2-oxa-6-azaspiro[3.3]heptane (92 mg, 74%). LCMS m / z=415.2 [M+H] + , R f = 0.56 min (column: Waters ACQUITY UPLC BEH C18 2.1 × 30 mm, 1.7 um, modifier: 0.1% (v / v) trifluoroacetic acid) Method: 95% H2O / 5% MeCN (initial condition), linear gradient to 5% H2O / 95% MeCN at 1.0 min, hold at 5% H2O / 95% MeCN until 1.3 min. Flow rate 0.7 mL / min.

[0404] Examples 119a and 119b: (S)-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane and (R)-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane. [ka] 70 mg of Rac-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane was dissolved in MeOH and CO 2 Purification on a CHIRALPAK AD-H 30×250 mm, 5 um column using 20% ​​methanol and 0.1% DEA in water (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) gave the following compounds, which were concentrated to dryness and then lyophilized: Peak 1 or Example 119a was arbitrarily assigned as (S)-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane (20.1 mg) as a white solid. LCMS m / z=415.2 (M+H) + .R f =1.99 minutes. Peak 2 or Example 119b was arbitrarily assigned as (R)-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-oxa-8-azaspiro[4.5]decane (23.5 mg) as a white solid. LCMS m / z=415.2 (M+H) + .R f =2.16 minutes.

[0405] Example 120: 7-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-7-azaspiro[3.5]nonan-2-amine [ka]

[0406] Synthesis of 1.7-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one [ka] The synthesis was carried out in a similar manner as described in step 1 of example 93 using 7-azaspiro[3.5]nonan-2-one and 3-cyclopropyl-1-methyl-1H-pyrazole-5-sulfonyl chloride (194 mg, 87%). LCMS m / z=324.0 [M+H] + , 1 H NMR (chloroform-d, 400 MHz) δ (ppm) 7.80 (d, 1H, J=8.5 Hz), 7.1-7.2 (m, 2H), 3.98 (s, 2H), 3.3-3.6 (m, 2H), 3.0-3.2 (m, 2H), 2.60 (s, 3H), 2.38 (d, 5H, J=10.5 Hz), 1.8-1.9 (m, 4H).

[0407] 2. Synthesis of 7-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-7-azaspiro[3.5]nonan-2-amine [ka] The synthesis was carried out in a similar manner as described in step 2 of example 93 using 7-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one and tetrahydro-2H-pyran-4-amine (94 mg, 78%). LCMS m / z=409.3 [M+H] + , 1 H NMR (chloroform-d, 500 MHz) δ (ppm) 6.34 (s, 1H), 4.00 (s, 3H), 3.95 (br d, 2H, J=11.3 Hz), 3.3-3.4 (m, 3H), 3.1-3.2 (m, 2H), 3.0-3.1 (m, 2H), 2.6-2.7 (m, 1H), 2.16 (ddd, 2H, J=2.4, 7.8, 9.9 Hz), 1.8-1.9 (m, 1H), 1.6-1.8 (m, 6H), 1.4-1.5 (m, 4H), 0.9-1.0 (m, 4H), 0.7-0.8 (m, 4H).

[0408] Example 121: 6-(7-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka]

[0409] 1. Synthesis of 7-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one [ka] The synthesis was carried out in a similar manner to that described in step 1 of example 91 using 7-azaspiro[3.5]nonan-2-one and 6-(difluoromethoxy)-2-methylpyridine-3-sulfonyl chloride (90 mg, 31%). LCMS m / z=360.9 [M+H ]+ , 1HNMR (400 MHz, CDCl3) δ (ppm) 8.21 (d, J=8.4 Hz, 1H), 7.76-7.33 (m, 1H), 6.84 (d, J=8.4 Hz, 1H), 3.24-3.18 (m, 4H), 2.83-2.80 (m, 4H), 2.78-2.73 (m, 3H), 1.87-1.82 (m, 4H).

[0410] 2. Synthesis of 6-(7-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] Synthesis was performed in a similar manner as described in step 2 of example 91 using 7-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one and 2-oxa-6-azaspiro[3.3]heptane (88 mg, 28%). LCMS m / z=444.1 [M+H] + , 1 HNMR: (400 MHz, MeOD) δ (ppm) 8.25 (d, J=8.0 Hz, 1H), 7.88-7.41 (m, 1H), 6.97 (d, J=8.0 Hz, 1H), 4.72 (s, 4H), 3.35 (s, 4H), 3.18-3.13 (m, 2H), 3.12-3.05 (m, 3H), 2.75 (s, 3H), 1.96-1.87 (m, 2H), 1.71-1.64 (m, 2H), 1.64-1.60 (m, 2H), 1.59-1.51 (m, 2H).

[0411] Example 122: 6-(7-((3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka]

[0412] 1. Synthesis of 6-(7-((3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] To a solution of 7-azaspiro[3.5]nonan-2-one (150 mg, 853.94 umol, hydrochloride salt) and DIPEA (331.09 mg, 2.56 mmol, 446.21 uL) in DCM (6 mL) was added 7-[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]sulfonyl-7-azaspiro[3.5]nonan-2-one (240 mg, 719.96 umol) at 0-5 °C. The reaction mixture was stirred at 15 °C for 2 h. The reaction was diluted with water (15 mL) and extracted with DCM (25 mL x 3). The combined organic phase was washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column (10% to 40% EtOAc in petroleum ether) to give the desired compound (240 mg, 84%) as a colorless oil. LCMS m / z=334.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ (ppm)6.88 (s, 1H), 6.81-6.52 (m, 1H), 4.16-4.09 (m, 1H), 4.12 (s, 2H), 3.33-3.19 (m, 4H), 2.83 (s, 4H), 1.99-1.81 (m, 4H).

[0413] 2. Synthesis of 6-(7-((3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] Synthesis was performed in a similar manner as described in step 2 of example 91 using 6-(7-((3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane and 2-oxa-6-azaspiro[3.3]heptane (150 mg, 59%). LCMS m / z=417.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ (ppm)6.84 (s, 1H), 6.80-6.51 (m, 1H), 4.71 (s, 4H), 4.10 (s, 3H), 3.26 (s, 4H), 3.18-3.05 (m, 4H), 3.00-2.90 (m, 1H), 1.89-1.77 (m, 2H), 1.69-1.64 (m, 4H), 1.58-1.47 (m, 2H).

[0414] Example 123: 6-(7-((1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka]

[0415] Synthesis of 1.1-cyclopropyl-1H-pyrazole-3-carbaldehyde [ka] 1H-Pyrazole-3-carbaldehyde (5 g, 52.04 mmol), cyclopropylboronic acid (8.94 g, 104.07 mmol) and Na in DCE (150 mL) 2 CO 3 (11.03 g, 104.07 mmol) in DCE (50 mL) was stirred at 70 °C for 30 min, and the mixture was added 2-(2-pyridyl)pyridine (8.13 g, 52.04 mmol) and Cu(OAc) 2(9.45 g, 52.04 mmol) was added to a solution of 15° C. under air. The reaction was then heated to 70° C. for 4 h. The reaction was cooled to 15° C. and 5 mL of AcOH was added. The reaction mixture was concentrated in vacuo and the residue was diluted with H 2 The mixture was diluted with 200 mL of HO (100 mL) and extracted with EtOAc (100 mL × 3). The organic layer was washed with 1 M HCl, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 0 to 85 / 15) to give the desired compound (2.55 g, 32%) as a yellow oil. f =0.46, 1 H NMR (400 MHz, CDCl 3 ) δ (ppm)9.93 (s, 1H), 7.50 (d, J = 2.4 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 3.75-3.59 (m, 1H), 1.23-1.18 (m, 2H), 1.12-1.06 (m, 2H).

[0416] 2. Synthesis of 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole [ka] To a solution of 1-cyclopropyl-1H-pyrazole-3-carbaldehyde (5 g, 33.05 mmol, 90% purity) in DCM (180 mL) was added DAST (15.98 g, 99.15 mmol, 13.10 mL) at -30° C. The mixture was stirred at 20° C. for 12 h. The reaction mixture was diluted with saturated NH 4 Quenched with Cl (50 mL) at 15° C., then H 2 The mixture was diluted with 200 mL of HO (50 mL) and extracted with DCM (200 mL x 3). The combined organic layers were washed with Na 2 SO 4 The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate = 100 / 1 to 83 / 17) to give the desired compound (4.9 g, 84% yield) as a colorless oil. LCMS m / z = 159.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.47 (d, J = 2.4 Hz, 1H), 6.65 (t, J = 55.2 Hz, 1H), 6.43 (d, J = 1.2 Hz, 1H), 3.64-3.57 (m, 1H), 1.16-1.10 (m, 2H), 1.08-1.01 (m, 2H).

[0417] Synthesis of 3.5-bromo-1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole [ka] To a solution of 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole (4.9 g, 27.89 mmol, 90% purity) in THF (50 mL) was added n-BuLi (2.5 M, 16.73 mL, 1.5 equiv) at -70° C. over 0.5 h. CBr 4 (12.02 g, 36.25 mmol, 1.3 equiv.) was carefully added dropwise to the reaction mixture. The mixture was diluted with N 2 The reaction mixture was stirred at 25° C. for 1.5 h under reduced pressure. 4 The reaction mixture was quenched with Cl solution (30 mL) at 0° C. and warmed to 25° C. The reaction mixture was diluted with H 2 The mixture was diluted with 200 mL of 2H2O (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 80 / 20) to give the desired compound (2.5 g, 34%) as a yellow oil. LCMS: m / z = 236.7 [M + H] + . 1 H NMR (400 MHz, CDCl 3) δ (ppm) 6.73-6.41 (m, 2H), 3.52-3.46 (m Hz, 1H), 1.23-1.19 (m, 2H), 1.14-1.08 (m, 2H).

[0418] 4. Synthesis of 5-(benzylthio)-1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole [ka] DMF (50 mL) and H 2 Benzyl bromide (4.87 g, 28.48 mmol, 3.38 mL) in O (2 mL), K 2 CO 3 To a solution of 5-bromo-1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole (2.5 g, 9.49 mmol) was added 5-bromo-1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole (13.12 g, 94.92 mmol), CuI (180.77 mg, 949.19 umol) and thiourea (2.89 g, 37.97 mmol), and the mixture was stirred at 100° C. for 12 hours. 2 The mixture was diluted with 200 mL of 2H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL) and 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave a residue which was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent of 0-10% ethyl acetate / petroleum ether gradient @ 25 mL / min) to give the desired compound (290 mg, 10%) as a yellow oil. LCMS m / z=281.9 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.31-7.27 (m, 3H), 7.21-7.17 (m, 2H), 6.72-6.41 (m, 2H), 4.02 (s, 2H), 3.47-3.39 (m, 1H), 1.14-1.08 (m, 2H), 0.96-0.91 (m, 2H).

[0419] 5. Synthesis of 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole-5-sulfonyl chloride [ka] DCM (10 mL) and H 2 A solution of 5-(benzylthio)-1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole (290 mg, 931.03 umol, 90% purity) in 20 (1 mL) was diluted with SO in DCM (0.5 mL). 2 Cl 2 (879.62 mg, 6.52 mmol, 651.57 uL) was added dropwise. The mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with H 2 The mixture was diluted with 20 mL of O and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with Na 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave the desired compound as a yellowish oil (230 mg, crude) which was used without purification.

[0420] 6. Synthesis of 7-((1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one [ka] Synthesis was performed in a similar manner as described in Example 122, Step 1 using 7-azaspiro[3.5]nonan-2-one and 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole-5-sulfonyl chloride (10 mg, 7%). LCMS m / z=360.0 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ (ppm) 6.81(s, 1H), 6.56 (t, J=68.5 Hz, 1H), 4.11 - 3.98 (m, 1H), 3.30 - 3.16 (m, 4H), 2.77(s, 4H), 1.86 - 1.76 (m, 4H), 1.34 - 1.27 (m, 2H), 1.08 - 0.98 (m, 2H).

[0421] 7. Synthesis of 6-(7-((1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] Synthesis was performed in a similar manner as described in step 2 of example 91 using 7-((1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one and 2-oxa-6-azaspiro[3.3]heptane (7 mg, 78%). LCMS m / z=443.2 [M+H] + . 1 H NMR (400 MHz, MeOD) δ (ppm) 8.56-8.28 (m, 0.5H), 6.95 (s, 1H), 6.72 (t, J = 54.8 Hz, 1H), 4.76 (s, 4H), 4.27-4.13 (m, 1H), 4.02-3.83 (m, 4H), 3.63-3.50 (m, 1H), 3.29-3.13 (m, 4H), 2.18-2.06 (m, 2H), 1.83-1.62 (m, 6H), 1.36-1.29 (m, 2H), 1.14-1.03 (m, 2H).

[0422] Example 124: 6-(8-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka]

[0423] Synthesis of 1.3-methoxy-1-methyl-1H-pyrazole [ka] To a solution of 1-methyl-1H-pyrazol-3-ol (10 g, 101.93 mmol) in THF (300 mL) was added NaH (6.12 g, 152.90 mmol, 60% purity) at 0° C. After 30 min, MeI (36.17 g, 254.83 mmol, 15.86 mL) was added and the mixture was purified with N 2 The mixture was stirred at 25° C. for 16 h under H 2 The mixture was quenched with 20 mL of O and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (20 mL x 2) and diluted with Na 2 SO 4 The filtrate was concentrated under reduced pressure and the residue was purified by flash column (0% to 30% EtOAc in petroleum ether) to give the desired compound (4.30 g, 37%) as a colorless oil. 1 H NMR (500 MHz, CDCl 3 ), δ (ppm) 7.10 (d, J=2.5 Hz, 1H), 5.59 (d, J=2.5 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 3H).

[0424] Synthesis of lithium 2.3-methoxy-1-methyl-1H-pyrazole-5-sulfinate [ka] To a solution of 3-methoxy-1-methyl-1H-pyrazole (500 mg, 4.46 mmol) in THF (10 mL), n-BuLi (2.5 M, 2.68 mL) was added 2 The mixture was then stirred at 0° C. for 1 h and cooled to −70° C. Excess SO 2 was bubbled into THF (2 mL) and then slowly added to the mixture via syringe over 3 min, maintaining the temperature below -65° C. The reaction was stirred at -65° C. for 1 h and then warmed to 25° C. The mixture was concentrated and the residue was triturated with petroleum ether (60 mL) and filtered. The filter cake was dried in vacuum to give the desired compound (900 mg, crude) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6) δ (ppm) 5.45 (s, 1H), 3.71 (s, 3H), 3.67 (s, 3H).

[0425] 3. Synthesis of 8-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one [ka] To a solution of 8-azaspiro[4.5]decan-2-one hydrochloride (375.21 mg, 1.98 mmol, HCl salt), DIEA (766.95 mg, 5.93 mmol, 1.03 mL) in DCM (6 mL) was added lithium 3-methoxy-1-methyl-1H-pyrazole-5-sulfinate (500 mg, 2.37 mmol) at 0-5 °C. The mixture was then stirred at 25 °C for 1 h. The combined mixture was concentrated in vacuo. The crude product was purified by flash column (0%-6% MeOH in DCM) to give the desired compound (700 mg, 88%) as a yellow oil. LCMS m / z=328.1 [M+H] + . 1 HNMR (400 MHz, CDCl 3 ) δ (ppm) 6.05 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.40-3.34 (m, 2H), 3.02-2.96 (m, 2H), 2.29 (t, J=8.0 Hz, 2H), 2.10 (s, 2H), 1.84 (t, J=8.0 Hz, 2H), 1.72-1.66 (m, 4H).

[0426] 4. Synthesis of 6-(8-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] A solution of 8-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one (300 mg, 916.31 μmol) and morpholine (119.74 mg, 1.37 mmol, 120.23 μL) in MeOH (10 mL) was adjusted to pH 5-6 with HOAc at 25-30 °C and stirred for 1 h at 25-30 °C with NaBH 3 CN (172.75 mg, 2.75 mmol) was added and the mixture was stirred at 25-30 °C for 1 h. The mixture was quenched with water (20 mL) and saturated NaHCO 3 The pH was adjusted to 7-8 with aqueous solution (30 mL). The reaction mixture was extracted with DCM (50 mL x 2), and the combined organic layer was washed with brine (50 mL) and sodium 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Boston Green ODS 150*30mm*5um, conditions: water (NH 4 HCO 3 )-ACN, flow rate (ml / min) 25) to give the desired compound (150 mg, 40%) as a colorless oil. LCMS m / z=399.4 [M+H] + . 1 HNMR (400 MHz, CDCl 3 ) δ (ppm) 6.01 (s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.67-3.65 (m, 4H), 3.10-3.08 (m, 4H), 2.54-2.46 (m, 1H), 2.40 (br s, 4H), 1.87-1.82 (m, 1H), 1.74-1.69 (m, 1H), 1.64-1.56 (m, 1H), 1.55-1.48 (m, 4H), 1.47-1.37 (m, 2H) 1.25-1.20 (m, 1H).

[0427] Example 125: 6-(8-((3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka]

[0428] 1. Synthesis of 3-(difluoromethyl)-1-methyl-1H-pyrazole [ka] To a -20°C solution of 1-methyl-1H-pyrazole-3-carbaldehyde (7 g, 63.57 mmol) in DCM (100 mL) was added DAST (30.74 g, 190.71 mmol, 25.20 mL) dropwise over 5 min, then the reaction mixture was stirred at 15°C for 2 h. The mixture was diluted with saturated NaHCO 3 It was quenched with aqueous solution (40 mL) and extracted with DCM (30 mL x 2). The combined organic phase was washed with brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired compound (6.5 g, crude) as a brown oil. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.38 (d, J = 2.0 Hz, 1H), 6.67 (t, J = 55.2 Hz, 1H), 6.48 - 6.42 (m, 1H), 3.92 (s, 3H).

[0429] 2. Synthesis of lithium 3-(difluoromethyl)-1-methyl-1H-pyrazole-5-sulfinate [ka] To a solution of 3-(difluoromethyl)-1-methyl-1H-pyrazole (3 g, 22.71 mmol) in THF (60 mL) at −40 to −50 °C, n-BuLi (2.5 M, 14.53 mL) was added dropwise over 10 min under nitrogen, and the mixture was then stirred at −40 to −50 °C for 1 h. Excess SO 2 was bubbled into a solution of THF (10 mL) for 10 min and then added to the above solution at −50° C. The mixture was concentrated in vacuo to give the desired compound (4.5 g, crude) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6) δ (ppm) 6.87 (t, J = 55.2 Hz, 1H), 6.29 (s, 1H), 3.91 (s, 3H).

[0430] 3. Synthesis of 3-(difluoromethyl)-1-methyl-1H-pyrazole-5-sulfonyl chloride [ka] To a 0-5°C solution of lithium 3-(difluoromethyl)-1-methyl-1H-pyrazole-5-sulfinate (4.5 g, 22.27 mmol) in DCM (35 mL) and water (35 mL), NCS (4.46 g, 33.40 mmol) was added under nitrogen, and the mixture was then stirred at 0-5°C for 1 h. The mixture was diluted with water (10 mL) and extracted with DCM (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column (EtOAc in petroleum ether = 0%-10%) to give the desired compound (1.26 g, 24%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.22 (s, 1H), 6.69 (t, J = 54.4 Hz, 1H), 4.24 (s, 3H).

[0431] 4. Synthesis of 8-((3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one [ka] To a solution of 8-azaspiro[4.5]decan-2-one (240 mg, 1.27 mmol, HCl salt) and DIPEA (490.58 mg, 3.80 mmol, 661.16 μL) in DCM (15 mL) at 0-5 °C, 3-(difluoromethyl)-1-methyl-1H-pyrazole-5-sulfonyl chloride (320.98 mg, 1.39 mmol) was added and the reaction mixture was stirred at 15 °C for 1 h. The mixture was concentrated in vacuo. The residue was purified by flash column (MeOH in DCM = 0%-3%) to give the desired compound (220 mg, 50%) as a yellow oil. LCMS m / z = 348.0 [M+H] + . 1 H NMR (500 MHz, CDCl 3 ) δ (ppm) 6.87 (s, 1H), 6.767 (t, J = 55.0 Hz, 1H), 4.12 (s, 3H), 3.46-3.38 (m, 2H), 3.10-3.03 (m, 2H), 2.30 (t, J = 8.0 Hz, 2H), 2.12 (s, 2H), 1.87 (t, J = 8.0 Hz, 2H), 1.74-1.66 (m, 4H).

[0432] 5. Synthesis of 6-(8-((3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] To a solution of 8-((3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one (170 mg, 489.38 μmol) and 2-oxa-6-azaspiro[3.3]heptane (53.36 mg, 538.32 μmol) in MeOH (8 mL) was added acetic acid (58.77 mg, 978.76 μmol, 56.03 μL) and the resulting mixture was stirred at 15 °C for 1 h, followed by addition of NaBH 3CN (92.26 mg, 1.47 mmol) was added. The mixture was stirred at 15° C. for 2 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (column: Welch Xtimate C18 150*30 mm*5 um, condition: water (10 mM NH 4 HCO 3 )-ACN, 32%-61%, flow rate (mL) / min):25) to give the title compound (92.53 mg, 44%) as a yellow oil. LCMS m / z=431.2[M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 6.85 (s, 1H), 6.67 (t, J = 54.8 Hz, 1H), 4.71 (s, 4H), 4.10 (s, 3H), 3.26 (s, 4H), 3.20-3.11 (m, 4H), 2.66-2.56 (m, 1H), 1.71-1.62 (m, 4H), 1.55-1.50 (m, 3H), 1.45-1.36 (m, 2H), 1.16-1.12 (m, 1H).

[0433] Example 126: 4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-3-chlorobenzonitrile [ka]

[0434] 1. Synthesis of tert-butyl 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decane-8-carboxylate [ka] To a solution of tert-butyl 3-oxo-8-azaspiro[4.5]decane-8-carboxylate (100 mg, 394.73 umol) in MeOH (20 mL) was added 2-oxa-6-azaspiro[3.3]heptane:oxalic acid (113.80 mg, 394.73 umol). Sodium cyanoborohydride (74.42 mg, 1.18 mmol) was added and the mixture was stirred at 25° C. for 12 hours. Water (50 ml) was added and the mixture was extracted with EtOH (3×50 mL). The combined organics were washed with Na 2 SO 3 The mixture was filtered and concentrated in vacuo to give the crude product which was not further purified.

[0435] 2. Synthesis of tert-butyl 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decane-8-carboxylate [ka] To a solution of tert-butyl 3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decane-8-carboxylate (100 mg, 297.21 umol) in DCM (2 mL) was added TFA (67.77 mg, 594.41 umol, 45.52 uL) at 25° C. The mixture was then stirred at 25° C. for 3 h. DIPEA (0.3 mL) was added and the mixture was filtered and concentrated under vacuum to give 6-(8-azaspiro[4.5]decan-3-yl)-2-oxa-6-azaspiro[3.3]heptane (120 mg, crude, trifluoroacetate salt) as a colorless oil.

[0436] 3. Synthesis of 4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-3-chlorobenzonitrile [ka] To a solution of 6-(8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane (50 mg, 211 mmol) in DCM (5 mL) was added DIPEA at 25° C. Then 2-chloro-4-cyanobenzenesulfonyl chloride (49.9 mg, 211 mmol) was added to the mixture at 25° C. The mixture was stirred at 25° C. for 0.5 h. The reaction was filtered to obtain the crude reaction mixture. The residue was dissolved in DMSO (0.5 mL) and purified by preparative HPLC (Column: YMC Actus Trial C18 20×100 mm, 5 um, Method: water-MeOH-NH as mobile phase). 3 0.1%) to give the desired product (24 mg, 26%). LCMS m / z=436.0 [M+H] + , R f =1.80 minutes.

[0437] Example 127: 5-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-2-fluorobenzonitrile [ka] Synthesis was performed in a similar manner as described in Example 126, Step 3 using 6-(8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane and 3-cyano-4-fluorobenzenesulfonyl chloride (15 mg, 17%). LCMS m / z=420.1 [M+H] + , R f =1.72 min (Column: Waters ACQUITY UPLC BEH C18 2.1×30 mm, 1.7 um, Modifier: Trifluoroacetic acid at a concentration of 0.1% (v / v), Method: 95% H2O / 5% MeCN (initial condition), linear gradient to 5% H2O / 95% MeCN at 1.0 min, hold 5% H2O / 95% MeCN until 1.3 min. Flow rate: 0.7 mL / min.)

[0438] Example 128: 5-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-azaspiro[4.5]decan-8-yl)sulfonyl)-2-methylbenzonitrile [ka] Synthesis was performed in a similar manner as described in Example 126, Step 3 using 6-(8-azaspiro[4.5]decan-2-yl)-2-oxa-6-azaspiro[3.3]heptane and 3-cyano-4-methylbenzenesulfonyl chloride (21 mg, 24%). LCMS m / z=416.1 [M+H] + , R f =1.75 min (Column: Waters ACQUITY UPLC BEH C18 2.1×30 mm, 1.7 um, Modifier: Trifluoroacetic acid at a concentration of 0.1% (v / v), Method: 95% H2O / 5% MeCN (initial condition), linear gradient to 5% H2O / 95% MeCN at 1.0 min, hold 5% H2O / 95% MeCN until 1.3 min. Flow rate: 0.7 mL / min.)

[0439] Example 129...

Claims

1. Compounds represented by formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof [In the formula, X is O, CH ２ or a bond, provided that when X is a bond, p and q are 1; p is 0 or 1, provided that when p is 0, then q is 1; q is 0 or 1, provided that when q is 0, p is 1; R １ and R ２ are each independently H, C １－６ Alkyl, C ３－８ Cycloalkyl, C ３－８ cycloalkenyl, 6- to 10-membered bicyclic heterocycle, and 4- to 6-membered monocyclic heterocyclyl, wherein １－６ Alkyl, C ３－８ Cycloalkyl, C ３－８ Cycloalkenyl, 6- to 10-membered bicyclic heterocycle, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more R ４ is substituted with, where R １ and R ２ At least one of them is not H, Or, R １ and R ２ together with the N atom to which they are attached form a 4- to 7-membered monocyclic heterocycle or a 6- to 10-membered bicyclic heterocycle, each of which may be joined by one or more R ４ is optionally replaced by Each R ４ are independently OR ４ａ , Haro, C １－３ Alkyl, C ３－８ cycloalkyl, and 4- to 6-membered monocyclic heterocyclyl; R ４ａ is H and C １－３ alkyl, wherein said C １－３ the alkyl is optionally substituted with one or more halo; R ３ is phenyl, a 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, or a 6- to 10-membered bicyclic heterocycle, wherein said phenyl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, and 6- to 10-membered bicyclic heterocycle each optionally comprises one or more R ５ is replaced by Each R ５ are independently １－３ Alkyl, C ３－６ Cycloalkyl, OR ５ａ , cyano, halo, and 5- or 6-membered monocyclic heteroaryl, wherein said C １－３ Alkyl, C ３－６ Cycloalkyl and heteroaryl are each a group consisting of one or more R ５ｂ is optionally replaced by R ５ａ is H, C １－３ Alkyl, and C ３－６ cycloalkyl, wherein said C １－３ the alkyl is optionally substituted with one or more halo; R ５ｂ is OR ５ａ , C １－３ selected from alkyl, cyano, and halo; R ６ is, at each occurrence, independently a halo or C １－３ alkyl or two R ６ Together -C １－３ Forming an alkylene n is 0, 1, or 2; m is 0, 1, or 2; with the proviso that said compound is not any of the compounds shown in Table I].

2. (i) When X is O, R １ and R ２ together with the N atom to which they are attached form an unsubstituted morpholine, an unsubstituted pyrrolidine, or an unsubstituted N-methylpiperazine, and R ３ each optionally containing one or more substituents R ５ a 9- or 10-membered bicyclic heteroaryl or a 6- to 10-membered bicyclic heterocycle, or phenyl, substituted with at least two R ５ group or OR ５ａ One R ５ (ii) when X is O, R １ and R ２ Both are C １－６ alkyl, and R １ and R ２ The C represented by １－６ At least one of the alkyls is OR ４ａ , Haro, C ３－８ one or more R selected from cycloalkyl and 4- to 6-membered monocyclic heterocyclyl ４ and (iii) when X is a bond, R １ and R ２ Both are C １－６ alkyl, and R １ and R ２ The C represented by １－６ At least one of the alkyls is selected from one or more R ４ or (iv) if p is 0, then q is 1 and X is O, or a pharmaceutically acceptable salt thereof. (a) The compound has formula (II): 【Chemistry 2】 Represented by: (b) the compound has formula (IIA) or (IIB): 【Transformation 3】 Represented by: (c) the compound has formula (III) or (IV): 【Chemistry 4】 or (d) the compound has the formula (IIIA), (IIIB), (IVA), or (IVB): 【Transformation 5】 is expressed as 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

4. (a) R ３ is phenyl, a 5- or 6-membered monocyclic heteroaryl, a 9- to 10-membered bicyclic heteroaryl, or an 8- to 10-membered bicyclic heterocycle, wherein said phenyl, 5- or 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl, and 8- to 10-membered bicyclic heterocycle each optionally comprises one to three R ５ is replaced by; (b) R 3 is selected from the group consisting of pyridyl, pyrimidinyl, phenyl, thiazolyl, pyrazolyl, pyrazinyl, triazolyl, imidazopyridinyl, quinolinyl, tetrahydropyranopyrazolyl, thiophenyl, benzothiophenyl, furanyl, indazolyl, indolizinyl, pyrazolo[1,5-a]pyridinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, and benzofuranyl, each of which is each optionally substituted with 1 to 3 R 5 ; (c) R 3 is a group represented by the following formula: 【Transformation 6】 wherein each of the above formulas is optionally substituted with 1 to 3 R 5 ; or (d) R 3 is a group represented by the following formula: 【Chemistry 7-1】 【Chemistry 7-2】 is expressed as 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

5. (a) R ５ is independently, for each occurrence, cyano, C １－４ Alkyl, C ３－６ cycloalkyl, 5- or 6-membered monocyclic heteroaryl, OR ５ａ and halo, wherein said C １－４ Alkyl is one to three R ５ｂ and 5- or 6-membered monocyclic heteroaryl is optionally substituted by C １－３ optionally substituted with alkyl; R ５ａ is H, C １－３ Alkyl or C ３－６ cycloalkyl, where C １－３ the alkyl is optionally substituted with 1 to 3 halo; R ５ｂ is independently selected from halo and -OR at each occurrence. ５ａ or (b) R 5 at each occurrence is independently selected from —CH 3 , —CHF 2 , —C(CH 3 ) 3 , —CH 2 CH 3 , —CH 2 CN, —CF 3 , —CH 2 OCH 3 , —OCH 3 , —OCHF 2 , —OCF 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OH, —F, —Cl, cyclopropyl, cyclopropyloxy, 4-methyloxazol-2-yl, and —CN; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

6. (a) R １ and R ２ together with the N atom to which they are attached form a 4- to 6-membered monocyclic heterocycle or a 6- to 10-membered bicyclic heterocycle, each of which is substituted with one or two R ４ is optionally replaced by; (b) R 1 and R 2 together with the nitrogen atom to which they are attached form a group of the formula: 【Transformation 8】 each of the above formulae is optionally substituted with one or two R 4 ; or (c) R 1 and R 2 together with the nitrogen atom to which they are attached form a group of the formula: 【Chemistry 9】 forming a group represented by 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

7. (a) R ４ is independently for each occurrence, halo, C １－３ Alkyl and -OR ４ａ and R ４ａ is H or C １－３ is alkyl; or (b) R 4 at each occurrence is independently selected from —OCH 3 , —F, —OH, and —CH 3 ; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

8. (a) R １ is H or 1 to 3 R ４ C optionally substituted with １－３ is alkyl, R ２ is C １－３ Alkyl, C ３－６ Cycloalkyl, C ３－６ cycloalkenyl, 6- to 10-membered bicyclic heterocyclyl, or 4- to 6-membered monocyclic heterocyclyl, wherein １－３ Alkyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkenyl, 6- to 10-membered bicyclic heterocyclyl, and 4- to 6-membered monocyclic heterocyclyl are each optionally selected from the group consisting of C １－３ Alkyl, C １－３ substituted with 1 or 2 substituents independently selected from alkoxy, halo, and 4- to 6-membered monocyclic heterocyclyl; (b) R 1 is H or C 1-3 alkyl optionally substituted with 1 to 3 R 4 , and R 2 is C 1-3 alkyl substituted with C 1-3 alkoxy or 4-6 membered monocyclic heterocyclyl, C 3-6 cycloalkyl optionally substituted with 1 to 2 halo, 6-10 membered bicyclic heterocyclyl, or 4-6 membered monocyclic heterocyclyl optionally substituted with 1 or 2 C 1-3 alkyl; or (c) R 1 is H or methyl and R 2 is 2-methoxyethyl, —CH 2 -tetrahydropyranyl, 4,4-difluorocyclohexyl, 4-fluorocyclohex-3-en-1-yl, 2,2-difluoroethyl, 4-methylpiperidinyl, tetrahydro-2H-pyran-4-yl, oxetan-3-yl, 3-methyloxetan-3-yl, tetrahydrofuran-3-yl, 3-methyltetrahydrofuran-3-yl, and 2-oxaspiro[3.3]heptan-6-yl; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

9. The compound has the following formula: 【Chemistry 10】 or a pharmaceutically acceptable salt thereof, wherein X is O or CH ２ and R １ is H or 1 to 3 R ４ C optionally substituted with １－３ is alkyl, R ２ is C １－３ C substituted with alkoxy or 4-6 membered monocyclic heterocyclyl １－３ alkyl, C optionally substituted with 1 to 2 halo ３－６ cycloalkyl, 6- to 10-membered bicyclic heterocyclyl, or one or two C １－３ 4-6 membered monocyclic heterocyclyl optionally substituted with alkyl; Or, R １ and R ２ together with the N atom to which they are attached form a 4- to 6-membered monocyclic heterocycle, a 7- to 9-membered bicyclic heterocycle, each of which may be joined by one or two R ４ is optionally replaced by R ４ is independently calculated for each occurrence of C １－３ Alkoxy, OH, halo, and C １－３ alkyl, R ３ is phenyl, a 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, or a 9- or 10-membered bicyclic heterocycle, wherein said phenyl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, and 9- or 10-membered bicyclic heterocycle each optionally comprises one to three R ５ is replaced by R ５ is cyano, C １－４ Alkyl, C ３－６ Cycloalkyl, OR ５ａ and halo, wherein said C １－４ Alkyl is one to three R ５ｂ is optionally replaced by R ５ａ is C optionally substituted with 1 to 3 halo １－３ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

10. (a) R １ is H or 1 to 3 R ４ C optionally substituted with １－３ alkyl, and R ２ is C １－３ C substituted with alkoxy or 4-6 membered monocyclic heterocyclyl １－３ alkyl, 6- to 10-membered bicyclic heterocyclyl, or halo and C １－３ is a 4- to 6-membered monocyclic heterocyclyl optionally substituted with 1 or 2 substituents independently selected from alkyl; Or, R １ and R ２ together with the N atom to which they are attached form the following formula: 【Chemistry 11】 Each of these groups is represented by one or two R ４ is optionally replaced by R ３ teeth, 【Chemistry 12】 and each of these is one to three R ５ optionally replaced by; or (b) R 1 is H or C 1-3 alkyl optionally substituted with 1 to 3 R 4 , and R 2 is C 1-3 alkyl substituted with C 1-3 alkoxy, or 4-6 membered monocyclic heterocyclyl optionally substituted with 1 or 2 substituents independently selected from halo and C 1-3 alkyl; Or, R 1 and R 2 together with the N atom to which they are attached form the following formula: 【Chemistry 13】 each of which is optionally substituted with one or two R 4 ; R 3 is 【Chemistry 14】 each of which is optionally substituted with 1 to 3 R 5 ; 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof.

11. R ３ is the following formula: 【Chemistry 15】 wherein: (1) R １ is H or CH ３ and R ２ is 2-methoxyethyl, oxatan-3-ylmethyl, 3-methyltetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, —CH ２ -tetrahydropyranyl, or 2-oxaspiro[3.3]heptan-6-yl, or (2) R １ and R ２ together with the nitrogen atom to which they are attached form the following formula: 【Chemistry 16】 The compound according to claim 10, or a pharmaceutically acceptable salt thereof, which forms a group represented by the following formula:

12. (a) R ４ is independently for each occurrence, halo, C １－３ Alkyl and -OR ４ａ and R ４ａ is H or C １－３ is alkyl; or (b) R 4 at each occurrence is independently selected from —OCH 3 , F, —OH, or —CH 3 ; 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof.

13. (a) R ５ is independently, for each occurrence, cyano, C １－４ Alkyl, C ３－６ Cycloalkyl, OR ５ａ and halo, wherein said C １－４ Alkyl is one to three R ５ｂ is optionally replaced by R ５ａ is H, C ３－６ C optionally substituted with cycloalkyl or 1 to 3 halo １－３ is alkyl, R ５ｂ is, for each occurrence, independently, a halo and C １－３ alkoxy; or (b) R 5 at each occurrence is independently selected from —CH 3 , —CF 3 , —OCH 3 , —OCHF 2 , —OCF 3 , —OH, —CN, F, Cl, —CH 2 OCH 3 , cyclopropyl, and cyclopropyloxy; 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof. (a) The compound has formula (V): 【Chemistry 17】 or (b) the compound has the formula (VA) or (VB): [Chemistry 18] is expressed as 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

15. X is CH ２ 15. The compound of claim 14, wherein:

16. (A)R ３ is (a) phenyl or 5- or 6-membered monocyclic heteroaryl, wherein said phenyl or 5- or 6-membered monocyclic heteroaryl each optionally contains 1 to 2 substituents R ５ is replaced by; (b) selected from the group consisting of pyridyl, phenyl, and pyrazolyl; (c) a compound of the formula: 【Chemistry 19】 wherein each of the above formulas is optionally substituted with 1-2 R 5 ; or (d) a compound of the formula: 【Chemistry 20】 or (B) R 5 is (1) each occurrence independently selected from cyano, C 1-4 alkyl, OR 5a , C 3-4 cycloalkyl, and halo, wherein said C 1-4 alkyl is optionally substituted with one to three R 5b ; R 5a is C 1-3 alkyl optionally substituted with 1 to 3 halo; R 5b at each occurrence is halo; or (2) each occurrence is independently selected from —CH 3 , —CHF 2 , —CH 2 CH 3 , —CF 3 , —OCH 3 , —OCHF 2 , —OCF 3 , —F, —Cl, cyclopropyl, and —CN; or (C)(i) when R 1 and R 2 are both C 1-6 alkyl, at least one of said C 1-6 alkyl is further substituted with at least one R 4 ; (ii) R 1 is H or C 1-3 alkyl and R 2 is C 1-3 alkyl optionally substituted with C 1-3 alkoxy or 4- to 6-membered heterocyclyl; (iii) R 1 is H or —CH 3 and R 2 is —CH 2 CH 2 OCH 3 or tetrahydropyranyl; (iv) R 1 and R 2 together with the N atom to which they are attached form a 4- to 6-membered monocyclic heterocycle or a 6- or 7-membered bicyclic heterocycle, each of which is optionally substituted with one or two R 4 ; or (v) R 1 and R 2 together with the nitrogen atom to which they are attached form a group of the formula: 【Chemistry 21】 forming a group represented by and each R 4 is independently —OH; 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof. (a) The compound has the formula (VI): 【Chemistry 22】 or (b) the compound has formula (VIA) or (VIB): 【Chemistry 23】 is expressed as 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

18. (a) R ３ is one or two R ４ or is phenyl optionally substituted with (b) R 3 is a group represented by the following formula: 【Chemistry 24】 is expressed as and R 1 and R 2 together with the nitrogen atom to which they are attached form the following formula: 【Chemistry 25】 forming a group represented by 18. The compound of claim 17.

19. The compound has the formula (VII): 【Chemistry 26】 wherein: X is O, CH ２ , or a bond, R １ is H and R ２ is a 4- to 6-membered monocyclic heterocyclyl or a 6- to 10-membered bicyclic heterocyclyl; or R １ and R ２ together with the N atom to which they are attached form a 4- to 7-membered monocyclic heterocycle or a 6- to 10-membered bicyclic heterocycle; R ３ is phenyl or 5- or 6-membered monocyclic heteroaryl, each of which is substituted by one or two R ５ is optionally replaced by Each R ５ are independently １－３ Alkyl, C １－３ Haloalkyl, C ３－４ Cycloalkyl, OR ５ａ , cyano, and halo; R ５ａ is C １－３ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is haloalkyl. (a) The compound is (III) or (IV): 【Chemistry 27】 or (b) the compound has the formula (IIIA), (IIIB), (IVA), or (IVB): 【Chemistry 28】 is expressed as 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof.

21. (i) (a) R ３ is phenyl, pyrazolyl, or pyridinyl, each of which is selected from one or two R ５ is optionally replaced by; (b) R 3 is a group represented by the following formula: 【Chemistry 29】 wherein each of the above formulas is optionally substituted with 1-2 R 5 ; or (c) R 3 is a group represented by the following formula: 【Transformation 30】 or (ii) (1) R 2 is a group represented by the following formula: 【Chemistry 31】 or (2) R 1 and R 2 together with the N atom to which they are attached form the following formula: 【Chemistry 32】 or forming a group represented by (iii) each R 5 is independently selected from —CH 3 , —CF 3 , —F, —CN, and —OCHF 2 ; 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof.

22. (a) The compound has the formula (VIII): 【Transformation 33】 or (b) the compound has the formula (VIIIA) or (VIIIB): 【Transformation 34】 is expressed as 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof.

23. (i) R ３ (a) pyrazolyl or pyridinyl, each of which is selected from the group consisting of one or two R ５ is optionally replaced by; (b) a compound of the formula: 【Chemistry 35】 wherein each of the above formulas is optionally substituted with 1-2 R 5 ; or (c) a compound of the formula: 【Transformation 36】 or (ii) (1) R 2 is a group represented by the following formula: 【Chemistry 37】 or (2) R 1 and R 2 together with the N atom to which they are attached form the following formula: 【Transformation 38】 or forming a group represented by (iii) each R 5 is independently selected from —CH 3 , —CF 3 , and cyclopropyl; 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof.

24. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the following: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

26. 25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in a method for treating a disease mediated by emopamil-binding protein or a method for treating an autoimmune disease, the method comprising administering to a subject an effective amount of the compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition according to claim 25 for use in a method for treating a disease mediated by emopamil-binding protein or a method for treating an autoimmune disease, the method comprising administering to a subject an effective amount of the pharmaceutical composition according to claim 25.