Emopamil binding protein inhibitors and uses thereof

Abstract

Provided are compounds of Formula (I): # imgabs0 #, or a pharmaceutically acceptable salt thereof, which are useful for inhibiting EBP and treating a variety of EBP-mediated conditions or diseases, such as multiple sclerosis.

Description

[0001] Related applications

[0002] This application claims the benefit under 35 USC §119(e) of the filing date of U.S. Provisional Application No. 63 / 309,923, filed on February 14, 2022. The entire contents of the foregoing application are expressly incorporated herein by reference. Technical Field

[0003] The present disclosure relates to inhibitors of emopamide binding protein (EBP) and pharmaceutically acceptable salts thereof, compositions of these compounds, methods for their preparation, their use in the treatment of diseases, their use, optionally in combination with a pharmaceutically acceptable carrier, for the manufacture of pharmaceutical preparations, the use of such pharmaceutical preparations in the treatment of diseases, and methods for treating diseases comprising administering an EBP inhibitor to a warm-blooded animal, particularly a human. Background Art

[0004] Emopamil binding protein (EBP) is a Δ8-Δ7 sterol isomerase that isomerizes the double bond in the sterol molecule, moving the double bond from the 8-9 position to the 7-8 position. Specifically, during the biosynthesis of cholesterol, EBP converts zymostenol into lathosterol, or converts zymostenol into dehydrolathosterol (Silve et al., 1996, J Biol Chem. 271 (37), 22434-22440). It has been confirmed that the accumulation of 8-9 unsaturated sterols activates the formation of oligodendrocytes and remyelination (Hubler et al., 2019, Nature 560 (7718), 372-376).

[0005] Myelin is a lipid-based molecule that forms a protective layer (myelin sheath) around the axons of nerve cells and isolates the axons. Demyelination or myelin-related diseases are the result of these myelin sheaths being damaged, degenerated or reduced in thickness. The loss of myelin can disrupt the electronic signals from the brain and may cause 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 patient's immune system targets and decomposes its own myelin sheath. The ability to repair and regenerate myelin is the key to treating these myelin-related diseases. Due to the function of converting 8-9 sterols, inhibiting EBP is a potential target for activating myelin regeneration because its inhibition can lead to an increase in these 8-9 sterol raw materials (Theodoropoulous et al., 2020, J.Am.Chem.Soc., 142, (13), 6128-6138).

[0006] In addition to its role in myelin regeneration, EBP has been shown to be a key enzyme in certain colorectal cancers as it can reduce essential lipids such as cholesterol (Theodoropoulous et al., 2020, J. Am. Chem. Soc., 142, (13), 6128-6138).

[0007] Therefore, there is a need for EBP inhibitors as potential therapeutic agents for treating diseases or conditions responsive to EBP inhibition. Summary of the Invention

[0008] The present disclosure provides compounds that are EBP inhibitors. In a first aspect, the present disclosure relates to compounds having Formula I:

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein:

[0011] X is O, CH2, or a bond, provided that when X is a bond, p and q are 1;

[0012] p is 0 or 1, provided that when p is 0, q is 1;

[0013] q is 0 or 1, provided that when q is 0, p is 1;

[0014] R 1 and R 2 Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 cycloalkenyl, 6 to 10 membered bicyclic heterocyclyl and 4 to 6 membered monocyclic heterocyclyl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 The cycloalkenyl, 6- to 10-membered bicyclic heterocyclyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by one or more R 4 Replace, provided that R 1 and R 2 At least one of them is not H;

[0015] or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered monocyclic heterocycle or a 6- to 10-membered bicyclic heterocycle, each of which is optionally substituted by one or more R 4 replace;

[0016] Each R 4 Independently selected from OR 4a , halo, C 1-3 Alkyl, C 3-8 Cycloalkyl and 4- to 6-membered monocyclic heterocyclyl;

[0017] R 4a Selected from H and C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups;

[0018] R 3 is phenyl, 5 or 6 membered monocyclic heteroaryl, 9 or 10 membered bicyclic heteroaryl or 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 are each optionally substituted by one or more R 5 replace;

[0019] Each R 5 Independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, OR 5a , cyano, halo and 5 or 6-membered monocyclic heteroaryl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl and heteroaryl groups are optionally substituted by one or more R 5b replace;

[0020] R 5a Selected from H, C 1-3 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups;

[0021] R 5b Selected from OR 5a 、C 1-3 Alkyl, cyano and halo groups;

[0022] R 6 Each occurrence is independently halo or C 1-3 Alkyl, or two R 6 Together to form –C 1-3 Alkylene

[0023] n is 0, 1, or 2;

[0024] m is 0, 1 or 2.

[0025] In some embodiments, the compound of formula (I) is not any of the compounds listed in Table I below.

[0026] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0027] In another aspect, the present disclosure provides a method for treating a disease or condition 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 pharmaceutically 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 suffering from a myelin-related disorder.

[0028] Another aspect of the present disclosure relates to the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease or condition responsive to inhibition of EBP. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition responsive to inhibition of EBP. DETAILED DESCRIPTION

[0029] The present disclosure provides compounds and pharmaceutical compositions thereof, which are useful for treating diseases or conditions caused by mediating EBP function / activity, such as multiple sclerosis or other myelin-related disorders. In some embodiments, the compounds of the present disclosure are EBP inhibitors.

[0030] Compounds and compositions

[0031] In a first aspect, the present disclosure provides compounds of formula (I):

[0032]

[0033] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (I) are as defined above in the first embodiment. In some embodiments, the compound of formula (I) is not any of the compounds listed in Table I below.

[0034] In a first embodiment, the present disclosure relates to compounds having Formula I:

[0035]

[0036] or a pharmaceutically acceptable salt thereof, wherein:

[0037] X is O, CH2, or a bond, provided that when X is a bond, p and q are 1;

[0038] p is 0 or 1, provided that when p is 0, q is 1;

[0039] q is 0 or 1, provided that when q is 0, p is 1;

[0040] R 1 and R 2 Each independently selected from H, C 1-6 Alkyl, C3-8 Cycloalkyl, C 3-8 Cycloalkenyl and 4 to 6 membered monocyclic heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 The cycloalkenyl group and the 4- to 6-membered monocyclic heterocyclyl group are each optionally substituted by one or more R 4 Replace, provided that R 1 and R 2 At least one of them is not H;

[0041] or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered monocyclic heterocycle or a 6- to 10-membered bicyclic heterocycle, each of which is optionally substituted by one or more R 4 replace;

[0042] R 4 Selected from OR 4a , halo, C 1-3 Alkyl or C 3-8 Cycloalkyl;

[0043] R 4a Selected from H and C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups;

[0044] R 3 is phenyl, 5 or 6 membered monocyclic heteroaryl, 9 or 10 membered bicyclic heteroaryl or 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 are each optionally substituted by one or more substituents R 5 replace;

[0045] R 5 Selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, OR 5a , cyano, halo and 5 or 6-membered monocyclic heteroaryl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl and heteroaryl groups are optionally substituted by one or more R 5b replace;

[0046] R 5a Selected from H, C 1-3 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups;

[0047] R 5b Selected from OR 5a 、C 1-3Alkyl, cyano and halo groups;

[0048] R 6 Each occurrence is independently halo or C 1-3 Alkyl, or two R 6 Together to form –C 1-3 alkylene;

[0049] n is 0, 1, or 2;

[0050] m is 0, 1 or 2.

[0051] 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.

[0052] In a second embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, (i) when X is O, and R 1 and R 2 When taken together with the nitrogen atom to which they are attached to form unsubstituted morpholine, unsubstituted pyrrolidine or unsubstituted N-methylpiperazine, then R 3 are each optionally substituted by one or more substituents R 5 substituted 9- or 10-membered bicyclic heteroaryl or 6- to 10-membered bicyclic heterocycle, or phenyl or 5- or 6-membered monocyclic heteroaryl, each of which is replaced by at least two R 5 Group or as OR 5a An R 5 (ii) when X is O, and R 1 and R 2 All C 1-6 When it is an alkyl group, R 1 and R 2 The C 1-6 At least one of the alkyl groups is replaced by one or more selected from OR 4a , halo and C 3-8 R of cycloalkyl 4 Substitution; (iii) when X is a bond, and R 1 and R 2 All C 1-6 When it is an alkyl group, R 1 and R 2 The C 1-6 At least one of the alkyl groups is replaced by one or more R 4 or (iv) when p is 0 and q is 1, then X is O. In an alternative second embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, (i) when X is O, and R 1 and R 2When taken together with the nitrogen atom to which they are attached to form unsubstituted morpholine, unsubstituted pyrrolidine or unsubstituted N-methylpiperazine, then R 3 are each optionally substituted by one or more substituents R 5 substituted 9- or 10-membered bicyclic heteroaryl or 6- to 10-membered bicyclic heterocycle, or phenyl or 5- or 6-membered monocyclic heteroaryl, each of which is replaced by at least two R 5 Group or as OR 5a An R 5 (ii) when X is O, and R 1 and R 2 All C 1-6 When it is an alkyl group, R 1 and R 2 The C 1-6 At least one of the alkyl groups is replaced by one or more selected from OR 4a , halo and C 3-8 R of cycloalkyl 4 Substitution; (iii) when X is a bond, and R 1 and R 2 All C 1-6 When it is an alkyl group, R 1 and R 2 The C 1-6 At least one of the alkyl groups is replaced by one or more R 4 or (iv) when p is 0 and q is 1, then X is O.

[0053] In a third embodiment, the compounds of the present disclosure are represented by formula (II):

[0054]

[0055] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (II) are as defined above in the first aspect or the first embodiment or the second embodiment.

[0056] In a fourth embodiment, the compounds of the present disclosure are represented by formula (IIA) or (IIB):

[0057]

[0058] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (IIA) and (IIB) are as defined above in the first aspect or first embodiment or second embodiment.

[0059] In a fifth embodiment, the compounds of the present disclosure are represented by formula (III) or (IV):

[0060]

[0061] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (III) or (IV) are as defined above in the first aspect or first embodiment or second embodiment.

[0062] In a sixth embodiment, the compounds of the present disclosure are represented by formula (IIIA), (IIIB), (IVA), or (IVB):

[0063]

[0064] or a pharmaceutically acceptable salt thereof, wherein the variables in Formula (IIIA), (IIIB), (IVA) or (IVB) are as defined above in the first aspect or first embodiment or second embodiment.

[0065] In a seventh embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 3 is phenyl, 5- or 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl, or 8- to 10-membered bicyclic heterocycle, wherein each of the phenyl, 5- or 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl, and 8- to 10-membered bicyclic heterocycle is optionally substituted by one to three R 5 and the remaining variables are as described in the first aspect or the first embodiment or the second embodiment.

[0066] In an eighth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 3 is pyridyl, phenyl, thiazolyl, pyrazolyl, pyrazinyl, imidazopyridinyl, quinolinyl, tetrahydropyranopyrazolyl, thienyl, benzothienyl, furanyl, indazolyl, indolizinyl or benzofuranyl, each of which is optionally substituted by one to three R 5 and the remaining variables are as described in the first aspect or the first embodiment or the 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 pharmaceutically acceptable salt thereof, R 3selected from the group consisting of pyridyl, pyrimidinyl, phenyl, thiazolyl, pyrazolyl, pyrazinyl, triazolyl, imidazopyridinyl, quinolinyl, tetrahydropyranopyrazolyl, thienyl, benzothienyl, furanyl, indazolyl, indolizinyl, pyrazolo[1,5-a]pyridinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl and benzofuranyl, each of which is optionally substituted by one to three R 5 and the remaining variables are as described in the first aspect or the first embodiment or the second embodiment.

[0067] In a ninth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 3 is pyridyl, phenyl, pyrazolyl, thienyl, thiazolyl, quinolyl, tetrahydropyranopyrazolyl or benzofuranyl; each of which is optionally substituted by one to three R 5 and the remaining variables are as described in the first aspect, first embodiment, or second embodiment.

[0068] In a tenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 3 for

[0069] Each of which is optionally replaced by one to three R 5 and the remaining variables are as described in the first aspect or the first embodiment or the 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 pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula:

[0070]

[0071] wherein each formula depicted above is optionally replaced by one to three R 5 and the remaining variables are as described in the first aspect or the first embodiment or the second embodiment.

[0072] In an eleventh embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 3 for

[0073] Each of which is optionally replaced by one to three R 5 and the remaining variables are as described in the first aspect or the first embodiment or the second embodiment.

[0074] In a twelfth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 3 for

[0075]

[0076] and the remaining variables are as described in the first aspect or the first embodiment or the 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 pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula:

[0077]

[0078]

[0079] and the remaining variables are as described in the first aspect or the first embodiment or the second embodiment

[0080] In a thirteenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 3 for

[0081]

[0082] And the remaining variables are as described in the first aspect or the first embodiment or the second embodiment.

[0083] In a fourteenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 5 Each occurrence is independently selected from cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5- or 6-membered monocyclic heteroaryl, OR 5a and halo, wherein the C 1-4 The alkyl group is optionally substituted by one to three R 5b 取代 , and the 5 or 6-membered monocyclic heteroaryl is optionally replaced by C 1-3 Alkyl substitution; R 5a H, C 1-3 Alkyl or C 3-6 Cycloalkyl, wherein C 1-3 The alkyl group is optionally substituted with one to three halo groups; R 5b Each occurrence is independently selected 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 therein.

[0084] In a fifteenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 5 Each occurrence is independently selected from -CH3, -C(CH3)3, -CH2CH3, -CH2CN, -CF3, -CHOCH3, -OCH3, -OCHF2, -OCF3, -OCH2CH3, -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 therein. In an alternative fifteenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 5and -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 therein.

[0085] In a sixteenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the N atom to which they are attached, they form a 4- to 6-membered monocyclic heterocycle or a 6- to 10-membered bicyclic heterocycle, each of which is optionally substituted by 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 therein.

[0086] In a seventeenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the N atoms to which they are attached are

[0087] Each of which is optionally replaced by 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 therein. In an alternative seventeenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the following formula:

[0088]

[0089] wherein each formula depicted above is optionally replaced by 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 therein.

[0090] In an eighteenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the N atoms to which they are attached are Each of which is optionally replaced by 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 therein.

[0091] In a nineteenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the N atoms to which they are attached are

[0092]

[0093] 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 therein. In an alternative nineteenth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the following formula:

[0094] 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 therein.

[0095] In a twentieth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the N atoms to which they are attached are 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 therein.

[0096] In a twenty-first embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 4 Each occurrence is independently selected from halo, C 1-3 Alkyl and –OR 4a ; and R 4a H or C 1-3 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 therein.

[0097] In a twenty-second embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 4 and -CH3; 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 therein.

[0098] In a twenty-third embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 1 is H or optionally substituted by one to three R 4 Substituted C 1-3 Alkyl; R 2 C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl or 4 to 6 membered monocyclic heterocyclic group, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 The cycloalkenyl and 4 to 6 membered monocyclic heterocyclyl groups are each optionally substituted by one or two independently selected 1-3 Alkyl, C 1-3 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 therein. In an alternative twenty-third embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, R 1 is H or optionally substituted by one to three R 4 Substituted C 1-3 alkyl; and R 2 C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkenyl, 6 to 10 membered bicyclic heterocyclic group or 4 to 6 membered monocyclic heterocyclic group, wherein the 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 substituted by one or two independently selected 1-3 Alkyl, C 1-3 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 therein.

[0099] In a twenty-fourth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 1 is H or optionally substituted by one to three R 4 Substituted C 1-3 Alkyl; R 2 It is C 1-3 Alkoxy-substituted C 1-3 Alkyl, optionally substituted by one to two halo groups, C 3-6 Cycloalkyl, or optionally substituted by one or two C 1-3 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 therein. In an alternative twenty-fourth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, R 1 is H or optionally substituted by one to three R 4 Substituted C 1-3 alkyl; and R 2 It is C 1-3 Alkoxy or 4 to 6 membered monocyclic heterocyclic group substituted C 1-3 Alkyl, optionally substituted by one to two halo groups, C 3-6 Cycloalkyl, 6 to 10 membered bicyclic heterocyclic group, or optionally substituted by one or two C 1-3 alkyl-substituted 4- to 6-membered monocyclic heterocyclyl; and the remainder of the 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 therein.

[0100] In a twenty-fifth embodiment, for a compound of Formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically 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 - methyloxetane - 3 - yl, oxetane - 3 - ylmethyl, tetrahydrofuran - 3 - yl and 2 - oxaspiro[3.3]hept - 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 therein. In an alternative twenty - fifth embodiment, for a compound of formula (I), (II), (IIA), (IIB), (III), (IV), (IIIA), (IIIB), (IVA) or (IVB) or a pharmaceutically acceptable salt thereof, R 1 is H or methyl, and R 2 is 2 - methoxyethyl, - CH2 - tetrahydropyranyl, 4,4 - difluorocyclohexyl, 4 - fluorocyclohex - 3 - en - 1 - yl, 2,2 - difluoroethyl, 4 - methylpiperidinyl, tetrahydro - 2H - pyran - 4 - yl, oxetane - 3 - yl, 3 - methyloxetane - 3 - yl, tetrahydrofuran - 3 - yl, 3 - methyltetrahydrofuran - 3 - yl and 2 - oxaspiro[3.3]hept - 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 therein.

[0101] In a twenty - sixth embodiment, the compounds of the present disclosure are represented by the following formula:

[0102]

[0103] or a pharmaceutically acceptable salt thereof, wherein:

[0104] X is O or CH 2；

[0105] R 1 is H or C 4 alkyl optionally substituted with one to three R 1-3 ;

[0106] R 2 is C 1-3 alkyl substituted with C 1-3 alkoxy, C 3-6 cycloalkyl optionally substituted with one to two halogen atoms, or a 4 - to 6 - membered monocyclic heterocyclic group optionally substituted with one or two C 1-3 alkyl;

[0107] or R 1 and R2 Together with the nitrogen atom to which they are attached, they form a 4- to 6-membered monocyclic heterocycle, a 7- to 9-membered bicyclic heterocycle, each of which is optionally substituted by one or two R 4 replace;

[0108] R 4 Each occurrence is independently selected from C 1-3 Alkoxy, OH, halo and C 1-3 alkyl;

[0109] R 3 is phenyl, 5 or 6 membered monocyclic heteroaryl, 9 or 10 membered bicyclic heteroaryl or 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 are each optionally substituted by one to three R 5 replace;

[0110] R 5 For cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, OR 5a and halo, wherein the C 1-4 The alkyl group is optionally substituted by one to three R 5b replace;

[0111] R 5a is C optionally substituted by one to three halo groups 1-3 alkyl.

[0112] In some embodiments, for the compound of the twenty-sixth embodiment or a pharmaceutically acceptable salt thereof, (i) when X is O, and R 1 and R 2 When R is taken together with the nitrogen atom to which they are attached to form an unsaturated morpholine, an unsaturated pyrrolidine or an unsaturated N-methylpiperazine, 3 are each optionally substituted by one or more substituents R 5 substituted 9- or 10-membered bicyclic heteroaryl or 6- to 10-membered bicyclic heterocycle, or phenyl or 5- or 6-membered monocyclic heteroaryl, each of which is replaced by at least two R 5 Group or as OR 5a An R 5 (ii) when X is O, and R 1 and R 2 All C 1-6 When it is an alkyl group, R 1 and R 2 The C 1-6 At least one of the alkyl groups is replaced by one or more selected from OR 4a , halo and C 3-8 R of cycloalkyl 4 Substitution; (iii) when X is a bond, and R1 and R 2 All C 1-6 When it is an alkyl group, R 1 and R 2 The C 1-6 At least one of the alkyl groups is replaced by one or more R 4 or (iv) when p is 0 and q is 1, then X is O.

[0113] In an alternative twenty-sixth embodiment, the compounds of the present disclosure are represented by the formula:

[0114]

[0115] or a pharmaceutically acceptable salt thereof, wherein:

[0116] X is O or CH2;

[0117] R 1 is H or optionally substituted by one to three R 4 Substituted C 1-3 alkyl;

[0118] R 2 It is C 1-3 Alkoxy or 4 to 6 membered monocyclic heterocyclic group substituted C 1-3 Alkyl, optionally substituted by one to two halo groups, C 3-6 Cycloalkyl, 6 to 10 membered bicyclic heterocyclic group, or optionally substituted by one or two C 1-3 an alkyl-substituted 4- to 6-membered monocyclic heterocyclic group;

[0119] or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 4- to 6-membered monocyclic heterocycle, a 7- to 9-membered bicyclic heterocycle, each of which is optionally substituted by one or two R 4 replace;

[0120] R 4 Each occurrence is independently selected from C 1-3 Alkoxy, OH, halo and C 1-3 alkyl;

[0121] R 3 is phenyl, 5 or 6 membered monocyclic heteroaryl, 9 or 10 membered bicyclic heteroaryl or 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 are each optionally substituted by one to three R 5 replace;

[0122] R 5 For cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, OR5a and halo, wherein the C 1-4 The alkyl group is optionally substituted by one to three R 5b replace;

[0123] R 5a is C optionally substituted by one to three halo groups 1-3 alkyl.

[0124] In the twenty-seventh embodiment, for the compound of the twenty-sixth embodiment or a pharmaceutically acceptable salt thereof, R 1 is H or optionally substituted by one to three R 4 Substituted C 1-3 Alkyl, and R 2 It is C 1-3 Alkoxy-substituted C 1-3 Alkyl, or optionally substituted by one or two independently selected from halo and C 1-3 a 4- to 6-membered monocyclic heterocyclic group substituted by an alkyl substituent;

[0125] or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the following formula:

[0126]

[0127] Each of which is optionally replaced by one or two R 4 replace;

[0128] R 3 for Each of which is optionally replaced by one to three R 5 and the remaining variables are as described in the twenty-sixth embodiment.

[0129] In an alternative twenty-seventh embodiment, for the compound of the twenty-sixth embodiment or a pharmaceutically acceptable salt thereof, R 1 is H or optionally substituted by one to three R 4 Substituted C 1-3 Alkyl, and R 2 It is C 1-3 Alkoxy or 4 to 6 membered monocyclic heterocyclic group substituted C 1-3 alkyl, 6 to 10 membered bicyclic heterocyclic group, or optionally substituted by one or two independently selected from halo and C 1-3 a 4- to 6-membered monocyclic heterocyclic group substituted by an alkyl substituent;

[0130] or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the following formula:

[0131]

[0132] Each of which is optionally replaced by one or two R 4 replace;

[0133] R 3 for Each of which is optionally replaced by one to three R 5 and the remaining variables are as described in the twenty-sixth embodiment.

[0134] In the twenty-eighth embodiment, for the compound of the twenty-sixth embodiment or a pharmaceutically acceptable salt thereof, R 3 for

[0135] R 1 and R 2 Together with the nitrogen atoms to which they are attached are and the remaining variables are as described in the twenty-sixth or twenty-seventh embodiment, or any alternative embodiment described therein.

[0136] In an alternative twenty-eighth embodiment, for the compound of the twenty-sixth embodiment or a pharmaceutically acceptable salt thereof, R 3 for

[0137]

[0138] and

[0139] (1)R 1 is H or CH3, and R 2 is 2-methoxyethyl, oxetan-3-ylmethyl, 3-methyltetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, -CH2-tetrahydropyranyl or 2-oxaspiro[3.3]hept-6-yl; or

[0140] (2)R 1 and R 2 Together with the nitrogen atoms to which they are attached are and the remaining variables are as described in the twenty-sixth or twenty-seventh embodiment, or any alternative embodiment described therein.

[0141] In the twenty-ninth embodiment, for the compound of the twenty-sixth embodiment or a pharmaceutically acceptable salt thereof, R 4 Each occurrence is independently selected from halo, C 1-3 Alkyl and –OR 4a ; and R 4a H or C 1-3 alkyl; and the remainder of the variables are as described in the twenty-sixth, twenty-seventh, or twenty-eighth embodiment, or any alternative embodiment described therein.

[0142] In the thirtieth embodiment, for the compound of the twenty-sixth embodiment or a pharmaceutically acceptable salt thereof, R 4 Each occurrence is independently selected from -OCH3, F, -OH, or -CH3; and the remainder of the variables are as described in the twenty-sixth, twenty-seventh, or twenty-eighth embodiment, or any alternative embodiment described therein.

[0143] In the thirty-first embodiment, for the compound of the twenty-sixth embodiment or a pharmaceutically acceptable salt thereof, R 5 Each occurrence is independently selected from cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, OR 5a and halo, wherein the C 1-4 The alkyl group is optionally substituted by one to three R 5b Replacement; R 5a H, C 3-6 Cycloalkyl or C optionally substituted by one to three halo groups 1-3 Alkyl; R 5b Each occurrence is independently selected from halo and C 1-3 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 therein. In some embodiments, R 5a is a C substituted by one to three halo groups 1-3 alkyl.

[0144] In the thirty-second embodiment, for the compound of the twenty-sixth embodiment or a pharmaceutically acceptable salt thereof, R 5 and wherein each occurrence is independently selected from -CH3, -CF3, -OCH3, -OCHF2, -OCF3, -OH, -CN, F, Cl, -CH2OCH3, 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 therein.

[0145] In a thirty-third embodiment, the compounds of the present disclosure are represented by formula (V):

[0146]

[0147] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (V) are as defined above in the first aspect or the first embodiment or the second embodiment.

[0148] In a thirty-fourth embodiment, the compounds of the present disclosure are represented by formula (VA) or (VB),

[0149]

[0150] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (VA) or (VB) are as defined above in the first aspect or first embodiment or second embodiment.

[0151] In a thirty-fifth embodiment, for the compound of Formula (V), (VA) or (VB), or a pharmaceutically acceptable salt thereof, X is CH2; and the remaining variables are as described in the first aspect or the first embodiment or the second embodiment.

[0152] In a thirty-sixth embodiment, for the compound of Formula (V), (VA) or (VB) or a pharmaceutically acceptable salt thereof, R 3 is phenyl or 5 or 6-membered monocyclic heteroaryl, wherein the phenyl or 5 or 6-membered monocyclic heteroaryl are each optionally substituted by one to two substituents R 5 and the remaining variables are as described in the first aspect or the first, second or thirty-fifth embodiment.

[0153] In a thirty-seventh embodiment, for the compound of Formula (V), (VA) or (VB) or a pharmaceutically acceptable salt thereof, R 3 is pyridinyl, phenyl or pyrazolyl; and the remaining variables are as described in the first aspect or the first, second or thirty-fifth embodiment.

[0154] In a thirty-eighth embodiment, for the compound of Formula (V), (VA) or (VB) or a pharmaceutically acceptable salt thereof, R 3 for Each of which is optionally replaced by one or two R 5 and the remaining variables are as described in the first aspect or the first, second or thirty-fifth embodiment.

[0155] In a thirty-ninth embodiment, for the compound of Formula (V), (VA) or (VB) or a pharmaceutically acceptable salt thereof, R 3 for and the remaining variables are as described in the first aspect or the first, second or thirty-fifth embodiment.

[0156] In the fortieth embodiment, for the compound of Formula (V), (VA) or (VB) or a pharmaceutically acceptable salt thereof, R 5 Each occurrence is independently selected from cyano, C 1-4 Alkyl, OR 5a and halo, wherein the C 1-4 The alkyl group is optionally substituted by one to three R 5b Replacement, R 5a is C optionally substituted by one to three halo groups 1-3 Alkyl, R 5b 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 40th embodiment, for a compound of Formula (V), (VA) or (VB) or a pharmaceutically acceptable salt thereof, R 5 Each occurrence is independently selected from cyano, C 1-4 Alkyl, OR 5a 、C 3-4 Cycloalkyl and halo, wherein the C 1-4 The alkyl group is optionally substituted by one to three R 5b Replacement, R 5a is C optionally substituted by one to three halo groups 1-3 Alkyl, R 5b Each occurrence is 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.

[0157] In a forty-first embodiment, for a compound of Formula (V), (VA) or (VB), or a pharmaceutically acceptable salt thereof, R 5 Each occurrence is independently selected from -CH3, -CH2CH3, -CF3, -OCH3, -OCHF2, -OCF3, -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 a compound of Formula (V), (VA), or (VB), or a pharmaceutically acceptable salt thereof, R 5Each occurrence is independently selected from -CH3, -CHF2, -CH2CH3, -CF3, -OCH3, -OCHF2, -OCF3, -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.

[0158] In a 42nd embodiment, for a compound of Formula (V), (VA) or (VB) or a pharmaceutically acceptable salt thereof, if R 1 and R 2 All C 1-6 alkyl, then at least one of the C 1-6 The alkyl group is further supported by 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 therein.

[0159] In a forty-third embodiment, for a compound of Formula (V), (VA) or (VB) or a pharmaceutically acceptable salt thereof, R 1 H or C 1-3 Alkyl, and R 2 is optionally C 1-3 Alkoxy-substituted C 1-3 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 therein. In an alternative forty-third embodiment, for a compound of Formula (V), (VA) or (VB) or a pharmaceutically acceptable salt thereof, R 1 H or C 1-3 Alkyl, and R 2 is optionally C 1-3 Alkoxy-substituted C 1-3 alkyl or a 4 to 6 membered heterocyclyl; and the remainder of the 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 therein.

[0160] In a forty-fourth embodiment, for a compound of Formula (V), (VA) or (VB) or a pharmaceutically acceptable salt thereof, R 1 is –CH3 and R 2is -CH2OCH3; 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 therein. In an alternative forty-fourth embodiment, for a compound of Formula (V), (VA) or (VB) or a pharmaceutically acceptable salt thereof, R 1 is –CH3 and R 2 is -CH2CH2OCH3 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 therein.

[0161] In a forty-fifth embodiment, for a compound of Formula (V), (VA) or (VB) or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 4- to 6-membered monocyclic heterocycle or a 6- or 7-membered bicyclic heterocycle, each of which is optionally substituted by 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 therein.

[0162] In a forty-sixth embodiment, for a compound of Formula (V), (VA) or (VB) or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the N atoms to which they are attached are 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 therein. In an alternative forty-sixth embodiment, for a compound of Formula (V), (VA) or (VB) or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the N atoms to which they are attached are 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 therein.

[0163] In a forty-seventh embodiment, the compounds of the present disclosure are represented by formula (VI),

[0164]

[0165] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (VI) are as defined above in the first aspect or the first embodiment or the second embodiment.

[0166] In a forty-eighth embodiment, the compounds of the present disclosure are represented by formula (VIA) or (VIB),

[0167]

[0168] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (VIA) or (VIB) are as defined above in the first aspect or first embodiment or second embodiment.

[0169] In a forty-ninth embodiment, for the compound of Formula (VIA) or (VIB), or a pharmaceutically acceptable salt thereof, X is O; and the remaining variables are as described in the first aspect, or the first embodiment, or the second embodiment.

[0170] In a fiftieth embodiment, for the compound of Formula (VIA) or (VIB) or a pharmaceutically acceptable salt thereof, R 3 is optionally replaced by one or two R 4 substituted phenyl; and the remainder of the variables are as described in the first aspect or the first, second or forty-ninth embodiment.

[0171] In a fifty-first embodiment, for a compound of Formula (VIA) or (VIB) or a pharmaceutically acceptable salt thereof, R 3 for and the remaining variables are as described in the first aspect or the first, second or forty-ninth embodiment.

[0172] In a fifty-second embodiment, for the compound of Formula (VIA) or (VIB) or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the nitrogen atoms to which they are attached are and the remaining variables are as described in the first aspect or the first, second, forty-ninth, fiftieth or fifty-first embodiment.

[0173] In a fifty-third embodiment, the compounds of the present disclosure are represented by formula (VII):

[0174]

[0175] or a pharmaceutically acceptable salt thereof, wherein:

[0176] X is O, CH2 or a bond;

[0177] R 1 H and R 2 is a 4- to 6-membered monocyclic heterocyclic group or a 6- to 10-membered bicyclic heterocyclic group;

[0178] or R 1 and R 2 together with the nitrogen atom to which they are attached, form a 4- to 7-membered monocyclic heterocycle or a 6- to 10-membered bicyclic heterocycle;

[0179] R 3 is phenyl or a 5- or 6-membered monocyclic heteroaryl group, each of which is optionally substituted by one or two R 5 replace;

[0180] Each R 5 Independently selected from C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-4 Cycloalkyl, OR 5a , cyano and halo; and

[0181] R 5a C 1-3 Halogenated alkyl.

[0182] In a fifty-fourth embodiment, the compounds of the present disclosure are represented by formula (III) or (IV):

[0183]

[0184] or a pharmaceutically acceptable salt thereof; and the remaining variables are as described in the fifty-third embodiment.

[0185] In a fifty-fifth embodiment, the compounds of the present disclosure are represented by formula (IIIA), (IIIB), (IVA), or (IVB):

[0186]

[0187] or a pharmaceutically acceptable salt thereof; and the remaining variables are as described in the fifty-third embodiment.

[0188] In a fifty-sixth embodiment, for a compound of Formula (VII), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 3 is phenyl, pyrazolyl or pyridinyl, each of which is optionally substituted by one or two R 5 and the remaining variables are as described in the fifty-third, fifty-fourth or fifty-fifth embodiment.

[0189] In a fifty-seventh embodiment, for a compound of Formula (VII), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: wherein each formula depicted above is optionally replaced by one to two R 5 and the remaining variables are as described in the fifty-sixth embodiment.

[0190] In a fifty-eighth embodiment, for a compound of Formula (VII), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: And the remaining variables are as described in the fifty-sixth embodiment.

[0191] In a fifty-ninth embodiment, for a compound of Formula (VII), (III), (IV), (IIIA), (IIIB), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof:

[0192] (1)R 2 It is expressed by the following formula:

[0193] or

[0194] (2)R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the following formula:

[0195] And the remaining variables are as described in the fifty-third, fifty-fourth, fifty-fifth, fifty-sixth, fifty-seventh or fifty-eighth embodiment.

[0196] In the sixtieth embodiment, for the compound of Formula (VII), (III), (IV), (IIIA), (IIIB), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, each R 5 is independently selected from -CH3, -CF3, -F, -CN, and -OCHF2; and the remaining variables are as described in the fifty-third, fifty-fourth, fifty-fifth, fifty-sixth, fifty-seventh, fifty-eighth or fifty-ninth embodiment.

[0197] In a sixty-first embodiment, the compounds of the present disclosure are represented by formula (VIII):

[0198]

[0199] And the remaining variables are as described in the fifty-third embodiment.

[0200] In a sixty-second embodiment, the compounds of the present disclosure are represented by formula (VIIIA) or (VIIIB):

[0201]

[0202] And the remaining variables are as described in the fifty-third or sixty-first embodiment.

[0203] In the sixty-third embodiment, for the compound of Formula (VII), (VIII), (VIIIA), (VIIIB), or a pharmaceutically acceptable salt thereof, R 3 is pyrazolyl or pyridinyl, each of which is optionally substituted by one or two R 5 and the remaining variables are as described in the fifty-third, sixty-first or sixty-second embodiment.

[0204] In the sixty-fourth embodiment, for the compound of Formula (VII), (VIII), (VIIIA), (VIIIB), or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: wherein each formula depicted above is optionally replaced by one to two R 5 and the remaining variables are as described in the fifty-third, sixty-first, sixty-second or sixty-third embodiment.

[0205] In the sixty-fifth embodiment, for the compound of Formula (VII), (VIII), (VIIIA), (VIIIB), or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: And the remaining variables are as described in the fifty-third, sixty-first, sixty-second, sixty-third or sixty-fourth embodiment.

[0206] In the sixty-sixth embodiment, for the compound of Formula (VII), (VIII), (VIIIA), (VIIIB) or a pharmaceutically acceptable salt thereof:

[0207] (1)R 2 It is expressed by the following formula: or

[0208] (2)R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the following formula: And the remaining variables are as described in the fifty-third, sixty-first, sixty-second, sixty-third, sixty-fourth or sixty-fifth embodiment.

[0209] In the sixty-seventh embodiment, for the compound of Formula (VII), (VIII), (VIIIA), (VIIIB), or a pharmaceutically acceptable salt thereof, each R 5 is independently selected from -CH3, -CF3 and cyclopropyl; and the remaining variables are as described in the fifty-third, sixty-first, sixty-second, sixty-third, sixty-fourth, sixty-fifth or sixty-sixth embodiment.

[0210] In a sixty-eighth embodiment, the present disclosure provides a compound as described herein (eg, a compound of any one of Examples 1 to 144), or a pharmaceutically acceptable salt thereof.

[0211] In the sixty-ninth embodiment, the present disclosure provides a compound selected from the group consisting of:

[0212] 8-(Benzofuran-2-ylsulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane;

[0213] 8-((3-chloro-5-(methoxymethyl)phenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane;

[0214] 2-((3-morpholino-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-3-(trifluoromethoxy)phenol;

[0215] 8-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane;

[0216] 8-((5-methylthien-3-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane;

[0217] (R)- or (S)-8-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane;

[0218] 8-((4-Fluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane;

[0219] 4-((3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-3-chlorobenzonitrile;

[0220] 6-(8-((3-fluoro-4-methoxyphenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0221] 3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile;

[0222] 6-(8-((4-Fluorophenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0223] 3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile;

[0224] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]decane;

[0225] 4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile;

[0226] (R)-4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile;

[0227] (S)-4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile;

[0228] 4-Fluoro-3-((3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile;

[0229] 8-((2-methyl-4-(trifluoromethyl)phenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane;

[0230] 8-((2-fluoro-5-methylphenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane;

[0231] 8-((2,5-difluorophenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane;

[0232] 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane;

[0233] 4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine;

[0234] (R)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine;

[0235] (S)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine;

[0236] 4-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine;

[0237] 2-methyl-3-((2-morpholino-8-azaspiro[4.5]dec-8-yl)sulfonyl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole;

[0238] 4-(8-((3,5-dimethylpyridin-2-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine;

[0239] 4-(8-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine;

[0240] 5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;

[0241] (1R,4R)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;

[0242] 8-((4,6-dimethylpyridin-3-yl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane;

[0243] 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;

[0244] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane;

[0245] (S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((R)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane;

[0246] (S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((S)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane;

[0247] (R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((R)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane;

[0248] (R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((S)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane;

[0249] 4-(8-((7-fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine;

[0250] 4-(8-((5-cyclopropyloxypyridin-2-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine;

[0251] 4-(8-((3-fluoro-2-methoxypyridin-4-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine;

[0252] 4-(7-((1-ethyl-3-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine;

[0253] 4-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine;

[0254] 4-(7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine;

[0255] 4-(7-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine;

[0256] 4-(8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azaspiro[bicyclo[3.2.1]octane-3,1′-cyclobutane]-3′-yl)morpholine;

[0257] 7-((4-(difluoromethoxy)phenyl)sulfonyl)-3-morpholino-1-oxa-7-azaspiro[3.5]nonane;

[0258] 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-8-azaspiro[4.5]dec-2-amine;

[0259] 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(3-methyloxetan-3-yl)-8-azaspiro[4.5]dec-2-amine;

[0260] 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(3-methyltetrahydrofuran-3-yl)-8-azaspiro[4.5]dec-2-amine;

[0261] 2-(8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-6-oxa-2-azaspiro[3.4]octane;

[0262] 4-Fluoro-3-((3-((2-methoxyethyl)amino)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile;

[0263] 3-((3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-fluorobenzonitrile;

[0264] 3-((3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-fluorobenzonitrile;

[0265] 4-Fluoro-3-((3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile;

[0266] 3-((3-((4,4-difluorocyclohexyl)amino)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-fluorobenzonitrile;

[0267] 8-((2-chloro-4-methylphenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane;

[0268] 1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)-3-methylazetidin-3-ol;

[0269] 8-((2-chloro-4-methylphenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-1-oxa-8-azaspiro[4.5]dec-3-amine;

[0270] 1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)azetidin-3-ol;

[0271] (R)-1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)azetidin-3-ol;

[0272] (S)-1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)azetidin-3-ol;

[0273] 8-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane;

[0274] 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane;

[0275] 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane;

[0276] (R)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0277] (S)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0278] 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane;

[0279] 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]dec-3-amine;

[0280] 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-1-oxa-8-azaspiro[4.5]dec-3-amine;

[0281] 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane;

[0282] 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane;

[0283] (R)-8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane;

[0284] (S)-8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane;

[0285] 3-((3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-chlorobenzonitrile;

[0286] 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]dec-3-amine;

[0287] 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-(methyl-d3)-1-oxa-8-azaspiro[4.5]dec-3-amine;

[0288] 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-1-oxa-8-azaspiro[4.5]dec-3-amine;

[0289] 6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0290] (R)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0291] (S)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0292] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(6-oxa-2-azaspiro[3.4]oct-2-yl)-1-oxa-8-azaspiro[4.5]decane;

[0293] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane;

[0294] 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;

[0295] 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;

[0296] (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;

[0297] (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;

[0298] (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;

[0299] (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;

[0300] 4-(7-((4-(difluoromethoxy)phenyl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine;

[0301] 4-(7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine;

[0302] 6-(7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0303] 6-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0304] 6-(7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]non-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0305] 6-(7-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0306] 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;

[0307] 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;

[0308] 5-(7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]non-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;

[0309] (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;

[0310] 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;

[0311] (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;

[0312] 7-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-7-azaspiro[3.5]nonan-2-amine;

[0313] 7-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-7-azaspiro[3.5]nonan-2-amine;

[0314] 1-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-4-methylpiperidin-4-ol;

[0315] (R)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile;

[0316] (S)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile;

[0317] (1R,4R)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;

[0318] (1S,4S)-5-((R)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;

[0319] (1R,4R)-5-((R)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;

[0320] (1S,4S)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;

[0321] (1S,4S)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;

[0322] (1S,4S)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;

[0323] 7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-7-azaspiro[3.5]nonan-2-amine;

[0324] 6-(7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0325] 6-(7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]non-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0326] (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;

[0327] 1-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)azetidin-3-ol;

[0328] 3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-7-azaspiro[3.5]nonan-7-yl)sulfonyl)-5-fluorobenzonitrile;

[0329] 3-(((S)-2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile;

[0330] 3-Fluoro-5-((3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile;

[0331] 1-(8-((2-methoxy-6-methyl-2H-112-pyridin-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)azetidin-3-ol;

[0332] 8-((2-methoxy-6-methyl-2H-112-pyridin-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-8-azaspiro[4.5]dec-2-amine;

[0333] 6-(8-((5-(trifluoromethyl)furan-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0334] 6-(8-((7-Fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0335] 6-(8-(Quinolin-3-ylsulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0336] 3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-2-fluorobenzonitrile;

[0337] 6-(8-((2-methylfuran-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0338] 6-(8-((5-chloro-6-methoxypyridin-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0339] 6-(8-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0340] 6-(8-((4-ethoxyphenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0341] 6-(8-((5,6-dimethylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0342] 6-(8-((6-methoxypyridin-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0343] 6-(8-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0344] 6-(8-((2-methoxypyridin-4-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0345] 6-(8-((5-fluoro-2-methoxypyridin-4-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0346] 8-((5-chloro-6-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane;

[0347] 6-(8-((5-(trifluoromethoxy)pyridin-2-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0348] 8-((5-fluoro-2-methoxypyridin-4-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane;

[0349] 8-((2,4-dimethylphenyl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]dec-3-amine;

[0350] 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane;

[0351] Rac-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane;

[0352] (R)-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane;

[0353] (S)-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane;

[0354] 7-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-7-azaspiro[3.5]nonan-2-amine;

[0355] 6-(7-((6-(difluoromethoxy)-2-methyl-2,3,4,5-tetrahydropyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0356] 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;

[0357] 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;

[0358] 6-(8-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0359] 6-(8-((3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0360] 4-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-3-chlorobenzonitrile;

[0361] 5-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-2-fluorobenzonitrile;

[0362] 5-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-2-methylbenzonitrile;

[0363] 6-(8-((2-fluoro-4-methoxyphenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0364] 6-(8-((6-isopropoxypyridin-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0365] 6-(8-(pyrazolo[1,5-a]pyridin-6-ylsulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0366] 6-(8-((5-Fluoroquinolin-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0367] 6-(8-((3-Fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0368] 6-(8-((4-cyclopropyloxyphenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0369] 6-(8-(Benzofuran-6-ylsulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0370] 8-((2-fluoro-4-methoxyphenyl)sulfonyl)-N-methyl-N-(2-oxaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]dec-3-amine;

[0371] 8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]dec-3-amine;

[0372] 8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-1-oxa-8-azaspiro[4.5]dec-3-amine;

[0373] 8-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]dec-3-amine;

[0374] N-methyl-8-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decan-3-amine;

[0375] (S)-4-Fluoro-3-((3-(4-hydroxy-4-methylpiperidin-1-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile;

[0376] 6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0377] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(6-oxa-2-azaspiro[3.5]non-2-yl)-1-oxa-8-azaspiro[4.5]decane; and

[0378] 6-(8-(Quinolin-7-ylsulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0379] or a pharmaceutically acceptable salt thereof.

[0380] In some embodiments, compounds of Table I, or pharmaceutically acceptable salts thereof, are excluded from the compounds of the present disclosure (eg, compounds of Formula (I)).

[0381] Table I.

[0382]

[0383] In the 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 pharmaceutically acceptable salt thereof.

[0384] In the seventy-first embodiment, the present disclosure provides a method of treating a disease or condition 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 one to sixty-nine) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the fifty-fifth embodiment.

[0385] In the 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 one to sixty-nine) or a pharmaceutically acceptable salt thereof for use in treating a disease or condition mediated by EBP.

[0386] In the 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 one to sixty-nine) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or condition mediated by EBP.

[0387] In some embodiments, the compound useful in the methods and uses disclosed herein is any one of the compounds in Table 1 or a pharmaceutically acceptable salt thereof.

[0388] The compounds and intermediates described herein can be isolated and used as the compounds themselves. Alternatively, when there is a moiety capable of forming a salt, the compound or intermediate can be isolated and used as its corresponding salt. As used herein, the term "salt" refers to an acid addition salt or a base addition salt of the compound described herein. "Salt" particularly includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compound described herein and is generally not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are able to form acid salts and / or basic salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0389] Pharmaceutically acceptable acid addition salts can be formed with inorganic or organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

[0390] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0391] 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.

[0392] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0393] 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; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0394] 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, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0395] The salt can be synthesized from a compound containing an alkaline or acidic part by conventional chemical methods. Generally speaking, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, where feasible, it is desirable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Additional lists of suitable salts can be found in, for example, "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0396] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples and preparations using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed. In one embodiment, the present disclosure provides a deuterated compound as described herein or a pharmaceutically acceptable salt thereof.

[0397] Pharmaceutically acceptable solvates according to the present invention include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, d6-acetone, d6-DMSO.

[0398] 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 should be understood that substituents may be attached at chiral centers of carbon atoms. Therefore, the present disclosure includes enantiomers, diastereomers, or racemates of the compounds.

[0399] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the terms "racemic" or "rac" are used to specify a racemic mixture. When specifying the stereochemistry of the compound of the present invention, a single stereoisomer (e.g., (1S, 2S)) with the relative and absolute configuration of two known chiral centers is specified using the conventional RS system. "Diastereomers" 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 R-S system. When a compound is a pure enantiomer, the stereochemistry of each chiral carbon can be specified by R or S. The unknown splitting compound of absolute configuration can be specified as (+) or (-) according to the direction (right-handed or left-handed) of their rotation of plane polarized light at the sodium D line wavelength. Alternatively, the splitting compound can be defined by the respective retention times of the corresponding enantiomers / diastereomers via chiral HPLC.

[0400] Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

[0401] Unless otherwise indicated, 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 can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separation on a chiral SFC or HPLC column (such as CHIRALPAK available from DAICEL Corp. RTM and CHIRALCEL RTM ) are separated using an appropriate solvent or solvent mixture to achieve good separation. If the compound contains a double bond, the substituents may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0402] How to use

[0403] 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 a detectable decrease in EBP activity in vivo or in vitro (e.g., a decrease in EBP activity of at least 10% as measured by a given assay, such as a bioassay described in the Examples and known in the art).

[0404] In certain embodiments, the present disclosure provides a method of treating a disease or condition responsive to inhibition of EBP activity (referred to herein as an "EBP-mediated disease or condition" or "a disease or condition mediated by EBP") in a subject in need of treatment. The method comprises administering to the subject a compound described herein (e.g., a compound described in any one of the first to sixty-ninth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0405] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to sixty-ninth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an EBP-mediated condition or disease in a subject in need of treatment.

[0406] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to sixty-ninth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for use in treating an EBP-mediated condition or disease in a subject in need of treatment.

[0407] In certain embodiments, the EBP-mediated disorder is colorectal cancer.

[0408] In certain embodiments, the present disclosure provides a method for treating an autoimmune disease in a subject in need of treatment, comprising administering to the subject a compound as described herein (e.g., a compound described in any one of the first to sixty-ninth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0409] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to sixty-ninth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an autoimmune disease in a subject in need of treatment.

[0410] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to sixty-ninth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for use in treating an autoimmune disease in a subject in need of treatment.

[0411] 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 forms of multiple sclerosis), relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, and clinically isolated syndrome (hereinafter referred to as "CIS").

[0412] Relapsing forms of multiple sclerosis (or relapsing forms of multiple sclerosis) include clinically isolated syndrome, relapsing-remitting multiple sclerosis, and active secondary progressive multiple sclerosis.

[0413] Relapsing-remitting multiple sclerosis is a stage of MS characterized by unpredictable relapses followed by periods of relative calm (remission) lasting months to years, with no new signs of disease activity. The deficits experienced during an attack may resolve or remain, the latter occurring in about 40% of attacks and becoming more common the longer a person has had the disease. This describes the initial course of disease in 80% of donors with multiple sclerosis.

[0414] Secondary progressive MS develops in approximately 65% ​​of individuals with an initial relapsing-remitting MS. These individuals eventually experience progressive neurological decline between acute attacks without any clear remissions. Occasional relapses and minor remissions may occur. The most common interval between disease onset and transition from relapsing-remitting MS to secondary progressive MS is 19 years.

[0415] Primary progressive MS is characterized by the same symptoms as secondary progressive MS, namely, progressive neurologic decline between acute attacks without any clear remission periods and without preceding relapsing-remitting episodes.

[0416] CIS is the first attack of neurological symptoms due to central nervous system inflammation and demyelination. This attack, which must continue for at least 24 hours by definition, is a feature of multiple sclerosis, but the diagnostic criteria for MS are not yet met, because the person experiencing CIS may or may not go on to develop MS. When CIS is accompanied by lesions similar to those seen in MS on brain MRI (magnetic resonance imaging), the person has a high probability of secondary attacks of neurological symptoms and is diagnosed as relapsing-remitting MS. When CIS is not accompanied by MS-like lesions on brain MRI, the likelihood of the person developing MS is much lower.

[0417] In certain embodiments, the present disclosure provides a method for promoting myelination in a subject suffering from a myelin-related disease or condition in a subject in need of treatment. The method includes administering a compound as described herein (e.g., a compound described in any one of the first to sixty-ninth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject.

[0418] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to sixty-ninth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for promoting myelination in a subject with a myelin-related disease or disorder in need of treatment.

[0419] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to sixty-ninth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically 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.

[0420] In certain embodiments, the myelin-related disease or disorder is selected from multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), acute disseminated encephalomyelitis (ADEM), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease (PMD), white matter ablative encephalopathy, Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, disease), spinal cord injury, traumatic brain injury, post-radiation injury, neurologic complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome, autism, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillian-Barre syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination, such as neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophy, neonatal white matter injury, age-related dementia, and schizophrenia.

[0421] In certain embodiments, the present disclosure provides a method for treating cancer in a subject in need of treatment, comprising administering to the subject a compound as described herein (e.g., a compound described in any one of the first to sixty-ninth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0422] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to sixty-ninth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer in a subject in need of treatment.

[0423] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to sixty-ninth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject in need of treatment.

[0424] In certain embodiments, the cancer is colorectal cancer.

[0425] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the subject is a mammal. In certain embodiments, the subject is a primate. In certain embodiments, the subject is a human.

[0426] As used herein, "effective amount" and "therapeutically effective amount" are used interchangeably. It means an amount that is effective to treat one or more of the diseases, conditions, or disorders described herein or to lessen their severity. In some embodiments, the effective dose may be between 10 μg and 500 mg.

[0427] According to the methods of the present disclosure, the compounds and compositions 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-mentioned diseases, conditions, or disorders.

[0428] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the compound is administered parenterally. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectal, intrathecal, topically, or intranasally. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the compound is administered systemically.

[0429] The compound of the present invention can be used as a pharmaceutical composition (for example, a compound of the present invention and at least one pharmaceutically acceptable carrier). As used herein, the term "pharmaceutically acceptable carrier" includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (for example, antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, pharmaceutical stabilizers, buffers (for example, maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.) and combinations thereof, as known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th edition Mack Printing Company, 1990, pages 1289-1329). Except for the case where any conventional carrier is incompatible with the active ingredient, its use in treatment or pharmaceutical compositions is considered. For the purposes of this disclosure, solvates and hydrates are considered to be pharmaceutical compositions comprising the compound of the present invention and solvent (that is, solvate) or water (that is, hydrate).

[0430] The formulations can be prepared using conventional dissolution and mixing procedures. For example, the raw drug substance (i.e., a 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 a readily controllable drug dosage and provide patients with an elegant and easy-to-handle product.

[0431] The pharmaceutical composition (or preparation) for application can be packaged in a variety of ways according to the method for administering the drug. Generally speaking, the article for distribution includes a container in which a pharmaceutical preparation in an appropriate form is placed. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, etc. The container can also include a tamper-proof component to prevent inadvertent contact with the contents of the package. In addition, a label describing the contents of the container is also placed on the container. The label can also include appropriate warnings.

[0432] Pharmaceutical compositions containing compounds of the present disclosure are typically formulated for use as suppositories for parenteral or oral administration or alternatively.

[0433] For example, the pharmaceutical oral compositions of the present disclosure can be prepared into solid forms (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or liquid forms (including but not limited to solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations, such as sterilization, and / or can contain conventional inert diluents, lubricants or buffers and adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

[0434] Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient together with

[0435] a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0436] b) lubricants, for example silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets, also

[0437] c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; and, if desired,

[0438] d) disintegrants, for example starch, agar, alginic acid or its sodium salt or effervescent mixtures; and / or

[0439] e) absorbents, colorants, flavorings and sweeteners.

[0440] Tablets may be film coated or enteric coated according to methods known in the art.

[0441] Suitable compositions for oral administration include 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 manufacturing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavorings, colorants, and preservatives to provide pharmaceutically elegant and palatable preparations. Tablets may contain active ingredients mixed with non-toxic, pharmaceutically acceptable excipients suitable for making tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained effect over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g. calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium (e.g. peanut oil, liquid paraffin or olive oil).

[0442] Parenteral compositions (e.g., intravenous (IV) formulations) are aqueous isotonic solutions or suspensions. Parenteral compositions can be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts for regulating osmotic pressure, and / or buffers. In addition, they can also contain other therapeutically valuable substances. Said compositions are typically prepared according to conventional mixing, granulation, or coating methods, respectively, and contain about 0.1-75% or about 1-50% active ingredient.

[0443] The compounds of the present disclosure or their pharmaceutical compositions for subjects (e.g., people) are typically administered orally or parenterally in therapeutic doses. When administered intravenously via infusion, the dosage may depend on the infusion rate of the IV preparation. Generally speaking, the therapeutically effective dose of a compound, pharmaceutical composition, or its combination depends on the species, body weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity. A physician, pharmacist, clinician, or veterinarian of ordinary skill can easily determine the effective amount of each active ingredient required for preventing, treating, or suppressing disorder or disease progression.

[0444] The above-mentioned dosage characteristics can be demonstrated by in vitro and in vivo tests, advantageously using mammals, such as mice, rats, dogs, monkeys or their isolated organs, tissues and preparations. The compounds of the present invention can be applied in vitro in the form of solutions, such as aqueous solutions, and can be applied in vivo enterally, parenterally, advantageously intravenously, for example as a suspension or in the form of an aqueous solution. In vitro dosages may range from about 10<-3 > molar to 10<-9 > molar concentrations.

[0445] definition

[0446] As used herein, "patient," "subject," or "individual" are used interchangeably and refer to a human or non-human animal. The terms include mammals, such as humans. Typically, the animal is a mammal. Subject also refers to, for example, primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the animal is a primate. Preferably, the subject is a human.

[0447] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to a reduction or suppression of a given condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0448] As used herein, the terms "treat," "treating," or "treatment" of any disease, disorder, or condition refer to the management and care of a patient for the purpose of combating the disease, disorder, or condition, and include the administration of a compound of the present invention to obtain the 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, disorder, or condition; improving or ameliorating clinical symptoms, complications, or indicators associated with the disease, disorder, or condition; or delaying, inhibiting, or reducing the likelihood of progression of the disease, disorder, or condition; or eliminating the disease, disorder, or condition. In certain embodiments, the effect may be preventing the onset of symptoms or complications of the disease, disorder, or condition.

[0449] As used herein, the term "cancer" has the meaning generally accepted in the art. The term can broadly refer to abnormal cell growth.

[0450] As used herein, the term "autoimmune disease" has the meaning generally accepted in the art. The term can broadly refer to a disease in which the host's immune system targets or attacks the host's normal or healthy tissues.

[0451] As used herein, the term "myelination" has the meaning generally accepted in the art. The term can broadly refer to the process of myelin production.

[0452] As used herein, the terms "myelin-related diseases or disorders," "demyelinating disorders," or "demyelinating disorders" have the meanings generally accepted in the art. These terms broadly refer to diseases or disorders involving myelin damage.

[0453] As used herein, a subject (preferably a human) is "in need of" treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0454] As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "optionally substituted" refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described in the definitions and in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent at each position may be the same or different.

[0455] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms. The term "C 1-3 Alkyl" and "C 1-2 Alkyl" should be interpreted accordingly. 1-4 Representative examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Similarly, the alkyl portion of an alkoxy group (i.e., an alkyl moiety) 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 one to three substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl groups).

[0456] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (ie, --O--C 1-4 Alkyl, where C 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, the alkoxy has about 1-4 carbon atoms, more preferably about 1-2 carbon atoms. The term "C 1-2 "Alkoxy" should be interpreted accordingly.

[0457] As used herein, the term "C 1-4 Alkoxy C1-4 "Alkyl" means a C 1-4 Alkyl groups in which at least one of the hydrogen atoms is replaced by a C 1-4 Alkoxy substitution. C 1-4 Alkoxy C 1-4 The alkyl group is attached to the rest of the molecule described herein through the alkyl group.

[0458] 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.

[0459] "Halogen" or "halo" may be fluorine, chlorine, bromine or iodine.

[0460] As used herein, the term "halo-substituted C 1-4 Alkyl" or "C 1-4 "Haloalkyl" refers to a C 1-4 Alkyl group in which at least one of the hydrogen atoms is replaced by a halogen atom. 1-4 The haloalkyl group may be a monohalogenated-C 1-4 Alkyl, dihalogenated-C 1-4 Alkyl or polyhalogenated-C 1-4 Alkyl (including perhalogenated-C 1-4 alkyl). Monohalogenated-C 1-4 The alkyl group may have one iodine, bromine, chlorine or fluorine within the alkyl group. 1-4 Alkyl and polyhalogenated-C 1-4 An alkyl group may have two or more of the same halogenated atoms or a combination of different halogenated groups within the alkyl group. 1-4 The alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halogen groups. 1-4 Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. 1-4 Alkyl refers to a C-H group in which all hydrogen atoms are replaced by halogen atoms. 1-4 Alkyl group.

[0461] The term "aryl" refers to an aromatic carbocyclic monocyclic ring or two fused ring systems containing 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0462] The term "heteroaryl" refers to a 5 to 12-membered aromatic group containing 1 to 4 heteroatoms selected from N, O and S. In some cases, the nitrogen atom in the heteroaryl group can be quaternized. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic." A heteroaryl group can be monocyclic or bicyclic. Monocyclic heteroaryls include, for example, pyrazolyl, imidazolyl, oxazolyl, pyridyl, furyl, oxadiazolyl, thienyl, etc. Bicyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaromatic rings. Non-limiting examples include pyrazolopyridyl, pyrazolopyridyl, benzotriazolyl, imidazopyridyl, and indolyl.

[0463] The term "carbocycle" or "carbocyclyl" refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring and can exist as a monocycle, a bicyclic ring (including fused, spiral or bridged carbocycles) or a spirocycle. Bicyclic carbocyclyl groups include, for example, unsaturated carbocyclic groups fused to another unsaturated carbocyclic group, a cycloalkyl group or an aryl group, such as 2,3-dihydroindenyl, decahydronaphthyl and 1,2,3,4-tetrahydronaphthyl. Unless otherwise indicated, carbocycles typically contain 4 to 10 ring members.

[0464] The term "C 3-6 "Cycloalkyl" refers to a fully saturated carbocyclic ring (eg, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0465] The term "heterocycle" or "heterocyclyl" refers to a 4 to 12-membered saturated or partially unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from N, O and S. The heterocyclyl group can be a monocyclic or bicyclic ring (for example, bridged, fused or spiral bicyclic). The example of a monocyclic saturated or partially unsaturated heterocyclyl includes but is not limited to oxetane, tetrahydrofuranyl, tetrahydropyranyl and piperidinyl. Bicyclic heterocyclyl groups include, for example, unsaturated heterocyclyls fused to another unsaturated heterocyclyl, cycloalkyl, aryl or heteroaryl ring, such as tetrahydro-3H-[1,2,3]triazolo[4,5-c]pyridyl, 2-oxa-6-azaspiro[3.3]heptyl, 5-oxabicyclo[2.1.1]hexyl and 9-azabicyclo[3.3.1]nonyl. In some embodiments, the heterocyclyl group is a 4 to 6-membered monocyclic heterocyclyl group. In some embodiments, the heterocyclyl group is a 4- to 6-membered monocyclic saturated heterocyclyl group. In some embodiments, the heterocyclyl group is an 8- to 10-membered bicyclic heterocyclyl group. In some embodiments, the heterocyclyl group is an 8- to 10-membered bicyclic saturated heterocyclyl group.

[0466] As used herein, the term "spiro" ring refers to a bicyclic ring system in which the two rings share a common carbon atom. Examples of spiro rings include 2-oxa-6-azaspiro[3.3]heptyl and the like.

[0467] The term "fused" ring refers to two ring systems that share two adjacent ring atoms. A fused heterocycle has at least one ring system containing a ring atom that is a heteroatom selected from O, N, and S (e.g., 3-oxabicyclo[3.1.0]hexane).

[0468] As used herein, the term "bridged" refers to a 5- to 10-membered cyclic moiety that is linked at two non-adjacent ring atoms (eg, 5-oxabicyclo[2.1.1]hexane).

[0469] The language "pharmaceutically acceptable" means that the substance, composition or dosage form must be compatible chemically and / or toxicologically with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0470] Unless otherwise indicated, the term "compound of the present disclosure" refers to a compound of formula (I) and all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers, isotope-labeled compounds (including deuterium substitution). When there is a moiety capable of forming a salt, the salt (particularly a pharmaceutically acceptable salt) is also included.

[0471] As used herein, the terms "a / an", "the", and similar terms used in the context of the present invention (particularly in the context of the claims) should be interpreted as covering both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present invention and does not limit the scope of the invention as originally claimed.

[0472] The intermediates and compounds of the present invention may also 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 can be interconverted via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via the migration of a proton, such as keto-enol and imine-enamine isomerizations. The specific example of a proton tautomer is an imidazole moiety in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0473] In one embodiment, the present disclosure relates to a compound of formula (I) as defined herein in free form. In another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in salt form. In another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in acid addition salt form. In yet another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in pharmaceutically acceptable salt form. In yet another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in pharmaceutically acceptable acid addition salt form. In yet another embodiment, the present disclosure relates to any one of the compounds in the Examples in free form. In yet another embodiment, the present disclosure relates to any one of the compounds in the Examples in salt form. In yet another embodiment, the present disclosure relates to any one of the compounds in the Examples in acid addition salt form. In yet another embodiment, the present disclosure relates to any one of the compounds in the Examples in pharmaceutically acceptable salt form. In yet another embodiment, the present disclosure relates to any one of the compounds in the Examples in pharmaceutically acceptable acid addition salt form.

[0474] The compounds of the present disclosure can be synthesized by synthetic routes including methods analogous 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 are readily prepared using methods well known to those skilled in the art (e.g., by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, Vols. 1-19, Wiley, New York (1967-1999 editions) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

[0475] For illustrative purposes, the reaction scheme described below provides a possible approach for synthesizing compounds disclosed herein and key intermediates. For a more detailed description of each reaction step, see the Examples section below. Although specific parent material and reagent are described and discussed below in the scheme, other parent material and reagent can be easily replaced to provide multiple derivatives and / or reaction conditions.

[0476] Example

[0477] abbreviation:

[0478] PE = Petroleum Ether

[0479] EtOAc=EA=ethyl acetate

[0480] ESI = Electrospray Ionization

[0481] MeOH = methanol

[0482] EtOH = ethanol

[0483] DCE = 1,2-dichloroethane

[0484] DCM = dichloromethane

[0485] CHCl3=chloroform

[0486] HCl = hydrochloric acid

[0487] H2O=water

[0488] IPA = Isopropyl alcohol

[0489] LCMS = Liquid Chromatography Mass Spectrometry

[0490] HFIP = Hexafluoro-2-isopropanol

[0491] HPLC = High Pressure Liquid Chromatography

[0492] THF = Tetrahydrofuran

[0493] MeCN=ACN=acetonitrile

[0494] MgSO4 = magnesium sulfate

[0495] DMSO = dimethyl sulfoxide

[0496] AcOH = acetic acid

[0497] TFA = trifluoroacetic acid

[0498] DIPEA = diisopropylethylamine

[0499] N2 = Nitrogen

[0500] NH4HCO3=ammonium bicarbonate

[0501] t-BuOH = tert-butyl alcohol

[0502] NH4Cl = ammonium chloride

[0503] NaH = Sodium Hydride

[0504] Na2SO4=Sodium sulfate

[0505] K2CO3=potassium carbonate

[0506] NaHCO3 = Sodium bicarbonate

[0507] NaBH(OAc)3=STAB=sodium triacetoxyborohydride

[0508] SiO2 = silicon dioxide or silica;

[0509] PDA = Photodiode Array Detection

[0510] General approach

[0511] LCMS instrument specifications:

[0512] Agilent Technologies 1200 Series LC / MSD system: DAD / ELSD Alltech 3300 and Agilent LC / MSD G6130A, G6120B mass spectrometers.

[0513] Agilent Technologies 1260 Infinity LC / MSD system: DAD\ELSD Alltech 3300 and Agilent LC\MSD G6120B mass spectrometer.

[0514] Agilent Technologies 1260 Infinity II LC / MSD system: DAD\ELSD G7102A1290 Infinity II and Agilent LC\MSD G6120B mass spectrometer.

[0515] Agilent 1260 Series LC / MSD system: DAD\ELSD and Agilent LC\MSD (G6120B) mass spectrometer.

[0516] UHPLC Agilent 1290 Series LC / MSD system: DAD\ELSD and Agilent LC\MSD (G6125B) mass spectrometer.

[0517] HPLC analysis method specifications:

[0518] Column: Agilent Poroshell 120SB-C18 4.6x 30mm 2.7μm, with UHPLC GuardInfinity Lab Poroshell 120SB-C18 4.6x 5mm 2.7μm

[0519] Column temperature, 60°C

[0520] Injection volume 0.5 μL

[0521] Modifier: Formic acid concentration 0.1% (v / v).

[0522] 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.

[0523] UV scanning: 207-223nm, 246-262nm, 272-288nm

[0524] QC analysis LC / MS method conditions:

[0525] Ammonium hydroxide (alkaline pH) conditions

[0526] MS mode: MS: ESI+ scan range 165-650 Daltons

[0527] PDA: 200-400nm scanning range

[0528] Column: Waters ACQUITY UPLC BEH C18 2.1 x 50 mm, 1.7 μm; part number 186002350

[0529] Modifier: ammonium hydroxide concentration 0.2% (v / v).

[0530] Method: Linear gradient from 95% water / 5% MeCN (initial conditions) at 3.75 minutes to 5% water / 95% MeCN, hold at 5% water / 95% MeCN until 4 minutes. Flow rate: 0.8 mL / min.

[0531] Trifluoroacetic acid (acidic pH) conditions

[0532] MS mode: MS: ESI+ scan range 165-650 Daltons

[0533] PDA: 200-400nm scanning range

[0534] Column: Waters ACQUITY UPLC BEH C18 2.1 x 50 mm, 1.7 μm; part number 186002350

[0535] Modifier: trifluoroacetic acid concentration 0.1% (v / v)

[0536] Method: Linear gradient from 95% water / 5% MeCN (initial conditions) at 3.75 minutes to 5% water / 95% MeCN, hold at 5% water / 95% MeCN until 4 minutes. Flow rate: 0.8 mL / min.

[0537] General preparative HPLC conditions:

[0538] Ammonium hydroxide (alkaline pH) conditions

[0539] Flow rate: 30mL / min

[0540] MS mode: MS: ESI+ scan range 165-650 Daltons

[0541] PDA: 200-400nm scanning range

[0542] Column: Waters XSELECT CSH C18 PREP 19x100 mm, 5 μm; part number 186005421

[0543] Modifier: 0.2% ammonium hydroxide (v / v) concentration

[0544] Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN at 8 min, increasing to 5% water / 95% MeCN at 8.5 min, maintaining 5% water / 95% MeCN until 10 min.

[0545] Flow rate: 50mL / min

[0546] MS mode: MS: ESI+ scan range 165-650 Daltons

[0547] PDA: 200-400nm scanning range

[0548] Column: Waters XSELECT CSH C18 PREP 30x100 mm, 5 μm; part number 186005425

[0549] Modifier: 0.2% NH4OH (v / v) concentration.

[0550] Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN at 8 min, increasing to 5% water / 95% MeCN at 8.5 min, maintaining 5% water / 95% MeCN until 10 min.

[0551] Flow rate, 60mL / min

[0552] MS mode: MS: ESI+ scan range 165-650 Daltons

[0553] PDA: 200-400nm scanning range

[0554] Column: Waters XSELECT CSH C18 PREP 30x50 mm, 5 μm; part number 186005423

[0555] Modifier: 0.2% NH4OH (v / v) concentration.

[0556] Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN at 8 min, increasing to 5% water / 95% MeCN at 8.5 min, maintaining 5% water / 95% MeCN until 10 min.

[0557] Trifluoroacetic acid (acidic pH) conditions

[0558] Flow rate, 30mL / min

[0559] MS mode: MS: ESI+ scan range 165-650 Daltons

[0560] PDA: 200-400nm scanning range

[0561] Column: Waters Sunfire OBD C18 PREP 19x100 mm, 5 μm; part number 186002567

[0562] Modifier: 0.1% trifluoroacetic acid (v / v) concentration

[0563] Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN at 8 min, increasing to 5% water / 95% MeCN at 8.5 min, maintaining 5% water / 95% MeCN until 10 min.

[0564] Flow rate, 50mL / min

[0565] MS mode: MS: ESI+ scan range 165-650 Daltons

[0566] PDA: 200-400nm scanning range

[0567] Column: Waters Sunfire OBD C18 PREP 30x100 mm, 5 μm; part number 186002572

[0568] Modifier: 0.1% trifluoroacetic acid (v / v) concentration

[0569] Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN at 8 min, increasing to 5% water / 95% MeCN at 8.5 min, maintaining 5% water / 95% MeCN until 10 min.

[0570] Flow rate, 60mL / min

[0571] MS mode: MS: ESI+ scan range 165-650 Daltons

[0572] PDA: 200-400nm scanning range

[0573] Column: Waters Sunfire OBD C18 PREP 30x50 mm, 5 μm; part number 186002570

[0574] Modifier: 0.1% trifluoroacetic acid (v / v) concentration

[0575] Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN at 8 min, increasing to 5% water / 95% MeCN at 8.5 min, maintaining 5% water / 95% MeCN until 10 min.

[0576] Preparation of intermediates

[0577] Intermediate A: 3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride

[0578]

[0579] 1. Synthesis of tert-butyl 3-morpholino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

[0580] The reaction vessel was charged with tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-formate (2 g, 7.8 mmol), morpholine (1.0 mL, 11.8 mmol) and NaBH(OAc)3(3.3 g, 15.7 mmol) in DCE (20 mL), and the resulting solution was stirred at room temperature for 24 hours. The reaction mixture was evaporated and diluted with 2M K2CO3 aqueous solution (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-formate was used in the next step without further purification. LCMS m / z=327.1[M+H] + .

[0581] 2. Synthesis of 3-morpholino-1-oxa-8-azaspiro[4.5]decane

[0582] The reaction vessel was charged with tert-butyl 3-morpholino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (2.4 g, 7.4 mmol) and 10% HCl in dioxane (10.4 mL, 29.4 mmol) in dioxane (10 mL) and the resulting solution was stirred at 50° C. for 24 hours. The reaction mixture was filtered, 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] + .

[0583] Examples 1 to 5

[0584] The title compound was prepared in a single-step library at a scale of approximately 50 mg of desired product using the following protocol.

[0585]

[0586] The appropriate sulfonyl chloride (1.1 eq) was added to a solution of 3-(morpholino-4-yl)-1-oxa-8-azaspiro[4.5]decane dihydrochloride (1.0 eq) and DIPEA (4.5 eq + 1.1 eq per acid equivalent for the sulfonyl chloride building block salt) in anhydrous 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 20x100 5 mm; method: water-MeOH-NH3 0.1% as mobile phase) to give the pure product.

[0587]

[0588]

[0589] Example 6: 7-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-7-azaspiro[3.5]nonan-2-amine

[0590]

[0591] 1. Synthesis of 7-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one

[0592]

[0593] At <5 DEG C, DIPEA (0.6mL, 3.4mmol) is added dropwise into the bottle equipped with 7-azaspiro [3.5] nonyl-2-one hydrochloride (184mg, 1.1mmol) in anhydrous DCM (4mL). After 5 minutes, 4-methyl-6-(trifluoromethyl) pyridine-3-sulfonyl chloride (351mg, 1.4mmol) is added. The reaction is allowed to reach room temperature and stirred for 30 minutes, and the reaction is quenched by slowly adding 1M NaOH aqueous solution and stirred for another 10 minutes. The two-phase mixture is directly loaded onto silica gel and purified by column chromatography (20-70% EtOAc in heptane), 7-((4-methyl-6-(trifluoromethyl) pyridin-3-yl) sulfonyl)-7-azaspiro [3.5] nonyl-2-one (285mg, 75%) is obtained as a white solid, which is not further purified and used for the next step. LCMS m / z=363.2(M+H) + . 1 H-NMR (500MHz, DCM-d2) 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).

[0594] 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

[0595]

[0596] 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 the dropwise addition of AcOH (30 μL, 0.5 mmol) at room temperature. After 15 minutes, NaBH(OAc) (199 mg, 0.94 mmol) was added. After 6 hours, the reaction mixture was quenched with saturated aqueous NH4Cl, stirred for 10 minutes and extracted with DCM (3x). The organic layer was dried over anhydrous MgSO4. 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 afford 7-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-7-azaspiro[3.5]nonan-2-amine (30 mg, 28%) as a colorless film. LCMS m / z = 448.2 (M+H) + .1 H-NMR (500MHz, CDCl3) 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).

[0597] Example 7: (R)- or (S)-8-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane

[0598]

[0599] 1. Synthesis of (R)-3-morpholino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester and (S)-3-morpholino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[0600]

[0601] NaBH(OAc) (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 stirred at 20° C. under N for 12 hours. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (0% to 60%, EtOAc in PE) to give tert-butyl 3-morpholino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (20 g, 87%). This was further purified by prep-SFC (column: ChiralPak AD-3 150×4.6 mm ID, 3 μm; mobile phase: A: CO 2 B: ethanol (0.05% DEA); gradient: 5% to 40% B in 4.5 minutes, then 5% B for 1.5 minutes; flow rate: 2.5 mL / min; column temperature: 40° C.; pressure 100 bar) to give:

[0602] The first eluting peak E1 (5.1 g, 22%) was a white solid. LCMS m / z = 327.2 [M+H] + . v (400MHz, CDCl3) δ (ppm): 4.00 (dd, J=6.8, 8.4Hz, 1H), 3.74-3.66 (m, 5H), 3.56 (s, 2H), 3.35-3.24 (m, 2H), 2.96 (d, J=7.6Hz, 1H),2.54-2.43(m,2H),2.42-2.32(m,2H),1.96(dd,J=7.6,12.0Hz,1H),1.66-1.58(m,4H),1.53-1.46(m,1H),1.44(s,9H).

[0603] and the second eluting peak E2 (6.2 g, 27%) as a white solid. LCMS m / z=327.2 [M+H] + . 1 H-NMR: (400MHz, CDCl3) δ (ppm): 4.00 (dd, J=6.8, 8.4Hz, 1H), 3.75-3.67 (m, 5H), 3.63-3.51 (m, 2H), 3.36-3.25 (m, 2H), 2.96 (d, J=7 .6Hz,1H),2.54-2.44(m,2H),2.43-2.34(m,2H),1.96(dd,J=7.6,12.0Hz,1H),1.65-1.59(m,4H),1.53-1.47(m,1H),1.44(s,9H).

[0604] 2. Synthesis of (R) or (S)-3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride

[0605]

[0606] To a solution of (R)- or (S)-3-morpholino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (326 mg, 1.0 mmol) in EtOAc (2 mL) was added HCl (1 M, 3.0 mL) in EtOAc and the reaction was stirred at room temperature overnight. The resulting white suspension was filtered and washed with Et2O to give (R)- or (S)-3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride as a white solid. LCMS m / z=227.1[M+H] + .

[0607] 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

[0608]

[0609] 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 hours. The organic phase was washed with saturated NaHCO and water, dried over MgSO, filtered and concentrated. 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 (400MHz, CD3OD): δ (ppm): 7.11 (s, 1H), 4.14 (s, 3H), 3.98 (dd, J = 8.7, 6.9Hz, 1H), 3.67 (t, J = 4.8Hz, 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).

[0610] Intermediate B: Synthesis of 3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane

[0611]

[0612] 1. Synthesis of tert-butyl 3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

[0613] 2- oxa -6- azaspiro [3.3] heptane hydrochloride (186mg, 1.9mmol) is added to a solution of 3- oxo -1- oxa -8- azaspiro [4.5] decane -8- tert-butyl formate (400mg, 1.6mmol) in DCM (40mL) and the reaction is stirred at room temperature for 15 minutes. Acetic acid (180 μ L, 3.1mmol) is added dropwise, followed by addition of NaBH (OAc) after 30 minutes (1.3g, 6.3mmol). The reaction mixture is stirred at room temperature until starting material is consumed. Add salt solution (20mL) and DCM (40mL), separate each layer, organic layer is washed with water (20mL) and salt solution (20mL), through Na SO Drying, filter and evaporated under reduced pressure, obtain 3- (2- oxa -6- azaspiro [3.3] heptane -6- bases) -1- oxa -8- azaspiro [4.5] decane -8- tert-butyl formate. LCMS m / z=339.1[M+H] + .

[0614] 2. Synthesis of 3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane

[0615] To a solution of tert-butyl 3-(2-oxa-6-azaspiro[3.3]hept-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 hour. 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]hept-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] + .

[0616] Intermediate C: Synthesis of 6-(8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane

[0617]

[0618] 1. Synthesis of tert-butyl 3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

[0619] 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]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.0 g, 81%) as a light yellow oil. LCMS m / z=337.2 [M+H] + .

[0620] 2. Synthesis of 6-(8-azaspiro[4.5]dec-3-yl)-2-oxa-6-azaspiro[3.3]heptane

[0621] To a solution of tert-butyl 3-(2-oxa-6-azaspiro[3.3]hept-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) was added TFA (410 μL, 5.4 mmol), and the mixture was stirred at 25 ° C for 1 hour. DIPEA (3 mL, 17.3 mmol) was added, and the resulting mixture was concentrated under reduced pressure to give 6-(8-azaspiro[4.5]dec-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] + .

[0622] Examples 8 to 13

[0623] The title compound was prepared in a single-step library scale at approximately 60 mg of desired product using the following protocol.

[0624]

[0625] The appropriate sulfonyl chloride (1.0 equiv) is added to a solution of 3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane (1.0 equiv) or 6-(8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane (1.0 equiv) and DIPEA (2.0 equiv) in anhydrous DCM (10 mL) and the reaction mixture is stirred at room temperature for 30 minutes. The solid is filtered off and the filtrate is concentrated under reduced pressure. The resulting residue is purified by preparative HPLC (column: Welch Xtimate C18 150x25mm x 5um; condition: water (10mM NH4HCO3)-MeCN) with an appropriate gradient to give the desired product.

[0626]

[0627]

[0628] Example 14: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]decane

[0629]

[0630] 1. Synthesis of tert-butyl 3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

[0631]

[0632] 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 minutes. Acetic acid (180 μL, 3.1 mmol) was added dropwise, the solution was stirred for another 30 minutes, NaBH(OAc) 3 (1.3 g, 6.3 mmol) was added, and the reaction was stirred at room temperature for 6 hours. The reaction was quenched with saturated NH 4 Cl aqueous solution and diluted with DCM. The organic matter was washed with water and brine, then concentrated in vacuo to give the desired product (450 mg, 70%) without further purification. LCMS m / z=325.2[M+H] + .

[0633] 2. Synthesis of 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]decane

[0634]

[0635] Step A: TFA (180 μL, 2.3 mmol) was added to a solution of tert-butyl 3-(1-piperidinyl)-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 within 90 minutes. The reaction mixture was concentrated in vacuo and then diluted with DMF (8 mL). The material was filtered through a 10 g hyperSep SCX column (eluted with 2N NH3 in MeOH) 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.

[0636] Step B:3-(piperidin-1-yl)-1-oxa-8-azaspiro [4.5] decane (85mg, 0.4mmol) is dissolved in DMF (2mL), DIPEA (660 μL, 3.8mmol) and 4-(difluoromethoxy)benzenesulfonyl chloride (92mg, 0.4mmol) are added and the reaction is stirred for 30 minutes. The reaction is quenched with water and the mixture is extracted with EtOAc (3x). The combined organic matter is washed with saturated NaHCO3 aqueous solution (2x), then dried over Na2SO4. The crude material is purified by silica gel chromatography (0-65% EtOAc to 3:1EtOAc:EtOH) to obtain 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(piperidin-1-yl)-1-oxa-8-azaspiro [4.5] decane (27mg, 16%). LCMS m / z=431.2[M+H] + . 1 H-NMR (400 MHz, CDCl3) 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 (quintet, 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).

[0637] Examples 15a and 15b: (R)-4-Methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile and (S)-4-Methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile

[0638]

[0639] 1. Synthesis of 4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile

[0640]

[0641] DIPEA (335 μ L, 1.9 mmol) is 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 minutes, 5-cyano-2-methyl-benzenesulfonyl chloride (71.5 mg, 0.3 mmol) is added, and the resulting reaction mixture is stirred at room temperature for 1 hour. The reaction is quenched with water, the aqueous layer is separated and extracted with EtOAc (3x). The combined organic matter is washed with saturated NaHCO3 aqueous solution (2x), through Na2SO4 dried and concentrated in vacuo. The crude material is purified by silica gel chromatography (0-65% EtOAc to 3: 1EtOAc: EtOH) to obtain 4-methyl-3-((3-morpholino-1-oxa-8-azaspiro [4.5] decane-8-yl) sulfonyl) benzonitrile (27 mg, 16%).

[0642] 2. Isolation of 4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile

[0643]

[0644] 4-Methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile was further purified by SFC (LUX Cellulose-2 LC 30 x 250 mm, 5 μm column). Method: 30% MeOH in CO (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40°C) to provide two enantiomers of arbitrarily specified stereochemistry:

[0645] Peak 1, (R)-4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile: LCMS m / z=406.2 [M+H]+ . R f =4.01 minutes, ee=98.86%

[0646] Peak 2, (S)-4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile, its stereochemistry was arbitrarily assigned. : LCMS m / z = 406.2 [M+H] + . R f =4.31 minutes, ee=90.62%

[0647] Example 16: 4-Fluoro-3-((3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile

[0648]

[0649] Following the procedure described in Step 1 of Example 16, 4-fluoro-3-((3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile (15 mg, 35%) was obtained from 2,6-difluoro-4-methyl-benzenesulfonyl chloride and 3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride (Intermediate A). LCMS m / z = 417.2 [M+H] + . 1H-NMR (400MHz, CDCl3) δ (ppm): 6.82 (d, J=9.8Hz, 2H), 4.13 (q, J=7.0Hz, 1H), 3.95 (dd, J=6.9, 8.4Hz, 1H), 3.70 (t, J= 4.6Hz,4H),3.68-3.58(m,2H),3.02-2.88(m,2H),2.54-2.29(m,7H),1.95(dd,J=7.7,12.4Hz,1H),1.85-1.58(m,6H).

[0650] Example 17: 8-((2-methyl-4-(trifluoromethyl)phenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane

[0651]

[0652] Following the procedure described in Step 1 of Example 16, 8-((2-methyl-4-(trifluoromethyl)phenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane (26 mg, 46%) was obtained from 2-methyl-4-(trifluoromethyl)benzenesulfonyl chloride and 3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride (Intermediate A). LCMS m / z = 449.1 [M+H] +. 1 H-NMR (400MHz, CDCl3) δ (ppm): 8.10-7.90 (m, 1H), 7.58 (br s,2H),3.98(dd,J=6.8,8.3Hz,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).

[0653] Example 18: 8-((2-fluoro-5-methylphenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane

[0654]

[0655] Following the procedure described in Step 1 of Example 16, 8-((2-fluoro-5-methylphenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane (41 mg, 61%) was obtained from 3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride (Intermediate A) and 2-fluoro-5-methylbenzenesulfonyl chloride. LCMS m / z = 399.2 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.62 (dd, J=1.6, 6.7Hz, 1H), 7.50-7.30 (m, 1H), 7.09 (dd, J=8.5, 9.8Hz, 1H) ,3.95(dd,J=6.8,8.5Hz,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).

[0656] Example 19: 8-((2,5-difluorophenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane

[0657]

[0658] Following the procedure described in Step 1 of Example 16, 8-((2,5-difluorophenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane (41 mg, 61%) was obtained from 2,5-difluorobenzenesulfonyl chloride and 3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride (Intermediate A). LCMS m / z=403.1 [M+H] + . 1 H-NMR (400 MH Z, CDCl3) δ (ppm): 7.56 (ddd, J=3.1, 5.0, 7.7Hz, 1H), 7.30-7.10 (m, 2H), 3.96 (dd, J=6.8, 8.5Hz,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).

[0659] Example 20: 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane

[0660]

[0661] Following the procedure described in Step 1 of Example 16, 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane (42 mg, 61%) was obtained from 6-methoxy-2-methyl-pyridine-3-sulfonyl chloride and 3-morpholino-1-oxa-8-azaspiro[4.5]decane hydrochloride (Intermediate A). LCMS m / z = 412.2 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 8.00 (d, J = 8.8Hz, 1H), 6.64 (d, J = 8.5Hz, 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).

[0662] Example 21: 4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0663]

[0664] 1. Synthesis of 2-morpholino-8-azaspiro[4.5]decane-8-carboxylate

[0665]

[0666] 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 minutes, NaBH (OAc) 3 (7.0 g, 33 mmol) was added portionwise. After completion of the addition, the reaction was warmed to room temperature and stirred for 5 hours. The reaction was quenched with 2M NaOH aqueous solution and the mixture was stirred at room temperature for 20 minutes. The phases were separated and the aqueous phase was extracted with DCM (3x). The combined organic extracts were dried over MgSO 4 , filtered and concentrated under reduced pressure to give 2-morpholino-8-azaspiro[4.5]decane-8-carboxylate. LCMS m / z = 325.2 (M + H) + .

[0667] 2. Synthesis of 4-(8-azaspiro[4.5]dec-2-yl)morpholine hydrochloride

[0668]

[0669] 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 warmed 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]dec-2-yl)morpholine hydrochloride (2.79 g, 99%) as a white solid. LCMS m / z=225.1 (M+H) + . 1 H-NMR (500MHz, CD3OD) δ (ppm): 4.06 (br d, J = 12.8Hz, 2H), 3.83 (br t, J = 11.3Hz, 2H), 3.71 (quintet, J = 8.7Hz, 1H), 3.52 (br t,J=12.2Hz,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).

[0670] 3. Synthesis of 4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0671]

[0672] To a solution of 4-(8-azaspiro[4.5]dec-2-yl)morpholine hydrochloride (81 mg, 0.3 mmol) in anhydrous THF (1 mL) was added dropwise DIPEA (320 μL, 1.8 mmol) and DMAP (4 mg, 0.04 mmol) at <5°C. After 5 minutes, 2,5-dimethylpyrazole-3-sulfonyl chloride (88.3 mg, 0.5 mmol) was added to the cold solution and the reaction was warmed to room temperature and stirred for 30 minutes. The reaction mixture was quenched with 2M NaOH aqueous solution and stirred at room temperature for 10 minutes. 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]dec-2-yl)morpholine (80 mg, 64%). LCMS m / z=383.1(M+H) + . 1 H-NMR(500MHz,DMSO-d6)δ(ppm):6.59(s,1H),3.92(s,3H),3.53(br t,J=4.3Hz,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).

[0673] Examples 22a and 22b: (R)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine and (S)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0674]

[0675] 1. Synthesis of (R)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine and (S)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0676]

[0677] 4-(8-((1,3-Dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine (Example 22, 74 mg, 0.2 mmol) was purified on a Lux Cellulose-4 30 x 250 mm, 5 μm column eluting with 40% MeOH in CO. Flow rate: 100 mL / min; ABPR 120 bar; MBPR 40 psi, column temperature 40°C to afford two enantiomers of arbitrarily specified stereochemistry:

[0678] Peak 1, (R)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine (enantiomer 1, t R =2.35 min) (25 mg, 32%). LCMS m / z=383.2 [M+H] + . 1 H-NMR(500MHz,DMSO-d6)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).

[0679] Peak 2, (S)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine (enantiomer 2, t R =2.68 min) (25 mg, 33%). LCMS m / z=383.3 [M+H] + . 1 H-NMR(500MHz,DMSO-d6)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).

[0680] Example 23: 4-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0681]

[0682] To a solution of 4-(8-azaspiro[4.5]dec-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 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: Boston Prime C18 150 x 30 mm x 5 μm; method: water (0.05% NH4OH v / v)-MeCN start B 34 end B 64; flow rate (30 mL / min) to give 4-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine (98 mg, 46%) as a yellow gum. LCMS m / z = 431.2 (M+H) + . 1 H-NMR(400MHz,DMSO-d6)7.80(d,J=8.8Hz,2H),7.62-7.21(m,3H),3.51(br t,J=4.4Hz,4H),2.96-2.80(m,4H),2.35-2.23(m,5H),1.78-1.03(m,10H).

[0683] Example 24: 2-Methyl-3-((2-morpholino-8-azaspiro[4.5]dec-8-yl)sulfonyl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole

[0684]

[0685] 1. Synthesis of 2-methyl-3-((2-morpholino-8-azaspiro[4.5]dec-8-yl)sulfonyl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole

[0686]

[0687] To a solution of 4-(8-azaspiro[4.5]dec-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) at <5 °C. After 5 minutes, 2-methyl-6,7-dihydro-4H-pyrans [4,3-c]pyrazole-3-sulfonyl chloride (89 mg, 0.4 mmol) was added, and the reaction was warmed to room temperature and stirred for 30 minutes. The heterogeneous reaction mixture was quenched with a 2M NaOH aqueous solution, and the mixture was stirred at room temperature for 10 minutes. The biphasic mixture was loaded onto a silica gel column and purified with (20-80% 3:1 EtOAc:EtOH in heptane) to give 2-methyl-3-((2-morpholino-8-azaspiro[4.5]dec-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 (500MHz, DMSO-d6) δ (ppm): 4.63 (s, 2H), 3.94 (s, 3H), 3.84 (t, J = 5.8Hz, 2H), 3.53 (br t, J = 4.0Hz, 4H), 3.08 (br t,J=5.5Hz,4H),2.67(t,J=5.8Hz,2H),2.48-2.44(m,1H),2.37-2.27(m,4H),1.81-1.73(m,1H),1.69 (dd,J=7.3,12.8Hz,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).

[0688] Example 25: 4-(8-((3,5-dimethylpyridin-2-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0689]

[0690] 1. Synthesis of 4-(8-((3,5-dimethylpyridin-2-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0691]

[0692] To a solution of 4-(8-azaspiro[4.5]dec-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 minutes 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 the addition of Ca(NTf2)2 (195 mg, 0.3 mmol) in portions. The resulting mixture was heated at 60°C for 19 hours. The reaction mixture was allowed to reach room temperature, quenched with 2M NaOH aqueous solution, 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 further purified by preparative HPLC using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with a mobile phase of water (A) and MeCN (B) with a gradient of 5-60% B (0.2% NH 4 OH final v / v % modifier) ​​at a flow rate of 80 mL / min to afford 4-(8-((3,5-dimethylpyridin-2-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine (30 mg, 24%) as a white solid. LCMS m / z=394.4 (M+H) + . 1 H-NMR(500MHz,DMSO-d6)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).

[0693] Example 26: 4-(8-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0694]

[0695] 1. Synthesis of 4-(8-((3-bromo-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0696]

[0697] Following the procedure described in step 1 of example 23, 4-(8-((3-bromo-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine (582 mg, 84%) was obtained from 4-(8-azaspiro[4.5]dec-2-yl)morpholine hydrochloride and 5-bromo-2-methyl-pyrazole-3-sulfonyl chloride. 1 H-NMR (500MHz, DCM-d2) δ (ppm): 6.66 (s, 1H), 4.04 (s, 3H), 3.62 (t, J = 4.6Hz, 4H), 3.16-3.09 (m, 4H), 2.55-2.50 (m, 1H), 2.42-2.35 (m, 4H),

[0698] 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).

[0699] 2. Synthesis of 4-(8-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0700]

[0701] A vial containing 4-(8-((3-bromo-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine (152 mg, 0.3 mmol), tert-butyl BrettPhos (50 mg, 0.1 mmol), tert-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 backfilled with N2. Degassed MeOH (400 μL, 9.9 mmol) was added dropwise and the resulting mixture was heated at 55°C for 24 hours. The reaction was cooled to room temperature, diluted with water and extracted with DCM (3x). The combined organic layers were dried over anhydrous MgSO4, 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 obtained product was further purified by HPLC using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with a mobile phase of water (A) and MeCN (B) and a gradient of 5-50% B (0.2% NH 4 OH final v / v % modifier) ​​at a flow rate of 60 mL / min to give 4-(8-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine (6 mg, 4%) as a colorless film. LCMS m / z=399.3 [M+H] + . 1 H-NMR(500MHz,DCM-d2)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).

[0702] Example 27: (1R,4R)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[0703]

[0704] 1. Synthesis of tert-butyl 2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-8-azaspiro[4.5]decane-8-carboxylate

[0705]

[0706] To a solution of tert-butyl 3-oxo-8-azaspiro [4.5] decane-8-formate (247 mg, 1.0 mmol) in anhydrous DCM (3 mL) and acetic acid (200 μ L, 3.5 mmol) was added (1R, 4R) -2- oxa-5-azabicyclo [2.2.1] heptane hydrochloride (295 mg, 2.2 mmol) and DIPEA (430 μ L, 2.5 mmol) in anhydrous DCM (3 mL). After 15 minutes, NaBH (OAc) (857 mg, 4.0 mmol) was added portionwise, and the reaction mixture was stirred at room temperature for 20 hours. The reaction was quenched with a 2M NaOH aqueous solution and the mixture was stirred at room temperature for 20 minutes. The biphasic mixture was extracted with DCM (3x), and the combined organic extracts were dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure to give tert-butyl 2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-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) + .

[0707] 2. Synthesis of (1R,4R)-5-(8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride

[0708]

[0709] A solution of tert-butyl 2-((1R, 4R)-2-oxa-5-azabicyclo[2.2.1]hept-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 1 M HCl in EtOAc (1 M, 3.5 mL) was added dropwise. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 5 days. The reaction mixture was concentrated under reduced pressure to give (1R, 4R)-5-(8-azaspiro[4.5]dec-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) + .

[0710] 3. Synthesis of (1R,4R)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[0711]

[0712] At <5 ° C, to (1R, 4R) -5- (8- azaspiro [4.5] decane -2- bases) -2- oxa -5- azabicyclo [2.2.1] heptane hydrochloride (124 mg, 0.5 mmol) in anhydrous THF (2 mL) was added dropwise DIPEA (500 μ L, 2.9 mmol). After 5 minutes, 4- (difluoromethoxy) benzenesulfonyl chloride (120 μ L, 0.8 mmol) was added, the reaction was warmed to room temperature and stirred for 30 minutes. The reaction mixture was quenched with 2M NaOH aqueous solution, and the resulting biphasic mixture was stirred at room temperature for 10 minutes. The biphasic mixture was loaded onto silica gel and purified by column chromatography (15-85% 3: 1 EtOAc: EtOH in heptane). The product was further purified by HPLC using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with a mobile phase of water (A) and MeCN (B) and a gradient of 5-70% B (0.2% NH 4 OH final v / v % modifier) ​​at a flow rate of 80 mL / min to afford (1R,4R)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (67 mg, 30%) as a beige solid. LCMS m / z=443.3 [M+H] + . 1 H-NMR (600MHz, DMSO-d6)d=7.80(d,J=9.4Hz,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=5.1,9.4Hz,1H),1.63(br d,J=8.7Hz,2H),1.58-1.53(m,2H),1.52-1.46(m,6H),1.42-1.35(m,3H),1.28(br dd,J=4.4,8.0Hz,1H),1.15-1.11(m,1H).

[0713] 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

[0714]

[0715] 1. Synthesis of tert-butyl 3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

[0716]

[0717] At room temperature, TEA (601 μ L, 4.3 mmol) is slowly added to a solution of 3-oxo-1-oxa-8-azaspiro [4.5] decane-8-tert-butyl formate (500 mg, 2.0 mmol) and 2-oxa-7-azaspiro [4.4] nonane (299 mg, 2.4 mmol) in DCM (15 mL). After 15 minutes, acetic acid (280 μ L, 4.90 mmol) is slowly added, and after another 30 minutes, NaBH (OAc) is added (1.7 g, 7.8 mmol). Continue to stir at room temperature for 1 day, add saturated NH4Cl aqueous solution. Phase separation is carried out and aqueous phase is extracted with EtOAc. The organic phase merged is washed with salt water, through anhydrous Na2SO4, dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-100% EtOH:EtOAc 1:3 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] + .

[0718] 2. Synthesis of 3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane hydrochloride

[0719]

[0720] tert-Butyl 3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane-8-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] + .

[0721] 3. Synthesis of 8-((4,6-dimethylpyridin-3-yl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane

[0722]

[0723] At room temperature, DMA (83 μ L), DMAP (1 mg, 0.01 mmol) and 4,6-dimethylpyridine-3-sulfonyl chloride (29 mg, 0.1 mmol) were added to a solution of 3- (2- oxa -7- azaspiro [4.4] nonyl -7- yl) -1- oxa -8- azaspiro [4.5] decane hydrochloride (36 mg, 0.1 mmol) in THF (1 mL). DCM (1 mL), DMF (0.5 mL) and DIPEA (80 μ L, 0.5 mmol) were added and the reaction was stirred for 15 minutes. Saturated NH4Cl aqueous solution and saline were added to quench the reaction mixture. 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 5 μm OBD 30 x 100 mm; method: (A) 95% water / / (B) 5% MeCN with 0.1% TFA to 70% (A) / 30% (B) over 7.5 minutes (flow rate: 50 mL / 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]decane trifluoroacetate (7.9 mg, 14%) as a clear oil. LCMS m / z = 436.2 [M+H] + .

[0724] 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

[0725]

[0726] 1. Synthesis of 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

[0727]

[0728] 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) was added DIPEA (120 μL, 0.7 mmol) followed by DMAP (1 mg, 0.01 mmol). 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 NH4Cl 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 5 μm OBD 30 x 100 mm; method: (A) 95% water / / (B) 5% MeCN with 0.1% TFA to 50% (A) / 50% (B) over 7.5 minutes (flow rate: 50 mL / 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]decane trifluoroacetate (7.4 mg, 13%) as a yellow oil. LCMS m / z = 425.3 [M+H] + .

[0729] Examples 30a, 30b, 30c, and 30d: (S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((R)-2-oxa-7-azaspiro[4.4]non-7-yl)-1-oxa-8-azaspiro[4.5]decane, (S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((R)-2-oxa-7-azaspiro[4.4]non-7-yl)-1-oxa-8-azaspiro[4.5]decane, [4.5]decane, (R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((R)-2-oxa-7-azaspiro[4.4]non-7-yl)-1-oxa-8-azaspiro[4.5]decane, and (R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((S)-2-oxa-7-azaspiro[4.4]non-7-yl)-1-oxa-8-azaspiro[4.5]decane.

[0730]

[0731] 1. Synthesis of 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane

[0732]

[0733] Following a reaction analogous to that described in Example 28, Step 3, 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.

[0734] 2. Isolation of 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane

[0735]

[0736] 8-((4-(Difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane was purified by chiral SFC (CHIRALPAK AD-H 30x250 mm, 5 μm; method: 30% EtOH containing 0.1% DEA in CO2 (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40°C) to give the following enantiomers of arbitrarily specified stereochemistry:

[0737] Peak 1, enantiomer 1 (4.1 mg, 3%), R f =4.82 min. LCMS m / z=473.2[M+H] +

[0738] Peak 2, enantiomer 2, (4.4 mg, 3%). f =5.43 min LCMS m / z=473.2 [M+H] + . 1 H-NMR (400 MHz, CD3OD) 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 (quintet, 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).

[0739] Peak 3, enantiomer 3 (1.2 mg, 1%), R f =6.27 min. LCMS m / z=473.2[M+H] +

[0740] Peak 4, enantiomer 4 (1.3 mg, 1%), R f = 6.50 min. LCMS m / z = 473.2 [M+H] +

[0741] Example 31: 4-(8-((7-fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0742]

[0743] 1. Synthesis of 7-fluoroquinoline-6-sulfonyl fluoride

[0744]

[0745] A microwave vial was charged with 6-bromo-7-fluoroquinoline (45 mg, 0.2 mmol), DABSO (48 mg, 0.2 mmol) and Pd(amphos)Cl2 (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 an inert atmosphere, the vial was sealed, sparged with N2 for 5 minutes and heated at 110°C under microwave irradiation for 1 hour.

[0746] The reaction mixture was allowed to reach room temperature, NFSI (95 mg, 0.3 mmol) was added, and the resulting mixture was stirred for 3 hours. The reaction mixture was diluted with EtOAc, washed with water (3 mL), and extracted with EtOAc (5 mL, 2x). The combined organic phases were dried over anhydrous MgSO4 and concentrated in vacuo to afford 7-fluoroquinoline-6-sulfonyl fluoride, which was used in the next step without further purification. LCMS m / z = 230.0 [M+H] +

[0747] 2. Synthesis of 4-(8-((7-fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0748]

[0749] To a solution of 7-fluoroquinoline-6-sulfonyl fluoride (23 mg, 0.1 mmol) and 4-(8-azaspiro[4.5]dec-2-yl)morpholine (22 mg, 0.1 mmol) in THF (1.0 mL) was added Ca(NTf ) (66 mg, 0.1 mmol) and DABCO (17 mg, 0.2 mmol), and the heterogeneous reaction solution was heated at 60° C. for 16 hours. The reaction mixture was allowed to reach room temperature, quenched with water, and extracted with EtOAc (2 mL, 3×). The combined organic phases were dried over anhydrous MgSO and concentrated in vacuo. 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]dec-2-yl)morpholine (3.2 mg, yield: 7%). LCMS m / z=434.0 (M+H) + . R f =1.72 minutes.

[0750] Example 32: 4-(8-((5-cyclopropyloxypyridin-2-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0751]

[0752] 1. Synthesis of 5-cyclopropyloxypyridine-2-sulfonyl fluoride

[0753]

[0754] 5-Cyclopropyloxypyridine-2-sulfonyl fluoride was obtained from 2-bromo-5-cyclopropyloxypyridine following a procedure similar to that described in Step 1 of Example 31. LCMS m / z = 218.0 (M+H) +

[0755] 2. Synthesis of 4-(8-((5-cyclopropyloxypyridin-2-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0756]

[0757] Following the procedure described in Step 2 of Example 31, 4-(8-((5-cyclopropyloxypyridin-2-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine (11 mg, 27%) was obtained from 5-cyclopropyloxypyridin-2-sulfonyl fluoride and 4-(8-azaspiro[4.5]dec-2-yl)morpholine. LCMS m / z = 422.0 [M+H] + . R f=1.80 minutes.

[0758] Example 33: 4-(8-((3-fluoro-2-methoxypyridin-4-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0759]

[0760] 1. Synthesis of 3-fluoro-2-methoxypyridine-4-sulfonyl fluoride

[0761]

[0762] 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 hours. The reaction mixture was extracted with EtOAc (2 mL, 3×). The combined organic phases were dried over anhydrous MgSO 4 and concentrated in vacuo to afford 3-fluoro-2-methoxypyridine-4-sulfonyl fluoride, which was used in the next step without further purification (assuming a 100% yield). LCMS m / z=210.0 [M+H] +

[0763] 2. Synthesis of 4-(8-((3-fluoro-2-methoxypyridin-4-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine

[0764]

[0765] To a solution of 3-fluoro-2-methoxypyridine-4-sulfonyl fluoride (21 mg, 0.1 mmol) and 4-(8-azaspiro[4.5]dec-2-yl)morpholine (34 mg, 0.2 mmol) in 2-methyl-2-butanol (0.5 mL) was added Ca(NTf ) (90 mg, 0.2 mmol) and the resulting heterogeneous reaction mixture was heated at 60° C. for 16 hours. After cooling to room temperature, the reaction was quenched with water and extracted with EtOAc (2 mL, 3×). The combined organic phases were dried over anhydrous MgSO and concentrated in vacuo. The residue was purified by preparative HPLC using a Waters SunFire Prep C18 column (5 μm OBD 30 x 100 mm, purification gradient: 5-55%, purification modifier: TFA) to give 4-(8-((3-fluoro-2-methoxypyridin-4-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine (2.3 mg, yield: 6%). LCMS m / z = 414.0 (M+H) + . R f =1.93 minutes.

[0766] Example 34: 4-(7-((1-ethyl-3-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine

[0767]

[0768] 1. Synthesis of tert-butyl 2-morpholino-7-azaspiro[3.5]nonane-7-carboxylate

[0769]

[0770] Following a reaction similar to that described in Step 1 of Example 21, tert-butyl 2-morpholino-7-azaspiro[3.5]nonane-7-carboxylate (2.9 g, 96%) was obtained from morpholine and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate. LCMS m / z = 311.2 [M+H] +

[0771] 2. Synthesis of 4-(7-azaspiro[3.5]non-2-yl)morpholine hydrochloride

[0772]

[0773] Following the procedure described in step 2 of Example 21, 4-(7-azaspiro[3.5]nonan-2-yl)morpholine hydrochloride (2.1 g, 93%) was obtained as a light yellow solid from tert-butyl 2-morpholino-7-azaspiro[3.5]nonane-7-carboxylate. 1 H-NMR(500MHz,CD3OD)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=3.1,12.2Hz,2H),2.43-2.35(m,2H),2.31-2.22(m,2H),1.94-1.86(m,4H). LCMS m / z=211.2(M+H) + .

[0774] 3. Synthesis of 4-(7-((1-ethyl-3-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine

[0775]

[0776] DIPEA (320 μL, 1.8 mmol) was added dropwise to 4-(7-azaspiro[3.5]non-2-yl)morpholine hydrochloride (78 mg, 0.3 mmol) at <5°C.

[0777] The mixture was stirred for 3 hours at room temperature for 10 minutes.Then the mixture was stirred for 3 hours at room temperature for 10 minutes.Then the mixture was stirred for 3 hours at room temperature for 10 minutes.Then the mixture was stirred for 3 hours at room temperature for 10 minutes.Then the mixture was stirred for 3 hours at room temperature for 10 minutes.Then the mixture was stirred for 3 hours at room temperature for 10 minutes.Then the mixture was stirred for 3 hours at room temperature for 10 minutes.The mixture was stirred for 3 hours at room temperature for 10 minutes.The mixture was stirred for 3 hours at room temperature for 10 minutes.The mixture was stirred for 3 hours at room temperature for 10 minutes.The mixture was stirred for 3 hours at room temperature for 10 minutes.The mixture was stirred for 3 hours at room temperature for 10 minutes.The mixture was stirred for 3 hours at room temperature for 10 minutes.The mixture was stirred for 3 hours at room temperature for 10 minutes.The mixture was stirred for 3 hours at room temperature for 10 minutes.The mixture was stirred for 3 hours at room temperature for 10 minutes.The mixture was stirred for 3 hours at room temperature for 10 minutes.The mixture was stirred for 3 hours at room temperature for 10 minutes.The mixture was stirred for 3 hours at room temperature for 10 minutes.The mixture was stirred for 3 hours at room temperature for 10 minutes. + . 1 H-NMR (500MHz, DMSO-d6) δ (ppm): 6.56 (s, 1H), 4.28 (q, J = 7.3Hz, 2H), 3.54 (br t,J=4.3Hz,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).

[0778] Example 35: 4-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine

[0779]

[0780] Following a reaction analogous to that described in Example 23, 4-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine (92 mg, 58%) 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. LCMS m / z = 434.2 (M+H) + . 1H-NMR(500MHz,DMSO-d6)δ(ppm):8.41(d,J=7.9Hz,1H),7.96(d,J=7.9Hz,1H),3.53(br t,J=4.0Hz,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=2.4,7.8,9.9Hz,2H),1.63-1.59(m,2H),1.54-1.47(m,4H).

[0781] Example 36: 4-(7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine

[0782]

[0783] 1. Synthesis of 4-(7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine

[0784]

[0785] To a solution of 4- (7- azaspiro [3.5] decyl -2- bases) morpholine hydrochloride (embodiment 34, step 2, 69 mg, 0.3 mmol) in anhydrous DMF (4 mL) was added DIPEA (244 μ L, 1.4 mmol). After 5 minutes, 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 hour. The reaction was quenched with water and the mixture (3x) was extracted with EtOAc. The combined organic matter was washed with saturated NaHCO aqueous solution (2x), dried over anhydrous NaSO, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0-25% EtOAc to 3: 1 EtOAc: EtOH) to obtain 4- (7- ((2- methoxy -5- methylpyridin-3-yl) sulfonyl) -7- azaspiro [3.5] nonyl -2- bases) morpholine as a yellow oil. LCMS m / z=396.2(M+H) + . 1H-NMR (400MHz, CDCl3) δ (ppm): 8.09 (dd, J = 0.8, 2.3Hz, 1H), 8.00-7.90 (m, 1H), 4.01 (s, 3H), 3.70 (t, J = 4.6Hz, 4 H),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).

[0786] Example 37: 4-(7-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine

[0787]

[0788] Following the procedure described in Example 36, 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. LCMS m / z = 395.3 (M+H) + . 1 H-NMR (400 MHz, CDCl3) 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 (quintet, 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).

[0789] Example 38: 4-(8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azaspiro[bicyclo[3.2.1]octane-3,1′-cyclobutane]-3′-yl)morpholine

[0790]

[0791] 1. Synthesis of tert-butyl 3'-morpholino-8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclobutane]-8-carboxylate

[0792]

[0793] Following the procedure described in step 1 of Example 27, tert-butyl 3'-morpholino-8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclobutane]-8-carboxylate (986 mg, crude) was obtained from morpholine and tert-butyl 3'-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclobutane]-8-carboxylate. LCMS m / z = 337.2 [M+H] + .

[0794] 2. Synthesis of 4-(8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclobutane]-3'-yl)morpholine

[0795]

[0796] A solution of tert-butyl 3'-morpholinospiro[8-azabicyclo[3.2.1]octane-3,1'-cyclobutane]-8-formate (986 mg, 2.9 mmol) in MeOH (3 mL) was cooled in an ice-water bath, 4M HCl (2.2 mL) in dioxane was added dropwise and the reaction was allowed to warm to room temperature and stirred for 20 hours. The yellow solution was concentrated under reduced pressure and the yellow residue was ground with a few drops of MeOH in EtOAc. The heterogeneous mixture was filtered to give 4-(8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclobutane]-3'-yl)morpholine hydrochloride (602 mg, crude) as a white solid, which was used in the next step without purification. LCMS m / z=237.2 (M+H) + . 1 H-NMR(500MHz,CD3OD)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 =4.9,7.6,11.9Hz,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).

[0797] 3. Synthesis of 4-(8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclobutane]-3'-yl)morpholine

[0798]

[0799] At <5 DEG C, to 4- spiral shell (8- azabicyclo [3.2.1] octane -3,3 '- cyclobutane) -1 '- base morpholine hydrochloride (61mg, 0.2mmol) in anhydrous DCM (0.5mL) solution, DIPEA (171mg, 1.3mmol) was added dropwise. After 5 minutes, 2- methyl -6- (trifluoromethyl) pyridine -3- sulfonyl chloride (82mg, 0.3mmol) was added and the reaction was warmed to room temperature and stirred for 30 minutes. The reaction was quenched with the 1M NaOH aqueous solution, and the mixture was stirred at room temperature for 20 minutes. The two-phase mixture was extracted with DCM (3x), and the organic extracts combined were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude material was purified by HPLC using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with a mobile phase consisting of water (A) and MeCN (B) with a gradient from 5 to 60% B (0.2% NH 4 OH final v / v % modifier) ​​at a flow rate of 60 mL / min to afford 4-(8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azaspiro[bicyclo[3.2.1]octane-3,1′-cyclobutane]-3′-yl)morpholine (7.9 mg, 7%) as a colorless film. LCMS m / z=460.3 (M+H) + . 1 H-NMR (500MHz, DCM-d2)d=8.41(d,J=8.5Hz,1H),7.65(d,J=7.9Hz,1H),4.22-4.18(m,1H),4.13 -4.09(m,1H),3.61(t,J=4.6Hz,4H),2.89(s,3H),2.68-2.62(m,1H),2.43-2.38(m,1H),2.21(br d, J=2.4Hz, 4H), 2.02-1.93 (m, 4H), 1.84-1.75 (m, 6H), 1.68-1.63 (m 1H).

[0800] Example 39: 7-((4-(difluoromethoxy)phenyl)sulfonyl)-3-morpholino-1-oxa-7-azaspiro[3.5]nonane

[0801]

[0802] 1. Synthesis of tert-butyl 3-morpholino-1-oxa-7-azaspiro[3.5]nonane-7-carboxylate

[0803]

[0804] To a solution of tert-butyl 3-oxo-1-oxa-7-azaspiro [3.5] nonane-7-formate (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) at room temperature. After 15 minutes, NaBH (OAc) (1.76 g, 8.29 mmol) was added in batches, and the reaction was stirred at room temperature for 20 hours. The reaction was quenched with saturated NH4Cl aqueous solution and then extracted with DCM (3x). The combined organics were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give tert-butyl 3-morpholino-1-oxa-7-azaspiro [3.5] nonane-7-formate (625 mg, crude product), which was used in the next step without purification. LCMS m / z=313.1 (M+H)+.

[0805] 2. Synthesis of 3-morpholino-1-oxa-7-azaspiro[3.5]nonane trifluoroacetate

[0806]

[0807] To tert-butyl 3-morpholino-1-oxa-7-azaspiro[3.5]nonane-7-carboxylate (625 mg, 2.0

[0808] To a solution of 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 hours. 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) +.

[0809] 3. Synthesis of 7-((4-(difluoromethoxy)phenyl)sulfonyl)-3-morpholino-1-oxa-7-azaspiro[3.5]nonane

[0810]

[0811] At<5 ℃, to 3-morpholino-1-oxa--7-azaspiro [3.5] nonane trifluoroacetate (130mg, 0.4mmol) in anhydrous THF (2mL) solution, DIPEA (500 μ L, 2.9mmol) and DMAP (6mg, 0.05mmol) are added dropwise. The gained solution is stirred 5 minutes, then 4-(difluoromethoxy) benzenesulfonyl chloride (137mg, 0.6mmol) is added. The reaction mixture is made to reach room temperature and stirred 30 minutes. The reaction is quenched with the 1M NaOH aqueous solution, the mixture is stirred 10 minutes, then the two-phase mixture (3x) is extracted with EtOAc. By the organic matter saturated NaHCO3 aqueous solution (2x) washing merged, through anhydrous Na2SO4 drying, filter and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (25-100% EtOAc in heptane) to afford 7-((4-(difluoromethoxy)phenyl)sulfonyl)-3-morpholino-1-oxa-7-azaspiro[3.5]nonane as a colorless film, which was triturated with MeOH to afford a white solid (10 mg, 6%). LCMS m / z = 419.1 (M+H) + . 1 H-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=7.6Hz,1H),2.37-2.18(m,3H),2.18-2.04(m,4H),1.85(br dd,J=1.8,13.4Hz,1H),1.73-1.62(m,2H).

[0812] Examples 40 to 43

[0813] 1. Synthesis of 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one

[0814]

[0815] At <5 ° C, DIPEA (2.2 mL, 12.4 mmol) was added dropwise to a vial containing 8-azaspiro [4.5] decane-3-one hydrochloride (605 mg, 3.2 mmol) in anhydrous DCM (20 mL). After 5 minutes, 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 minutes, the homogeneous reaction mixture was quenched with 1 M NaOH aqueous solution and the mixture was stirred at room temperature for 10 minutes. Each phase was separated and the aqueous layer was washed with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, 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] + .

[0816] The title compound was prepared in a single-step library scale at approximately 85 mg of desired product using the following protocol.

[0817]

[0818] DIPEA (2.0 equivalents) is added in the solution of suitable amine (1.5 equivalents) in DCM (1mL).After 15 minutes, this solution is added in 8-((2-methoxyl group-5-picoline-3-yl) sulfonyl)-8-azaspiro [4.5] last 2-ketone (1.0 equivalents) in DCM (1mL).After at room temperature stirring for 15 minutes, acetic acid (4.0 equivalents) is dripped, then NaBH (OAc) is dripped (8.0 equivalents), and reaction mixture is stirred at room temperature and spend the night.Add saturated NH the Cl aqueous solution (5mL) and DCM (5mL), and separate water layer and extract with DCM (3x 5mL).By the organic layer water (5mL) and salt solution (5mL) washing merged, through Na sO dry, filter and concentrate. The obtained residue was purified by preparative HPLC (flow rate: 30 mL / min; column: Waters XSELECT CSH C18 PREP 19x100 mm, 5 um; modifier: 0.2% NH4OH (v / v) concentration; method: A% water / B% MeCN linear gradient within 8 minutes) to obtain the corresponding product.

[0819]

[0820]

[0821] Example 44: 4-Fluoro-3-((3-((2-methoxyethyl)amino)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile

[0822]

[0823] 1. Synthesis of 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride

[0824]

[0825] 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 warmed to room temperature and stirred overnight. The reaction mixture was filtered to give 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride (300 mg, 99%) as a white solid.

[0826] 2. Synthesis of 4-fluoro-3-((3-oxo-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile

[0827]

[0828] DIPEA (1.1 mL, 6.5 mmol) was added to 1-oxa-8-azaspiro [4.5] decane-3-one hydrochloride (250 mg, 1.3 mmol) in anhydrous DMF (2 mL). After 5 minutes, 5-cyano-2-fluoro-benzenesulfonyl chloride (287 mg, 1.3 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with water and the mixture was extracted with EtOAc (3x). The combined organic matter was washed with saturated NaHCO3 aqueous solution (2x), then dried over anhydrous Na2SO4, and concentrated in vacuo. 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] decane-8-yl) sulfonyl) benzonitrile (300 mg, 68%). LCMS m / z=339.0[M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 8.20 (dd, J=2.0, 6.3Hz, 1H), 7.90 (ddd, J=2.3, 4.5, 8.6Hz, 1H), 7.39 ( t,J=8.9Hz,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).

[0829] 3. Synthesis of 4-fluoro-3-((3-((2-methoxyethyl)amino)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile

[0830]

[0831] 2-Methoxyethylamine hydrochloride (119 mg, 1.1 mmol) is added to a solution of 4-fluoro-3-((3-oxo-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile (300 mg, 0.9 mmol) in DCM (25 mL) and the solution is stirred at room temperature for 15 minutes. Acetic acid (100 μL, 1.8 mmol) is added dropwise, the reaction is stirred for 30 minutes, NaBH(OAc) is added (752 mg, 3.6 mmol) and the reaction is stirred at room temperature for 3 hours. The reaction is quenched with saturated NH4Cl aqueous solution and diluted with DCM. The organic matter is 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 (w / 2% NH3OH)) to give 4-fluoro-3-((3-((2-methoxyethyl)amino)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile (210 mg, 59%). LCMS m / z = 398.1 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 8.18 (dd, 1H, J = 2.0, 6.3Hz), 7.87 (ddd, 1H, J = 2.1, 4.4, 8.5Hz), 7.35 (t, 1H, J = 8.8Hz), 3.93 (dd, 1H, J = 6.0 ,9.0Hz),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).

[0832] Example 45: 3-((3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-fluorobenzonitrile

[0833]

[0834] Following the procedure described in step 3 of Example 44, 3-((3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-fluorobenzonitrile (100 mg, 35%) 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]dec-8-yl)sulfonyl)benzonitrile. LCMS m / z = 422.1 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 8.20-8.10 (m, 1H), 7.86 (ddd, J = 1.8, 4.2, 8.3Hz, 1H), 7.40-7.30 (m, 1H), 4.37 (br s, 1H), 4.00 (br d,1H,J=7.8Hz),3.90-3.70(m,1H),3.70-3.50(m,4H),3.42(br d,J=19.1Hz,1H),3.31(dt,J=3.0,6.4Hz,1H),3.10-2.70(m,3H),2.60-2.30(m,1H),2.10-1.60(m,8H).

[0835] Example 46: 3-((3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-fluorobenzonitrile

[0836]

[0837] Following the procedure described in step 3 of Example 44, 3-((3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-fluorobenzonitrile (77 mg, 82%) was obtained from 2-oxa-6-azaspiro[3.3]heptane hydrochloride and 4-fluoro-3-((3-oxo-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile. LCMS m / z = 422.1 [M+H] + . 1H-NMR (400MHz, CDCl3) δ (ppm): 8.16 (dd, J=2.0, 6.3Hz, 1H), 7.86 (ddd, J=1.9, 4.3, 8.4Hz, 1H), 7.34 (t, J=8.8Hz,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).

[0838] Example 47: 4-Fluoro-3-((3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile

[0839]

[0840] Following the procedure described in Step 3 of Example 44, 4-fluoro-3-((3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile (41 mg, 45%) was obtained from 4-fluoro-3-((3-oxo-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile and piperidine hydrochloride. LCMS m / z = 408.1 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 8.17 (dd, J=2.1, 6.1Hz, 1H), 7.87 (ddd, J=2.0, 4.3, 8.5Hz, 1H), 7.35 (t, J=8.8Hz, 1H), 3.9 6(dd,J=7.0,8.3Hz,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).

[0841] Example 48: 3-((3-((4,4-difluorocyclohexyl)amino)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-fluorobenzonitrile

[0842]

[0843] Following the procedure described in step 3 of Example 44, 3-((3-((4,4-difluorocyclohexyl)amino)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-fluorobenzonitrile (61 mg, 44%) was obtained from 4,4-difluorocyclohexylamine hydrochloride and 4-fluoro-3-((3-oxo-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile. LCMS m / z = 458.1 [M+H]+ . 1 H-NMR (400MHz, CDCl3) δ (ppm): 8.19 (td, J=2.4, 6.1Hz, 1H), 7.88 (ddd, J=2.0, 4.2, 8.3Hz, 1H), 7.36 (dt, J=1.6, 8.8Hz, 1 H),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).

[0844] Example 49: 8-((2-chloro-4-methylphenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane

[0845]

[0846] 1. Synthesis of 8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one

[0847]

[0848] DIPEA (2.3 mL, 13.0 mmol) was added to a vial containing 1-oxa-8-azaspiro[4.5]dec-3-one hydrochloride (500 mg, 2.6 mmol) in anhydrous DMF (3 mL), and the solution was stirred for 5 minutes before adding 2-chloro-4-methyl-benzenesulfonyl chloride (587 mg, 2.6 mmol). The reaction was stirred at room temperature for 1 hour, then quenched with water and the mixture was extracted with EtOAc (3x). The combined organics were washed with saturated aqueous NaHCO3 (2x). The organic layer was separated, then dried over anhydrous Na2SO4 and concentrated in vacuo. 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]dec-3-one. LCMS m / z=344.0[M+H] + .

[0849] 2. Synthesis of 8-((2-chloro-4-methylphenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane

[0850]

[0851] 2- oxa -6- aza spiro [3.3] heptane (29mg, 0.3mmol) is added to a solution of 8- (2- chloro- 4- methyl -phenyl) sulfonyl -1- oxa -8- aza spiro [4.5] decane -3- ketone (100mg, 0.3mmol) in DCM (10mL) and the solution is stirred at room temperature for 15 minutes. Acetic acid (40 μ L, 0.6mmol) is then added dropwise, followed by NaBH (OAc) (247mg, 1.16mmol), and the reaction is stirred at room temperature for 3 hours. The reaction is saturated with NH the Cl aqueous solution is quenched and diluted with DCM. The organic layer is washed with water and salt water, then concentrated in vacuo. The crude product was purified by silica gel column (0-100% EtOAc to 3:1 EtOAc:EtOH (w / 2% NH3OH)) to give 8-((2-chloro-4-methylphenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane (70 mg, 56%). LCMS m / z = 427.1 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.89 (d, J = 8.3Hz, 1H), 7.40-7.30 (m, 1H), 7.16 (d, J = 8.0Hz, 1H), 4.71 (s, 4H), 3.70 (dd, J = 5. 5,9.3Hz,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).

[0852] Example 50: 1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)-3-methylazetidin-3-ol

[0853]

[0854] Following the procedure described in step 2 of Example 49, 1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)-3-methylazetidin-3-ol (120 mg, 99%) was obtained from 3-methylazetidin-3-ol and 8-(2-chloro-4-methyl-phenyl)sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-one. LCMS m / z = 415.1 [M+H] + . 1H-NMR (400MHz, CDCl3) δ (ppm): 7.90 (d, J = 8.3Hz, 1H), 7.33 (d, J = 0.8Hz, 1H), 7.20-7.10 (m, 1H), 3.75 (dd, J = 5.5, 9 .3Hz,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).

[0855] Example 51: 8-((2-chloro-4-methylphenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-1-oxa-8-azaspiro[4.5]dec-3-amine

[0856]

[0857] Following the procedure described in step 2 of Example 49, 8-((2-chloro-4-methylphenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-1-oxa-8-azaspiro[4.5]decan-3-amine (199 mg, 84%) was obtained from tetrahydropyran-4-amine and 8-(2-chloro-4-methyl-phenyl)sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-one. LCMS m / z = 429.2 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.83 (d, J=8.0Hz, 1H), 7.26 (s, 1H), 7.20-7.10 (m, 1H), 3.88 (brdd, J=5.6, 8.2Hz, 3H), 3.60-3.40 (m, 4H), 3.31 (br t,J=11.7Hz,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).

[0858] Example 52: 1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)azetidin-3-ol

[0859]

[0860] Following the procedure described in step 2 of Example 49, 1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)azetidin-3-ol (110 mg, 94%) was obtained from azetidin-3-ol hydrochloride and 8-(2-chloro-4-methyl-phenyl)sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-one. LCMS m / z = 401.2 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 8.00-7.70 (m, 1H), 7.40-7.30 (m, 1H), 7.17 (d, J = 8.0Hz, 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).

[0861] Examples 53a and 53b: (R)-1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)azetidin-3-ol and (S)-1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)azetidin-3-ol

[0862]

[0863] 1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)azetidin-3-ol (Example 52) was separated on a CHIRALPAK AD-H 30 x 250 mm, 5 μm column. Method: 40% MeOH containing 0.1% DEA in CO (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) to give two enantiomers of arbitrarily specified stereochemistry:

[0864] Peak 1, Enantiomer 1, (R)-1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)azetidin-3-ol: LCMS m / z = 401.2 [M+H] + . R f =2.57 minutes. ee=100%.

[0865] Peak 2, Enantiomer 2, (S)-1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)azetidin-3-ol: LCMS m / z = 401.2 [M+H] + . R f =3.10 min. ee=100%.

[0866] Example 54: 8-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane

[0867]

[0868] 1. Synthesis of 8-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one

[0869]

[0870] DIPEA (800 μ L, 4.6 mmol) is added into the bottle equipped with 1-oxa-8-azaspiro [4.5] decane-3-one hydrochloride (800 μ L, 0.9 mmol) in anhydrous DMF (2 mL). After 5 minutes, 2-methyl-4-(trifluoromethoxy) benzenesulfonyl chloride (254 mg, 0.9 mmol) is added, and the reaction is stirred at room temperature for 1 hour. The reaction is quenched with water and the mixture is extracted with EtOAc (3x). The organic matter merged is washed with saturated NaHCO3 aqueous solution (2x) and through anhydrous Na2SO4 dry organic layer. The thick material is passed through silica gel column (0-40% hexane-EtOAc) purification to obtain 8-((2-methyl-4-(trifluoromethoxy) phenyl) sulfonyl)-1-oxa-8-azaspiro [4.5] decane-3-one (358 mg, 98%). LCMS m / z=394.1[M+H] + .

[0871] 2. Synthesis of 8-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane

[0872]

[0873] Morpholine hydrochloride (38 mg, 0.3 mmol) is added to a solution of 8-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decane-3-one (100 mg, 0.3 mmol) in DCM (8 mL) and the solution is stirred at room temperature for 15 minutes. Acetic acid (30 μL, 0.5 mmol) is added dropwise, followed by NaBH(OAc) (216 mg, 1.0 mmol) and the reaction is stirred at room temperature for 3 hours. The reaction is quenched with saturated NH4Cl aqueous solution, neutralized with saturated NaHCO3 aqueous solution, and diluted with DCM. The organics were washed with water and brine, the solvent was removed in vacuo, and the crude product was purified by silica gel column (0-100% EtOAc to 3:1 EtOAc:EtOH (w / 2% NH3OH)) to give 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 (400MHz, CDCl3) δ (ppm): 8.00-7.80 (m, 1H), 7.15 (br d,J=0.8Hz,2H),3.97(dd,J=6.8,8.5Hz,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=7.8,12.3Hz,1H),1.80-1.50(m,5H).

[0874] Example 55: 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane

[0875]

[0876] 1. Synthesis of 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one

[0877]

[0878] DIPEA (1.9mL, 11.2mmol) is added into the bottle of 1-oxa-8-azaspiro [4.5] decane-3-one hydrochloride (428mg, 2.2mmol) equipped with in DMF (4mL).After 5 minutes, 2-cyclopropylthiazole-5-sulfonyl chloride (500mg, 2.24mmol) is added, and the reaction mixture is stirred at room temperature for 1 hour.The reaction is quenched with water and the mixture (3x) is extracted with EtOAc.The organic matter merged is washed with saturated NaHCO3aqueous solution (2x).The organic layer is separated and dried over anhydrous Na2SO4.The crude material is passed through silica gel column (0-25% EtOAc to 3:1EtOAc:EtOH) purification, obtain 8-((2-cyclopropylthiazole-5-yl)sulfonyl)-1-oxa-8-azaspiro [4.5] decane-3-one (630mg, 82%) as a yellow solid. LCMS m / z=343.0[M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.94 (s, 1H), 3.97 (s, 2H), 3.60-3.50 (m, 2H), 2.93 (dt,J=3.5,11.2Hz,2H),2.40-2.20(m,3H),2.00-1.80(m,4H),1.40-1.10(m,4H).

[0879] 2. Synthesis of 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane

[0880]

[0881] 3-methoxyazetidine hydrochloride (42mg, 0.3mmol) is added to a solution of 8-(2-cyclopropylthiazol-5-yl)sulfonyl-1-oxa-8-azaspiro [4.5] decane-3-one (116mg, 0.3mmol) in DCM (10mL) and the solution is stirred at room temperature for 15 minutes.Acetic acid (40 μL, 0.7mmol) is then added, followed by addition of NaBH (OAc) (287mg, 1.4mmol), and the reaction is stirred at room temperature for 3 hours.The reaction is quenched with saturated NH4Cl aqueous solution and diluted with DCM.Organic matter is washed with water and salt water, and the solvent is removed in vacuo. The crude product was purified by silica gel column (0-100% EtOAc to 3:1 EtOAc:EtOH (w / 2% NH3OH)) to give 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 (400MHz, CDCl3) δ (ppm): 7.88 (s, 1H), 3.72 (dd, J = 5.4, 9.2Hz, 1H), 3.58 (dd, J = 3.8, 9.0Hz, 1H), 3.47 (td, J = 3.0, 7.5Hz, 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).

[0882] Example 56: 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane

[0883]

[0884] 1. Synthesis of 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one

[0885]

[0886] DIPEA (1.6mL, 9.4mmol) is added to the vial equipped with 1-oxa-8-azaspiro [4.5] decane-3-one hydrochloride (360mg, 1.9mmol) in DMF (4mL). After 5 minutes, 5-cyclopropyl-2-methyl-pyrazole-3-sulfonyl chloride (415mg, 1.9mmol) is added, and the reaction is stirred at room temperature for 1 hour. The reaction is quenched with water and the mixture is extracted with EtOAc (3x). The combined organic matter is washed with saturated NaHCO3 aqueous solution (2x). The organic layer is separated, then dried over Na2SO4 and concentrated in vacuo. The crude material is purified by silica gel column (0-25% EtOAc to 3:1EtOAc:EtOH) to obtain 8-((3-cyclopropyl-1-methyl-1H-pyrazole-5-yl)sulfonyl)-1-oxa-8-azaspiro [4.5] decane-3-one (610mg, 95%). LCMS m / z=340.1[M+H] + .

[0887] 2. Synthesis of 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane

[0888]

[0889] 2- oxa- -6- azaspiro [3.3] heptane (25mg, 0.3mmol) is added to a solution of 8- (5- cyclopropyl -2- methyl - pyrazole -3- bases) sulfonyl -1- oxa -8- azaspiro [4.5] decane -3- ketone (84mg, 0.3mmol) in DCM (15mL) and the solution is stirred at room temperature for 15 minutes. Acetic acid (30mg, 0.5mmol) is then added dropwise, followed by NaBH (OAc) (210mg, 1.0mmol), and the reaction is stirred at room temperature for 3 hours. The reaction is saturated with NH the Cl aqueous solution is quenched and diluted with DCM. Organic matter is washed with water and salt water, and the solvent is removed in vacuo. The crude product was purified by silica gel column (0-100% EtOAc to 3:1 EtOAc:EtOH (w / 2% NH3OH)) to give 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane (100 mg, 96%). LCMS m / z = 423.2 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 6.25 (s, 1H), 4.70-4.60 (m, 4H), 3.92 (s, 3H), 3.62 (dd, J = 5.3, 9.3Hz, 1H), 3.50-3.40 (m, 3H), 3.30-3.1 0(m,4H),2.90-2.70(m,3H),1.90-1.70(m,2H),1.70-1.50(m,4H),1.44(dd,J=3.8,13.1Hz,1H),0.90-0.80(m,2H),0.70-0.60(m,2H).

[0890] Examples 57a and 57b: (R)-8-((3-Cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-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]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane

[0891]

[0892] 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane (Example 56) was separated on a CHIRALPAK IA 30 x 250 mm, 5 μm column. Method: 30% MeOH, without modifier, in CO2 (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40°C) to give two enantiomers of arbitrarily specified stereochemistry:

[0893] Peak 1, Enantiomer 1, (R)-8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane: LCMS m / z = 423.2 [M+H] + , R f =2.09 minutes, ee=100%

[0894] Peak 2, Enantiomer 2, (S)-8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane: LCMS m / z = 423.2 [M+H] + , R f =2.25 minutes, ee=82.84%

[0895] Example 58: 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane

[0896]

[0897] Following the procedure described in step 2 of Example 56, 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane (78 mg, 77%) was obtained from 3-methoxyazetidine and 8-(5-cyclopropyl-2-methyl-pyrazol-3-yl)sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-one. LCMS m / z = 411.2 [M+H] + . 1H-NMR (400MHz, CDCl3) 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).

[0898] Example 59: 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]dec-3-amine

[0899]

[0900] Following the procedure described in Step 2 of Example 56, 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (80 mg, 73%) was obtained from 2-methoxyethylamine and 8-(5-cyclopropyl-2-methyl-pyrazol-3-yl)sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-one. LCMS m / z = 399.2 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 6.32 (s, 1H), 3.98 (s, 3H), 3.91 (dd, J = 6.0, 9.0Hz, 1H), 3.70-3.40 (m, 6H), 3.33 (s ,3H),2.93(dq,J=3.5,11.5Hz,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).

[0901] Example 60: 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-1-oxa-8-azaspiro[4.5]dec-3-amine

[0902]

[0903] 1. Synthesis of 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-1-oxa-8-azaspiro[4.5]dec-3-amine

[0904]

[0905] 8-(5-cyclopropyl-2-methyl-pyrazol-3-yl)sulfonyl-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decyl-3-amine (70 mg, 0.2 mmol) was dissolved in MeCN (3 mL), KCO (49 mg, 0.4 mmol) was added and the mixture was stirred for 30 minutes. Iodomethane (10 μL, 0.2 mmol) was added and the reaction was stirred overnight. The reaction was diluted with EtOAc and washed with water (3x). The organic phase was concentrated in vacuo and the residue was purified on a silica gel column (0-100% EtOAc to 3:1 EtOAc:EtOH (containing 2% NH3OH)) 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 (400MHz, CDCl3) 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, 3 H),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).

[0906] Example 61: 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane

[0907]

[0908] 1. Synthesis of 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one

[0909]

[0910] Following the procedure described in step 1 of Example 56, 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one (120 mg, 40%) was obtained from 5-chloro-2-methoxy-pyridine-3-sulfonyl chloride and 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride. LCMS m / z = 361.1 [M+H] + . 1H-NMR (400MHz, CDCl3) δ (ppm): 8.26 (d, J = 2.5Hz, 1H), 8.14 (d, J = 2.5Hz, 1H), 4.05 (s, 3H), 3. 98(s,2H),3.66(td,J=3.5,12.7Hz,2H),3.30-3.00(m,2H),2.37(s,2H),2.00-1.70(m,4H).

[0911] 2. Synthesis of 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane

[0912]

[0913] Following a synthetic procedure similar to that described in Step 2 of Example 56, 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane (40 mg, 60%) was obtained from 3-methoxyazetidine and 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one. LCMS m / z = 432.1 [M+H] + . 1 H-NMR (400MHz, CDCl3) 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=5.3,9.3Hz,1H),3.70-3.50(m,5H),3.26(s,3H),3.20-3.00(m,3H),2.87(td,J=6.4,19.3Hz,2H),2.00-1.50(m,6H).

[0914] Example 62: 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane

[0915]

[0916] Following a synthetic procedure similar to that described in Step 2 of Example 56, 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane (80 mg, 97%) 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. LCMS m / z = 444.1 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 8.16 (d, J = 2.5Hz, 1H), 8.04 (d, J = 2.5Hz, 1H), 4.70-4.60 (m, 4H), 3.95 (s, 3H), 3.63 (dd, J = 5.3, 9.3Hz ,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=3.9,12.9Hz,1H).

[0917] Examples 63a and 63b: (R)-8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-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]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane

[0918]

[0919] 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane (Example 62) was separated on a CHIRALPAK AD-H 30 x 250 mm, 5 μm column. Method: 25% MeOH containing 0.1% DEA in CO (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) to give two enantiomers of arbitrarily specified stereochemistry:

[0920] Peak 1, Enantiomer 1, (R)-8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane: LCMS m / z = 444.1 [M+H] + . R f =2.12 minutes. ee=100%

[0921] Peak 2, Enantiomer 2, (S)-8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane LCMS m / z=444.1 [M+H] + . R f =2.33 minutes, ee=96.9%.

[0922] Example 64: 3-((3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-chlorobenzonitrile

[0923]

[0924] 1. Synthesis of 4-chloro-3-((3-oxo-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile

[0925]

[0926] Following the procedure described in step 1 of Example 56, 4-chloro-3-((3-oxo-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile (210 mg, 57%) was obtained from 2-chloro-5-cyano-benzenesulfonyl chloride and 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride. LCMS m / z = 355.1 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 8.38 (d, J = 2.0Hz, 1H), 7.78 (dd, J = 2.0, 8.3Hz, 1H), 7.70-7.6 0(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).

[0927] 2. Synthesis of 3-((3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-chlorobenzonitrile

[0928]

[0929] Following a procedure similar to that described in step 2 of Example 56, 3-((3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-chlorobenzonitrile (68 mg, 79%) was obtained from 2-oxa-6-azaspiro[3.3]heptane and 4-chloro-3-((3-oxo-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile. LCMS m / z = 438.2 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 8.32 (d, J = 1.8Hz, 1H), 7.74 (dd, J = 2.0, 8.0Hz, 1H), 7.70-7.50 (m, 1H), 4.80-4.60 (m, 4 H),3.71(dd,J=5.4,9.4Hz,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=13.8Hz, 1H), 1.80-1.60 (m, 4H), 1.52 (dd, J=3.8, 13.1Hz, 1H).

[0930] Example 65: 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]dec-3-amine

[0931]

[0932] 1. Synthesis of 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one

[0933]

[0934] Following the procedure described in Step 1 of Example 56, 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one (260 mg, 73%) was obtained from 2-methoxy-5-methyl-pyridine-3-sulfonyl chloride and 1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride. LCMS m / z = 341.1 [M+H] + . 1H-NMR (400MHz, CDCl3) δ (ppm): 8.11 (d, J = 2.3Hz, 1H), 7.97 (d, J = 2.5Hz, 1H), 4.02 (s, 3H), 3.96 (s, 2H),3.61(td,J=3.8,12.7Hz,2H),3.30-3.10(m,2H),2.35(s,2H),2.30(s,3H),1.90-1.70(m,4H).

[0935] 2. Synthesis of 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]dec-3-amine

[0936]

[0937] Following a synthetic procedure similar to that described in Step 2 of Example 56, 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (85 mg, 72%) was obtained from 2-methoxyethylamine and 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one. LCMS m / z = 400.2 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 8.09 (dd, J=0.8, 2.5Hz, 1H), 7.96 (d, J=2.5Hz, 1 H),4.01(s,3H),3.92(dd,J=5.8,9.0Hz,1H),3.70-3.50(m,5H),3.41(qd,J=5. 8,7.5Hz,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=7.5,12.8Hz,1H),1.90-1.60(m,5H),1.56(dd,J=5.9,12.9Hz,1H).

[0938] Example 66: 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-(methyl-d3)-1-oxa-8-azaspiro[4.5]dec-3-amine

[0939]

[0940] 1. Synthesis of 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-(methyl-d3)-1-oxa-8-azaspiro[4.5]dec-3-amine

[0941]

[0942] 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]dec-3-amine (Example 65, 13 mg, 0.3 mmol) was dissolved in MeCN (3 mL), KCO (9 mg, 0.7 mmol) was added and the reaction was stirred for 30 minutes. Trideuterium(iodine)methane (5 mg, 0.03 mmol) was added and the reaction was stirred overnight. The reaction was diluted with EtOAc and washed with water (3x). 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% NH3OH) to afford 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 (400MHz, CDCl3) δ (ppm): 8.03 (dd, J=0.9, 2.4Hz, 1H), 7.90-7.80 (m, 1H), 4.00-3.90 (m, 3H), 3.89 (br dd,J=7.3,9.0Hz,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).

[0943] Example 67: 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-1-oxa-8-azaspiro[4.5]dec-3-amine

[0944]

[0945] Following the procedure described in Example 66, 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-1-oxa-8-azaspiro[4.5]dec-3-amine (Example 65) and iodomethane was used to obtain 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]dec-3-amine (27 mg, 60%). LCMS m / z = 414.2 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ (ppm): 8.12 (d, J = 2.3Hz, 1H), 7.98 (d, J = 2.5Hz, 1H), 4.10-4.00 (m, 3H), 3.97 ( dd,J=7.0,9.0Hz,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=8.3,12.3Hz,1H),1.90-1.50(m,9H).

[0946] Examples 68a and 68b: (R)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-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]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane

[0947]

[0948] 1. Synthesis of 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one

[0949]

[0950] A solution of 8-azaspiro [4.5] decane-3-one hydrochloride (2.5 g, 13.1 mmol) in anhydrous DCM (50 mL) was cooled to <5 ° C in an ice bath, followed by addition of DIPEA (9 mL, 51.7 mmol) and DMAP (123 mg, 1.0 mmol). After 5 minutes, 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 minutes. The reaction mixture was quenched with saturated NaHCO3 aqueous solution, stirred for 10 minutes, and extracted with DCM (3x). The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column eluting with (15-80% EtOAc in heptane) to give 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one (3.49 g, 81%) as a white solid. LCMS m / z = 312.1 (M+H) + . 1 H-NMR (500MHz, DCM-d2) δ (ppm): 6.46 (s, 1H), 4.01 (s, 3H), 3.37-3.32 (m, 2H), 2.95 (ddd, J = 4. 0,8.4,12.1Hz,2H),2.27-2.23(m,5H),2.06(s,2H),1.83(t,J=7.9Hz,2H),1.71-1.63(m,4H).

[0951] 2. Synthesis of 6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane

[0952]

[0953] A solution of 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decane-2-one (3.5 g, 11.1 mmol) in anhydrous DCM (40 mL) was cooled to <5°C. After 10 minutes, 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 at <5°C. After 20 minutes, NaBH(OAc) (8.6 g, 40.5 mmol) was added in portions and the mixture was warmed to room temperature and stirred for 2.5 hours. The reaction was quenched with saturated NaHCO aqueous solution. After 20 minutes, the biphasic mixture was extracted with DCM (3x). The combined organic extracts were dried over anhydrous MgSO, 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 afford 6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane (3.1 g, 67%) as a colorless oil. LCMS m / z = 395.3 (M+H) + . 1 H-NMR(500MHz,DMSO-d6)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),2.6 2-2.54(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=5.2,13.1Hz,1H).

[0954] 3. Synthesis of (R)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-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]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane

[0955]

[0956] 6-(8-((1,3-Dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane (3.1 g, 7.86 mmol) was purified on a Lux Cellulose 30x250 mm, 5 μm column using 40% MeOH in CO. Flow rate: 100 mL / min; ABPR 120 bar; MBPR 40 psi, column temperature 40°C to give two enantiomers of arbitrarily specified stereochemistry:

[0957] Peak 1, Enantiomer 1, (R)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane (E1, t R =1.86 min) as a colorless film (1.18 g, 36%). LCMS m / z=395.3 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) 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).

[0958] Peak 2, Enantiomer 2, (S)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane (E2, t R =2.24 minutes) as a colorless film (1.24 g, 38%). LCMS m / z=395.3 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)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).

[0959] Example 69: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(6-oxa-2-azaspiro[3.4]oct-2-yl)-1-oxa-8-azaspiro[4.5]decane

[0960]

[0961] 1. Synthesis of 8-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one

[0962]

[0963] To a vial containing 1-oxa-8-azaspiro [4.5] decane-3-one hydrochloride (1.0 g, 5.2 mmol) in THF (24 mL) was added DIPEA (3.6 mL, 20.9 mmol) followed by DMAP (64 mg, 0.5 mmol). After 5 minutes, 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 quenched with saturated NaHCO solution, extracted with EtOAc (3x), the organic layer was separated and washed with brine. The combined organic phases were dried over anhydrous NaSO, filtered and evaporated. The residue was purified by silica gel chromatography (0-75% EtOAc in heptane) to give 8-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-8-azaspiro [4.5] decane-3-one (1.69 g, 90%). LCMS m / z=362.0[M+H] + . 1 H-NMR(400MHz, DMSO-d6)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).

[0964] 2. Synthesis of 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(6-oxa-2-azaspiro[3.4]octan-2-yl)-1-oxa-8-azaspiro[4.5]decane

[0965]

[0966] By 8-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-8-azaspiro [4.5] decane-3-one (45mg, 0.1mmol) in DCM (1.5mL), then TEA (40 μ L, 0.3mmol) is added in 6-oxa-2-azaspiro [3.4] octane (17mg, 0.2mmol) and the solution is stirred for 15 minutes.Acetic acid (18 μ L, 0.3mmol) is added, the solution is stirred for 30 minutes, then NaBH (OAc) is added (106mg, 0.5mmol).Reactant mixture is stirred at room temperature for 1 day, quenched with saturated NH4Cl solution (2mL) and extracted with EtOAc (2x). The combined organic solutions were concentrated under reduced pressure, and the crude residue was purified by preparative HPLC (Waters SunFire Prep C18 5 μm OBD 30 x 100 mm; method: (A) 95% water / / (B) 5% MeCN with 0.1% TFA to 50% (A) / 50% (B) over 7.5 minutes (flow rate: 50 mL / min) to afford 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(6-oxa-2-azaspiro[3.4]octan-2-yl)-1-oxa-8-azaspiro[4.5]decane (13.1 mg, 18%) as a clear oil. LCMS m / z = 458.8 [M+H] + . 1 H-NMR(500MHz,DMSO-d6)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,4 H),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=13.43Hz,1H),1.61-1.48(m,2H).

[0967] Example 70: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane

[0968]

[0969] 1. Synthesis of 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane

[0970]

[0971] 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 following the procedure described in Step 2 of Example 69. The crude product was purified by preparative HPLC (Waters XSelect CSH Prep C18 5 μm OBD 30 x 100 mm; method: (A) 95% (water) / / (B) 5% (MeCN) containing 0.2% NH4OH to 35% (A) / 65% (B) in 7.5 minutes (flow rate: 50 mL / min) (0.5 mg, 1%) to a clear oil. LCMS m / z = 472.8 [M+H] + , R f =0.52 minutes.

[0972] 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

[0973]

[0974] 1. Synthesis of 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

[0975]

[0976] Following the procedure described in step 2 of Example 69, 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. The crude product was purified by preparative HPLC (Waters XSelect CSH Prep C18 5 μm OBD 30x100 mm; method: (A) 95% (water) / / (B) 5% (MeCN) containing 0.2% NH4OH to 40% (A) / 60% (B) over 7.5 minutes (flow rate: 50 mL / min) to afford 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 (14.9 mg, 26%) as a clear oil. LCMS m / z = 458.8 [M+H] + , R f =1.91 minutes.

[0977] Examples 72a, 72b, 72c, and 72d: (S)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-((R)-2-oxa-7-azaspiro[4.4]non-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]non-7-yl)-1-oxa-8-azaspiro[4.5]decane Heterospiro[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

[0978]

[0979] 1. Synthesis of 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one

[0980]

[0981] To a vial containing 1-oxa-8-azaspiro [4.5] decane-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 minutes, 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 hours. The reaction was quenched by adding saturated NaHCO3 solution, extracted with EtOAc, and washed with brine. The organic layer was dried over anhydrous Na2SO4, 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] decane-3-one (572.3 mg, 88%). LCMS m / z=314.0[M+H] + . 1 H-NMR (400MHz, CD3OD) δ (ppm): 6.57 (s, 1H) 4.00 (s, 3H) 3.96 (s, 2H) 3.55-3.47 (m, 2H) 3. 08(td,J=11.6,3.3Hz,2H)2.41(s,2H)2.25(s,3H)1.98-1.91(m,2H)1.89-1.80(m,2H).

[0982] 2. Synthesis of 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

[0983]

[0984] Hunig's base (110 μL, 0.6 mmol) was slowly added to a solution of 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decane-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 minutes, acetic acid (110 μL, 1.9 mmol) was added and the solution was stirred for 30 minutes. NaBH(OAc) (541 mg, 2.6 mmol) was added and stirred at room temperature for 1 day. The reaction was quenched with saturated NaHCO solution, extracted with EtOAc, washed with brine, dried over anhydrous NaSO, filtered and evaporated. The residue was purified by silica gel chromatography (0-100% EtOH:EtOAc (2% NH4OH) 1:3 in EtOAc) 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]decane.

[0985] 3. Isolation of 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

[0986] 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 further purified by chiral SFC (CHIRALPAK AD-H 30x250 mm, 5 μm; method: 20% EtOH containing 0.1% DEA in CO2 (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40°C) to give four enantiomers of arbitrarily specified stereochemistry:

[0987] 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 = 2.97 min LCMS m / z = 425.3 [M+H] + . 1H-NMR (400MHz, CD3OD) δ (ppm): 6.54 (s, 1H) 3.99 (s, 3H) 3.92 (dd, J = 8.8, 6.5Hz, 1H) 3.88-3.78 (m, 2H) 3.67-3.61 (m, 2H) 3.54 (d, J = 8 .0Hz,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).

[0988] 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] + .

[0989] 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 minutes. LCMS m / z=425.3 [M+H] + .

[0990] 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 =3.76 minutes. LCMS m / z=425.3 [M+H] + .

[0991] Example 73: 4-(7-((4-(difluoromethoxy)phenyl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine

[0992]

[0993] 1. Synthesis of 7-((4-(difluoromethoxy)phenyl)sulfonyl)-7-azaspiro[3.5]nonan-2-one

[0994]

[0995] To a vial containing 7-azaspiro [3.5] nonane-2-one hydrochloride (522 mg, 3.0 mmol) in anhydrous THF (10 mL) was added DIPEA (1.2 g, 9.2 mmol) at <5 ° C. After 5 minutes, 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 minutes. The reaction mixture was quenched with 1 M NaOH aqueous solution and stirred for 10 minutes. The biphasic mixture was loaded onto a silica gel column and purified with (10-50% EtOAc in heptane) to give 7- ((4- (difluoromethoxy) phenyl) sulfonyl) -7- azaspiro [3.5] nonane-2-one (977 mg, 95%) as a white solid, which was used in the next step without further purification. LCMS m / z = 346.1 (M + H) + . 1 H-NMR (500MHz, DMSO-d6) 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).

[0996] 2. Synthesis of 4-(7-((4-(difluoromethoxy)phenyl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine

[0997]

[0998] At room temperature, to a vial containing 7-((4-(difluoromethoxy)phenyl)sulfonyl)-7-azaspiro[3.5]nonane-2-one (84 mg, 0.2 mmol) in anhydrous DCM (2 mL), AcOH (10 μL, 0.2 mmol) was added, followed by dropwise addition of morpholine (50 μL, 0.6 mmol). After 15 minutes, NaBH(OAc) (212 mg, 1.0 mmol) was added portionwise to the reaction mixture. After 6.5 hours, the reaction was quenched with a 1 M NaOH aqueous solution, stirred for 20 minutes, and extracted with DCM (3x). The combined organic layers were dried over anhydrous MgSO, 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 (72 mg, 67%) as a colorless film. LCMS m / z = 417.2 (M+H) + . 1H-NMR(500MHz,DCM-d2)δ(ppm):7.77-7.73(m,2H),7.26(d,J=8.5Hz,2H),6.66(t,J=72.9Hz,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).

[0999] Example 74: 4-(7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine

[1000]

[1001] 4-(7-((1,3-Dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine was prepared following the two-step procedure described for Example 73 starting with 7-azaspiro[3.5]nonan-2-one hydrochloride and 1,3-dimethyl-1H-pyrazol-5-sulfonyl chloride to afford 7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (201 mg, 67%) as a white solid. LCMS m / z = 298.0 (M+H) + . 1 H-NMR (500MHz, CD3OD) 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).

[1002] Step 2: This compound was reacted with morpholine to give 4-(7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine (56 mg, 43%) as a peach oil. LCMS m / z = 369.3 (M+H) + . 1H-NMR (600MHz, DMSO-d6)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=5.1Hz,2H),3.00-2.94(m,2H),2.18(s,6H),1.87(br t,J=9.4Hz,3H),1.64-1.59(m,3H),1.56-1.47(m,6H).

[1003] 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

[1004]

[1005] 1. Synthesis of 7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one

[1006]

[1007] At <5 ° C, DIPEA (890 mg, 6.9 mmol) was added dropwise to a vial containing 7-azaspiro [3.5] nonane -2-one hydrochloride (375 mg, 2.1 mmol) in anhydrous THF (5 mL). After 5 minutes, 6-methoxy-2-methyl-pyridine -3-sulfonyl chloride (571 mg, 2.6 mmol) was added. The reaction was allowed to reach room temperature and stirred for 30 minutes, and the reaction was quenched by slowly adding 1M NaOH aqueous solution and stirred for another 10 minutes. The biphasic mixture was directly loaded 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] nonane -2-one (595 mg, 86%) as a white solid, which was used in the next step without further purification. LCMS m / z = 325.0 (M + H) + . 1 H-NMR(500MHz,DCM-d2)δ(ppm):8.04(d,J=9.2Hz,1H),6.69(d,J=8.5Hz,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).

[1008] 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

[1009]

[1010] 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 the dropwise addition of AcOH (10 μL, 0.2 mmol) at room temperature. After 15 minutes, NaBH(OAc) (156 mg, 0.7 mmol) was added. After 1.5 hours, the reaction mixture was quenched with 1 M aqueous NaOH, stirred for 10 minutes, and extracted with DCM (3x). The organic layer was dried over anhydrous MgSO. 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 (26 mg, 26%) as a colorless film. LCMS m / z = 408.3 (M+H) + . 1 H-NMR (500 MHz, DCM-d2) 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 (quintet, 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).

[1011] 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

[1012]

[1013] 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 with 7-azaspiro[3.5]nonan-2-one hydrochloride and 2-methyl-6-(trifluoromethyl)pyridin-3-sulfonyl chloride to afford 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 (500MHz, DCM-d2) 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).

[1014] Step 2: This compound was reacted with 2-oxa-6-azaspiro[3.3]heptane to give the title compound as a white solid (1.73 g, 60%). LCMS m / z = 446.2 (M+H) + . 1 H-NMR (500 MHz, DMSO-d6) 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 (quintet, 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).

[1015] Example 77: 6-(7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]non-2-yl)-2-oxa-6-azaspiro[3.3]heptane

[1016]

[1017] 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 following the two-step procedure described for Example 75 starting with 7-azaspiro[3.5]nonan-2-one hydrochloride and 6-chloro-2-methylpyridin-3-sulfonyl chloride to afford 7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (274 mg, 81%) as a white solid. LCMS m / z = 329.0 (M+H) + . 1 H-NMR(500MHz,CD3OD)δ(ppm):8.20(d,J=8.2Hz,1H),7.48(d,J=8.2Hz,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).

[1018] Step 2: This compound was reacted with 2-oxa-6-azaspiro[3.3]heptane to give the title compound as a white solid (32.5 mg, 35%). LCMS m / z = 412.2 (M+H) + . 1 H-NMR(500MHz,DMSO-d6)δ(ppm):8.14(d,J=8.2Hz,1H),7.58(d,J=8.5Hz,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).

[1019] 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

[1020]

[1021] 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 following the two-step procedure described for Example 75 starting with 7-azaspiro[3.5]nonan-2-one hydrochloride and 4-methyl-6-(trifluoromethyl)pyridin-3-sulfonyl chloride to afford 7-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (285 mg, 75%) as a white solid. LCMS m / z = 363.2 (M+H) + . 1 H-NMR (500MHz, DCM-d2) 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).

[1022] Step 2: This compound was reacted with 2-oxa-6-azaspiro[3.3]heptane to give the title compound (11 mg, 8%) as a colorless film. LCMS m / z = 446.2 (M+H) + . 1 H-NMR(500MHz,DMSO-d6)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).

[1023] 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

[1024]

[1025]

[0266] 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 following the two-step procedure described for Example 75 starting with 7-azaspiro[3.5]nonan-2-one hydrochloride and 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride (307 mg, 1.2 mmol) to afford 7-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (206 mg, 58%) as a white solid. 1 H-NMR (500MHz, DCM-d2) 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).

[1026] Step 2: This compound was reacted with 2-oxa-6-azaspiro[3.3]heptane to give the title compound (12 mg, 9%) as a colorless film. LCMS m / z = 435.3 (M+H) + . 1 H-NMR(500MHz,DMSO-d6)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=4.6,5.5Hz,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).

[1027] 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

[1028]

[1029] 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 following the two-step procedure described for Example 75 starting with 7-azaspiro[3.5]nonan-2-one hydrochloride and 5-cyclopropyl-2-methyl-pyrazole-3-sulfonyl chloride to afford 7-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (195 mg, 87%) as a white solid. LCMS m / z = 324.1 [M+H]+ . 1 H-NMR(500MHz,DCM-d2)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).

[1030] Step 2: This compound was reacted with 2-oxa-6-azaspiro[3.3]heptane to give the title compound (31 mg, 23%) as a colorless film. LCMS m / z = 407.3 (M+H) + . v (500MHz, DMSO-d6)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).

[1031] 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

[1032]

[1033] 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

[1034]

[1035] At room temperature, DIPEA (100 μL, 0.6 mmol) was added dropwise 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). After 15 minutes, AcOH (50 μL, 0.9 mmol) and 7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonane-2-one (Example 75, Step 1) (87 mg, 0.3 mmol) were added dropwise. After 30 minutes, NaBH(OAc) (200 mg, 1.0 mmol) was added portionwise to the reaction mixture, and the resulting mixture was stirred for 2.5 hours. The reaction was quenched with 1 M NaOH aqueous solution and stirred for another 10 minutes, then extracted with DCM (3x). The combined organic layers were dried over anhydrous MgSO, filtered and concentrated under reduced pressure. The residue was loaded onto silica gel and purified by column chromatography (25-100% 3:1 EtOAc:EtOH in heptane) to afford (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 (78 mg, 68%) as a colorless film. LCMS m / z = 408.3 (M+H) + . 1 H-NMR(500MHz,DMSO-d6)δ(ppm):7.99(d,J=9.2Hz,1H),6.82(d,J=8.5Hz,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).

[1036] 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

[1037]

[1038] (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 (500MHz, DMSO-d6) δ (ppm): 7.38 (s, 1H), 4.30 (s, 1H), 4.10 (s, 3H), 3.69 (d, J = 6.7Hz, 1H), 3.44 (br d,J=7.3Hz,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).

[1039] 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

[1040]

[1041] 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] + . 1H-NMR (CDCl3, 500MHz) δ (ppm): 6.88 (s, 1H), 4.12 (s, 3H), 3.92 (br d,J=11.3Hz,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=9.8Hz,2H),1.80-1.60(m,7H),1.48(br t,J=10.1Hz,2H),1.40-1.30(m,2H).

[1042] Example 84: 1-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-4-methylpiperidin-4-ol

[1043]

[1044] 1. Synthesis of 1-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-4-methylpiperidin-4-ol

[1045]

[1046] To a vial containing 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]decane-2-one (75 mg, 242 umol) in DCM (2 mL) was added AcOH (0.02 mL, 349 umol), followed by the careful dropwise addition of 4-methylpiperidin-4-ol (57 mg, 491 umol) at 23 ° C. After 15 minutes, NaBH(OAc) 3 (203 mg, 960 umol) was carefully added portionwise to the reaction mixture. After the addition of NaBH(OAc) 3 was complete, the reaction was stirred at 23 ° C. and monitored by LCMS. After 6.5 hours, a 1 M NaOH aqueous solution was slowly added to carefully quench the reaction. The mixture was stirred at 23 ° C. for 20 minutes, and then the biphasic mixture was extracted with DCM (3x). The organic extracts were pooled and then dried over MgSO 4. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (40-100% 3:1 EtOAc: ethanol in heptane). The 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 at a flow rate of 50 mL / min using a Waters XSelect CSH C18, 5 μm, 50 mm × 100 mm column with a mobile phase of H2O (A) and MeCN (B) and a gradient of 5-65% B (0.2% NH4OH final v / v% modifier). Fractions containing the desired product were pooled and concentrated under reduced pressure to give 1-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-4-methylpiperidin-4-ol (34 mg, 32%) as a yellow oil. LCMS m / z = 411.3 (M+H) + . 1 H NMR (600MHz, DMSO-d6) 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=6.5Hz,1H),1.75-1.69(m,1H),1.57-1.53(m,1H),1.50-1.33(m,14H),1.19(br d,J=10.9Hz,1H),1.07(s,4H).

[1047] Examples 85a and 85b: (R)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile or (S)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile

[1048]

[1049] 1. Synthesis of 3-fluoro-5-((2-oxo-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile

[1050]

[1051] To the flask equipped with 1-oxa-8-azaspiro [4.5] decane-3-one hydrochloride (3g, 16mmol) in DCM (60mL), DIPEA (8.5mL, 48.8mmol) was added dropwise. After 5 minutes, 3-cyano-5-fluoro-benzenesulfonyl chloride (4.13g, 18.8mmol) was added, and the reaction was stirred at room temperature for 30 minutes. The reaction was quenched with saturated NaHCO solution and then extracted with DCM (3x). The organic layer was collected and then washed with salt water. The organic phases merged were dried over Na2SO4, filtered and evaporated. Silica gel chromatography (0-75% EtOAc in heptane) was used to purify the residue to obtain 3-fluoro-5-((2-oxo-8-azaspiro [4.5] decane-8-yl) sulfonyl) benzonitrile (4.9g, 91%). 1 H NMR (500MHz, DCM-d2) 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=7.9Hz,2H),2.02-1.99(m,2H),1.79(t,J=7.9Hz,2H),1.73-1.64(m,4H).

[1052] 2. Synthesis of (R)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile and (S)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile

[1053]

[1054] A flask containing 3-fluoro-5-((2-oxo-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile (4.9 g, 14.6 mmol) in DCM (50 mL) was cooled to <5°C in an ice-water bath, 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 at <5°C. After 15 minutes, NaBH(OAc) (10.5 g, 49.4 mmol) was carefully added portionwise to the cold reaction mixture. After the addition was complete, the reaction was warmed to 23°C and monitored by LCMS. After 1 hour, a 1 M NaOH aqueous solution was slowly added to carefully quench the reaction. The mixture was stirred at 23°C for 20 minutes, and then the biphasic mixture was extracted with DCM (3x). The organic extracts were collected and then dried over MgSO. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (35-95% 3:1 EtOAc:ethanol in heptane). The desired fractions were pooled and then concentrated under reduced pressure to afford (R)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile and (S)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile (4.6 g, 71%) as white solids, which were submitted to chiral SFC purification. LCMS m / z=420.4 (M+H) + . 1 H NMR (500MHz, DMSO-d6) δ (ppm) = 8.27 (br d, J = 8.2Hz, 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=5.0,13.3Hz,1H).

[1055] 3. Synthesis of (R)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile or (S)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile

[1056]

[1057] (R)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile and (S)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-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 LuxCellulose-4LC 30 x 250 mm, 5 μm 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:

[1058] - Peak 1 or Example 85a was a white solid arbitrarily designated as (R)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile (2.1 g, 45%). LCMS m / z = 420.3 (M+H) + . 1 H NMR (500MHz, DMSO-d6) 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=5.2,13.1Hz,1H).

[1059] - Peak 2 or Example 85b is a white solid arbitrarily designated as (S)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile (2.1 g, 45% yield). LCMS m / z = 420.3 (M+H) + . 1 H NMR (500MHz, DMSO-d6) δ (ppm) = 8.30-8.25 (m, 1H), 8.07 (s, 1H), 7.97-7.93 (m, 1H), 4.54 (s, 4H), 3.11 (br s,4H),3.00-2.92(m,4H),2.60-2.55(m,1H),1.54-1.49(m,3H),1.43-1.33(m,4H),1.30-1.23(m,2H),1.01(dd,J=5.2,13.1Hz,1H).

[1060] Examples 86a and 86b: (1R,4R)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane and (1R,4R)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[1061]

[1062] 1. Synthesis of 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-one

[1063]

[1064] At <5 ℃, DIPEA (10.5mL, 60mmol) was carefully added dropwise to a flask containing 8-azaspiro [4.5] decane-3-one hydrochloride (2.8g, 15mmol) in DCM (30mL). After 15 minutes, 4-(difluoromethoxy)benzenesulfonyl chloride (4.3g, 17.6mmol) was carefully added to the cold solution. After the addition of sulfonyl chloride was complete, the reaction was warmed to 23 ℃ and monitored by LCMS. After 30 minutes, saturated NaHCO3 aqueous solution was slowly added to quench the reaction carefully. The mixture was stirred at 23 ℃ for 20 minutes, then the two-phase mixture (3x) was extracted with DCM. The organic extracts were collected and then dried over MgSO4. After filtering and concentrating under reduced pressure, the residue was loaded onto a silica gel column and purified with (25-75% EtOAc in heptane). The desired fractions were pooled and concentrated under reduced pressure to give 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-2-one (4.9 g, 92%) as a white solid. LCMS m / z=360.1 (M+H) + . 1 H NMR (500MHz, DCM-d2) δ (ppm) = 7.79-7.75 (m, 2H), 7.28 (d, J = 8.5Hz, 2H), 6.67 (t, J = 72.9Hz, 1H), 3.30-3.22 (m, 2H) ,2.75(ddd,J=3.4,8.8,12.0Hz,2H),2.21(t,J=7.9Hz,2H),1.98(s,2H),1.77(t,J=8.1Hz,2H),1.72-1.61(m,4H).

[1065] 2. Synthesis of (1R,4R)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane and (1R,4R)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[1066]

[1067] 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 added AcOH (3 mL, 52 mmol), followed by the careful dropwise addition of 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 minutes, NaBH(OAc) (12 g, 57 mmol) was carefully added portionwise to the reaction mixture. After the addition of NaBH(OAc) was complete, the reaction was stirred at 23 °C and monitored by LCMS. After 3 hours, a 1 M aqueous NaOH solution was slowly added to carefully quench the reaction. The mixture was stirred at 23 °C for 45 minutes, and then the biphasic mixture was extracted with DCM (3x). The organic extracts were collected and then dried over MgSO4. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (20-80% 3:1 EtOAc:ethanol in heptane). The desired fractions were collected and then concentrated under reduced pressure to give a viscous white waxy product (1R, 4R)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane and (1R, 4R)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (5 g, 83%), which was submitted to chiral SFC purification. LCMS m / z=443.2(M+H) + . 1H NMR (500MHz, DMSO-d6) 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=1.5,9.8,15.0Hz,1H),2.27(dd,J=4.3,9.8Hz,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).

[1068] 3. Synthesis of (1R,4R)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane or (1R,4R)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[1069]

[1070] (1R,4R)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane and (1R,4R)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (5 g, 11 mmol) were dissolved in methanol (50 mL) and purified on a Lux Cellulose-4 30x250 mm, 5 μm column using 45% methanol in CO2. 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:

[1071] - Peak 1 or Example 86a (E1, R f = 2.31 minutes) was an off-white solid arbitrarily designated as (1R,4R)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (1.9 g, 36%). LCMS m / z = 443.2 (M+H) + . 1H NMR (500MHz, DMSO-d6) δ (ppm) = 7.80 (d, J = 8.9Hz, 2H), 7.59-7.27 (m, 3H), 4.25 (br s, 1H), 3.79 (br d,J=7.0Hz,1H),3.45-3.37(m,2H),2.99-2.90(m,2H),2.85(br s,3H),2.75(br d,J=9.2Hz,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).

[1072] - Peak 2 or Example 86b (E2, R f = 3.98 minutes) was an off-white solid arbitrarily designated as (1R,4R)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (2.4 g, 46%). LCMS m / z = 443.2 (M+H) + . 1 H NMR (500MHz, DMSO-d6) δ (ppm) = 7.80 (d, J = 8.9Hz, 2H), 7.60-7.28 (m, 3H), 4.25 (br s, 1H), 3.79 (br d,J=7.3Hz,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).

[1073] Example 87: (1S,4S)-5-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[1074]

[1075] 1. Synthesis of (1S,4S)-5-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[1076] (1S,4S)-5-(8-((1,3-Dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane can be synthesized similarly to the method used to prepare Example 21, but starting with (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]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (33 mg, 20%). LCMS m / z = 395.3 (M+H) + . 1 H NMR (500MHz, DMSO-d6) δ (ppm) = 6.59 (s, 1H), 4.27 (br s, 1H), 3.92 (s, 3H), 3.82 (d, J = 7.9Hz, 1H), 3.45 (br d,J=7.3Hz,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).

[1077] Example 88: (1R,4R)-5-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[1078]

[1079] 1. Synthesis of (1R,4R)-5-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[1080] (1R,4R)-5-(8-((1,3-Dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane can be synthesized similarly to the method used to prepare Example 21, but starting with (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]dec-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-d6) δ (ppm) = 6.58 (s, 1H), 3.92 (s, 3H), 3.82 (d, J = 8.0Hz, 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=10.2Hz,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).

[1081] Example 89: (1S,4S)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[1082]

[1083] 1. Synthesis of (1S,4S)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[1084] (1S,4S)-5-(8-((1,3-Dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane can be synthesized similarly to the method used to prepare Example 21, but starting with 4-(difluoromethoxy)benzenesulfonyl chloride. (1S,4S)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-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-d6) δ (ppm) = 7.80 (d, J = 8.7Hz, 2H), 7.58-7.27 (m, 3H), 3.81-3.78 (m,1H),2.96-2.84(m,5H),2.73(dd,J=9.8,17.1Hz,1H),2.29-2.26(m,1H),1.63(br d,J=9.4Hz,2H),1.58-1.53(m,2H),1.52-1.46(m,6H),1.42-1.35(m,3H),1.28(br dd,J=4.0,7.6Hz,1H),1.15-1.11(m,1H).

[1085] Examples 90a and 90b: (1S,4S)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane or (1S,4S)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[1086]

[1087] 1. Synthesis of (1S,4S)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane or (1S,4S)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[1088]

[1089] (1S,4S)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (80 mg, 181 umol) was dissolved in methanol (8 mL) and then purified on a Chiralpak AD-H 30 x 250 mm, 5 um column using 45% methanol and 0.1% DEA in CO2. Flow rate: 100 mL / min; ABPR 120 bar; MBPR 40 psi, column temperature 40°C to give the following compound, which was concentrated to dryness and then lyophilized:

[1090] - Peak 1 or Example 90a (E1, R f= 2.43 minutes) was a white solid arbitrarily designated as (1S,4S)-5-[(3R)-8-[4-(difluoromethoxy)phenyl]sulfonyl-8-azaspiro[4.5]dec-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (26 mg, 31%). LCMS m / z = 443.3 (M+H) + . 1 H NMR (500MHz, DMSO-d6) δ (ppm) = 7.80 (d, J = 8.9Hz, 2H), 7.59-7.29 (m, 3H), 4.25 (br s, 1H), 3.79 (br d, J = 7.3Hz, 1H), 3.41 (br d,J=11.9Hz,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),1.76-1.6 9(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).

[1091] - Peak 2 or Example 90b (E2, R f = 2.62 minutes) was a white solid arbitrarily designated as (1S,4S)-5-[(3S)-8-[4-(difluoromethoxy)phenyl]sulfonyl)-8-azaspiro[4.5]dec-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (34 mg, 40%). LCMS m / z = 443.2 (M+H) + . 1 H NMR (500MHz, DMSO-d6) δ (ppm) = 7.80 (d, J = 8.9Hz, 2H), 7.60-7.28 (m, 3H), 4.25 (s, 1H), 3.79 (d, J = 7.6Hz, 1H), 3.42 (br d,J=5.8Hz,2H),2.94-2.83(m,5H),2.72(br d,J=9.8Hz,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).

[1092] Example 91: 7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-7-azaspiro[3.5]nonan-2-amine

[1093]

[1094] 1. Synthesis of 7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one

[1095]

[1096] To a vial containing 7-azaspiro[3.5]nonane-2-one hydrochloride (177 mg, 1.01 mmol) in THF (2 mL) was carefully added dropwise DIPEA (0.54 mL, 3.1 mmol) at <5 °C. After 5 minutes, 2,5-dimethylpyrazole-3-sulfonyl chloride (222 mg, 1.14 mmol) was carefully added to the cold solution. After the addition of sulfonyl chloride was complete, the reaction was warmed to 23 °C and monitored with LCMS. After 30 minutes, a 1 M NaOH aqueous solution was slowly added and the reaction mixture was carefully quenched. The mixture was stirred at 23 °C for 10 minutes, and the biphasic mixture was then loaded onto a silica gel column and purified with (15-80% EtOAc in heptane). The fractions containing the product were pooled and concentrated under reduced pressure to give 7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (201 mg, 67%) as a white solid, which was used without further purification. LCMS m / z = 298.0 (M+H) + . 1 H NMR (500MHz, methanol-d4) 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).

[1097] 2. Synthesis of 7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-7-azaspiro[3.5]nonan-2-amine

[1098]

[1099] 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 added AcOH (0.02 mL, 349 umol), followed by the careful dropwise addition of 2-methoxy-N-methyl-ethylamine (57 mg, 644 umol) at 23 ° C. After 15 minutes, NaBH(OAc) 3 (279 mg, 1.32 mmol) was carefully added portionwise to the reaction mixture. After the addition of NaBH(OAc) 3 was complete, the reaction was stirred at 23 ° C. and monitored by LCMS. After 2 hours, a 1 M NaOH aqueous solution was slowly added to carefully quench the reaction. The mixture was stirred at 23 ° C. for 20 minutes, and then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then dried over MgSO 4. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (20-90% 3:1 EtOAc: ethanol in heptane). The 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 reverse phase HPLC purification. Liquid chromatography was performed using a Waters XSelect CSH C18, 5 μm, 50 mm × 100 mm column with a mobile phase of H2O (A) and MeCN (B) and a gradient of 5-60% B (0.2% NH4OH final v / v% modifier) ​​at a flow rate of 60 mL / min. The fractions containing the desired product were pooled and concentrated under reduced pressure to give 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) as a clear oil. LCMS m / z = 371.3 (M+H) + . 1 H NMR (500MHz, DMSO-d6) 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).

[1100] Example 92: 6-(7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]non-2-yl)-2-oxa-6-azaspiro[3.3]heptane

[1101]

[1102] 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

[1103]

[1104] 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 added AcOH (0.02 mL, 349 umol), followed by the careful dropwise addition of 2-oxa-6-azaspiro[3.3]heptane (62 mg, 623 umol) at 23 °C. After 15 minutes, NaBH(OAc)3 (238 mg, 1.12 mmol) was carefully added portionwise to the reaction mixture. After the addition of NaBH(OAc)3 was complete, the reaction was stirred at 23 °C and monitored by LCMS. After 2 hours, a 1 M aqueous NaOH solution was slowly added to carefully quench the reaction. The mixture was stirred at 23 °C for 20 minutes, and then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then dried over MgSO4. After filtration and concentration under reduced pressure, the residue was dissolved in DMSO and a few drops of water and then filtered. The homogeneous solution was subjected to mass-guided reverse phase HPLC purification. Using Waters XSelect CSH C18, 5μm, 50mm×100mm column, liquid chromatography was performed at a flow rate of 60mL / min with a mobile phase of H2O (A) and MeCN (B) and a gradient of 5-40% B (0.2% NH4OH final v / v% modifier). The fractions containing the desired product were pooled and then concentrated under reduced pressure to give a clear oil 6-(7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]non-2-yl)-2-oxa-6-azaspiro[3.3]heptane (13mg, 11%). LCMS m / z=381.3(M+H) + . 1 H NMR (500MHz, METHANOL-d4) 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).

[1105] 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

[1106]

[1107] 1. Synthesis of 7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one

[1108]

[1109] At <5°C, DIPEA (0.73mL, 4.2mmol) was carefully added dropwise to a vial containing 7-azaspiro [3.5] nonane-2-one hydrochloride (183mg, 1.04mmol) in DCM (4mL). After 5 minutes, 2-methoxy-5-methyl-pyridine-3-sulfonyl chloride (243mg, 1.10mmol) was carefully added to the cold solution. After the addition of the sulfonyl chloride solution was complete, the reaction was warmed to 23°C and monitored with LCMS. After 30 minutes, the reaction was carefully quenched by slowly adding a 1M NaOH aqueous solution. The mixture was stirred at 23°C for 20 minutes, and then the two-phase mixture was extracted three times with DCM. The organic extracts were collected and then dried over MgSO4. After filtering and concentrating under reduced pressure, the residue was loaded onto a silica gel column and purified with (15-65% EtOAc in heptane). The desired fractions were collected and concentrated under reduced pressure to give 7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (337 mg, 99%) as a white solid, which was used without further purification. LCMS m / z = 325.1 (M+H) + . 1 HNMR (400MHz, DCM-d2) 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).

[1110] 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

[1111]

[1112] To a vial containing 7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonane-2-one (62 mg, 192 umol) in DCM (2 mL) was added AcOH (0.01 mL, 201 umol), followed by careful dropwise addition of 2-oxa-6-azaspiro[3.3]heptane (40 mg, 406 umol) at 23 ° C. After 15 minutes, NaBH(OAc) 3 (163 mg, 771 umol) was carefully added portionwise to the reaction mixture. After the addition of NaBH(OAc) 3 was complete, the reaction was stirred at 23 ° C. and monitored by LCMS. After 19 hours, a 1 M NaOH aqueous solution was slowly added to quench the reaction. The mixture was stirred at 23 ° C. for 20 minutes, and the biphasic mixture was then extracted three times with DCM. The organic extracts were collected and then dried over MgSO 4 . After filtration and concentration under reduced pressure, the residue was dissolved in DMSO and a few drops of water and then filtered. The homogeneous solution was subjected to mass-directed reverse phase HPLC purification. Liquid chromatography was performed using a Waters XSelect CSH C18, 5μm, 50mm×100mm column with a mobile phase of H2O (A) and MeCN (B) and a gradient of 5-50% B (0.2% NH4OH final v / v% modifier) ​​at a flow rate of 60mL / min. The fractions containing the desired product were pooled and then concentrated under reduced pressure to give a colorless film of 6-(7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]non-2-yl)-2-oxa-6-azaspiro[3.3]heptane (8mg, 10%). LCMS m / z=408.3(M+H) + . 1 HNMR (400 MHz, DCM-d2) 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 (quintet, 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).

[1113] 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

[1114]

[1115] 1. Synthesis of 7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one

[1116]

[1117] At <5°C, DIPEA (0.7mL, 4.02mmol) was carefully added dropwise to a vial containing 7-azaspiro [3.5] nonane-2-one hydrochloride (180mg, 1.02mmol) in DCM (4mL). After 5 minutes, 6-chloro-2-methyl-pyridine-3-sulfonyl chloride (300mg, 1.33mmol) was carefully added to the cold solution. After the addition of the sulfonyl chloride solution was complete, the reaction was warmed to 23°C and monitored by LCMS. After 30 minutes, the reaction was carefully quenched by slowly adding a 1M NaOH aqueous solution. The mixture was stirred at 23°C for 20 minutes, and then the two-phase mixture was extracted three times with DCM. The organic extracts were collected and then dried over MgSO4. After filtering and concentrating under reduced pressure, the residue was loaded onto a silica gel column and purified with (25-80% EtOAc in heptane). The desired fractions were pooled and concentrated under reduced pressure to give 7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (274 mg, 81%) as a white solid, which was used without further purification. LCMS m / z = 329.0 (M+H) + . 1 HNMR (500MHz, Methanol-d4) δ (ppm) = 8.20 (d, J = 8.2Hz, 1H), 7.48 (d, J = 8.2Hz, 1 H),3.27-3.23(m,4H),2.84-2.81(m,4H),2.81-2.78(m,3H),1.87-1.82(m,4H).

[1118] 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

[1119]

[1120] To a vial containing 7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonane-2-one (80 mg, 244 umol) in DCM (2 mL) was added AcOH (0.08 mL mg, 1.40 mmol), and then 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 was carefully added dropwise at 23 ° C. After 15 minutes, NaBH(OAc) 3 (222 mg, 1.05 mmol) was carefully added portionwise to the reaction mixture. After the addition of NaBH(OAc) 3 was complete, the reaction was stirred at 23 ° C and monitored by LCMS. After 2 hours, a 1 M NaOH aqueous solution was slowly added to carefully quench the reaction. The mixture was stirred at 23°C for 20 minutes, and then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then dried over MgSO4. After filtration and concentration under reduced pressure, the residue was dissolved in DMSO and a few drops of water and then filtered. The homogeneous solution was subjected to mass-directed reverse-phase HPLC purification. Liquid chromatography was performed using a Waters XSelect CSHC18, 5μm, 50mm×100mm column with a mobile phase of H2O (A) and MeCN (B) and a gradient of 5-60% B (0.2% NH4OH final v / v% modifier) ​​at a flow rate of 60mL / min. Fractions containing the desired product were pooled and concentrated under reduced pressure to give (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%) as a colorless film. LCMS m / z = 412.2 (M+H) + . 1 H NMR (500MHz, DMSO-d6) δ (ppm) = 8.15 (d, J = 8.5Hz, 1H), 7.58 (d, J = 8.5Hz, 1H), 4.30 (s, 1H), 3.6 8(d,J=7.3Hz,1H),3.43(dd,J=1.7,7.2Hz,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=1.4,9.9Hz,1H),2.34(d,J=10.1Hz,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).

[1121] Example 95: 1-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)azetidin-3-ol

[1122]

[1123] 1. Synthesis of 7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one

[1124]

[1125] At room temperature, DIPEA (2 mL, 11.51 mmol) was carefully added dropwise to a vial containing 7-azaspiro [3.5] nonane-2-one hydrochloride (531 mg, 3.02 mmol) in DCM (10 mL). After 10 minutes, 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (789 mg, 3.04 mmol) was carefully added to the mixture. After the addition of sulfonyl chloride was complete, the reaction was maintained at 23 ° C and monitored by LCMS. After 1 hour, NaHCO 3 saturated aqueous solution was slowly added to carefully quench the reaction mixture. The heterogeneous mixture was extracted three times with DCM. The organic extracts were collected and then dried over MgSO 4. After filtering and concentrating under reduced pressure, the residue was loaded onto a silica gel column and purified with (5-60% EtOAc in heptane). The desired fractions were pooled and concentrated under reduced pressure to give 7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one (925 mg, 84%) as a white solid, which was used without further purification. LCMS m / z = 363.0 (M+H) + . 1 H NMR (500MHz, DMSO-d6) δ (ppm) = 8.45 (d, J = 8.2Hz, 1H), 7.97 (d, J = 7.9Hz, 1H), 3.25-3.17 (m, 4H), 2.83 (s, 3H), 2.80 (s, 4H), 1.79-1.73 (m, 4H).

[1126] 2. Synthesis of 1-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)azetidin-3-ol

[1127]

[1128] The vial containing azetidin-3-ol hydrochloride (66mg, 601umol) in methanol (2mL) is cooled in an ice-water bath, and DIPEA (0.2mL, 1.15mmol) is then carefully added to the raw material free base. After 20 minutes, 7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro [3.5] nonyl-2-one (102mg, 282umol) and AcOH (0.08mL, 1.40mmol) are carefully added to the cooling mixture. After 15 minutes, NaBH (OAc) (345mg, 1.63mmol) is carefully added to the cooling reaction solution portion by portion. After NaBH (OAc) addition is completed, the reaction is maintained at <5°C and monitored with LCMS. After 1.5 hours, saturated NaHCO3 aqueous solution is slowly added, and the reaction is carefully quenched. The mixture is stirred at 23°C for 30 minutes, then the mixture is extracted three times with DCM. The organic extracts were collected and then dried over MgSO4. After filtering and concentrating under reduced pressure, the residue was loaded onto a silica gel column and purified with (40-100% 3:1 EtOAc: ethanol in heptane). The desired fractions were collected 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 a mobile phase of H2O (A) and MeCN (B) and a gradient of 5-50% B (0.2% NH4OH final v / v% modifier) ​​at a flow rate of 30 mL / min. The desired fractions were pooled and concentrated under reduced pressure to give 1-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)azetidin-3-ol (8 mg, 6%) as a colorless film. LCMS m / z = 420.1 (M+H) + . 1 H NMR (500MHz, DCM-d2) 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).

[1129] Example 96: 3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-7-azaspiro[3.5]non-7-yl)sulfonyl)-5-fluorobenzonitrile

[1130]

[1131] 1. Synthesis of 3-fluoro-5-((2-oxo-7-azaspiro[3.5]nonan-7-yl)sulfonyl)benzonitrile

[1132]

[1133] At <5 ° C, DIPEA (0.6 mL, 3.44 mmol) was carefully added dropwise to a vial containing 7-azaspiro [3.5] nonane-2-one hydrochloride (188 mg, 1.07 mmol) in DCM (4 mL). After 5 minutes, 3-cyano-5-fluoro-benzenesulfonyl chloride (341 mg, 1.55 mmol) was carefully added to the cold solution. After the addition of sulfonyl chloride was complete, the reaction was warmed to 23 ° C and monitored with LCMS. After 30 minutes, the 1 M NaOH aqueous solution was slowly added to carefully quench the reaction. The mixture was stirred at 23 ° C for 20 minutes, and then the two-phase mixture was extracted three times with DCM. The organic extracts were collected and then dried over MgSO4. After filtering and concentrating under reduced pressure, the residue was loaded onto a silica gel column and purified with (20-80% EtOAc in heptane). The desired fractions were pooled and concentrated under reduced pressure to give 3-fluoro-5-((2-oxo-7-azaspiro[3.5]nonan-7-yl)sulfonyl)benzonitrile (267 mg, 78%) as a white solid which was used without further purification. 1 H NMR (500MHz, DCM-d2) 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).

[1134] 2. Synthesis of 3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-7-azaspiro[3.5]non-7-yl)sulfonyl)-5-fluorobenzonitrile

[1135]

[1136] 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 added AcOH (0.02 mL, 349 umol), followed by the careful dropwise addition of 2-oxa-6-azaspiro[3.3]heptane (72 mg, 728 umol) at 23 ° C. After 15 minutes, NaBH(OAc) 3 (278 mg, 1.31 mmol) was carefully added portionwise to the reaction mixture. After the addition of NaBH(OAc) 3 was complete, the reaction was stirred at 23 ° C. and monitored by LCMS. After 1 hour, a 1 M NaOH aqueous solution was slowly added to carefully quench the reaction. The mixture was stirred at 23 ° C. for 20 minutes, and then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then dried over MgSO 4. After filtration and concentration under reduced pressure, the residue was dissolved in DMSO and a few drops of water and then filtered. The homogeneous solution was subjected to mass-directed reverse phase HPLC purification. Using Waters XSelect CSH C18, 5μm, 50mm×100mm column, liquid chromatography was performed at a flow rate of 60mL / min with a mobile phase of H2O (A) and MeCN (B) and a gradient of 5-55% B (0.2% NH4OH final v / v% modifier). The fractions containing the desired product were pooled and then concentrated under reduced pressure to give 3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-7-azaspiro[3.5]non-7-yl)sulfonyl)-5-fluorobenzonitrile (32mg, 22%) as a white solid. LCMS m / z=406.2(M+H) + . 1 H NMR (500MHz, DMSO-d6) δ (ppm) = 8.27 (br d,J=8.5Hz,1H),8.06(s,1H),7.95(dd,J=1.5,7.9Hz,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=4.3Hz,4H),1.39-1.33(m,2H).

[1137] Example 97: 3-((2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile

[1138]

[1139] 1. Synthesis of 3-((2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile

[1140]

[1141] To a vial containing 3-fluoro-5-[(3-oxo-8-azaspiro[4.5]dec-8-yl)sulfonyl]benzonitrile (99 mg, 294 umol) in DCM (5 mL) was added AcOH (0.08 mL, 1.4 mmol), followed by the careful dropwise addition of 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 minutes, NaBH(OAc) 3 (311 mg, 1.47 mmol) was carefully added portionwise to the reaction mixture. After the addition of NaBH(OAc) 3 was complete, the reaction was stirred at 23 ° C. and monitored by LCMS. After 1 hour, a 1 M aqueous NaOH solution was slowly added to carefully quench the reaction. The mixture was stirred at 23 ° C. for 20 minutes, and then the biphasic mixture was extracted three times with DCM. The organic extracts were pooled and then dried over MgSO4. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (45-100% 3:1 EtOAc:methanol in heptane). The desired fractions were pooled and then concentrated under reduced pressure to give 3-((2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile (49 mg, 38%) as a colorless film. LCMS m / z=420.3 (M+H) + . 1 HNMR (500MHz, DMSO-d6) δ (ppm) = 8.27 (brd, J = 8.2Hz, 1H), 8.08 (s, 1H), 7.97 (br d, J = 7.6Hz, 1H), 4.25 (br s, 1H), 3.80 (br d,J=7.0Hz,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=9.5Hz,1H),1.76-1.61(m,2H),1.55-1.25(m,9H),1.19-1.11(m,1H).

[1142] Example 98: 3-Fluoro-5-((3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile

[1143]

[1144] 1. Synthesis of 3-fluoro-5-((3-oxo-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile

[1145]

[1146] At <5 ℃, DIPEA (0.7mL, 4.02mmol) was carefully added dropwise to a vial containing 1-oxa-8-azaspiro [4.5] decane-3-one hydrochloride (139mg, 897umol) in DCM (3mL). After 5 minutes, 3-cyano-5-fluoro-benzenesulfonyl chloride (293mg, 1.33mmol) was carefully added to the cold solution. After the addition of sulfonyl chloride was complete, the reaction was warmed to 23 ℃ and monitored with LCMS. After 30 minutes, the 1M NaOH aqueous solution was slowly added to carefully quench the reaction. The mixture was stirred at 23 ℃ for 20 minutes, then the two-phase mixture was extracted three times with DCM. The organic extracts were collected and then dried over MgSO4. After filtering and concentrating under reduced pressure, the residue was loaded onto a silica gel column and purified with (20-80% EtOAc in heptane). The desired fractions were pooled and concentrated under reduced pressure to give 3-fluoro-5-((3-oxo-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile (169 mg, 56%) as a sticky white foam which was used without further purification. 1 H NMR (500MHz, DCM-d2) δ (ppm) = 7.88 (s, 1H), 7.73 (td, J = 1.8, 7.6Hz, 1H), 7.63 (dd, J = 1.2, 7.6Hz, 1 H), 3.90 (s, 2H), 3.57-3.53 (m, 2H), 2.86 (dt, J = 3.4, 11.4Hz, 2H), 2.34 (s, 2H), 1.93-1.84 (m, 4H).

[1147] 2. Synthesis of 3-fluoro-5-((3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile

[1148]

[1149] To a vial containing 3-fluoro-5-((3-oxo-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile (81 mg, 239 umol) in DCM (3 mL) was added AcOH (0.02 mL, 349 umol), followed by the careful dropwise addition of tetrahydropyran-4-ylmethylamine (60 mg, 521 umol) at 23 ° C. After 15 minutes, NaBH(OAc) 3 (200 mg, 943 mmol) was carefully added portionwise to the reaction mixture. After the addition of NaBH(OAc) 3 was complete, the reaction was stirred at 23 ° C. and monitored by LCMS. After 18 hours, a 1 M NaOH aqueous solution was slowly added to carefully quench the reaction. The mixture was stirred at 23 ° C. for 20 minutes, and the biphasic mixture was then extracted three times with DCM. The organic extracts were pooled and then dried over MgSO 4 . After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (35-90% 3:1 EtOAc:methanol in heptane). The desired fractions were pooled and then concentrated under reduced pressure to give 3-fluoro-5-((3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile (42 mg, 38%) as a colorless film. LCMS m / z = 438.3 (M+H) + . 1 H NMR (500MHz, DMSO-d6) δ (ppm) = 8.27 (br d, J = 8.5Hz, 1H), 8.10 (s, 1H), 7.98 (br d, J = 7.6Hz, 1H), 3.80 (br dd,J=3.4,11.3Hz,2H),3.74(dd,J=6.1,8.5Hz,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=5.6,12.7Hz,1H),1.07(br s,2H).

[1150] Example 99: 1-(8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)azetidin-3-ol

[1151]

[1152] 1. Synthesis of 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one

[1153]

[1154] At <5 ℃, DIPEA (3.6mL, 21mmol) was carefully added dropwise into a flask equipped with 8-azaspiro [4.5] decane-3-one hydrochloride (1.0g, 5.3mmol) in DCM (35mL). After 5 minutes, 6-methoxy-2-methyl-pyridine-3-sulfonyl chloride (1.4g, 6.1mmol) was carefully added to the cold solution. After the addition of sulfonyl chloride was complete, the reaction was warmed to 23 ℃ and monitored with LCMS. After 30 minutes, the 1M NaOH aqueous solution was slowly added to carefully quench the reaction mixture. The mixture was stirred at 23 ℃ for 10 minutes, and the phase of the biphasic mixture was then separated. The aqueous phase was washed with DCM (10mL x 2), and the organic phase merged was dried over Na2SO4, filtered and concentrated to obtain a crude material. The crude material was loaded onto a silica gel column and purified with (10-55% EtOAc in heptane). The desired fractions were pooled and concentrated under reduced pressure to give 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]decan-2-one (1.7 g, 97%) as a white solid. LCMS m / z = 338.9 (M+H) + .

[1155] 2. Synthesis of 1-(8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)azetidin-3-ol

[1156]

[1157] The vial containing azetidin-3-ol hydrochloride (24mg, 323umol) in methanol (2mL) is cooled in an ice-water bath, and then DIPEA (0.15mL, 652umol) is carefully added to the raw material free base. After 20 minutes, 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-8-azaspiro [4.5] decane-2-one (73mg, 215umol) and AcOH (0.05mL, 862umol) are carefully added to the cooling mixture. After 15 minutes, NaBH (OAc) 3 (365mg, 1.73mmol) is carefully added to the cooling reaction solution portion by portion. After NaBH (OAc) 3 addition is completed, the reaction is maintained at <5 DEG C and monitored with LCMS. After 18 hours, the 1M NaOH aqueous solution is slowly added to carefully quench the reaction. The mixture is stirred at 23 DEG C for 20 minutes, then the two-phase mixture is extracted three times with DCM. The organic extracts were collected and then dried over MgSO4. After filtering and concentrating under reduced pressure, the residue was dissolved in DMSO and a few drops of water and then filtered. The homogeneous solution was subjected to mass-guided reverse phase HPLC purification. Using Waters XSelect CSH C18, 5μm, 50mm×100mm column, liquid chromatography was performed at a flow rate of 60mL / min with a mobile phase of H2O (A) and MeCN (B) and a gradient of 5-65% B (0.2% NH4OH final v / v% modifier). The fractions containing the desired product were collected and then concentrated under reduced pressure to give 1-(8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)azetidin-3-ol (56mg, 66%) as a white solid. LCMS m / z=396.2(M+H) + . 1 H NMR (600MHz, DMSO-d6) δ (ppm) = 7.96 (d, J = 8.7Hz, 1H), 6.78 (d, J = 8.7Hz, 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=1.8,3.6Hz,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).

[1158] Example 100: 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-8-azaspiro[4.5]dec-2-amine

[1159]

[1160] 1. Synthesis of 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-8-azaspiro[4.5]dec-2-amine

[1161]

[1162] 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-8-azaspiro[4.5]dec-2-amine was prepared in a manner similar to that of Example 99, Step 2, using 2-methoxy-N-methylethan-1-amine (0.03 mL, 323 umol) to give 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-8-azaspiro[4.5]dec-2-amine (50 mg, 57%) as a colorless film. LCMS m / z = 412.3 (M+H) + . 1 H NMR (600MHz, DMSO-d6) δ (ppm) = 8.01 (d, J = 9.1Hz, 1H), 6.82 (d, J = 8.7Hz, 1H), 3.50-3.30 (m, 4H), 3.25 (s, 3H), 3.10-2.99 (m, 5 H),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).

[1163] Example 101: 6-(8-((5-(trifluoromethyl)furan-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane

[1164]

[1165] 1. Synthesis of Benzyl 2-Oxo-8-azaspiro[4.5]decane-8-carboxylate

[1166]

[1167] Under argon, to a flask containing 8-azaspiro[4.5]decane-3-one hydrochloride (10 g, 53 mmol) suspended in DCM (200 ml) was added TEA (8.4 mL, 61 mmol), and then benzyl chloroformate (8.3 mL, 58 mmol) was added dropwise to the reaction mixture with stirring at 0°C. The mixture was stirred at room temperature under an argon atmosphere, and then the reaction mixture was washed with brine (2 x 50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The yellow oil was identified as benzyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate (14 g, 88%) and used without further purification. 1 H NMR (400MHz, CDCl3) 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 = 7.9Hz, 2H), 2.18 (s, 2H), 1.88 (br t,J=7.9Hz,2H),1.55(br s,4H).

[1168] 2. Synthesis of Benzyl 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]decane-8-carboxylate

[1169]

[1170] To 2-oxo-8-azaspiro [4.5] decane-8-benzyl formate (14g, 49mmol) and 2-oxa-6-azaspiro [3.3] heptane oxalate (11g, 59mmol) in DCE (250mL) solution, add AcOH (2.8mL, 49mmol) and STAB (21g, 97mmol). Obtained mixture was at room temperature stirred for 72 hours. The reaction mixture was concentrated under reduced pressure, then carefully added NaHCO solution to pH 8-9. After extraction with ethyl acetate (100mL x 3), the organic layer merged was washed with water (50mL), then washed with salt water (50mL). After drying over Na2SO4, filtration, and concentration in vacuo, the yellow oil was identified as benzyl 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]decane-8-carboxylate (11 g, 59%) and used without further purification. LCMS m / z = 371.2 (M+H) + .

[1171] 3. Synthesis of 6-(8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane

[1172]

[1173] To a solution of benzyl 2-(2-oxa-6-azaspiro[3.3]hept-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 a hydrogen atmosphere. After 4 hours, nitrogen was bubbled through the reaction mixture and then carefully filtered through a celite plug. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (Interchim, SiO2 (40 g), EtOAc / methanol, methanol was 0-95%, flow rate = 60 mL / min, Rt = 24 minutes) to give 6-(8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane (6 g, 51%) as a white solid. LCMS m / z = 237.2 (M+H) + .

[1174] 4. Synthesis of 6-(8-((5-(trifluoromethyl)furan-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane

[1175]

[1176] 4-Bromo-2-(trifluoromethyl)furan (0.25 g, 1.2 mmol) was suspended in DMSO (2 mL) under argon, followed by the addition of sodium formate (87 mg, 1.3 mmol), disodium (sulfinyloxy)sulfinate (782 mg, 2.33 mmol), 1,10-phenanthroline (31 mg, 174 umol), triphenylphosphine (305 mg, 1.2 mmol), and Pd(PPh3)4 (134 mg, 116 umol). The mixture was heated to 60°C. After 14 hours, the reaction mixture was cooled to room temperature and NFSI (550 mg, 1.74 mmol) was added. After 14 hours, the suspension was diluted with water (5 mL) and then extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL) and then dried over Na2SO4. After filtration and concentration under reduced pressure, the crude sulfonyl fluoride was dissolved in THF (2 mL). 6-(8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane (60 mg, 1.2 mmol), Ca(NTf2)2 (1.05 g, 1.74 mmol) and DABCO (0.26 mL, 2.33 mmol) were added and the mixture was stirred at 60°C under an argon atmosphere. After 14 hours, the reaction was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL) and then dried over Na2SO4. After filtration and concentration under reduced pressure, the residue was purified by HPLC (column: XBridge BEH C18 5um 130A; 35-35-55% 0-1-6 min H2O / ACN / 0.1% NH4OH, flow rate: 30 mL / min) to give 6-(8-((5-(trifluoromethyl)furan-3-yl)sulfonyl)-8-azaspiro[4.5]dec-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.

[1177] Example 102: 6-(8-((7-fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane

[1178]

[1179] 1. Synthesis of 6-(8-((7-fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane

[1180]

[1181] Example 102 was prepared in a manner similar to Example 101, step 4, starting with 6-bromo-7-fluoro-quinoline to give 6-(8-((7-fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane (28 mg, 29%). LCMS m / z = 446.2 (M+H) + LCMS Rf (2 min) = 0.86.

[1182] Examples 103-111

[1183] The title compound was prepared in a single-step library scale at approximately 25 mg of desired product using the following protocol.

[1184]

[1185] The appropriate sulfonyl chloride (1.1 eq) was added to a solution of 6-(8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane (1.0 eq) and DIPEA (4.5 eq + 1.1 eq per acid equivalent for the sulfonyl chloride building block salt) in anhydrous MeCN (0.7 mL), and the reaction mixture was stirred at room temperature for 24 h. The solvent was evaporated in vacuo and the residue was dissolved in DMSO (0.2 mL) and purified by preparative HPLC (column: YMC Actus Trial C18 20x100 mm, 5 um; method: water-MeOH-NH3 0.1% as mobile phase) to give the pure product.

[1186]

[1187]

[1188] Examples 112-114

[1189] The title compound was prepared in a single-step library scale at approximately 60 mg of desired product using the following protocol.

[1190]

[1191] The appropriate sulfonyl fluoride (1.0 equiv) was added to a solution of 6-(8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane (1.0 equiv), Ca(NTf2)2 (1.1 equiv) and DABCO (1.5 equiv) in anhydrous THF. The reaction mixture was stirred at 60°C for 16 hours. 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 x 100 mm, 5 μm; method: water-MeOH-NH3 0.1% as mobile phase) to give the pure product.

[1192]

[1193]

[1194] Example 114

[1195] The title compound was prepared in a single-step library scale at approximately 60 mg of desired product using the following protocol.

[1196]

[1197] The appropriate sulfonyl chloride (1.1 equivalents) is added to a solution of 3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane as a bis(trifluoroacetic acid) salt (1.0 equivalents) and DIPEA (6.0 equivalents) in anhydrous ACN (1.2 mL), and the reaction mixture is stirred at room temperature for 24 hours. The solid is filtered off and the filtrate is concentrated under reduced pressure. The gained residue is dissolved in DMSO (0.5 mL) and then purified by preparative HPLC (Waters SunFire C18 19x100 5 mm column; gradient mixture H o-MeOH-TFA 0.1% as mobile phase or YMC Actus Trial C18 20x 100 mm, 5 μ m column; gradient mixture H o-MeOH-ammonia 0.1% as mobile phase) to obtain the desired product.

[1198]

[1199] Example 115

[1200] The title compound was prepared in a single-step library scale at approximately 60 mg of desired product using the following protocol.

[1201]

[1202] The appropriate sulfonyl fluoride (1.0 equiv) was added to a solution of 3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane as bis(trifluoroacetic acid) salt (1.6 equiv), Ca(NTf2)2 (1.2 equiv) and DABCO (5 equiv) in anhydrous THF. The reaction mixture was stirred at 60°C for 16 hours. 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 20x100 mm, 5 um; method: water-MeOH-NH3 0.1% as mobile phase) to give the pure product.

[1203]

[1204] Example 116: 8-((2,4-Dimethylphenyl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]dec-3-amine

[1205]

[1206] 1. Synthesis of 8-((2,4-dimethylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one

[1207]

[1208] The synthesis was carried out in a manner similar to that described in Example 56, Step 1, 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).

[1209] 2. Synthesis of 8-((2,4-dimethylphenyl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]dec-3-amine

[1210]

[1211] Following a synthetic procedure similar to that described in Step 2 of Example 56, 8-((2,4-dimethylphenyl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (100 mg, 84%) was obtained from 2-methoxyethylamine and 8-((2,4-dimethylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one. LCMS m / z = 382.2 [M+H] + , 1 H NMR (chloroform-d, 400MHz) δ (ppm) 7.75 (d, 1H, J = 8.8Hz), 7.0-7.2 (m, 2H), 3.92 (dd, 1H, J = 6.0, 9.0Hz), 3.70 (q, 1H, J = 7.0Hz), 3.57 (dd, 1H, J = 5.5, 9.0Hz), 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=6.0,12.8Hz).

[1212] Example 117: 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane

[1213]

[1214] Following a synthetic procedure similar to that described in Step 2 of Example 56, 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane (150 mg, 80%) 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. LCMS m / z = 424.2 [M+H] + , 1H NMR (CHLOROFORM-d, 400MHz) δ (ppm) 8.05 (dd, 1H, J = 0.8, 2.3Hz), 7.90 (d, 1H, J = 2.5Hz), 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=3.9,5.3,7.3Hz),2.25(s,3H),1.84(br d,1H,J=13.6Hz),1.5-1.7(m,4H),1.45(dd,1H,J=4.0,13.1Hz).

[1215] Example 118: rac-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane

[1216]

[1217] 1. Synthesis of rac-8-((2,4-dimethylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-one

[1218]

[1219] The synthesis was carried out in a manner similar to that described in Example 56, Step 1, 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).

[1220] 2. Synthesis of rac-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane

[1221] The synthesis was carried out in a manner similar to that described in Example 56, Step 2, 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 2.1x30 mm, 1.7 um, modifier: trifluoroacetic acid 0.1% (v / v) concentration.

[1222] Method: 95% H20 / 5% MeCN (initial conditions) linear gradient to 5% H20 / 95% MeCN at 1.0 min, maintain 5% H20 / 95% MeCN until 1.3 min. Flow rate, 0.7 mL / min).

[1223] Examples 119a and 119b: (S)-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane and (R)-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane

[1224]

[1225] 70 mg of rac-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane was dissolved in MeOH and purified on a CHIRALPAK AD-H 30x250 mm, 5 μm column using 20% ​​methanol and 0.1% DEA in CO 2 . 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:

[1226] - Peak 1 or Example 119a is a white solid (20.1 mg) arbitrarily designated as (S)-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane. LCMS m / z = 415.2 (M+H) + . R f =1.99 minutes.

[1227] - Peak 2 or Example 119b is a white solid (23.5 mg) arbitrarily designated as (R)-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane. LCMS m / z = 415.2 (M+H) + . R f =2.16 minutes.

[1228] 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

[1229]

[1230] 1. Synthesis of 7-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one

[1231]

[1232] The synthesis was carried out in a manner similar to that described in Example 93, Step 1, 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).

[1233] 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

[1234]

[1235] The synthesis was carried out in a manner similar to that described in Example 93, Step 2, 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] + , 1H NMR (chloroform-d, 500MHz) δ (ppm) 6.34 (s, 1H), 4.00 (s, 3H), 3.95 (br d,2H,J=11.3Hz),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= 2.4,7.8,9.9Hz),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).

[1236] 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

[1237]

[1238] 1. Synthesis of 7-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-one

[1239]

[1240] The synthesis was carried out in a manner similar to that described in Example 91, Step 1, 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 ]+ , 1 HNMR (400MHz, CDCl3) δ (ppm) 8.21 (d, J = 8.4Hz, 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).

[1241] 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

[1242]

[1243] The synthesis was carried out in a manner similar to that described in Example 91, Step 2, 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: (400MHz, 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), 3.1 8-3.13(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).

[1244] 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

[1245]

[1246] 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

[1247]

[1248] To a solution of 7-azaspiro [3.5] nonan-2-one (150 mg, 853.94 umol, hydrochloride) 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 hours. The reaction was diluted with water (15 mL) and extracted with DCM (25 mL x 3). The combined organic phases were 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 (EtOAc in petroleum ether = 10% to 40%) to give the desired compound (240 mg, 84%) as a colorless oil. LCMS m / z=334.1[M+H] + .1 HNMR (400MHz, CDCl3) 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).

[1249] 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

[1250]

[1251] The synthesis was carried out in a manner similar to that described in Example 91, Step 2, 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 (400MHz, CDCl3) δ (ppm) 6.84 (s, 1H), 6.80-6.51 (m, 1H), ...

Claims

1. A compound represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is O, CH2 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, q is 1; q is 0 or 1, provided that when q is 0, p is 1; R 1 and R 2 Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 cycloalkenyl, 6 to 10 membered bicyclic heterocyclic group and 4 to 6 membered monocyclic heterocyclic group, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 The cycloalkenyl, 6- to 10-membered bicyclic heterocyclyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by one or more R 4 Replace, provided that 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, they form a 4- to 7-membered monocyclic heterocyclic ring or a 6- to 10-membered bicyclic heterocyclic ring, each of which is optionally substituted by one or more R 4 replace; Each R 4 Independently selected from OR 4a , halo, C 1-3 Alkyl, C 3-8 Cycloalkyl and 4- to 6-membered monocyclic heterocyclyl; R 4a Selected from H and C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups; R 3 is phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl or 6 to 10-membered bicyclic heterocycle, wherein the phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl and 6 to 10-membered bicyclic heterocycle are each optionally substituted by one or more R 5 replace; Each R 5 Independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, OR 5a , cyano, halo and 5 or 6-membered monocyclic heteroaryl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl and heteroaryl are optionally substituted by one or more R 5b replace; R 5a Selected from H, C 1-3 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups; R 5b Selected from OR 5a , C 1-3 Alkyl, cyano and halo groups; R 6 Each occurrence is independently halo or C 1-3 Alkyl, or two R 6 Together to form –C 1-3 Alkylene n is 0, 1 or 2; m is 0, 1 or 2; The prerequisite is that the compound is not any of the compounds shown in Table I.

2. The compound according to claim 1, wherein the compound is represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is O, CH2 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, q is 1; q is 0 or 1, provided that when q is 0, p is 1; R 1 and R 2 Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl and 4 to 6 membered monocyclic heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 The cycloalkenyl group and the 4- to 6-membered monocyclic heterocyclic group are each optionally substituted by one or more R 4 Replace, provided that 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, they form a 4- to 7-membered monocyclic heterocyclic ring or a 6- to 10-membered bicyclic heterocyclic ring, each of which is optionally substituted by one or more R 4 replace; R 4 Selected from OR 4a , halo, C 1-3 Alkyl or C 3-8 Cycloalkyl; R 4a Selected from H and C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups; R 3 is phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl or 6 to 10-membered bicyclic heterocycle, wherein the phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl and 6 to 10-membered bicyclic heterocycle are each optionally substituted by one or more R 5 replace; Each R 5 Independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, OR 5a , cyano, halo and 5 or 6-membered monocyclic heteroaryl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl and heteroaryl are optionally substituted by one or more R 5b replace; R 5a Selected from H, C 1-3 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups; R 5b Selected from OR 5a , C 1-3 Alkyl, cyano and halo groups; R 6 Each occurrence is independently halo or C 1-3 Alkyl, or two R 6 Together to form –C 1-3 Alkylene n is 0, 1 or 2; m is 0, 1 or 2; The prerequisite is that the compound is not any of the compounds shown in Table I.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein (i) when X is O, and R 1 and R 2 When R and the N atom to which they are attached form an unsaturated morpholine, an unsaturated pyrrolidine or an unsaturated N-methylpiperazine, 3 are selected from each optionally substituted by one or more R 5 substituted 9- or 10-membered bicyclic heteroaryl or 6- to 10-membered bicyclic heterocycle, or phenyl or 5- or 6-membered monocyclic heteroaryl, each of which is substituted by at least two R 5 Group or as OR 5a An R 5 (ii) when X is O, and R 1 and R 2 Both C 1-6 When it is an alkyl group, R 1 and R 2 The C 1-6 At least one of the alkyl groups is replaced by one or more selected from OR 4a , halo, C 3-8 Cycloalkyl and 4- to 6-membered monocyclic heterocyclic groups R 4 substitution; (iii) when X is a bond, and R 1 and R 2 Both C 1-6 When it is an alkyl group, R 1 and R 2 The C 1-6 At least one of the alkyl groups is replaced by one or more R 4 or (iv) when p is 0 and q is 1, then X is O.

4. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein (i) when X is O, and R 1 and R 2 When R and the N atom to which they are attached form an unsaturated morpholine, an unsaturated pyrrolidine or an unsaturated N-methylpiperazine, 3 are selected from each optionally substituted by one or more R 5 substituted 9- or 10-membered bicyclic heteroaryl or 6- to 10-membered bicyclic heterocycle, or phenyl or 5- or 6-membered monocyclic heteroaryl, each of which is substituted by at least two R 5 Group or as OR 5a An R 5 (ii) when X is O, and R 1 and R 2 Both C 1-6 When it is an alkyl group, R 1 and R 2 The C 1-6 At least one of the alkyl groups is replaced by one or more selected from OR 4a , halo and C 3-8 R of cycloalkyl 4 substitution; (iii) when X is a bond, and R 1 and R 2 Both C 1-6 When it is an alkyl group, R 1 and R 2 The C 1-6 At least one of the alkyl groups is replaced by one or more R 4 or (iv) when p is 0 and q is 1, then X is O.

5. The compound according to any one of claims 1 to 4, wherein the compound is represented by formula (II): or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5, wherein the compound is represented by formula (IIA) or (IIB): or a pharmaceutically acceptable salt thereof.

7. The compound of claim 5, wherein the compound is represented by formula (III) or (IV): or a pharmaceutically acceptable salt thereof.

8. The compound of claim 7, wherein the compound is represented by formula (IIIA), (IIIB), (IVA) or (IVB): or a pharmaceutically acceptable salt thereof.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 3 is phenyl, 5- or 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl, or 8- to 10-membered bicyclic heterocycle, wherein the phenyl, 5- or 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl, and 8- to 10-membered bicyclic heterocycle are each optionally substituted by one to three R 5 replace.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of pyridyl, pyrimidinyl, phenyl, thiazolyl, pyrazolyl, pyrazinyl, triazolyl, imidazopyridinyl, quinolyl, tetrahydropyranopyrazolyl, thienyl, benzothienyl, furanyl, indazolyl, indolizinyl, pyrazolo[1,5-a]pyridinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl and benzofuranyl, each of which is optionally substituted by one to three R 5 replace.

11. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of pyridyl, phenyl, thiazolyl, pyrazolyl, pyrazinyl, imidazopyridyl, quinolyl, tetrahydropyranopyrazolyl, thienyl, benzothienyl, furanyl, indazolyl, indolizinyl and benzofuranyl, each of which is optionally substituted by one to three R 5 replace.

12. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of pyridyl, phenyl, pyrazolyl, thienyl, thiazolyl, quinolyl, tetrahydropyranopyrazolyl and benzofuranyl, each of which is optionally substituted by one to three R 5 replace.

13. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: Wherein each formula depicted above is optionally replaced by one to three R 5 replace.

14. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: Wherein each formula depicted above is optionally replaced by one to three R 5 replace.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: Wherein each formula depicted above is optionally replaced by one to three R 5 replace.

16. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula:

17. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula:

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula:

19. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein: R 5 Each occurrence is independently selected from cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5- or 6-membered monocyclic heteroaryl, OR 5a and a halo group, wherein the C 1-4 The alkyl group is optionally substituted by one to three R 5b and the 5 or 6-membered monocyclic heteroaryl is optionally substituted by C 1-3 Alkyl substitution; R 5a H, C 1-3 Alkyl or C 3-6 Cycloalkyl, wherein C 1-3 The alkyl group is optionally substituted with one to three halo groups; R 5b Each occurrence is independently selected from halo and -OR 5a .

20. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein R 5 Each occurrence is independently selected from –CH3, –CHF2, –C(CH3)3, –CH2CH3, –CH2CN, –CF3, –CH2OCH3, –OCH3, –OCHF2, –OCF3, –OCH2CH3, –OCH(CH3)2, –OH, –F, –Cl, cyclopropyl, cyclopropyloxy, 4-methyloxazol-2-yl and –CN.

21. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein R 5 Each occurrence is independently selected from -CH3, -C(CH3)3, -CH2CH3, -CH2CN, -CF3, -CH2OCH3, -OCH3, -OCHF2, -OCF3, -OCH2CH3, -OH, -F, -Cl, cyclopropyl, cyclopropyloxy, 4-methyloxazol-2-yl and -CN.

22. A compound as claimed in any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the N atom to which they are attached, they form a 4- to 6-membered monocyclic heterocyclic ring or a 6- to 10-membered bicyclic heterocyclic ring, each of which is optionally substituted by one or two R 4 replace.

23. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula: Wherein each formula depicted above is optionally replaced by one or two R 4 replace.

24. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula: Wherein each formula depicted above is optionally replaced by one or two R 4 replace.

25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula: Wherein each formula depicted above is optionally replaced by one or two R 4 replace.

26. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula:

27. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula:

28. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula:

29. A compound as described in any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 4 Each occurrence is independently selected from halo, C 1-3 Alkyl and –OR 4a ; and R 4a H or C 1-3 alkyl.

30. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein R 4 Each occurrence is independently selected from -OCH3, F, -OH and -CH3.

31. A compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein: R 1 is H or optionally one to three R 4 Substituted C 1-3 Alkyl; and R 2 C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkenyl, 6 to 10 membered bicyclic heterocyclic group or 4 to 6 membered monocyclic heterocyclic group, wherein the 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 substituted by one or two independently selected 1-3 Alkyl, C 1-3 The substituents of the alkoxy group, the halo group and the 4- to 6-membered monocyclic heterocyclic group are substituted.

32. A compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein: R 1 is H or optionally one to three R 4 Substituted C 1-3 Alkyl; and R 2 C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl or 4 to 6 membered monocyclic heterocyclic group, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 The cycloalkenyl and 4 to 6 membered monocyclic heterocyclic groups are each optionally substituted by one or two independently selected 1-3 Alkyl, C 1-3 Substituents of the alkoxy and halo groups are substituted.

33. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R 1 is H or optionally one to three R 4 Substituted C 1-3 alkyl; and R 2 Is C 1-3 Alkoxy or 4 to 6-membered monocyclic heterocyclic group substituted C 1-3 Alkyl, optionally substituted by one to two halo groups 3-6 Cycloalkyl, 6 to 10 membered bicyclic heterocyclic group, or optionally substituted by one or two C 1-3 Alkyl-substituted 4- to 6-membered monocyclic heterocyclic group.

34. The compound of claim 32 or a pharmaceutically acceptable salt thereof, wherein R 1 is H or optionally one to three R 4 Substituted C 1-3 alkyl; and R 2 Is C 1-3 Alkoxy substituted C 1-3 Alkyl, optionally substituted by one to two halo groups 3-6 Cycloalkyl, or optionally substituted by one or two C 1-3 Alkyl-substituted 4- to 6-membered monocyclic heterocyclic group.

35. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R 1 is H or methyl; and R 2 It is 2-methoxyethyl, -CH2-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]hept-6-yl.

36. The compound of claim 32 or a pharmaceutically acceptable salt thereof, wherein R 1 is H or methyl; and R 2 The 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, tetrahydrofuran-3-yl and 2-oxaspiro[3.3]hept-6-yl groups are shown.

37. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt thereof, wherein: X is O or CH 2； R 1 is H or optionally one to three R 4 Substituted C 1-3 alkyl; R 2 Is C 1-3 Alkoxy or 4 to 6-membered monocyclic heterocyclic group substituted C 1-3 Alkyl, optionally substituted by one to two halo groups 3-6 Cycloalkyl, 6 to 10 membered bicyclic heterocyclic group, or optionally substituted by one or two C 1-3 an alkyl-substituted 4- to 6-membered monocyclic heterocyclic group; or R 1 and R 2 Together with the N atom to which they are attached, they form a 4- to 6-membered monocyclic heterocyclic ring, a 7- to 9-membered bicyclic heterocyclic ring, each of which is optionally substituted by one or two R 4 replace; R 4 Each occurrence is independently selected from C 1-3 Alkoxy, OH, halide and C 1-3 alkyl; R 3 is phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl or 9 or 10-membered bicyclic heterocycle, wherein the phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl and 9 or 10-membered bicyclic heterocycle are each optionally substituted by one to three R 5 replace; R 5 For cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, OR 5a and a halo group, wherein the C 1-4 The alkyl group is optionally substituted by one to three R 5b replace; R 5a is C optionally substituted by one to three halo groups 1-3 alkyl.

38. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein: X is O or CH 2； R 1 is H or optionally one to three R 4 Substituted C 1-3 alkyl; R 2 Is C 1-3 Alkoxy substituted C 1-3 Alkyl, optionally substituted by one to two halo groups 3-6 Cycloalkyl, or optionally substituted by one or two C 1-3 an alkyl-substituted 4- to 6-membered monocyclic heterocyclic group; or R 1 and R 2 Together with the N atom to which they are attached, they form a 4- to 6-membered monocyclic heterocyclic ring, a 7- to 9-membered bicyclic heterocyclic ring, each of which is optionally substituted by one or two R 4 replace; R 4 Each occurrence is independently selected from C 1-3 Alkoxy, OH, halide and C 1-3 alkyl; R 3 is phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl or 9 or 10-membered bicyclic heterocycle, wherein the phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl and 9 or 10-membered bicyclic heterocycle are each optionally substituted by one to three R 5 replace; R 5 For cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, OR 5a and a halo group, wherein the C 1-4 The alkyl group is optionally substituted by one to three R 5b replace; R 5a is C optionally substituted by one to three halo groups 1-3 alkyl.

39. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein: R 1 is H or optionally one to three R 4 Substituted C 1-3 Alkyl, and R 2 Is C 1-3 Alkoxy or 4 to 6-membered monocyclic heterocyclic group substituted C 1-3 alkyl, 6 to 10 membered bicyclic heterocyclic group, or optionally substituted by one or two independently selected from halo and C 1-3 a 4- to 6-membered monocyclic heterocyclic group substituted by a substituent of the alkyl group; or R 1 and R 2 Together with the N atom to which they are attached, they form a group represented by the formula: Each of which is optionally represented by one or two R 4 replace; R 3 for Each of which is optionally replaced by one to three R 5 replace.

40. The compound of claim 38 or a pharmaceutically acceptable salt thereof, wherein: R 1 is H or optionally one to three R 4 Substituted C 1-3 Alkyl, and R 2 Is C 1-3 Alkoxy substituted C 1-3 alkyl, or optionally substituted by one or two independently selected from halo and C 1-3 a 4- to 6-membered monocyclic heterocyclic group substituted by a substituent of the alkyl group; or R 1 and R 2 Together with the N atom to which they are attached, they form a group represented by the formula: Each of which is optionally represented by one or two R 4 replace; R 3 for Each of which is optionally replaced by one to three R 5 replace.

41. A compound as described in any one of claims 37 to 40, or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: And among them: (1)R 1 is H or CH3, and R 2 is 2-methoxyethyl, oxetan-3-ylmethyl, 3-methyltetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, -CH2-tetrahydropyranyl or 2-oxaspiro[3.3]hept-6-yl; or (2)R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula:

42. A compound as described in any one of claims 37 to 40, or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: And where R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula:

43. A compound as described in any one of claims 37 to 42, or a pharmaceutically acceptable salt thereof, wherein R 4 Each occurrence is independently selected from halo, C 1-3 Alkyl and –OR 4a ; and R 4a H or C 1-3 alkyl.

44. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein R 4 Each occurrence is independently selected from -OCH3, F, -OH or -CH3.

45. A compound as described in any one of claims 37 to 44, or a pharmaceutically acceptable salt thereof, wherein R 5 Each occurrence is independently selected from cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, OR 5a and a halo group, wherein the C 1-4 The alkyl group is optionally substituted by one to three R 5b replace; R 5a H, C 3-6 Cycloalkyl or C optionally substituted by one to three halo groups 1-3 alkyl; R 5b Each occurrence is independently selected from halo and C 1-3 Alkoxy.

46. ​​The compound of claim 45 or a pharmaceutically acceptable salt thereof, wherein R 5 Each occurrence is independently selected from -CH3, -CF3, -OCH3, -OCHF2, -OCF3, -OH, -CN, F, Cl, -CH2OCH3, cyclopropyl and cyclopropyloxy.

47. A compound as described in any one of claims 1 to 4, wherein the compound is represented by formula (V): or a pharmaceutically acceptable salt thereof.

48. The compound of claim 47, wherein the compound is represented by formula (VIA) or (VIB): or a pharmaceutically acceptable salt thereof.

49. The compound of claim 47 or 48, wherein X is CH2.

50. A compound as described in any one of claims 47 to 49, or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl or 5 or 6-membered monocyclic heteroaryl, wherein the phenyl or 5 or 6-membered monocyclic heteroaryl are each optionally substituted by one to two substituents R 5 replace.

51. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of pyridyl, phenyl and pyrazolyl.

52. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: Wherein each formula depicted above is optionally replaced by one to two R 5 replace.

53. The compound of claim 52 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula:

54. The compound of claim 52 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula:

55. A compound as described in any one of claims 47 to 54, or a pharmaceutically acceptable salt thereof, wherein: R 5 Each occurrence is independently selected from cyano, C 1-4 Alkyl, OR 5a , C 3-4 Cycloalkyl and halo, wherein the C 1-4 The alkyl group is optionally substituted by one to three R 5b replace; R 5a is C optionally substituted by one to three halo groups 1-3 alkyl; R 5b Each occurrence is halo.

56. A compound as described in any one of claims 47 to 54, or a pharmaceutically acceptable salt thereof, wherein: R 5 Each occurrence is independently selected from cyano, C 1-4 Alkyl, OR 5a and a halo group, wherein the C 1-4 The alkyl group is optionally substituted by one to three R 5b replace; R 5a is C optionally substituted by one to three halo groups 1-3 alkyl; R 5b Each occurrence is halo.

57. The compound of claim 55 or a pharmaceutically acceptable salt thereof, wherein R 5 Each occurrence is independently selected from -CH3, -CHF2, -CH2CH3, -CF3, -OCH3, -OCHF2, -OCF3, -F, -Cl, cyclopropyl and -CN.

58. The compound of claim 56 or a pharmaceutically acceptable salt thereof, wherein R 5 Each occurrence is independently selected from -CH3, -CH2CH3, -CF3, -OCH3, -OCHF2, -OCF3, -F and -CN.

59. A compound as described in any one of claims 47 to 58, or a pharmaceutically acceptable salt thereof, wherein if R 1 and R 2 Both C 1-6 alkyl, then at least one of the C 1-6 The alkyl group is further substituted with at least one R 4 replace.

60. A compound as described in any one of claims 47 to 58, or a pharmaceutically acceptable salt thereof, wherein R 1 H or C 1-3 Alkyl, and R 2 is optionally C 1-3 Alkoxy substituted C 1-3 Alkyl or 4 to 6-membered heterocyclic group.

61. A compound as described in any one of claims 47 to 58, or a pharmaceutically acceptable salt thereof, wherein R 1 H or C 1-3 Alkyl, and R 2 is optionally C 1-3 Alkoxy substituted C 1-3 alkyl.

62. The compound of claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 is H or –CH3 and R 2 It is –CH2CH2OCH3 or tetrahydropyranyl.

63. The compound of claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 is –CH3 and R 2 is –CH2OCH3.

64. A compound as described in any one of claims 47 to 58, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the N atom to which they are attached, they form a 4- to 6-membered monocyclic heterocyclic ring or a 6- or 7-membered bicyclic heterocyclic ring, each of which is optionally substituted by one or two R 4 replace.

65. The compound of claim 64 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula:

66. The compound of claim 64 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula:

67. A compound as described in any one of claims 64 to 66, or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently -OH.

68. A compound as described in any one of claims 1 to 4, wherein the compound is represented by formula (VI): or a pharmaceutically acceptable salt thereof.

69. The compound of claim 68, wherein the compound is represented by formula (VIA) or (VIB): or a pharmaceutically acceptable salt thereof.

70. The compound of claim 68 or 69, wherein X is O.

71. The compound of any one of claims 68 to 70, wherein R 3 is optionally replaced by one or two R 4 Substituted phenyl.

72. The compound of claim 71, wherein R 3 It is expressed by the following formula:

73. A compound as described in any one of claims 68 to 72, wherein R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula:

74. A compound as described in any one of claims 1 to 4, wherein the compound is represented by formula (VII): or a pharmaceutically acceptable salt thereof, wherein: X is O, CH2 or a bond; R 1 H and R 2 is a 4- to 6-membered monocyclic heterocyclic group or a 6- to 10-membered bicyclic heterocyclic group; 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 a 5- or 6-membered monocyclic heteroaryl group, each of which is optionally substituted by one or two R 5 replace; Each R 5 Independently selected from C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-4 Cycloalkyl, OR 5a , cyano and halo; R 5a C 1-3 Halogenated alkyl.

75. The compound of claim 74, wherein the compound is represented by formula (III) or (IV): or a pharmaceutically acceptable salt thereof.

76. The compound of claim 75, wherein the compound is represented by formula (IIIA), (IIIB), (IVA) or (IVB): or a pharmaceutically acceptable salt thereof.

77. A compound as described in any one of claims 74 to 76, or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl, pyrazolyl or pyridinyl, each of which is optionally substituted by one or two R 5 replace.

78. The compound of claim 77 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: Wherein each formula depicted above is optionally replaced by one to two R 5 replace.

79. The compound of claim 77 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula:

80. A compound as described in any one of claims 74 to 79, or a pharmaceutically acceptable salt thereof, wherein: (1)R 2 It is expressed by the following formula: (2)R 1 and R 2 Together with the N atom to which they are attached, they form a group represented by the formula:

81. A compound as described in any one of claims 74 to 79, or a pharmaceutically acceptable salt thereof, wherein each R 5 Independently selected from -CH3, -CF3, -F, -CN and -OCHF2.

82. The compound of claim 74, wherein the compound is represented by formula (VIII): or a pharmaceutically acceptable salt thereof.

83. The compound of claim 82, wherein the compound is represented by formula (VIIIA) or (VIIIB): or a pharmaceutically acceptable salt thereof.

84. A compound as described in any one of claims 74, 82 or 83, or a pharmaceutically acceptable salt thereof, wherein R 3 is pyrazolyl or pyridinyl, each of which is optionally substituted by one or two R 5 replace.

85. The compound of claim 84 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: Wherein each formula depicted above is optionally replaced by one to two R 5 replace.

86. The compound of claim 85 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula:

87. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 74 or 82 to 86, wherein: (1)R 2 It is expressed by the following formula: (2)R 1 and R 2 Together with the N atom to which they are attached, they form a group represented by the formula:

88. A compound as described in any one of claims 74 or 82 to 87, or a pharmaceutically acceptable salt thereof, wherein each R 5 Independently selected from -CH3, -CF3 and cyclopropyl.

89. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 8-(Benzofuran-2-ylsulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane; 8-((3-chloro-5-(methoxymethyl)phenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane; 2-((3-morpholino-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-3-(trifluoromethoxy)phenol; 8-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane; 8-((5-methylthien-3-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane; (R)- or (S)-8-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane; 8-((4-Fluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane; 4-((3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-3-chlorobenzonitrile; 6-(8-((3-fluoro-4-methoxyphenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile; 6-(8-((4-fluorophenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile; 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]decane; 4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile; (R)-4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile; (S)-4-methyl-3-((3-morpholino-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile; 4-Fluoro-3-((3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile; 8-((2-methyl-4-(trifluoromethyl)phenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane; 8-((2-fluoro-5-methylphenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane; 8-((2,5-difluorophenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane; 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane; 4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine; (R)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine; (S)-4-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine; 4-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine; 2-methyl-3-((2-morpholino-8-azaspiro[4.5]dec-8-yl)sulfonyl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole; 4-(8-((3,5-dimethylpyridin-2-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine; 4-(8-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine; 5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane; (1R,4R)-5-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane; 8-((4,6-dimethylpyridin-3-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; 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane; (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; (R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-((S)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane; 4-(8-((7-fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine; 4-(8-((5-cyclopropyloxypyridin-2-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine; 4-(8-((3-fluoro-2-methoxypyridin-4-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)morpholine; 4-(7-((1-ethyl-3-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine; 4-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine; 4-(7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine; 4-(7-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine; 4-(8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azaspiro[bicyclo[3.2.1]octane-3,1′-cyclobutane]-3′-yl)morpholine; 7-((4-(difluoromethoxy)phenyl)sulfonyl)-3-morpholino-1-oxa-7-azaspiro[3.5]nonane; 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-8-azaspiro[4.5]decan-2-amine; 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(3-methyloxetan-3-yl)-8-azaspiro[4.5]decan-2-amine; 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(3-methyltetrahydrofuran-3-yl)-8-azaspiro[4.5]decan-2-amine; 2-(8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-6-oxa-2-azaspiro[3.4]octane; 4-Fluoro-3-((3-((2-methoxyethyl)amino)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile; 3-((3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-fluorobenzonitrile; 3-((3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-fluorobenzonitrile; 4-Fluoro-3-((3-(piperidin-1-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile; 3-((3-((4,4-difluorocyclohexyl)amino)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-fluorobenzonitrile; 8-((2-chloro-4-methylphenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane; 1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)-3-methylazetidin-3-ol; 8-((2-chloro-4-methylphenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-1-oxa-8-azaspiro[4.5]decan-3-amine; 1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)azetidin-3-ol; (R)-1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)azetidin-3-ol; (S)-1-(8-((2-chloro-4-methylphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-yl)azetidin-3-ol; 8-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-3-morpholino-1-oxa-8-azaspiro[4.5]decane; 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane; 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane; (R)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; (S)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane; 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decan-3-amine; 8-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-1-oxa-8-azaspiro[4.5]decan-3-amine; 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(3-methoxyazetidin-1-yl)-1-oxa-8-azaspiro[4.5]decane; 8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane; (R)-8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane; (S)-8-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane; 3-((3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)-4-chlorobenzonitrile; 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]dec-3-amine; 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-(methyl-d3)-1-oxa-8-azaspiro[4.5]dec-3-amine; 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-1-oxa-8-azaspiro[4.5]decan-3-amine; 6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; (R)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; (S)-6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(6-oxa-2-azaspiro[3.4]octan-2-yl)-1-oxa-8-azaspiro[4.5]decane; 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-1-oxa-8-azaspiro[4.5]decane; 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; 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; (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-azaspiro[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; (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; 4-(7-((4-(difluoromethoxy)phenyl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine; 4-(7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)morpholine; 6-(7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(7-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(7-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 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; 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; 5-(7-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane; (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; 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; (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; 7-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-7-azaspiro[3.5]nonan-2-amine; 7-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-7-azaspiro[3.5]nonan-2-amine; 1-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-4-methylpiperidin-4-ol; (R)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile; (S)-3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile; (1R,4R)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane; (1S,4S)-5-((R)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane; (1R,4R)-5-((R)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane; (1S,4S)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane; (1S,4S)-5-((S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane; (1S,4S)-5-((R)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane; 7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-7-azaspiro[3.5]nonan-2-amine; 6-(7-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(7-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane; (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; 1-(7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)azetidin-3-ol; 3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-7-azaspiro[3.5]non-7-yl)sulfonyl)-5-fluorobenzonitrile; 3-(((S)-2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-5-fluorobenzonitrile; 3-Fluoro-5-((3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile; 1-(8-((2-methoxy-6-methyl-2H-112-pyridin-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)azetidin-3-ol; 8-((2-methoxy-6-methyl-2H-112-pyridin-5-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-8-azaspiro[4.5]dec-2-amine; 6-(8-((5-(trifluoromethyl)furan-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-((7-fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-(Quinolin-3-ylsulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 3-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-2-fluorobenzonitrile; 6-(8-((2-methylfuran-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-((5-chloro-6-methoxypyridin-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-((4-ethoxyphenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-((5,6-dimethylpyridin-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-((6-methoxypyridin-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-((2-methoxypyridin-4-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-((5-fluoro-2-methoxypyridin-4-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 8-((5-chloro-6-methoxypyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane; 6-(8-((5-(trifluoromethoxy)pyridin-2-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 8-((5-fluoro-2-methoxypyridin-4-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane; 8-((2,4-dimethylphenyl)sulfonyl)-N-(2-methoxyethyl)-1-oxa-8-azaspiro[4.5]decan-3-amine; 8-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane; Rac-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane; (R)-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane; (S)-8-((3,5-difluorophenyl)sulfonyl)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decane; 7-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-7-azaspiro[3.5]nonan-2-amine; 6-(7-((6-(difluoromethoxy)-2-methyl-2,3,4,5-tetrahydropyridin-3-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 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; 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; 6-(8-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-((3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 4-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-3-chlorobenzonitrile; 5-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-2-fluorobenzonitrile; 5-((2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-8-azaspiro[4.5]dec-8-yl)sulfonyl)-2-methylbenzonitrile; 6-(8-((2-fluoro-4-methoxyphenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-((6-isopropoxypyridin-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-(Pyrazolo[1,5-a]pyridin-6-ylsulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-((5-fluoroquinolin-3-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-((3-fluoroquinolin-6-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-((4-cyclopropyloxyphenyl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(8-(Benzofuran-6-ylsulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 8-((2-fluoro-4-methoxyphenyl)sulfonyl)-N-methyl-N-(2-oxaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decan-3-amine; 8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decan-3-amine; 8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-1-oxa-8-azaspiro[4.5]dec-3-amine; 8-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decan-3-amine; N-methyl-8-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-1-oxa-8-azaspiro[4.5]decan-3-amine; (S)-4-Fluoro-3-((3-(4-hydroxy-4-methylpiperidin-1-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile; 6-(8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(6-oxa-2-azaspiro[3.5]non-2-yl)-1-oxa-8-azaspiro[4.5]decane; and 6-(8-(Quinolin-7-ylsulfonyl)-8-azaspiro[4.5]dec-2-yl)-2-oxa-6-azaspiro[3.3]heptane; or a pharmaceutically acceptable salt thereof.

90. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 89 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

91. A method for treating a disease mediated by emopamide binding protein, comprising administering to a subject an effective amount of a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 89, or a pharmaceutical composition as claimed in claim 90.

92. A method for treating a disease mediated by emopamide binding protein, comprising administering to a subject an effective amount of a compound represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is O, CH2 or bond, provided that when X is a bond, p and q are 1; p is 0 or 1, provided that when p is 0, q is 1; q is 0 or 1, provided that when q is 0, p is 1; R 1 and R 2 Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 cycloalkenyl, 6 to 10 membered bicyclic heterocyclic rings and 4 to 6 membered monocyclic heterocyclic rings, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 The cycloalkenyl group and the 4- to 6-membered monocyclic heterocyclic group are each optionally substituted by one or more R 4 Replace, provided that 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, they form a 4- to 7-membered monocyclic heterocyclic ring or a 6- to 10-membered bicyclic heterocyclic ring, each of which is optionally substituted by one or more R 4 replace; Each R 4 Independently selected from OR 4a , halo, C 1-3 Alkyl, C 3-8 Cycloalkyl and 4- to 6-membered monocyclic heterocyclyl; R 4a Selected from H and C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups; R 3 is phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl or 6 to 10-membered bicyclic heterocycle, wherein the phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl and 6 to 10-membered bicyclic heterocycle are each optionally substituted by one or more substituents R 5 replace; Each R 5 Independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, OR 5a , cyano, halo and 5 or 6-membered monocyclic heteroaryl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl and heteroaryl are optionally substituted by one or more R 5b replace; R 5a Selected from H, C 1-3 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups; R 5b Selected from OR 5a , C 1-3 Alkyl, cyano and halo groups; R 6 Each occurrence is independently halo or C 1-3 Alkyl, or two R 6 Together to form –C 1-3 Alkylene; n is 0, 1 or 2; m is 0, 1 or 2.

93. A method for treating a disease mediated by emopamide binding protein, comprising administering to a subject an effective amount of a compound represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is O, CH2 or bond, provided that when X is a bond, p and q are 1; p is 0 or 1, provided that when p is 0, q is 1; q is 0 or 1, provided that when q is 0, p is 1; R 1 and R 2 Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl and 4 to 6 membered monocyclic heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 The cycloalkenyl group and the 4- to 6-membered monocyclic heterocyclic group are each optionally substituted by one or more R 4 Replace, provided that 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, they form a 4- to 7-membered monocyclic heterocyclic ring or a 6- to 10-membered bicyclic heterocyclic ring, each of which is optionally substituted by one or more R 4 replace; R 4 Selected from OR 4a , halo, C 1-3 Alkyl or C 3-8 Cycloalkyl; R 4a Selected from H and C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups; R 3 is phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl or 6 to 10-membered bicyclic heterocycle, wherein the phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl and 6 to 10-membered bicyclic heterocycle are each optionally substituted by one or more substituents R 5 replace; R 5 Selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, OR 5a , cyano, halo and 5 or 6-membered monocyclic heteroaryl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl and heteroaryl are optionally substituted by one or more R 5b replace; R 5a Selected from H, C 1-3 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups; R 5b Selected from OR 5a , C 1-3 Alkyl, cyano and halo groups; R 6 Each occurrence is independently halo or C 1-3 Alkyl, or two R 6 Together to form –C 1-3 Alkylene; n is 0, 1 or 2; m is 0, 1 or 2.

94. A method for treating an autoimmune disease in a subject, comprising administering to the subject an effective amount of a compound represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is O, CH2 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, q is 1; q is 0 or 1, provided that when q is 0, p is 1; R 1 and R 2 Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 cycloalkenyl, 6 to 10 membered bicyclic heterocyclic rings and 4 to 6 membered monocyclic heterocyclic rings, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 The cycloalkenyl group and the 4- to 6-membered monocyclic heterocyclic group are each optionally substituted by one or more R 4 Replace, provided that 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, they form a 4- to 7-membered monocyclic heterocyclic ring or a 6- to 10-membered bicyclic heterocyclic ring, each of which is optionally substituted by one or more R 4 replace; Each R 4 Independently selected from OR 4a , halo, C 1-3 Alkyl, C 3-8 Cycloalkyl and 4- to 6-membered heterocyclic groups; R 4a Selected from H and C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups; R 3 is phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl or 6 to 10-membered bicyclic heterocycle, wherein the phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl and 6 to 10-membered bicyclic heterocycle are each optionally substituted by one or more substituents R 5 replace; Each R 5 Independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, OR 5a , cyano, halo and 5 or 6-membered monocyclic heteroaryl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl and heteroaryl are optionally substituted by one or more R 5b replace; R 5a Selected from H, C 1-3 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups; R 5b Selected from OR 5a , C 1-3 Alkyl, cyano and halo groups; R 6 Each occurrence is independently halo or C 1-3 Alkyl, or two R 6 Together to form –C 1-3 Alkylene; n is 0, 1 or 2; m is 0, 1 or 2.

95. A method for treating an autoimmune disease in a subject, comprising administering to the subject an effective amount of a compound represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is O, CH2 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, q is 1; q is 0 or 1, provided that when q is 0, p is 1; R 1 and R 2 Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl and 4 to 6 membered monocyclic heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 The cycloalkenyl group and the 4- to 6-membered monocyclic heterocyclic group are each optionally substituted by one or more R 4 Replace, provided that 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, they form a 4- to 7-membered monocyclic heterocyclic ring or a 6- to 10-membered bicyclic heterocyclic ring, each of which is optionally substituted by one or more R 4 replace; R 4 Selected from OR 4a , halo, C 1-3 Alkyl or C 3-8 Cycloalkyl; R 4a Selected from H and C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups; R 3 is phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl or 6 to 10-membered bicyclic heterocycle, wherein the phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl and 6 to 10-membered bicyclic heterocycle are each optionally substituted by one or more substituents R 5 replace; R 5 Selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, OR 5a , cyano, halo and 5 or 6-membered monocyclic heteroaryl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl and heteroaryl are optionally substituted by one or more R 5b replace; R 5a Selected from H, C 1-3 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups; R 5b Selected from OR 5a , C 1-3 Alkyl, cyano and halo groups; R 6 Each occurrence is independently halo or C 1-3 Alkyl, or two R 6 Together to form –C 1-3 Alkylene; n is 0, 1 or 2; m is 0, 1 or 2.

96. The method of any one of claims 91 to 95, wherein the autoimmune disease is multiple sclerosis.

97. The method of claim 96, wherein the compound or pharmaceutical composition repairs or forms new myelin sheaths in the subject.

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