Emopamil binding protein inhibitors and uses thereof

Abstract

Provided are compounds of Formula (I): # imgabs0 # (I), 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 priority to U.S. Provisional Application No. 63 / 389,482, filed on July 15, 2022. The entire contents of the foregoing application are expressly incorporated herein by reference. Technical Field

[0003] The present disclosure relates to inhibitors of Emopamil-Binding Protein (EBP) and pharmaceutically acceptable salts thereof, compositions of these compounds, methods for preparing the same, uses thereof in treating diseases, uses thereof optionally in combination with a pharmaceutically acceptable carrier for manufacturing a pharmaceutical preparation, uses of the pharmaceutical preparation in treating diseases, and methods for treating the diseases, the methods comprising administering the EBP inhibitor to warm-blooded animals, especially humans. Background Art

[0004] Emopamil binding protein (EBP) is a Δ8-Δ7 sterol isomerase that isomerizes double bonds in sterol molecules, moving double bonds from the 8-9 position to the 7-8 position. Specifically, during the biosynthesis of cholesterol, EBP converts zymostenol to 7-ene cholestanol, or zymosterol to dehydrogenated 7-ene cholestanol (Silve et al., 1996, J Biol Chem. 271 (37), 22434-22440). It has been shown that the accumulation of 8-9 unsaturated sterols can activate oligodendritic cell formation 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. Demyelinating diseases or myelin-related diseases are the result of these myelin sheaths being damaged, degraded or reduced in thickness. The loss of myelin sheaths can disrupt the electronic signals from the brain and may cause nerve damage, vision loss, numbness, muscle weakness, cognitive decline, motor function loss and other similar symptoms. In some myelin-related diseases such as multiple sclerosis, the subject's immune system targets and decomposes its own myelin sheath. The ability to repair and regenerate myelin sheaths is the key to treating these myelin-related diseases. Due to its function of converting 8-9 sterols, the inhibition of EBP is a potential target for activating myelin regeneration, because its inhibition can lead to an increase in these 8-9 sterol starting materials (Theodoropoulous et al., 2020, J. Am. Chem. Soc., 142, (13), 6128-6138).

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

[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 embodiment, the present disclosure relates to compounds having Formula I:

[0009] (I)

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

[0011] X is NR 1 or CR x ;

[0012] R x For-NR 1 R 2 ;

[0013] R 1 and R 2 Each independently selected from H, C 1-6 Alkyl, C 4-8 Cycloalkyl, Het or -Z-Het, wherein the C 1-6 Alkyl, C 4-8 Cycloalkyl and Het are each optionally substituted by one or more R 4 Replacement, the prerequisite is that R 1 and R 2 At least one of them is not H;

[0014] or R 1 and R 2 Together with the N atom to which it is attached, it forms 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;

[0015] Z is C 1-4 alkyl;

[0016] Het is a 4- to 6-membered monocyclic heterocyclic group or a 6- to 8-membered bicyclic heterocyclic group, each of which is optionally substituted by one or more R 4 replace;

[0017] R4 C independently at each occurrence 1-6 Alkyl or halide;

[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 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;

[0019] R 5 is independently selected at each occurrence from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Cycloalkyl, -OR 5a and cyano;

[0020] R 5a Selected from H, C 1-4 Alkyl and C 1-4 Haloalkyl;

[0021] The prerequisite is that the compound is not the following compound:

[0022] .

[0023] 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 pharmaceutical carrier.

[0024] In yet another aspect, the present disclosure provides a method of 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 with a myelin-related disorder.

[0025] 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 are compounds described herein, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition responsive to inhibition of EBP. DETAILED DESCRIPTION

[0026] The present disclosure provides compounds and pharmaceutical compositions thereof that are useful for treating diseases or disorders, such as multiple sclerosis or other myelin-related disorders, by mediating EBP function / activity. In some embodiments, the compounds of the present disclosure are EBP inhibitors.

[0027] Compounds and compositions

[0028] In a first embodiment, the present disclosure provides a compound of formula (I):

[0029] (I);

[0030] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (I) are as defined in the first embodiment above. In some embodiments, Z is C 1-2 In other embodiments, Z is -CH 2 -.

[0031] In a second embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, Het is a 4- to 6-membered oxygen-containing monocyclic saturated heterocyclyl or a 6- to 8-membered oxygen-containing bicyclic saturated heterocyclyl; and the remaining variables are as described in the first embodiment.

[0032] In a third embodiment, for a compound of formula (I) 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 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 and the remaining variables are as described in the first or second embodiment.

[0033] In a fourth embodiment, the compounds of the present disclosure are represented by formula (II):

[0034] (II);

[0035] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (II) are as defined above in the first, second or third embodiment.

[0036] In a fifth embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 3 is selected from the group consisting of phenyl, pyridyl, pyrimidinyl and pyrazolyl; and the remaining variables are as described in the fourth embodiment.

[0037] In a sixth embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: ; ; ;or wherein each of the formulae depicted above is optionally replaced by one to three R 5and the remaining variables are as described in the fifth embodiment.

[0038] In a seventh embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: ; ; ; ; ; ;or ; and the remaining variables are as described in the fifth embodiment. In an alternative seventh embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: ; ; ; ; ; ; ;or ; and the remaining variables are as described in the fifth embodiment.

[0039] In an eighth embodiment, for a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 5 is independently selected at each occurrence from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 5a and -CN; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth or seventh embodiment.

[0040] In a ninth embodiment, for a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 5 is independently selected at each occurrence from -Cl, -F, -CH 3 , -CF 3 、-OCH 3 and -CN; and the remaining variables are as described in the eighth embodiment.

[0041] In a tenth embodiment, for a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 1 is Het; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment. In an alternative tenth embodiment, for a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 1 -CH 2 -Het or Het; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment.

[0042] In an eleventh embodiment, for a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, Het is selected from the group consisting of tetrahydropyranyl and tetrahydrofuranyl; and the remaining variables are as described in the tenth embodiment. In an alternative eleventh embodiment, for a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, Het is selected from the group consisting of oxetanyl, 2-oxaspiro[3.3]heptyl, tetrahydropyranyl and 2-oxabicyclo[2.1.1]hexyl, 2-oxabicyclo[3.1.1]heptyl, tetrahydrofuranyl; and the remaining variables are as described in the tenth embodiment.

[0043] In a twelfth embodiment, for the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, Het is represented by the following formula: ;or wherein each of the formulae depicted above is optionally replaced by one or two R 4 and the remaining variables are as described in the eleventh embodiment. In some embodiments, R 4 C independently at each occurrence 1-2 In other embodiments, R 4 -CH 3 In an alternative twelfth embodiment, for the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, Het is represented by the following formula: , , , , or wherein each of the formulae depicted above is optionally replaced by one or two R 4 and the remaining variables are as described in the eleventh embodiment. In some embodiments, R 4 C independently at each occurrence 1-2 In other embodiments, R 4 -CH 3 .

[0044] In a thirteenth embodiment, for a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, Het is represented by the formula ;or ; and the remaining variables are as described in the eleventh embodiment. In an alternative thirteenth embodiment, for a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, Het is represented by the formula: , , , , or ; and the remaining variables are as described in the eleventh embodiment.

[0045] In a fourteenth embodiment, the compounds of the present disclosure are represented by formula (III):

[0046] (III);

[0047] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (III) are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment.

[0048] In a fifteenth embodiment, for a compound of formula (III) or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: ;or wherein each of the formulae depicted above is optionally replaced by one to three R 5 and the remaining variables are as described in the fourteenth embodiment.

[0049] In a sixteenth embodiment, for a compound of formula (III) or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: ;or ; and the remaining variables are as described in the fourteenth embodiment.

[0050] In a seventeenth embodiment, for a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, R 5 In each occurrence, independently selected from C 1-4 Alkyl and C 1-4 haloalkyl; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth or sixteenth embodiment.

[0051] In an eighteenth embodiment, for a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, R 5 independently selected at each occurrence from –CH 3 , -, and –CF 3 ; and the remaining variables are as described in the seventeenth embodiment.

[0052] In a nineteenth embodiment, the compounds of the present disclosure are represented by formula (IV):

[0053] (IV);

[0054] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (IV) are as defined above in the first, second or third embodiment.

[0055] In a twentieth embodiment, for a compound of formula (IV) or a pharmaceutically acceptable salt thereof, R 3 is selected from the group consisting of phenyl, pyridyl, and pyrazolyl; and the remaining variables are as described in the nineteenth embodiment.

[0056] In a twenty-first embodiment, for the compound of formula (IV) or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: ; ;or wherein each of the formulae depicted above is optionally replaced by one to three R 5 substituted; and the remaining variables are as described in the twentieth embodiment.

[0057] In a twenty-second embodiment, for a compound of formula (IV) or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: ; ; ; ; ;or ; and the remaining variables are as described in the twentieth embodiment.

[0058] In a twenty-third embodiment, for a compound of Formula (I) or (IV) or a pharmaceutically acceptable salt thereof, R 5 In each occurrence, independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 5a and C 3-8 cycloalkyl; and the remaining variables are as described in the first, second, third, nineteenth, twentieth, twenty-first, or twenty-second embodiment. In some embodiments, R 5a C 1-3 Alkyl or C 1-3 In other embodiments, R 5a C 1-2 Alkyl or C 1-2 Halogenated alkyl.

[0059] In a twenty-fourth embodiment, for a compound of Formula (I) or (IV) or a pharmaceutically acceptable salt thereof, R 5 independently selected at each occurrence from –CH 3 , -CF 3 、-OCH 3 、-OCHF 2and cyclopropyl; and the remaining variables are as described in the twenty-second embodiment.

[0060] In a twenty-fifth embodiment, for a compound of Formula (I) or (IV) or a pharmaceutically acceptable salt thereof, R 1 is Het or –Z-Het; and R 2 H or C 1-6 and the remaining variables are as described in the first, second, third, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, or twenty-fourth embodiment. In some embodiments, Z is C 1-2 In other embodiments, Z is -CH 2 -.

[0061] In a twenty-sixth embodiment, for the compound of Formula (I) or (IV), or a pharmaceutically acceptable salt thereof, Het is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, and 2-oxaspiro[3.3]heptyl; and the remaining variables are as described in the twenty-fifth embodiment.

[0062] In a twenty-seventh embodiment, for a compound of Formula (I) or (IV) or a pharmaceutically acceptable salt thereof, R 1 It is expressed by the following formula: ; ; ; ; ;or wherein each of the formulae depicted above is optionally replaced by one or two R 4 and the remaining variables are as described in the twenty-sixth embodiment. In some embodiments, R 4 C independently at each occurrence 1-2 alkyl.

[0063] In a twenty-eighth embodiment, for a compound of Formula (I) or (IV) or a pharmaceutically acceptable salt thereof, R 1 It is expressed by the following formula: ; ; ; ; ;or ; and the remaining variables are as described in the twenty-sixth embodiment. In some embodiments, R 4 C independently at each occurrence 1-2 alkyl.

[0064] In a twenty-ninth embodiment, for a compound of Formula (I) or (IV) or a pharmaceutically acceptable salt thereof, R 2 H or –CH 3; and the remaining variables are as described in the first, second, third, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh or twenty-eighth embodiment.

[0065] In a thirtieth embodiment, for a compound of Formula (I) or (IV) or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the N atom to which it is attached, it forms a 4- to 7-membered monocyclic heterocyclic ring, which is optionally replaced by one or more R 4 and the remaining variables are as described in the first, second, third, nineteenth, twentieth, twenty-first, twenty-second, twenty-third or twenty-fourth embodiment.

[0066] In a thirty-first embodiment, for a compound of Formula (I) or (IV) or a pharmaceutically acceptable salt thereof, R 1 and R 2 together with the N atom to which it is attached is selected from the group consisting of piperidinyl and morpholinyl; and the remaining variables are as described in the thirtieth embodiment.

[0067] In a thirty-second embodiment, for a compound of Formula (I) or (IV) or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the N atom to which it is attached, it is represented by the following formula: ;or wherein each of the formulae depicted above is optionally replaced by one or two R 4 substituted; and the remaining variables are as described in the thirty-first embodiment.

[0068] In a thirty-third embodiment, for a compound of Formula (I) or (IV) or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the N atom to which it is attached, it is represented by the following formula: ;or ; and the remaining variables are as described in the thirty-first embodiment.

[0069] In a thirty-fourth embodiment, for the compound of formula (IV) or a pharmaceutically acceptable salt thereof, R 4 For –CH 3 and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second or thirty-third embodiment.

[0070] In a thirty-fifth embodiment, the compounds of the present disclosure are represented by formula (II):

[0071] (II);

[0072] or a pharmaceutically acceptable salt thereof, wherein:

[0073] R 1 Het or -CH 2 -Het

[0074] Het is a 4- to 6-membered monocyclic heterocyclic group or a 6- to 8-membered bicyclic heterocyclic group, each of which is optionally substituted by one or more R 4 replace;

[0075] Each R 4 Independently for C 1-3 alkyl;

[0076] R 3 For one or more R 5 substituted 5- or 6-membered monocyclic heteroaryl;

[0077] Each R 5 Independently for C 1-3 Alkyl and C 1-3 Haloalkyl, wherein the remaining variables in formula (II) are as defined above in the first embodiment.

[0078] In a thirty-sixth embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 3 is pyridinyl, pyrimidinyl or pyrazolyl, and the remaining variables are as described in the thirty-fifth embodiment.

[0079] In a thirty-seventh embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: ; ;or wherein each of the formulae depicted above is optionally replaced by two or three R 5 substituted; and the remaining variables are as described in the thirty-sixth embodiment.

[0080] In a thirty-eighth embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: ; ; ;or ; and the remaining variables are as described in the thirty-sixth embodiment.

[0081] In the thirty-ninth embodiment, for the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 5 Selected from -CF 3 or -CH 3 ; and the remaining variables are as described in the thirty-fifth, thirty-sixth, thirty-seventh or thirty-eighth embodiment.

[0082] In the fortieth embodiment, for the compound of formula (II) or a pharmaceutically acceptable salt thereof, Het is tetrahydropyranyl or 2-oxabicyclo[2.1.1]hexyl; and the remaining variables are as described in the thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth or thirty-ninth embodiment.

[0083] In a 41st embodiment, for the compound of formula (II) or a pharmaceutically acceptable salt thereof, Het is represented by the following formula: or wherein each of the formulae depicted above is optionally replaced by one or two R 4 substituted; and the remaining variables are as described in the 40th embodiment.

[0084] In a forty-two embodiment, for the compound of formula (II) or a pharmaceutically acceptable salt thereof, Het is represented by the following formula: or ; and the remaining variables are as described in the 40th embodiment.

[0085] In the forty-third embodiment, for the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 1 It is expressed by the following formula: , or ; and the remaining variables are as described in the thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth or thirty-ninth embodiment.

[0086] In the forty-fourth embodiment, for the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 4 -CH 3 ; and the remaining variables are as described in the thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second or forty-third embodiment.

[0087] In a forty-fifth embodiment, the disclosure provides a compound described herein (eg, a compound of any one of Examples 1 to 62), or a pharmaceutically acceptable salt thereof.

[0088] In a forty-sixth embodiment, the present disclosure provides a compound selected from the group consisting of:

[0089] (3aR,5r,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;

[0090] (3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;

[0091] (3aR,5s,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole;

[0092] (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole;

[0093] (3aR,5r,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole;

[0094] (3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole;

[0095] (3aR,5s,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;

[0096] (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;

[0097] (3aR,5s,6aS)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;

[0098] (3aR,5s,6aS)-2-((4,6-dimethylpyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;

[0099] (3aR,5s,6aS)-2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;

[0100] (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;

[0101] 4-((3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)morpholine;

[0102] (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-yl)octahydrocyclopenta[c]pyrrol-5-amine;

[0103] (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydrofuran-3-yl)octahydrocyclopenta[c]pyrrol-5-amine;

[0104] (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine;

[0105] (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;

[0106] (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;

[0107] (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine;

[0108] (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine;

[0109] (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;

[0110] (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine;

[0111] (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;

[0112] (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine;

[0113] (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine;

[0114] (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;

[0115] (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;

[0116] (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine;

[0117] (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;

[0118] (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine;

[0119] (3aR,6aS)-2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole;

[0120] 2-(mesitylsulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole;

[0121] 3-Fluoro-5-(((3aR,6aS)-5-(tetrahydro-2H-pyran-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)benzonitrile;

[0122] (3aR,6aS)-2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole;

[0123] (3aR,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole;

[0124] (3aR,6aS)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole;

[0125] (3aR,6aS)-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole;

[0126] (3aR,6aS)-2-((2-chloro-6-methoxypyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole;

[0127] (3aR,6aS)-2-((3,5-difluorophenyl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole;

[0128] (3aR,6aS)-2-((6-methoxypyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole;

[0129] (3aR,6aS)-2-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole;

[0130] (3aR,6aS)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole;

[0131] (3aR,6aS)-2-((2,4-dimethylpyrimidin-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole;

[0132] (3aR,6aS)-2-((2,4-dimethylpyrimidin-5-yl)sulfonyl)-5-(tetrahydrofuran-3-yl)octahydropyrrolo[3,4-c]pyrrole;

[0133] (3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole;

[0134] (3aR,6aR)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole;

[0135] (3aS,6aS)-5-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2-(oxan-4-ylmethyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole;

[0136] (3aS,6aS)-5-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2-(2-oxaspiro[3.3]hept-6-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole;

[0137] (3aS,6aS)-5-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2-(oxan-4-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole;

[0138] rac-(3aR,6aR)-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-2-(2-oxaspiro[3.3]hept-6-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole;

[0139] rac-(3aR,6aR)-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-2-(oxan-4-ylmethyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole;

[0140] rac-(3aR,6aR)-5-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2-(2-oxaspiro[3.3]hept-6-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole;

[0141] rac-(3aR,6aR)-5-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2-(oxan-4-ylmethyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole;

[0142] rac-(3aR,6aR)-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-2-(oxan-4-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole;

[0143] (3aS,6aS)-2-[(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methyl]-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole;

[0144] rel-(3aR,6aR)-2-[(1-methyl-2-oxabicyclo[3.1.1]hept-5-yl)methyl]-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole;

[0145] (3aR,6aR)-2-[(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methyl]-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole;

[0146] (3aS,6aS)-2-[(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methyl]-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole;

[0147] rac-(3aR,6aR)-5-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2-(oxan-4-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole;

[0148] rac-(3aR,6aR)-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-2-(oxan-4-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole;

[0149] (3aR,6aRS)-5-(2,5-dimethylpyrazol-3-yl)sulfonyl-2-(oxan-4-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; and

[0150] rac-(3aR,6aR)-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-2-(oxetan-3-ylmethyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole;

[0151] or a pharmaceutically acceptable salt thereof.

[0152] In the forty-seventh embodiment, the present disclosure provides a pharmaceutical composition comprising a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof.

[0153] In the forty-eighth 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 according to any one of embodiments one to thirty-six, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the thirty-seventh embodiment.

[0154] In a forty-ninth embodiment, the present disclosure provides a compound according to any one of embodiments one to thirty-six for use in treating a disease or condition mediated by EBP.

[0155] In a fiftieth embodiment, the present disclosure provides the use of a compound according to any one of embodiments one to thirty-six in the manufacture of a medicament for treating a disease or condition mediated by EBP.

[0156] The compounds and intermediates described herein can be separated and used in the form of the compounds themselves. Alternatively, when there is a part that can form a salt, the compound or intermediate can be separated and used in the form of its corresponding salt. As used herein, the term "salt (salt / salts)" refers to the acid addition salt or base addition salt of the compound described herein. "Salt" especially 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 undesirable biologically or otherwise. In many cases, due to the presence of amino and / or carboxyl groups or groups similar thereto, the compounds of the present disclosure can form acid salts and / or basic salts.

[0157] 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, chlorophylline, 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, toluenesulfonate and trifluoroacetate.

[0158] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0159] 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.

[0160] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0161] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of 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.

[0162] 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, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0163] Salts can be synthesized from compounds containing alkaline or acidic parts by conventional chemical methods. Generally speaking, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K), or by reacting the free base forms 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 speaking, 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 "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0164] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations using appropriate isotopically labeled reagents in place of the unlabeled reagents previously used. In one embodiment, the present disclosure provides a deuterated compound described herein or a pharmaceutically acceptable salt thereof.

[0165] Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, for example D 2 O,d 6- Acetone, d 6 -DMSO.

[0166] Those skilled in the art will recognize that the compounds of the present invention may contain chiral centers and may therefore 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 the chiral center of a carbon atom. Therefore, the present disclosure includes enantiomers, diastereomers, or racemates of the compounds.

[0167] "Enantiomer" is a pair of stereoisomers of mirror images that do not overlap each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term "racemic / rac" is used to specify a racemic mixture. When specifying the stereochemistry of the compound of the present invention, a single stereoisomer with relative and absolute configurations of two known chiral centers is specified using a conventional RS system (e.g., (1S, 2S)). "Diastereomer" is a stereoisomer with at least two asymmetric atoms but not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon can be specified by R or S. The unknown analytical compound of absolute configuration can be specified as (+) or (-) according to the direction (right-handed or left-handed) of rotating plane polarized light at the wavelength of the sodium D line. Alternatively, the analytical compound can be defined by the corresponding retention time of the corresponding enantiomer / diastereomer via chiral HPLC.

[0168] 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 which may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

[0169] 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)-stereoisomers and (S)-stereoisomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., on a chiral SFC or HPLC column (such as CHIRALPAK available from DAICEL Corp.) RTM and CHIRALCEL RTM ) using an appropriate solvent or solvent mixture to achieve good separation. If the compound contains a double bond, the substituents may be in 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.

[0170] How to use

[0171] 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., at least a 10% decrease in EBP activity as measured by a given assay, such as a bioassay described in the Examples and known in the art).

[0172] In certain embodiments, the 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 such treatment. The method comprises administering to the subject a compound described herein (e.g., a compound described in any one of the first to forty-sixth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0173] 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 forty-sixth 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 disorder or disease in a subject in need of such treatment.

[0174] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to forty-sixth 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 disorder or disease in a subject in need of such treatment.

[0175] In certain embodiments, the EBP-mediated disorder is colorectal cancer.

[0176] In certain embodiments, the present disclosure provides a method for treating an autoimmune disease 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 forty-sixth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0177] 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 forty-sixth 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 such treatment.

[0178] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to forty-sixth 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.

[0179] In certain embodiments, the autoimmune disease is multiple sclerosis (MS). The compounds disclosed herein 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").

[0180] 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.

[0181] Relapsing-remitting multiple sclerosis is a stage of MS characterized by unpredictable relapses followed by periods of relative calm (remission) for months to years with no new signs of disease activity. The deficits that occur during an attack may resolve the problem, or they may remain, the latter occurring in about 40% of attacks and more often the longer the disease lasts. This describes the initial course of 80% of individual subjects with multiple sclerosis.

[0182] Approximately 65% ​​of people who initially have relapsing-remitting MS develop secondary progressive MS, and these people eventually experience progressive neurological decline between acute attacks without any clear periods of remission. Occasionally, there may be relapses and minor remissions. The most common length of time between onset and conversion from relapsing-remitting to secondary progressive MS is 19 years.

[0183] Primary progressive MS is characterized by the same symptoms as secondary progressive MS, namely progressive neurological decline between acute attacks without any clear remission periods and without a preceding relapsing-remitting phase.

[0184] CIS is the first attack of neurological symptoms caused by inflammation and demyelination of the central nervous system. According to the definition, the attack must last for at least 24 hours, which is unique to multiple sclerosis, but does not yet meet the diagnostic criteria of MS, because the people who experience CIS may or may not continue to develop into MS. When CIS is accompanied by lesions on brain magnetic resonance imaging (magnetic resonance imaging, MRI) similar to those seen in MS, the patient is very likely to have a second attack of neurological symptoms and be diagnosed as relapsing-remitting MS. When CIS is not accompanied by MS-like lesions on brain MRI, the possibility that the patient develops into MS is much lower.

[0185] In certain embodiments, the present disclosure provides a method of promoting myelination in a subject with a myelin-related disease or condition in a subject in need of treatment. The method includes administering to the subject a compound described herein (e.g., a compound described in any one of the first to forty-sixth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0186] 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 forty-sixth 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 a subject in need of treatment.

[0187] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to forty-sixth 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 with a myelin-related disease or disorder in a subject in need of treatment.

[0188] 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 diffuse encephalomyelitis (ADEM), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease (PMD), vanishing white matter disease, Wallerian Degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, disease), spinal cord injury, traumatic brain injury, post-radiation injury, neurological 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 diffuse 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.

[0189] In certain embodiments, the present disclosure provides a method of treating cancer 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 forty-sixth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0190] 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 forty-sixth 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 such treatment.

[0191] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to forty-sixth 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.

[0192] In certain embodiments, the cancer is colorectal cancer.

[0193] In certain embodiments, the disclosure relates to the above-mentioned methods, wherein the subject is a mammal. In certain embodiments, the subject is a primate. In certain embodiments, the subject is a human.

[0194] As used herein, "effective amount" and "therapeutically effective amount" are used interchangeably. It means an amount that is effective to treat or lessen the severity of one or more of the diseases, disorders, or conditions described herein. In some embodiments, the effective dose may be between 10 μg and 500 mg.

[0195]

[00136] 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 diseases, disorders, or conditions recited above.

[0196] In certain embodiments, the disclosure relates to the above-mentioned methods, wherein the compound is administered parenterally. In certain embodiments, the disclosure relates to the above-mentioned methods, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectal, intrathecally, topically or intranasally. In certain embodiments, the disclosure relates to the above-mentioned methods, wherein the compound is administered systemically.

[0197] The compound of the present invention can be used in the form of pharmaceutical composition (for example, compound of the present invention and at least one pharmaceutically acceptable carrier). As used herein, the term "pharmaceutically acceptable carrier" includes solvents, dispersion media, surfactants, antioxidants, preservatives (for example, antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, drug stabilizers, buffers (for example, maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.) known to those skilled in the art, etc. and combinations thereof (see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, pp. 1289-1329). Unless any conventional carrier is incompatible with active ingredient, its use in treatment or pharmaceutical composition is considered. For the purposes of this disclosure, it is believed that solvates and hydrates include pharmaceutical compositions of compounds of the present invention and solvents (i.e., solvates) or water (i.e., hydrates).

[0198] The formulation can be prepared using conventional dissolution and mixing procedures. For example, bulk drug substance (i.e., a compound of the invention or a stable 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 excipients described above. The compound of the invention is usually formulated into a pharmaceutical dosage form to provide an easily controlled drug dosage and to give the patient an aesthetically pleasing and easy-to-handle product.

[0199] The pharmaceutical composition (or formulation) for use can be packaged in a variety of ways, depending on the method used to administer the drug. Generally speaking, the article for distribution includes a container in which the pharmaceutical formulation 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 may also include a tamper-proof assembly to prevent inadvertent contact with the contents of the package. In addition, a label describing the contents of the container is placed on the container. The label may also include appropriate warnings.

[0200] Pharmaceutical compositions containing compounds of the present disclosure are typically formulated for parenteral or oral administration or alternatively as suppositories.

[0201] For example, the oral pharmaceutical composition of the present disclosure can be prepared in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories), or in liquid form (including but not limited to solutions, suspensions or emulsions). The pharmaceutical composition 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.

[0202] Typically, the pharmaceutical composition is a tablet or gelatin capsule, which contains the active ingredient and

[0203] a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0204] b) lubricants, for example silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets, also

[0205] c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if necessary,

[0206] d) disintegrants, for example starch, agar, alginic acid or its sodium salt or foaming mixtures; and / or

[0207] e) Absorbents, colorants, flavorings and sweeteners.

[0208] Tablets may be film-coated or enteric-coated according to methods known in the art.

[0209] 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 making pharmaceutical compositions, and the composition may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide pharmaceutically aesthetic and palatable preparations. Tablets may contain active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture. 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; adhesives such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used.Preparations for oral use may be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0210] Parenteral compositions (e.g., intravenous (IV) preparations) are isotonic aqueous solutions or suspensions. Parenteral compositions may be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, dissolution promoters, salts for regulating osmotic pressure and / or buffers. In addition, the compositions may also contain other therapeutically valuable substances. Compositions are usually prepared according to conventional mixing, granulation or coating methods, respectively, and contain about 0.1-75% or contain about 1-50% active ingredient.

[0211] The compounds of the present disclosure or their pharmaceutical compositions for subjects (e.g., humans) are generally administered orally or parenterally at therapeutic doses. When administered intravenously via infusion, the dosage may depend on the infusion rate of the IV preparation. In general, the therapeutically effective dose of a compound, pharmaceutical composition, or combination thereof 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 of the active ingredients required to prevent, treat, or inhibit the progression of a disorder or disease.

[0212] The above dosage characteristics can be advantageously demonstrated using in vitro and in vivo tests of mammals, such as mice, rats, dogs, monkeys or isolated organs, tissues and their products. The compounds of the present invention can be applied in vitro in the form of solutions (e.g., aqueous solutions), and in vivo in the form of enteral, parenteral, advantageously intravenous, such as as suspensions or aqueous solutions. The in vitro dose can be in the range of about 10-3 molar and 10-9 molar concentrations.

[0213] definition

[0214] As used herein, "patient", "subject" or "individual" are used interchangeably and refer to a human or non-human animal. The term includes 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 subject is a primate. Preferably, the subject is a human.

[0215] As used herein, the terms "inhibit", "inhibition" and "inhibiting" refer to reducing or suppressing a given condition, symptom, or disorder, or disease, or significantly reducing the baseline activity of a biological activity or process.

[0216] As used herein, the term "treat / treating / treatment" of any disease, disorder or condition refers to the management and care of a patient for the purpose of combating the disease, disorder or condition, and includes the administration of the compounds of the invention to obtain the desired pharmacological and / or physiological effects. The effect may be therapeutic, including partial or substantial achievement of one or more of the following results: partial or complete reduction in the extent of the disease, disorder or condition; alleviation or improvement of clinical symptoms, complications or indicators associated with the disease, disorder or condition; or delay, inhibition or reduction in the likelihood of progression of the disease, disorder or condition; or elimination of the disease, disorder or condition. In certain embodiments, the effect may be prevention of the onset of symptoms or complications of the disease, disorder or condition.

[0217] As used herein, the term "cancer" has the meaning generally accepted in the art. The term can broadly refer to abnormal cell growth.

[0218] 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.

[0219] As used herein, the term "myelination" has the meaning generally accepted in the art. The term can be broadly understood as the process of producing myelin.

[0220] As used herein, the terms "myelin-related diseases or disorders", "demyelinating disorders (demyelinatingdisorder / demyelation disorder)" have the meanings generally accepted in the art. These terms can broadly refer to diseases or disorders involving myelin damage.

[0221] As used herein, a subject (preferably a human) is "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from the treatment.

[0222] As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In general, the term "optionally substituted" refers to replacing a hydrogen group in a given structure with a group of a specific substituent. Specific substituents are described in the definitions and in the description of compounds and their embodiments. Unless otherwise indicated, the 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 by more than one substituent selected from a specified group, the substituent may be the same or different at each position. In some embodiments, the optionally substituted group may be substituted by one or more substituents, each of which may be the same or different. In some embodiments, "one or more" substituents may be 1, 2, 3, 4, 5, 6, etc., substituents, each of which may be the same or different. In some embodiments, "one or more" substituents may be 1 to 6, 1 to 4, 1 to 3, or 1 to 2 substituents, each of which may be the same or different.

[0223] 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" may 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., the 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 (typically one to three substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[0224] 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 groups, 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 carbons, more preferably about 1-2 carbons. The term "C 1-2 "Alkoxy" may be interpreted accordingly.

[0225] As used herein, the term "C 1-4 Alkoxy C 1-4 "Alkyl" means a C 1-4An alkyl group in which at least one hydrogen atom is replaced by a C 1-4 Alkoxy substitution. 1-4 Alkoxy C 1-4 The alkyl group is attached to the rest of the molecule described herein via the alkyl group.

[0226] The number of carbon atoms in a group is indicated herein by the prefix "C x-xx " specifies where x and xx are integers. For example, "C 1-3 "Alkyl" is an alkyl group having 1 to 3 carbon atoms.

[0227] "Halogen" or "halo" may be fluorine, chlorine, bromine or iodine.

[0228] 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 hydrogen atom is replaced by a halogen atom. 1-4 The haloalkyl group may be a monohalogen-C 1-4 Alkyl, dihalogen-C 1-4 Alkyl or polyhalogen-C 1-4 Alkyl, including perhalo-C 1-4 Alkyl. Monohalogen-C 1-4 The alkyl group may have one iodo, bromo, chloro or fluoro group within the alkyl group. 1-4 Alkyl and polyhalogen-C 1-4 The alkyl group may have two or more identical halogen atoms or a combination of different halogen atoms 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 halo groups. 1-4 Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. 1-4 An alkyl group is a C 1-4 Alkyl group.

[0229] 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.

[0230] 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 can be quaternized. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic". The heteroaryl group can be monocyclic or bicyclic. Monocyclic heteroaryl includes, for example, pyrazolyl, imidazolyl, oxazolyl, pyridyl, furyl, oxadiazolyl, thienyl, etc. Bicyclic heteroaryl includes a group in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include pyrazolopyridyl, pyrazolopyridyl, benzotriazolyl, imidazopyridyl and indolyl.

[0231] The term "carbocycle" or "carbocyclyl" refers to a 4 to 12-membered saturated or partially unsaturated hydrocarbon ring and may exist as a monocyclic, bicyclic (including fused, spiral or bridged carbocyclic rings) or spiral ring. Bicyclic carbocyclyls include, for example, unsaturated carbocyclic groups fused to another unsaturated carbocyclic group, cycloalkyl or aryl, such as, for example, 2,3-dihydroindenyl, decahydronaphthyl and 1,2,3,4-tetrahydronaphthyl. Unless otherwise indicated, carbocycles typically contain 4 to 10 ring members.

[0232] The term "C 3 - 6 "Cycloalkyl" refers to a fully saturated carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0233] 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 may be a monocyclic or bicyclic ring (e.g., a bridged, fused or spirobicyclic ring). Examples of monocyclic saturated or partially unsaturated heterocyclic groups include, but are not limited to, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and piperidinyl. Bicyclic heterocyclyls include, for example, unsaturated heterocyclic groups fused to another unsaturated heterocyclic group, cycloalkyl, aryl or heteroaryl ring, such as, for example, tetrahydro-3H-[1,2,3]triazolo[4,5-c]pyridinyl, 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.

[0234] As used herein, the term "spiro" ring means a bicyclic ring system in which both rings share one common atom. Examples of spiro rings include 2-oxa-6-azaspiro[3.3]heptyl and the like.

[0235] The term "fused" ring refers to two ring systems which share two adjacent ring atoms. A fused heterocycle has a ring system in which at least one ring atom contains a heteroatom selected from O, N and S (eg, 3-oxabicyclo[3.1.0]hexane).

[0236] 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).

[0237] The phrase "pharmaceutically acceptable" indicates that the substance, composition or dosage form must be compatible chemically and / or toxicologically with the other ingredients making up the formulation and / or the mammal to be treated therewith.

[0238] Unless otherwise indicated, the term "compound of the present disclosure" refers to a compound of formula (I), as well as all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers, isotope-labeled compounds (including deuterium substitution). When there is a part capable of forming a salt, then salts, particularly pharmaceutically acceptable salts, are also included.

[0239] As used herein, unless otherwise indicated herein or clearly contradictory to the context, the terms "a / an", "said" and similar terms used in the context of the present invention (especially in the context of the claims) should be interpreted as covering both the singular and the plural. 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 is not intended to limit the scope of the present invention otherwise claimed.

[0240] The intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A 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 of the bonded electrons.

[0241] In one embodiment, the disclosure relates to compounds of formula (I) as defined herein in free form. In another embodiment, the disclosure relates to compounds of formula (I) as defined herein in salt form. In another embodiment, the disclosure relates to compounds of formula (I) as defined herein in acid addition salt form. In yet another embodiment, the disclosure relates to compounds of formula (I) as defined herein in pharmaceutically acceptable salt form. In yet another embodiment, the disclosure relates to compounds of formula (I) as defined herein in pharmaceutically acceptable acid addition salt form. In yet another embodiment, the disclosure relates to any one of the compounds of the examples in free form. In yet another embodiment, the disclosure relates to any one of the compounds of the examples in salt form. In yet another embodiment, the disclosure relates to any one of the compounds of the examples in acid addition salt form. In yet another embodiment, the disclosure relates to any one of the compounds of the examples in pharmaceutically acceptable salt form. In yet another embodiment, the disclosure relates to any one of the compounds of the examples in pharmaceutically acceptable acid addition salt form.

[0242] The compounds of the present disclosure can be synthesized by synthetic routes including processes similar to those well known in the chemical arts, particularly according to the descriptions contained herein. The 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., prepared by methods generally described in the following references: 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)).

[0243] For illustrative purposes, the reaction schemes depicted below provide potential pathways for synthesizing compounds disclosed herein and key intermediates. For a more detailed description of individual reaction steps, see the Examples section below. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents may also be easily substituted to provide a variety of derivatives and / or reaction conditions.

[0244] example

[0245] abbreviation:

[0246] PE = Petroleum ether

[0247] EtOAc = EA = Ethyl acetate

[0248] ESI = electrospray ionization

[0249] MeOH = methanol

[0250] EtOH = ethanol

[0251] DCE = 1,2-dichloroethane

[0252] DCM = dichloromethane

[0253] CHCl 3 =Chloroform

[0254] HCl = hydrochloric acid

[0255] H 2 O = Water

[0256] IPA = Isopropyl Alcohol

[0257] LCMS = Liquid chromatography mass spectrometry

[0258] HFIP = Hexafluoro-2-propanol

[0259] HPLC = High Pressure Liquid Chromatography

[0260] THF = Tetrahydrofuran

[0261] MeCN = ACN = Acetonitrile

[0262] MgSO 4 =Magnesium sulfate

[0263] DMSO = dimethyl sulfoxide

[0264] AcOH = acetic acid

[0265] TFA = trifluoroacetic acid

[0266] DIPEA = diisopropylethylamine

[0267] N 2 =Nitrogen

[0268] NH 4 HCO 3 =Ammonium bicarbonate

[0269] t-BuOH = tert-butyl alcohol

[0270] NH 4 Cl = Ammonium chloride

[0271] NaH = Sodium hydride

[0272] Na2 SO 4 =Sodium sulfate

[0273] K 2 CO 3 =Potassium carbonate

[0274] NaHCO 3 =Sodium bicarbonate

[0275] NaBH(OAc) 3 = STAB = Sodium triacetoxyborohydride

[0276] SiO 2 =Silicon dioxide or silicon oxide

[0277] PDA = Photo Diode Array Detection

[0278] TosMIC = Tosylmethyl isocyanide

[0279] TLC = Thin Layer Chromatography

[0280] LiHMDS = Lithium Bis(trimethylsilyl)amide

[0281] General Methods

[0282] QC analysis LC / MS method conditions:

[0283] Ammonium Hydroxide (Alkaline pH) Conditions

[0284] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0285] PDA: 200-400 nm scanning range

[0286] Column: Waters ACQUITY UPLC BEH C18 2.1x50 mm, 1.7 μm; Part No. 186002350

[0287] Modifier: ammonium hydroxide concentration 0.2% (v / v).

[0288] Method: 95% water / 5% MeCN (initial conditions), linear gradient to 5% water / 95% MeCN at 3.75 min,

[0289] Maintain 5% water / 95% MeCN for 4 min. Flow rate 0.8 mL / min.

[0290] Trifluoroacetic acid (acidic pH) conditions

[0291] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0292] PDA: 200-400 nm scanning range

[0293] Column: Waters ACQUITY UPLC BEH C18 2.1x50 mm, 1.7 μm; Part No. 186002350

[0294] Modifier: trifluoroacetic acid concentration 0.1% (v / v).

[0295] Method: 95% water / 5% MeCN (initial conditions), linear gradient to 5% water / 95% MeCN at 3.75 min,

[0296] Maintain 5% water / 95% MeCN for 4 min. Flow rate 0.8 mL / min.

[0297] General preparative HPLC conditions:

[0298] Ammonium Hydroxide (Alkaline pH) Conditions

[0299] Flow rate: 30 mL / min

[0300] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0301] PDA: 200-400 nm scanning range

[0302] Column: Waters XSELECT CSH C18 PREP 19x100 mm, 5 μm; Part No. 186005421

[0303] Modifier: 0.2% ammonium hydroxide concentration (v / v).

[0304] Method: A% water / B% MeCN (initial conditions), linear gradient to A% water / B% MeCN at 8 min, increase to 5% water / 95% MeCN at 8.5 min, maintain 5% water / 95% MeCN until 10 min.

[0305] Flow rate: 50 mL / min

[0306] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0307] PDA: 200-400 nm scanning range

[0308] Column: Waters XSELECT CSH C18 PREP 30x100 mm, 5 μm; Part No. 186005425

[0309] Modifier: 0.2% NH 4 OH concentration (v / v).

[0310] Method: A% water / B% MeCN (initial conditions), linear gradient to A% water / B% MeCN at 8 min, increase to 5% water / 95% MeCN at 8.5 min, maintain 5% water / 95% MeCN until 10 min.

[0311] Flow rate, 60 mL / min

[0312] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0313] PDA: 200-400 nm scanning range

[0314] Column: Waters XSELECT CSH C18 PREP 30x50 mm, 5 μm; Part No. 186005423

[0315] Modifier: 0.2% NH 4 OH concentration (v / v).

[0316] Method: A% water / B% MeCN (initial conditions), linear gradient to A% water / B% MeCN at 8 min, increase to 5% water / 95% MeCN at 8.5 min, maintain 5% water / 95% MeCN until 10 min.

[0317] Trifluoroacetic acid (acidic pH) conditions

[0318] Flow rate, 30 mL / min

[0319] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0320] PDA: 200-400 nm scanning range

[0321] Column: Waters Sunfire OBD C18 PREP 19x100 mm, 5 μm; Part No. 186002567

[0322] Modifier: 0.1% trifluoroacetic acid concentration (v / v).

[0323] Method: A% water / B% MeCN (initial conditions), linear gradient to A% water / B% MeCN at 8 min, increase to 5% water / 95% MeCN at 8.5 min, maintain 5% water / 95% MeCN until 10 min.

[0324] Flow rate, 50 mL / min

[0325] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0326] PDA: 200-400 nm scanning range

[0327] Column: Waters Sunfire OBD C18 PREP 30x100 mm, 5 μm; Part No. 186002572

[0328] Modifier: 0.1% trifluoroacetic acid concentration (v / v).

[0329] Method: A% water / B% MeCN (initial conditions), linear gradient to A% water / B% MeCN at 8 min, increase to 5% water / 95% MeCN at 8.5 min, maintain 5% water / 95% MeCN until 10 min.

[0330] Flow rate, 60 mL / min

[0331] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0332] PDA: 200-400 nm scanning range

[0333] Column: Waters Sunfire OBD C18 PREP 30x50 mm, 5 μm; Part No. 186002570

[0334] Modifier: 0.1% trifluoroacetic acid concentration (v / v).

[0335] Method: A% water / B% MeCN (initial conditions), linear gradient to A% water / B% MeCN at 8 min, increase to 5% water / 95% MeCN at 8.5 min, maintain 5% water / 95% MeCN until 10 min.

[0336] Experimental Procedure

[0337] Example 1: (3aR, 5r, 6aS)-2-((2,4-dimethylphenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0338]

[0339] 1. Synthesis of tert-butyl (3aR,5r,6aS)-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0340]

[0341] To a mixture of (3aR,5r,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (213 mg, 0.9 mmol) and tetrahydro-2H-pyran-4-carbaldehyde (102 mg, 0.9 mmol) in DCM (5 mL) was added DIPEA (424 μL, 2.4 mmol). After stirring for 15 min, acetic acid (139 μL, 2.4 mmol) was added. After stirring for 15 min, sodium triacetoxyborohydride (687 mg, 3.2 mmol) was added and the reaction was stirred at rt for 1 day. Saturated NaHCO was carefully added. 3 The solution was added and saturated sodium chloride solution and the mixture was extracted with EtOAc. The solvent was evaporated to dryness and the residue was purified by SCX (2N NH 3 elution) to give (3aR,5r,6aS)-tert-butyl 5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (239 mg, 78%) without further purification. LCMS m / z =325.2 [M+H] + .

[0342] 2. Synthesis of tert-butyl (3aR,5r,6aS)-5-(((benzyloxy)carbonyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0343]

[0344] To a solution of tert-butyl (3aR,5r,6aS)-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (120 mg, 0.4 mmol) in DCM (2.5 mL) was added DIPEA (225 μL, 1.3 mmol) followed by a 3 M toluene solution of benzyl chloroformate (184 μL, 0.6 mmol). After stirring at rt for 4 h, the mixture was heated to 40 ℃ by careful addition of saturated NaHCO 3 The solution quenched the reaction. The mixture was extracted with DCM and the organic matter was evaporated. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to obtain (3aR, 5r, 6aS)-5-(((benzyloxy)carbonyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl carboxylate (119 mg, 70%). LCMS m / z = 481.3 [M+Na]+ .

[0345] 3. Synthesis of ((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[0346]

[0347] To a solution of tert-butyl (3aR,5r,6aS)-5-(((benzyloxy)carbonyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (119 mg, 0.3 mmol) in EtOAc (2 mL) was added HCl (298 μL, 1.2 mmol) in 4 M dioxane. After stirring at rt for 1 day, the reaction was evaporated to dryness to give benzyl ((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (122 mg, 119%) as the HCl salt which was used without further purification. LCMS m / z = 359.2 [M+H] + .

[0348] 4. Synthesis of benzyl ((3aR,5r,6aS)-2-((2,4-dimethylphenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[0349]

[0350] To a mixture of benzyl ((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (51 mg, 0.1 mmol) as HCl salt in THF (1.5 mL) was added DIPEA (113 μL, 0.6 mmol) followed by DMAP (16 mg, 0.1 mmol) and then 2,4-dimethylbenzenesulfonyl chloride (40 mg, 0.2 mmol). After stirring at rt for 2.5 h, the reaction was quenched by careful addition of saturated ammonium chloride solution. The mixture was extracted with EtOAc and the solvent was evaporated. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to give benzyl ((3aR,5r,6aS)-2-((2,4-dimethylphenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (49 mg, 71%). LCMS m / z = 527.2 [M+H] + .

[0351] 5. Synthesis of (3aR,5r,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0352]

[0353] To a solution of benzyl ((3aR,5r,6aS)-2-((2,4-dimethylphenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (49 mg, 0.1 mmol) in MeOH (5 mL) was added 10% palladium on carbon (10 mg, 0.01 mmol). The reaction vessel was evacuated and refilled with H 2 (three times), then in H 2 The mixture was hydrogenated under balloon pressure for 1 day. The reaction was filtered through Celite® and evaporated. The residue was purified by preparative HPLC (Waters Sunfire Preparative C18 5 μm OBD 30x100mm; Method: (A) 95% {H 2 O} / / (B) 5% {MeCN} with 0.1% TFA (initial condition held for 0.5 min) then a linear gradient to 40% (A) / 60% (B) over 7.5 min (flow rate: 50 mL / min)) to afford (3aR,5r,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (20 mg, 43%) as a white solid (TFA salt). LCMS m / z = 393.3 [M+H] + .t R =1.45 min (TFA). t R = 2.04 min (NH 4 OH).

[0354] Example 2: (3aR, 5r, 6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0355]

[0356] 1. Synthesis of benzyl ((3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[0357]

[0358] To a mixture of benzyl ((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (51 mg, 0.1 mmol) (Example 1, Step 3) as HCl salt in THF (1.5 mL) was added DIPEA (113 μL, 0.6 mmol) followed by DMAP (16 mg, 0.1 mmol) and then 4-(difluoromethoxy)benzenesulfonyl chloride (31 μL, 0.2 mmol). After stirring at rt for 3.5 h, the reaction was quenched by careful addition of saturated ammonium chloride solution. The mixture was extracted with EtOAc and the solvent was evaporated. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to give benzyl ((3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (50 mg, 69%). LCMS m / z = 565.3 [M+H] + .

[0359] 2. Synthesis of (3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0360]

[0361] (3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (33 mg, 69%) was obtained as a clear oil as its TFA salt from benzyl ((3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate following the procedure described in Example 1, Step 5. LCMS m / z = 431.2 [M+H] + . t R =1.38 min (TFA). t R = 1.88 min (NH 4 OH).

[0362] Example 3: (3aR, 5s, 6aS)-2-((2,4-dimethylphenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole

[0363]

[0364] 1. Synthesis of tert-butyl (3aR,5s,6aS)-5-(4-methylpiperidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0365]

[0366] To a mixture of tert-butyl (3aR,5s,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (350 mg, 1.3 mmol) as HCl salt and 1,5-dibromo-3-methylpentane (502 mg, 2.1 mmol) in MeCN (6 mL) was added K 2 CO 3 (638 mg, 4.6 mmol). The reaction was heated at 90 °C for 19 h, then cooled and filtered. The mixture was evaporated to dryness and purified by SCX (2N NH in MeOH). 3 elution) to give (3aR,5s,6aS)-tert-butyl 5-(4-methylpiperidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (352 mg, 86%). LCMS m / z = 309.1 [M+H] + .

[0367] 2. Synthesis of (3aR,5s,6aS)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole

[0368]

[0369] To a solution of tert-butyl (3aR,5s,6aS)-5-(4-methylpiperidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (117 mg, 0.4 mmol) in DCM (2 mL) was added TFA (2 mL, 26 mmol). The reaction was stirred at rt for 2 h and then evaporated to dryness. The residue was purified by SCX (2N NH 3 elution) to give (3aR,5s,6aS)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole (75 mg, 95%). LCMS m / z = 209.2 [M+H] + .

[0370] 3. Synthesis of (3aR,5s,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole

[0371]

[0372] To a solution of (3aR,5s,6aS)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole (38 mg, 0.2 mmol) in THF (2 mL) was added DIPEA (160 μL, 0.9 mmol) and DMAP (2 mg, 0.02 mmol), followed by 2,4-dimethylbenzenesulfonyl chloride (56 mg, 0.3 mmol). After stirring at rt for 1 day, the mixture was quenched by slowly adding saturated NaHCO 3 The reaction was quenched with the solution. The mixture was extracted with EtOAc and the solvent was evaporated. The residue was purified by preparative HPLC (Waters Sunfire preparative C18 5 μm OBD 30x100mm; method: (A) 95% {H 2 O} / / (B) 5% {MeCN} with 0.1% TFA (initial condition held for 0.5 min) then a linear gradient to 35% (A) / 65% (B) over 7.5 min (flow rate: 50 mL / min)) to afford (3aR,5s,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole (59 mg, 66%) as a clear oil (TFA salt). LCMS m / z = 377.2 [M+H] + . t R =1.59 min (TFA). t R = 2.50 min (NH 4 OH).

[0373] Example 4: (3aR, 5s, 6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole

[0374]

[0375] 1. Synthesis of (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole

[0376]

[0377] (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole (47 mg, 49%) was obtained as a TFA salt from (3aR,5s,6aS)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole (Example 3, Step 2) and 4-(difluoromethoxy)benzenesulfonyl chloride following the procedure described in Example 3, Step 3. LCMS m / z = 415.2 [M+H] + . t R = 1.52 min (TFA). t R = 2.27 min (NH 4 OH).

[0378] Example 5: (3aR, 5r, 6aS)-2-((2,4-dimethylphenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole

[0379]

[0380] 1. Synthesis of tert-butyl (3aR,5r,6aS)-5-(4-methylpiperidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0381]

[0382] To a mixture of tert-butyl (3aR,5r,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (290 mg, 1.3 mmol) and 1,5-dibromo-3-methylpentane (483 mg, 2.0 mmol) in MeCN (6 mL) was added K 2 CO 3 (614 mg, 4.4 mmol). The reaction was heated at 90 °C for 19 h, then cooled and filtered. The mixture was evaporated to dryness and purified by SCX (2N NH in MeOH). 3 elution) to give (3aR,5r,6aS)-tert-butyl 5-(4-methylpiperidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (305 mg, 77%). LCMS m / z = 309.1 [M+H] + .

[0383] 2. Synthesis of (3aR,5r,6aS)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole

[0384]

[0385] To a solution of (3aR, 5r, 6aS)-5-(4-methylpiperidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (152 mg, 0.5 mmol) in EtOAc (3 mL) was added 4 M dioxane solution of HCl (568 μL, 2.3 mmol). The reaction was stirred at rt for 5 h and ultrasonicated frequently to reduce agglomeration. Additional HCl (568 μL, 2.3 mmol) in 4 M dioxane solution was added and the reaction was stirred for another day. The reaction was evaporated to dryness to give crude (3aR, 5r, 6aS)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole (154 mg, 111%), assumed to be the bis-HCl salt. LCMS m / z =209.2 [M+H] + .

[0386] 3. Synthesis of (3aR,5r,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole

[0387]

[0388] To a mixture of (3aR,5r,6aS)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole (69 mg, 0.2 mmol) as bis-HCl salt in THF (2 mL) was added DIPEA (258 μL, 1.5 mmol) and DMAP (3 mg, 0.02 mmol) followed by 2,4-dimethylbenzenesulfonyl chloride (76 mg, 0.4 mmol). Additional DIPEA (258 μL, 1.5 mmol) was added to improve stirring. After stirring at rt for 2.5 h, the mixture was stirred for 2 hours by slowly adding saturated NaHCO 3 The reaction was quenched with the solution. The mixture was extracted with EtOAc and the solvent was evaporated. The residue was purified by preparative HPLC (Waters Sunfire preparative C18 5 μm OBD 30x100mm; method: (A) 95% {H 2 O} / / (B) 5% {MeCN} with 0.1% TFA (initial condition held for 0.5 min) then a linear gradient to 40% (A) / 60% (B) over 7.5 min (flow rate: 50 mL / min)) to afford (3aR,5r,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole (47 mg, 39%) as a brown oil (TFA salt). LCMS m / z = 377.4 [M+H] + . tR = 1.67 min (TFA). t R =2.81 min (NH 4 OH).

[0389] Example 6: (3aR, 5r, 6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole

[0390]

[0391] 1. Synthesis of (3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole

[0392]

[0393] A procedure similar to that described in Example 5, Step 3 was followed, except that the HPLC gradient used was from 95% {H 2 O} / 5% {MeCN} containing 0.1% TFA to 45% {H 2 (3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole (71 mg, 54%) was obtained as a white solid with TFA salt from (3aR,5r,6aS)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole bis-HCl salt (Example 5, Step 2) and 4-(difluoromethoxy)benzenesulfonyl chloride in a 5% HCl / 55% {MeCN} solution containing 0.1% TFA. LCMS m / z = 415.3 [M+H] + . t R = 1.63min (TFA). R = 2.58 min (NH 4 OH).

[0394] Example 7: (3aR, 5s, 6aS)-2-((2,4-dimethylphenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0395]

[0396] 1. Synthesis of tert-butyl (3aR,5s,6aS)-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0397]

[0398] To a mixture of (3aR,5s,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (300 mg, 1.1 mmol) and tetrahydro-2H-pyran-4-carbaldehyde (143 mg, 1.3 mmol) in DCM (6 mL) was added DIPEA (514 μL, 2.9 mmol). After stirring for 15 min, acetic acid (169 μL, 2.9 mmol) was added. After stirring for 15 min, sodium triacetoxyborohydride (968 mg, 4.6 mmol) was added and the reaction was stirred at rt for 1 day. Saturated NaHCO was carefully added. 3 The solution was added and saturated sodium chloride solution and the mixture was extracted with EtOAc. The solvent was evaporated to dryness and the residue was purified by SCX (2N NH 3 elution) to give (3aR,5s,6aS)-tert-butyl 5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (359 mg, 97%) without further purification. LCMS m / z = 325.2 [M+H] + .

[0399] 2. Synthesis of tert-butyl (3aR,5s,6aS)-5-(((benzyloxy)carbonyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0400]

[0401] Following the procedure described in Example 1, Step 2, (3aR,5s,6aS)-tert-butyl 5-(((benzyloxy)carbonyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (212 mg, 83%) was obtained from tert-butyl (3aR,5s,6aS)-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and benzyl chloroformate. LCMS m / z = 481.3 [M+Na] + .

[0402] 3. Synthesis of ((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[0403]

[0404] Following the procedure described in Example 1, Step 3, benzyl ((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate was obtained as the HCl salt from tert-butyl (3aR,5s,6aS)-5-(((benzyloxy)carbonyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. LCMS m / z = 359.2 [M+H] + .

[0405] 4. Synthesis of benzyl ((3aR,5s,6aS)-2-((2,4-dimethylphenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[0406]

[0407] Following the procedure described in Example 1, Step 4, benzyl ((3aR,5s,6aS)-2-((2,4-dimethylphenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (45 mg, 73%) was obtained from benzyl ((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate and 2,4-dimethylbenzenesulfonyl chloride. LCMS m / z = 527.2 [M+H] + .

[0408] 5. Synthesis of (3aR,5s,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0409]

[0410] To a solution of benzyl ((3aR,5s,6aS)-2-((2,4-dimethylphenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (45 mg, 0.08 mmol) in MeOH (5 mL) was added 10% palladium on carbon (9 mg, 0.008 mmol). The reaction vessel was evacuated and refilled with H 2 (three times), then in H 2 Hydrogenated under balloon pressure for 4 h. The reaction was filtered through Celite® and evaporated. The residue was purified by preparative HPLC (Waters XSelect CSH Preparative C18 5 μm OBD 30x100mm; Method: (A) 95% {H2 O} / / (B) 5% {MeCN} containing 0.2% NH 4 OH (initial condition held for 0.5 min) and then a linear gradient to 25% (A) / 75% (B) over 7.5 min (flow rate: 50 mL / min)) to afford (3aR,5s,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (16 mg, 47%) as an orange oil. LCMS m / z = 393.3 [M+H] + .t R = 1.43 min (TFA). t R = 1.99 min (NH 4 OH).

[0411] Example 8: (3aR, 5s, 6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0412]

[0413] 1. Synthesis of benzyl ((3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[0414]

[0415] Benzyl ((3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (46 mg, 71%) was obtained from benzyl ((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate as the HCl salt (Example 7, Step 3) and 4-(difluoromethoxy)benzenesulfonyl chloride following the procedure described in Example 1, Step 4. LCMS m / z = 565.3 [M+H] + .

[0416] 2. Synthesis of (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0417]

[0418] A procedure similar to that described in Example 7, Step 5 was followed, except that the HPLC gradient used was from 95% {H 2 O} / 5% {MeCN} containing 0.2% NH 4 OH to 30% {H 2 O} / 70% {MeCN} containing 0.2% NH 4 OH, (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (16 mg, 46%) was obtained as an orange solid from benzyl ((3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate. LCMS m / z =431.2 [M+H] + . t R = 1.37 min (TFA). t R = 1.83 min (NH 4 OH).

[0419] Example 9: (3aR, 5s, 6aS)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0420]

[0421] 1. Synthesis of benzyl ((3aR,5s,6aS)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[0422]

[0423] To a mixture of benzyl ((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (40 mg, 0.1 mmol) (Example 7, Step 3) in THF as HCl salt was added DIPEA (79 uL, 0.5 mmol), followed by DMAP (1 mg, 0.01 mmol) and then 2-methoxy-5-methylpyridine-3-sulfonyl chloride (33 mg, 0.2 mmol). After stirring at rt for 1 day, the mixture was heated to 40 ℃ and then dried over medium to obtain a 5% ethanol. The mixture was stirred for 1 day at rt and the mixture was heated to 40 ℃ and then dried over medium to obtain a 5% ethanol. 3The reaction was quenched with 4-nitropropene solution. The mixture was extracted with EtOAc and the solvent was evaporated to give crude benzyl ((3aR,5s,6aS)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate. LCMS m / z =544.3 [M+H] + .

[0424] 2. Synthesis of (3aR,5s,6aS)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0425]

[0426] A procedure similar to that described in Example 7, Step 5 was followed, except that the HPLC gradient used was from 95% {H 2 O} / 5% {MeCN} containing 0.2% NH 4 OH to 35% {H 2 O} / 65% {MeCN} containing 0.2% NH 4 OH, (3aR,5s,6aS)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (17 mg, 40%) was obtained as an orange oil from benzyl ((3aR,5s,6aS)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate. LCMS m / z = 410.4 [M+H] + . t R = 1.24 min (TFA). t R = 1.75 min (NH 4 OH).

[0427] Example 10: (3aR, 5s, 6aS)-2-((4,6-dimethylpyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0428]

[0429] 1. Synthesis of benzyl ((3aR,5s,6aS)-2-((4,6-dimethylpyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[0430]

[0431] Benzyl ((3aR,5s,6aS)-2-((4,6-dimethylpyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate was obtained from benzyl ((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate as the HCl salt (Example 7, Step 3) and 4,6-dimethylpyridine-3-sulfonyl chloride following the procedure described in Example 9, Step 1. LCMS m / z = 528.3 [M+H] + .

[0432] 2. Synthesis of (3aR,5s,6aS)-2-((4,6-dimethylpyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0433]

[0434] To a solution of benzyl ((3aR,5s,6aS)-2-((4,6-dimethylpyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate in MeOH (3 mL) was added 10% palladium on carbon (11 mg, 0.01 mmol). The reaction vessel was evacuated and refilled with H 2 (three times), then in H 2 The mixture was hydrogenated under balloon pressure for 2.5 h. The reaction was filtered through Celite® and evaporated. The residue was purified by preparative HPLC (Waters SunFire Preparative C18 5 μm OBD 30x100 mm; Method: (A) 95% {H 2 O} / / (B) 5% {MeCN} with 0.1% TFA (initial condition held for 0.5 min) then a linear gradient to 60% (A) / 40% (B) over 7.5 min (flow rate: 50 mL / min)) to afford (3aR,5s,6aS)-2-((4,6-dimethylpyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (45 mg, 88%) as a clear oil (TFA salt). LCMS m / z = 394.4 [M+H] + .t R =0.94 min (TFA). t R= 1.62 min (NH 4 OH).

[0435] Example 11: (3aR, 5s, 6aS)-2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0436]

[0437] 1. Synthesis of benzyl ((3aR,5s,6aS)-2-((4,6-dimethylpyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[0438]

[0439] Crude benzyl ((3aR,5s,6aS)-2-((4,6-dimethylpyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate was obtained from benzyl ((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate as the HCl salt (Example 7, Step 3) and 1,3-dimethyl-1H-pyrazole-5-sulfonyl chloride. LCMS m / z = 517.2 [M+H] + .

[0440] 2. Synthesis of (3aR,5s,6aS)-2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0441]

[0442] To a solution of benzyl ((3aR,5s,6aS)-2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate in MeOH (3 mL) was added 10% palladium on carbon (11 mg, 0.01 mmol). The reaction vessel was evacuated and refilled with H 2 (three times), then in H 2 Hydrogenated under balloon pressure for 2.5 h. Additional 10% palladium on carbon (11 mg, 0.01 mmol) was added, and the reaction vessel was evacuated and refilled with H 2 (three times), then in H 2The mixture was hydrogenated for another 2 h under balloon pressure. The reaction was filtered through Celite® and evaporated. The residue was purified by preparative HPLC (Waters SunFire Preparative C18 5 μm OBD 30x100mm; Method: (A) 95% {H 2 O} / / (B) 5% {MeCN} with 0.1% TFA (initial condition held for 0.5 min) then a linear gradient to 50% (A) / 50% (B) over 7.5 min (flow rate: 50 mL / min)) to afford (3aR,5s,6aS)-2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (20 mg, 40%) as a clear oil (TFA salt). LCMS m / z = 383.3 [M+H] + .t R = 1.13 min (TFA). t R = 1.63 min (NH 4 OH).

[0443] Example 12: (3aR, 5s, 6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0444]

[0445] 1. Synthesis of benzyl ((3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[0446]

[0447] Crude benzyl ((3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate was obtained from benzyl ((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate as HCl salt (Example 7, Step 3) and 3-cyclopropyl-1-methyl-1H-pyrazole-5-sulfonyl chloride. LCMS m / z = 543.3 [M+H] + .

[0448] 2. Synthesis of (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0449]

[0450] To a solution of benzyl ((3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate in MeOH (3 mL) was added 10% palladium on carbon (11 mg, 0.01 mmol). The reaction vessel was evacuated and refilled with H 2 (three times), then in H 2 Hydrogenated under balloon pressure for 2.5 h. Additional 10% palladium on carbon (11 mg, 0.01 mmol) was added, and the reaction vessel was evacuated and refilled with H 2 (three times), then in H 2 The mixture was hydrogenated for another 2 h under balloon pressure. The reaction was filtered through Celite® and evaporated. The residue was purified by preparative HPLC (Waters XSelect CSH Preparative C18 5 μm OBD 30x100mm; Method: (A) 95% {H 2 O} / / (B) 5%{MeCN} containing 0.2% NH 4 OH (initial condition held for 0.5 min) and then a linear gradient to 30% (A) / 70% (B) over 7.5 min (flow rate: 50 mL / min)) to afford (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (13 mg, 31%) as a light brown solid. LCMS m / z = 409.4 [M+H] + . t R = 1.33 min (TFA). t R = 1.84 min(NH 4 OH).

[0451] Example 13: 4-((3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)morpholine

[0452]

[0453] 1. Synthesis of tert-butyl (3aR,5s,6aS)-5-(((benzyloxy)carbonyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0454]

[0455] To a solution of tert-butyl (3aR,5s,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (400 mg, 1.8 mmol) in DCM (10 mL) was added DIPEA (1.1 mL, 6.2 mmol) followed by a 3 M toluene solution of benzyl chloroformate (884 μL, 2.7 mmol). After stirring at rt for 30 min, the mixture was stirred for 3 hours by carefully adding saturated NaHCO 3 The solution quenched the reaction. The mixture was extracted with DCM, dried over magnesium sulfate and filtered. The organics were evaporated and the residue was chromatographed on silica gel (0-100% 3:1 EtOAc / containing 2% NH 4 OH in EtOH in heptane) to give tert-butyl (3aR,5s,6aS)-5-(((benzyloxy)carbonyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (529 mg, 83%). LCMS m / z = 383.2 [M+Na] + .

[0456] 2. Synthesis of ((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)carbamic acid benzyl ester

[0457]

[0458] To a solution of tert-butyl (3aR,5s,6aS)-5-(((benzyloxy)carbonyl)amino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (200 mg, 0.6 mmol) in DCM (4 mL) was added HCl (1.4 mL, 5.6 mmol) in 4 M dioxane. After stirring at rt for 1 h, the reaction was evaporated to dryness to give benzyl ((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)carbamate as the HCl salt which was used without further purification. LCMS m / z = 261.1 [M+H] + .

[0459] 3. Synthesis of benzyl ((3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[0460]

[0461] To a mixture of benzyl ((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)carbamate as HCl salt in THF (4 mL) was added DIPEA (483 μL, 2.8 mmol), followed by DMAP (7 mg, 0.06 mmol) and then 4-(difluoromethoxy)benzenesulfonyl chloride (133 μL, 0.8 mmol). After stirring at rt for 1.25 h, the mixture was stirred for 1 h by careful addition of saturated NaHCO 3 The solution was quenched. The mixture was extracted with EtOAc, washed with saturated sodium chloride, dried over sodium sulfate and filtered. The solvent was evaporated and the residue was purified by silica gel chromatography (0-100% 3:1 EtOAc / containing 2% NH 4 OH in EtOH in heptane) to give benzyl ((3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate (230 mg, 89%). LCMS m / z = 467.1 [M+H] + .

[0462] 4. Synthesis of (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine

[0463]

[0464] To a mixture of benzyl ((3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate (230 mg, 0.5 mmol) in EtOAc (1 mL) was added 10% palladium on carbon (52 mg, 0.05 mmol). The reaction vessel was evacuated and refilled with H 2 (three times), then in H 2 The mixture was hydrogenated under balloon pressure for 1 day. The reaction was filtered through Celite® and evaporated. The residue was dissolved in MeOH (10 mL) and 10% palladium on carbon (52 mg, 0.05 mmol) was added thereto. The reaction vessel was evacuated and refilled with H 2 (three times), then in H 2 Hydrogenate under balloon pressure for 2 h. The reaction was filtered through Celite® and evaporated to give crude (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (164 mg, assumed 100%). LCMS m / z = 333.1 [M+H] + .

[0465] 5. Synthesis of 4-((3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)morpholine

[0466]

[0467] To a mixture of (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (41 mg, 0.1 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (23 μL, 0.2 mmol) in MeCN (1.5 mL) was added K 2 CO 3 (60 mg, 0.4 mmol). The reaction was heated at 90 °C for 1 day, then cooled and filtered. The residue was purified by preparative HPLC (Waters XSelect CSH Prep C18 5 μm OBD 30x100mm; Method: (A) 95% {H 2 O} / / (B) 5% {MeCN} containing 0.2% NH 4 OH (initial condition held for 0.5 min) and then a linear gradient to 35% (A) / 65% (B) over 7.5 min (flow rate: 50 mL / min)) to afford 4-((3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)morpholine (30 mg, 61%) as a white solid. LCMS m / z =403.2 [M+H] + . t R = 1.29 min (TFA). t R = 1.66 min (NH 4 OH).

[0468] Example 14: (3aR, 5s, 6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0469]

[0470] 1. Synthesis of (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0471]

[0472] To a stirred mixture of (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (41 mg, 0.1 mmol) (Example 13, Step 4) and oxetan-3-one (10 μL, 0.2 mmol) in DCM (2 mL) was added DIPEA (43 μL, 0.2 mmol). After 15 min, acetic acid (21 μL, 0.4 mmol) was added with stirring. After another 15 min, sodium triacetoxyborohydride (104 mg, 0.5 mmol) was added with stirring. The reaction was stirred at rt for 1 day and then quenched by slow addition of saturated NaHCO 3 The solution was quenched. The mixture was extracted with EtOAc and the solvent was evaporated. The residue was purified by preparative HPLC (Waters XSelect CSH Preparative C18 5 μm OBD 30x100mm; Method: (A) 95% {H 2 O} / / (B) 5% {MeCN} containing 0.2% NH 4 OH (initial condition held for 0.5 min) and then a linear gradient to 40% (A) / 60% (B) over 7.5 min (flow rate: 50 mL / min)) to afford (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-yl)octahydrocyclopenta[c]pyrrol-5-amine (19 mg, 40%) as a white solid. LCMS m / z = 389.2 [M+H] + . t R = 1.26 min (TFA). t R = 1.53 min (NH 4 OH).

[0473] Example 15: (3aR, 5s, 6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydrofuran-3-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0474]

[0475] 1. Synthesis of (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydrofuran-3-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0476]

[0477] A procedure similar to that described in Example 14 was followed, except that the HPLC gradient used was from 95% {H2 O} / 5% {MeCN} containing 0.2% NH 4 OH to 35% {H 2 O} / 65% {MeCN} containing 0.2% NH 4 OH, (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydrofuran-3-yl)octahydrocyclopenta[c]pyrrol-5-amine (23 mg, 47%) was obtained as a white solid from (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (Example 13, Step 4) and dihydrofuran-3(2H)-one. LCMS m / z = 403.2 [M+H] + . t R =1.29 min (TFA). t R = 1.62 min (NH 4 OH).

[0478] Example 16: (3aR, 5s, 6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0479]

[0480] 1. Synthesis of (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0481]

[0482] Following the procedure described in Example 15, (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine (23 mg, 45%) was obtained as a white solid from (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (Example 13, Step 4) and tetrahydro-4H-pyran-4-one. LCMS m / z = 417.2 [M+H] + .t R = 1.33 min (TFA). t R = 1.69 min(NH 4 OH).

[0483] Example 17: (3aR, 5s, 6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0484]

[0485] 1. Synthesis of tert-butyl (3aR,5s,6aS)-5-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0486]

[0487] To a solution of tert-butyl (3aR,5s,6aS)-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (78 mg, 0.2 mmol) (Example 7, Step 1) in DMF (2 mL) was added 60% NaH (19 mg, 0.5 mmol) followed by iodomethane (16 μL, 0.3 mmol). The reaction was stirred at rt for 2 h and then quenched by the addition of saturated NaHCO 3 The solution was quenched. The mixture was extracted with EtOAc, dried over sodium sulfate, filtered and evaporated. The residue was purified by SCX (2N NH 3 eluted) to give crude (3aR,5s,6aS)-tert-butyl 5-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (73 mg, 91%). LCMS m / z =339.2 [M+H] + .

[0488] 2. Synthesis of (3aR,5s,6aS)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0489]

[0490] To a solution of tert-butyl (3aR,5s,6aS)-5-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (73 mg, crude) in DCM (2 mL) was added HCl (543 μL, 2.2 mmol) in 4 M dioxane. The reaction was stirred at rt for 1 day. The reaction was evaporated to dryness to give crude (3aR,5s,6aS)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine, assumed as the bis-HCl salt. LCMS m / z = 239.2 [M+H] + .

[0491] 3. Synthesis of (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0492]

[0493] To a mixture of (3aR,5s,6aS)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (assumed 34 mg, 0.1 mmol) as bis-HCl salt in THF (1 mL) was added DIPEA (110 μL, 0.6 mmol) followed by DMAP (1 mg, 0.01 mmol) and then 4-(difluoromethoxy)benzenesulfonyl chloride (40 μL, 0.3 mmol). The reaction was stirred at rt for 3.5 h and then quenched by careful addition of saturated NaHCO 3 The reaction was quenched with the solution. The mixture was extracted with EtOAc. The solvent was evaporated and the residue was purified by preparative HPLC (Waters XSelect CSH Preparative C18 5 μm OBD 30x100mm; Method: (A) 95% {H 2 O} / / (B) 5% {MeCN} containing 0.2% NH 4 OH (initial condition held for 0.5 min) and then a linear gradient to 25% (A) / 75% (B) over 7.5 min (flow rate: 50 mL / min)) to afford (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (14 mg, 28%) as a white solid. LCMS m / z = 445.3 [M+H] + .t R=1.45 min (TFA). t R = 2.18 min (NH 4 OH).

[0494] Example 18: (3aR, 5s, 6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0495]

[0496] 1. Synthesis of (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0497]

[0498] To a mixture of (3aR,5s,6aS)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (assumed 34 mg, 0.1 mmol) (Example 17, Step 2) as a bis-HCl salt in THF (1 mL) was added DIPEA (110 μL, 0.6 mmol) followed by DMAP (1 mg, 0.01 mmol) and then 3-cyclopropyl-1-methyl-1H-pyrazole-5-sulfonyl chloride (55 mg, 0.3 mmol). The reaction was stirred at rt for 3.5 h and then quenched by careful addition of saturated NaHCO 3 The solution was quenched. The mixture was extracted with EtOAc. The solvent was evaporated and the residue was purified by preparative HPLC (Waters XSelect CSH Preparative C18 5 μm OBD 30x100mm; Method: (A) 95% {H 2 O} / / (B) 5% {MeCN} containing 0.2% NH 4 The mixture was purified by HPLC-MS / MS with 5% (4% (A) / 70% (B) (flow rate: 50 mL / min) (initial condition was maintained for 0.5 min) and then a linear gradient to 30% (A) / 70% (B) over 7.5 min (flow rate: 50 mL / min) to afford (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (12 mg, 23%) as a white solid. LCMS m / z = 423.4 [M+H] + . t R= 1.37 min (TFA). t R = 2.13 min (NH 4 OH).

[0499] Example 19: (3aR, 5s, 6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0500]

[0501] 1. Synthesis of (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0502]

[0503] Following the procedure described in Example 15, (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine (17 mg, 45%) was obtained as a yellow oil from (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (Example 13, Step 4) and 2-oxaspiro[3.3]heptan-6-one. LCMS m / z = 429.2 [M+H] + . t R = 1.40 min (TFA). t R =1.83 min (NH 4 OH).

[0504] Example 20: (3aR, 5s, 6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0505]

[0506] 1. Synthesis of benzyl ((3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate

[0507]

[0508] Benzyl ((3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate (141 mg, 89%) was obtained from benzyl ((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)carbamate as the HCl salt (Example 13, Step 2) and 3-cyclopropyl-1-methyl-1H-pyrazole-5-sulfonyl chloride following the procedure described in Example 13, Step 3. LCMS m / z = 445.2 [M+H] + .

[0509] 2. Synthesis of (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine

[0510]

[0511] To a mixture of benzyl ((3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate (141 mg, 0.3 mmol) in EtOAc (10 mL) was added 10% palladium on carbon (34 mg, 0.03 mmol). The reaction vessel was evacuated and refilled with H 2 (three times), then in H 2 Hydrogenated under balloon pressure for 1 day. The reaction was filtered through Celite® and evaporated to give crude (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (88 mg, 90%). LCMS m / z = 311.1 [M+H] + .

[0512] 3. Synthesis of (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0513]

[0514] To a mixture of (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (22 mg, 0.07 mmol) and 2-oxaspiro[3.3]heptan-6-one (9 mg, 0.08 mmol) in DCM (1 mL) was added DIPEA (32 μL, 0.2 mmol) with stirring. After 15 min, acetic acid (10 μL, 0.2 mmol) was added with stirring. After another 15 min, sodium triacetoxyborohydride (60 mg, 0.3 mmol) was added with stirring. The reaction was stirred at rt for 2.5 h and then quenched by slowly adding saturated NaHCO 3 The solution was quenched. The mixture was extracted with EtOAc and the solvent was evaporated. The residue was purified by preparative HPLC (Waters XSelect CSH Preparative C18 5 μm OBD 30x100mm; Method: (A) 95% {H 2 O} / / (B) 5% {MeCN} containing 0.2% NH 4 OH (initial condition held for 0.5 min) and then a linear gradient to 35% (A) / 65% (B) over 7.5 min (flow rate: 50 mL / min)) to afford (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine (12 mg, 43%) as a white solid. LCMS m / z = 407.3 [M+H] + .t R = 1.45 min (TFA). t R =1.71 min (NH 4 OH).

[0515] Example 21: (3aR, 5s, 6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0516]

[0517] 1. Synthesis of (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0518]

[0519] (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (13 mg, 48%) was obtained as a white solid from (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (Example 20, Step 2) and 3-methyloxetan-3-carbaldehyde. LCMS m / z = 395.3 [M+H] + .t R = 1.44 min (TFA). t R = 1.78 min (NH 4 OH).

[0520] Example 22: (3aR, 5s, 6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0521]

[0522] 1. Synthesis of benzyl ((3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate

[0523]

[0524] To a stirred mixture of (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (22 mg, 0.07 mmol) (Example 20, Step 2) and tetrahydro-4H-pyran-4-one (7 μL, 0.08 mmol) in DCM (2 mL) was added DIPEA (32 μL, 0.2 mmol). After 15 min, acetic acid (11 μL, 0.2 mmol) was added with stirring. After another 15 min, sodium triacetoxyborohydride (60 mg, 0.3 mmol) was added with stirring. The reaction was stirred at rt for 1 h and then quenched by slow addition of saturated NaHCO 3 The solution was quenched. The mixture was extracted with EtOAc and the solvent was evaporated. The residue was purified by preparative HPLC (Waters SunFire preparative C18 5 μm OBD30x100mm; method: (A) 95% {H 2O} / / (B) 5% {MeCN} with 0.1% TFA (initial condition held for 0.5 min) then linear gradient to 45% (A) / 55% (B) over 7.5 min (flow rate: 50 mL / min)) to afford (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine (11 mg, 30%) as a white solid (TFA salt). LCMS m / z = 395.3 [M+H] + .t R = 1.45min (TFA). R = 1.74 min (NH 4 OH).

[0525] Example 23: (3aR, 5s, 6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0526]

[0527] 1. Synthesis of tert-butyl (3aR,5s,6aS)-5-(((benzyloxy)carbonyl)(methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0528]

[0529] To a solution of tert-butyl (3aR,5s,6aS)-5-(((benzyloxy)carbonyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (123 mg, 0.3 mmol) (Example 13, Step 1) in DMF (3 mL) was added 60% NaH (109 mg, 2.7 mmol). The suspension was stirred for 10 min, then iodomethane (53 μL, 0.9 mmol) was added. The reaction was stirred at rt for 1 h, then quenched by the addition of saturated ammonium chloride solution. The mixture was extracted with EtOAc, washed with saturated sodium chloride, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (0-100% 3:1 EtOAc / containing 2% NH 4 OH in EtOH in heptane) to give tert-butyl (3aR,5s,6aS)-5-(((benzyloxy)carbonyl)(methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (109 mg, 85%). LCMS m / z = 397.3 [M+Na] + .

[0530] 2. Synthesis of Benzyl Methyl ((3aR,5s,6aS)-Octahydrocyclopenta[c]pyrrol-5-yl)carbamate

[0531]

[0532] To a solution of tert-butyl (3aR,5s,6aS)-5-(((benzyloxy)carbonyl)(methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (109 mg, 0.3 mmol) in DCM (2.5 mL) was added 4 M dioxane solution of HCl (728 μL, 2.9 mmol). The reaction was stirred at rt for 2 h. The reaction was evaporated to dryness to give crude benzyl methyl((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)carbamate as HCl. LCMS m / z = 275.2 [M+H] + .

[0533] 3. Synthesis of benzyl methyl ((3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate

[0534]

[0535] To a mixture of benzyl methyl((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)carbamate as HCl salt in DCM (2.5 mL) was added DIPEA (157 μL, 0.9 mmol) followed by 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (101 mg, 0.4 mmol). The reaction was stirred at rt for 1 day and then quenched by careful addition of saturated NaHCO 3 The solution was quenched and reacted. The mixture was extracted with DCM, and the combined organic extracts were dried over magnesium sulfate and filtered. The solvent was evaporated and the residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to obtain methyl ((3aR, 5s, 6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta [c] pyrrole-5-yl) benzyl carbamate (132 mg, 92%). LCMS m / z = 498.2 [M+H] + .

[0536] 4. Synthesis of (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine

[0537]

[0538] Following the procedure described in Example 13, Step 4, 97 mg of quantitative (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine was obtained from benzyl methyl((3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate. LCMS m / z = 364.2 [M+H] + .

[0539] 5. Synthesis of (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0540]

[0541] To a mixture of (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (24 mg, 0.07 mmol) and tetrahydro-2H-pyran-4-carbaldehyde (12 mg, 0.1 mmol) in DCM (1 mL) was added DIPEA (35 μL, 0.2 mmol) with stirring. After 15 min, acetic acid (11 μL, 0.2 mmol) was added with stirring. After another 15 min, sodium triacetoxyborohydride (56 mg, 0.3 mmol) was added with stirring. The reaction was stirred at rt for 1 day and then heated to room temperature by slowly adding saturated NaHCO 3 The solution was quenched. The mixture was extracted with EtOAc and the solvent was evaporated. The residue was purified by preparative HPLC (Waters SunFire Preparative C18 5 μm OBD 30x100mm; Method: (A) 95% {H 2 O} / / (B) 5% {MeCN} with 0.1% TFA (initial condition held for 0.5 min) then a linear gradient to 40% (A) / 60% (B) over 7.5 min (flow rate: 50 mL / min)) to afford (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (23 mg, 62%) as a yellow oil (TFA salt). LCMS m / z = 462.3 [M+H]+ . t R =1.57 min (TFA). t R = 2.24 min (NH 4 OH).

[0542] Example 24: (3aR, 5s, 6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0543]

[0544] 1. Synthesis of (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0545]

[0546] (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine (6 mg, 16%) was obtained as a yellow oil as a TFA salt from (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (Example 23, Step 4) and tetrahydro-4H-pyran-4-one following the procedure described in Example 23, Step 5. LCMS m / z = 448.3 [M+H] + .t R = 1.54 min (TFA). t R = 1.94 min (NH 4 OH).

[0547] Example 25: (3aR, 5s, 6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0548]

[0549] 1. Synthesis of (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0550]

[0551] To a stirred mixture of (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (24 mg, 0.07 mmol) (Example 23, Step 4) and 2-oxaspiro[3.3]heptan-6-one (12 mg, 0.1 mmol) in DCM (1 mL) was added DIPEA (35 μL, 0.2 mmol). After 15 min, acetic acid (11 μL, 0.2 mmol) was added with stirring. After another 15 min, sodium triacetoxyborohydride (56 mg, 0.3 mmol) was added with stirring. The reaction was stirred at rt for 1 day and then quenched by slow addition of saturated NaHCO 3 The solution was quenched. The mixture was extracted with EtOAc and the solvent was evaporated. The residue was purified by preparative HPLC (Waters XSelect CSH Preparative C18 5 μm OBD 30x100 mm; Method: (A) 95% {H 2 O} / / (B) 5% {MeCN} containing 0.2% NH 4 The mixture was purified by HPLC-MS / MS with 5% (4% (Isosorbide-5-Nitrae)-4-nitropropene (2-nitropropene) (4-nitropropene) (5-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (10-nitropropene) (2-nitropropene) (5-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (6-nitropropene) ( + .t R = 1.52 min (TFA). t R = 1.94 min (NH 4 OH).

[0552] Example 26: (3aR, 5s, 6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0553]

[0554] 1. Synthesis of (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0555]

[0556] A procedure similar to that described in Example 25 was followed except that the HPLC gradient used was method: (A) 90% {H 2 O} / / (B) 10% {MeCN} containing 0.2% NH 4 (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (15 mg, 51%) was obtained as a white solid from (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (Example 23, Step 4) and 3-methyloxetan-3-carbaldehyde. LCMS m / z = 448.3 [M+H] + .t R = 1.50 min (TFA). t R = 2.14 min (NH 4 OH).

[0557] Example 27: (3aR, 5s, 6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0558]

[0559] 1. Synthesis of benzyl ((3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate

[0560]

[0561] Benzyl ((3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate (235 mg, 77%) was obtained from benzyl ((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)carbamate as the HCl salt (Example 13, Step 2) and 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride following the procedure described in Example 23, Step 3. LCMS m / z = 484.1 [M+H] + .

[0562] 2. Synthesis of (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine

[0563]

[0564] To a mixture of benzyl ((3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate (235 mg, 0.5 mmol) in EtOAc (10 mL) was added 10% palladium on carbon (52 mg, 0.05 mmol). The reaction vessel was evacuated and refilled with H 2 (three times), then in H 2 Hydrogenate under balloon pressure for 1 day. The reaction was filtered through Celite®. 10% palladium on carbon (52 mg, 0.05 mmol) was added to the solution. The reaction vessel was evacuated and refilled with H 2 (three times), then in H 2 Hydrogenate under balloon pressure for 2 h. The reaction was filtered through Celite® and then washed with EtOAc. The solvent was evaporated to give crude (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (149 mg, 88%). LCMS m / z = 350.1 [M+H] + .

[0565] 3. Synthesis of (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0566]

[0567] Following the procedure described in Example 25, (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (10 mg, 58%) was obtained as an off-white solid from (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine and tetrahydro-2H-pyran-4-carbaldehyde. LCMS m / z = 448.1 [M+H] + .t R = 1.70 min(TFA). R = 2.21 min (NH 4 OH).

[0568] Example 28: (3aR, 5s, 6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0569]

[0570] 1. Synthesis of (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0571]

[0572] A procedure similar to that described in Example 25 was followed except that the HPLC gradient used was from 95% {H 2 O} / 5% {MeCN} containing 0.2% NH 4 OH to 30% {H 2 O} / 70% {MeCN} containing 0.2% NH 4 OH, (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (Example 27, Step 2) and tetrahydro-4H-pyran-4-one were used to obtain (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (11 mg, 67%) as a white solid. LCMS m / z = 434.1 [M+H] + .t R = 1.66 min (TFA). tR = 2.04 min (NH 4 OH).

[0573] Example 29: (3aR, 5s, 6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0574]

[0575] 1. Synthesis of (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine

[0576]

[0577] (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (18 mg, 48%) was obtained as a white solid from (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (Example 27, Step 2) and 3-methyloxetan-3-carbaldehyde following the procedure described in Example 25. LCMS m / z = 434.3 [M+H] + .t R = 1.50 min (TFA). t R = 1.93 min (NH 4 OH).

[0578] Example 30: (3aR, 5s, 6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0579]

[0580] 1. Synthesis of (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine

[0581]

[0582] A procedure similar to that described in Example 25 was followed except that the HPLC gradient used was from 95% {H 2 O} / 5% {MeCN} containing 0.2% NH 4 OH to 30% {H 2 O} / 70% {MeCN} containing 0.2% NH 4 OH, (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-amine (Example 27, Step 2) and 2-oxaspiro[3.3]heptan-6-one were obtained as a yellow oil (23 mg, 61%). LCMS m / z = 446.3 [M+H] + .t R = 1.49 min (TFA). t R = 1.78 min (NH 4 OH).

[0583] Example 31: (3aR, 6aS)-2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0584]

[0585] 1. Synthesis of tert-butyl (3aR,6aS)-5-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0586]

[0587] To a mixture of (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (156 mg, 0.73 mmol) and 2,5-dimethylpyrazole-3-sulfonyl chloride (136 mg, 0.70 mmol) in DCM (4 mL) was added DIPEA (0.24 μL, 1.40 mmol). The reaction mixture was stirred at rt overnight. The mixture was washed with saturated NaHCO 3, washed with water and concentrated. The crude material was purified by silica gel chromatography (20-100% EtOAc / heptane) to give tert-butyl (3aR,6aS)-5-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (225 mg, 87%) as a white solid. LCMS m / z = 393.2 [M+Na] + . 1 H-NMR (400 MHz, MeOH-d 4 ): δ (ppm) 6.64 -6.56 (m, 1H), 4.02 (s, 3H), 3.61 - 3.41 (m, 4H), 3.18 (br dd, J = 10.2, 3.6Hz, 4H), 3.00 - 2.85 (m, 2H), 2.25 (s, 3H), 1.45 (s, 9H).

[0588] 2. Synthesis of (3aR,6aS)-2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole

[0589]

[0590] To a reaction vial containing (3aR,6aS)-5-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (215 mg, 0.58 mmol) in 1,1,1,3,3,3-hexafluoropropane-2-ol (3 mL) was added trifluoroacetic acid (89 μL, 1.16 mmol) dropwise at rt and the reaction was stirred overnight at rt. The reaction was concentrated under reduced pressure and co-evaporated with MeCN (x3) to give (3aR,6aS)-2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole (TFA salt) (296 mg, 100%) as a white solid. LCMS m / z =271.1 [M+H] + .

[0591] 3. Synthesis of (3aR,6aS)-2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0592]

[0593] To a mixture of tetrahydro-4H-pyran-4-one (14 mg, 0.14 mmol) and (3aR,6aS)-2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole (47 mg, 0.093 mmol) in DCM (2 mL) was added DIPEA (48 μL, 0.28 mmol). The mixture was stirred at rt for 5 min, acetic acid (16 μL, 0.28 mmol) was added, and the solution was stirred for another 5 min. Sodium triacetoxyborohydride (78 mg, 0.37 mmol) was added once and the reaction was stirred overnight at rt. The reaction was heated to saturated NaHCO 3 It was quenched, diluted with DCM, and stirred for 5 min. The aqueous layer was removed, and the organic phase was washed with water and concentrated. The residue was purified by silica gel column (EtOAc / EtOH 3 / 1) to obtain (3aR, 6aS)-2-((1,3-dimethyl-1H-pyrazole-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (21 mg, 64%) as a white solid. LCMS m / z = 355.2 [M+H] + . 1 H-NMR (400 MHz, MeOH-d 4 ): δ (ppm) 6.59 (s, 1H), 4.02 (s, 3H), 3.95 - 3.87 (m, 2H), 3.40 (td,J = 11.8, 2.3 Hz, 2H), 3.27 - 3.19 (m, 2H), 3.18 - 3.11 (m, 2H), 2.93 (dd, J= 9.5, 7.5 Hz, 2H), 2.87 - 2.75 (m, 2H), 2.34 - 2.20 (m, 6H), 1.87 - 1.74 (m,2H), 1.58 - 1.41 (m, 2H).

[0594] Example 32: 2-(mesitylenesulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0595]

[0596] Following a reaction sequence analogous to that described in Example 31, Steps 1-3, 2-(mesitylsulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (20 mg, 37%) was obtained from tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, 2,4,6-trimethylbenzenesulfonyl chloride and tetrahydro-4H-pyran-4-one. LCMS m / z = 379.2 [M+H] + . 1 H-NMR (400 MHz, MeOH-d 4 ): δ (ppm) 7.04 – 6.90 (m, 2H), 3.92- 3.74 (m, 2H), 3.29 (td, J = 11.9, 2.1 Hz, 2H), 3.15 – 3.07 (m, 2H), 3.00 -2.91 (m, 4H), 2.80 - 2.67 (m, 2H), 2.53 (s, 6H), 2.21 (s, 3H), 2.19 - 2.12(m, 1H), 2.09 (dd, J = 9.4, 5.6 Hz, 2H), 1.77 - 1.66 (m, 2H), 1.39 (qd, J =12.0, 4.5 Hz, 2H).

[0597] Example 33: 3-Fluoro-5-(((3aR,6aS)-5-(tetrahydro-2H-pyran-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)benzonitrile

[0598]

[0599] 1. Synthesis of tert-butyl (3aR,6aS)-5-((3-cyano-5-fluorophenyl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0600]

[0601] To a vial containing (3aR,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid tert-butyl ester (431 mg, 2.0 mmol) in anhydrous DCM (10 mL) was added DIPEA (1.3 mL, 7.5 mmol) dropwise at <5°C. After 5 min, 3-cyano-5-fluorobenzenesulfonyl chloride (540 mg, 2.5 mmol) was carefully added to the cold solution. Once the addition was complete, the reaction was warmed to 23°C and stirred for 30 min. The reaction was quenched by slowly adding 1 M aqueous sodium hydroxide solution. The mixture was stirred at 23°C for 20 min, and then the biphasic mixture was extracted three times with DCM. The combined organic extracts were dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified by (10-75% EtOAc / heptane) to give tert-butyl (3aR,6aS)-5-((3-cyano-5-fluorophenyl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (740 mg, 92%) as a white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm)8.32 - 8.28 (m, 1H), 8.16 (t, J = 1.4 Hz, 1H), 8.06 - 8.02 (m, 1H), 3.47 -3.36 (m, 3H), 3.16 - 2.68 (m, 7H), 1.35 (s, 9H).

[0602] 2. Synthesis of 3-fluoro-5-(((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)benzonitrile

[0603]

[0604] To a vial containing tert-butyl (3aR,6aS)-5-((3-cyano-5-fluorophenyl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (292 mg, 0.7 mmol) in anhydrous MeOH (4 mL) at 23 °C was added 4 M HCl in dioxane (0.55 mL) dropwise. Once the addition was complete, the reaction was stirred at rt for 21 h. The mixture was filtered to give 3-fluoro-5-(((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)sulfonyl)benzonitrile (HCl salt) (180 mg) as a white solid which was used without purification. LCMS m / z = 296.1 [M+H] + .

[0605] 3. Synthesis of 3-fluoro-5-(((3aR,6aS)-5-(tetrahydro-2H-pyran-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)benzonitrile

[0606]

[0607] A vial containing 3-fluoro-5-(((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)benzonitrile (102 mg, 0.3 mmol) as the HCl salt in anhydrous MeOH (3 mL) was cooled in an ice-water bath and DIPEA (0.2 mL, 1.1 mmol) was added. After 20 min, tetrahydro-4H-pyran-4-one (0.06 mL, 0.65 mmol) and acetic acid (0.1 mL, 1.7 mmol) were added to the cooled mixture. After 15 min, sodium triacetoxyborohydride (326 mg, 1.5 mmol) was added portionwise to the cooled solution and the reaction mixture was stirred at <5 °C for 2 h. The reaction mixture was stirred for 2 h by slowly adding saturated NaHCO 3 The reaction was quenched with an aqueous solution. The mixture was stirred at 23 ° C for 30 min and then extracted three times with DCM. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was loaded onto a silica gel column and purified by (40-100% 3: 1 EtOAc / EtOH in heptane) to give 3-fluoro-5-(((3aR, 6aS)-5-(tetrahydro-2H-pyran-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)sulfonyl)benzonitrile (62 mg, 50%) as a white solid. LCMS m / z = 380.2 [M+H] + . 1 H-NMR (400 MHz, DCM-d 2) δ (ppm) 7.91 (t, J = 1.5 Hz, 1H), 7.78 - 7.75 (m, 1H), 7.63 (ddd, J = 1.5, 2.5, 7.8 Hz, 1H), 3.85 (br t, J= 3.5 Hz, 1H), 3.83 - 3.81 (m, 1H), 3.35 - 3.30 (m, 4H), 2.97 - 2.94 (m, 2H), 2.77 - 2.73 (m, 2H), 2.60 - 2.56 (m, 2H), 2.42 - 2.39 (m, 2H), 2.19 - 2.14(m, 1H), 1.70 - 1.65 (m, 2H), 1.43 - 1.36 (m, 2H).

[0608] Example 34: (3aR, 6aS)-2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0609]

[0610] 1. Synthesis of tert-butyl (3aR,6aS)-5-(tetrahydro-2H-pyran-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0611]

[0612] To a solution of tetrahydro-4H-pyran-4-one (637 mg, 6.4 mmol) and (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (900 mg, 4.2 mmol) in MeOH (10 mL) was added acetic acid (0.1 mL) and sodium cyanoborohydride (1.1 g, 17.0 mmol) at rt, and the reaction was heated at 30 °C for 1 h. The mixture was washed with saturated NaHCO 3 The mixture was quenched with aqueous solution (until pH = 8), diluted with water (150 mL) and extracted with DCM (3 x 90 mL). The combined organic layers were washed with Na 2 SO 4 Dried, filtered and concentrated to give a residue which was purified by column chromatography (0% to 10% MeOH / DCM) to give tert-butyl (3aR,6aS)-5-(tetrahydro-2H-pyran-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.1 g, 88%) as a light yellow solid. 1H-NMR (400 MHz, CDCl 3 ) δ (ppm): 4.09 - 3.94 (m,2H), 3.59 - 3.45 (m, 2H), 3.45 - 3.36 (m, 2H), 3.34 - 3.22 (m, 2H), 3.11 -2.81 (m, 3H), 2.50 - 2.28 (m, 2H), 1.89 - 1.77 (m, 2H), 1.71 - 1.57 (m, 4H), 1.48 (s, 9H).

[0613] 2. Synthesis of (3aR,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0614]

[0615] A solution of tert-butyl (3aR,6aS)-5-(tetrahydro-2H-pyran-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (500 mg, 1.7 mmol) in 1N HCl / MeOH (30 mL) was stirred for 2 h at 19° C. The mixture was concentrated under reduced pressure to give (3aR,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (450 mg, HCl salt) as a brown solid, which was used without further purification. 1 H-NMR (400 MHz, MeOH-d 4 ) δ (ppm):4.10 - 3.93 (m, 3H), 3.86 - 3.78 (m, 1H), 3.62 (s, 2H), 3.54 - 3.49 (m, 2H), 3.49 - 3.34 (m, 7H), 2.08 (br d, J = 12.4 Hz, 3H), 1.84 - 1.68 (m, 1H).

[0616] 3. Synthesis of (3aR,6aS)-2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0617]

[0618] To a solution of (3aR,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (90 mg, 0.4 mmol) and 6-methoxy-2-methyl-pyridine-3-sulfonyl chloride (86 mg, 0.4 mmol) in DCM (2 mL) as HCl salt was added DIPEA (270 μL, 1.6 mmol) at 20 °C. After 2 h, the mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography (MeOH / DCM 0% to 10%). The product was purified by preparative HPLC (column: Waters Xbridge 150*25mm 10 μm; conditions: (A) water (NH 4 HCO 3 )-(B) MeCN; Start B: 25; End B: 55; Gradient time (min): 8; Flow rate (mL / min): 30) to give ((3aR,6aS)-2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (61 mg, 41%) as a white solid. LCMS m / z = 382.1 [M+H] + . 1 H-NMR (400 MHz, MeOH-d 4 ) δ (ppm): 8.07 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 3.98 (s, 3H), 3.95 - 3.89 (m, 2H), 3.44 - 3.37 (m,2H), 3.21 - 3.15 (m, 2H), 3.11 - 3.05 (m, 2H), 3.00 - 2.93 (m, 2H), 2.85 -2.79 (m, 2H), 2.76 (s, 3H), 2.28 - 2.20 (m, 3H), 1.86-1.77 (m, 2H), 1.53 -1.43 (m, 2H).

[0619] Example 35: (3aR, 6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0620]

[0621] Following a procedure analogous to that described in Example 34, Step 3, except that the HPLC gradient used was (A) water (NH4 HCO 3 )-(B) MeCN; Start B: 31; End B: 61; Gradient time (min): 8; Flow rate (mL / min): 30, (3aR,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (72 mg, 44%) was obtained as a white solid from 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride and (3aR,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole as HCl salt (Example 34, Step 2). LCMS m / z: 420.0 [M+H] + . 1 H-NMR (400 MHz, MeOH-d 4 ) δ (ppm): 8.40 (d, J =8.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 4.03 - 3.89 (m, 2H), 3.44 - 3.32 (m,4H), 3.23 - 3.09 (m, 2H), 3.01 - 2.92 (m, 3H), 2.90 - 2.75 (m, 4H), 2.45 -2.31 (m, 2H), 2.28 - 2.17 (m, 1H), 1.78-1.68 (m, 2H), 1.61 - 1.46 (m, 2H).

[0622] Example 36: (3aR, 6aS)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0623]

[0624] A method similar to that described in Example 34, step 3 was followed, except that the crude material was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5μm; conditions: (A) water (NH 3 H 2(3aR,6aS)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (32 mg, 20%) was obtained as a white solid from 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride and (3aR,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole as HCl salt (Example 34, Step 2). LCMS m / z = 409.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.00 (s, 1H), 4.17 (s, 3H), 4.00- 3.93 (m, 2H), 3.42 - 3.34 (m, 4H), 3.28 - 3.18 (m, 2H), 3.02 - 2.73 (m,4H), 2.51 - 2.24 (m, 3H), 1.80 - 1.72 (m, 2H), 1.63 - 1.50 (m, 2H).

[0625] Example 37: (3aR, 6aS)-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0626]

[0627] A procedure similar to that described in Example 34, Step 3 was followed, except that the crude material was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5μm, conditions: (A) water (NH 4 HCO 3)-(B) MeCN, 30%~60%, flow rate (mL / min): 25) was purified from 4-methyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride and (3aR,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole as HCl salt (Example 34, Step 2) to obtain (3aR,6aS)-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (6 mg, 4%) as a white solid. LCMS m / z = 421.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ(ppm): 9.24 (s, 1H), 3.96 (d, J = 10.0 Hz, 2H), 3.54 - 3.47 (m, 2H), 3.41 -3.34 (m, 2H), 3.20 (d, J = 10.4 Hz, 2H), 2.97 (s, 3H), 2.89 (s, 2H), 2.72 (s,2H), 2.45 (d, J = 6.8 Hz, 2H), 2.22 (s, 1H), 1.73 (d, J = 12.0 Hz, 2H), 1.51(br s, 2H).

[0628] Example 38: (3aR, 6aS)-2-((2-chloro-6-methoxypyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0629]

[0630] A procedure similar to that described in Example 34, Step 3 was followed, except that the crude material was purified by preparative HPLC (column: Welch Xtimate: C18 150*25mm*5μm; conditions: (A) water (NH 4 HCO 3)-(B) MeCN; Start B: 24%; End B: 54%; Flow rate (mL / min): 25) was purified from 2-chloro-6-methoxy-pyridine-3-sulfonyl chloride and (3aR,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole as a HCl salt (Example 34, Step 2) to obtain (3aR,6aS)-2-((2-chloro-6-methoxypyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole as a white solid. LCMS m / z = 402.1 [M+H] + . 1 H-NMR (400 MHz, MeOH-d 4 ) δ (ppm):8.24 (d, J = 12.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.00 (s, 3H), 3.92 (brdd, J = 4.0, 12.0 Hz, 2H), 3.45 - 3.32 (m, 4H), 3.22 (dd, J = 8.0, 12.0 Hz, 2H), 3.02 - 2.93 (m, 2H), 2.88 - 2.76 (m, 2H), 2.36 - 2.12 (m, 3H), 1.82 (brdd, J = 4.0, 12.0 Hz, 2H), 1.54 - 1.42 (m, 2H).

[0631] Example 39: (3aR, 6aS)-2-((3,5-difluorophenyl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0632]

[0633] A procedure similar to that described in Example 34, Step 3 was followed, except that the crude material was purified by preparative HPLC (Boston Prime C18 150*30mm*5μm, conditions: (A) water (NH 3 H 2 O+NH 4 HCO 3)-(B) MeCN, flow rate (mL / min): 25) was purified from 3,5-difluorobenzenesulfonyl chloride and (3aR,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole as HCl salt (Example 34, Step 2) to obtain (3aR,6aS)-2-((3,5-difluorophenyl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (65 mg, 34%) as a white solid. LCMS m / z = 373.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.37 - 7.32 (m, 2H), 7.10 -7.05 (m, 1H), 3.94 - 3.91 (m, 2H), 3.40 - 3.34 (m, 2H), 3.16 - 3.06 (m, 4H), 2.88 - 2.78 (m, 4H), 2.29 - 2.19 (m, 3H), 1.75 - 1.72 (m, 2H), 1.54 - 1.44(m, 2H).

[0634] Example 40: (3aR, 6aS)-2-((6-methoxypyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0635]

[0636] A procedure similar to that described in Example 34, Step 3 was followed, except that the crude material was purified by preparative HPLC (Welch Xtimate C18 150*25mm*5μm, conditions: water (NH 4 HCO 3 )-MeCN, flow rate (mL / min): 25) was purified from 6-methoxypyridine-3-sulfonyl chloride and (3aR,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole as HCl salt (Example 34, Step 2) to obtain (3aR,6aS)-2-((6-methoxypyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole as a white solid (22 mg, 17%). LCMS m / z = 368.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 8.61 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 2.4, 8.8 Hz, 1H), 6.65 (d, J = 8.8Hz, 1H), 4.02 (s, 3H), 3.96 - 3.93(m, 2H), 3.40 - 3.34 (m, 2H), 3.13 - 3.11 (m, 2H), 3.03 (m, 3H), 2.83 - 2.82(m, 2H), 2.36 - 2.31 (m, 2H), 1.78 - 1.75 (m, 2H), 1.66 - 1.58 (m, 4H).

[0637] Example 41: (3aR, 6aS)-2-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0638]

[0639] A procedure similar to that described in Example 34, Step 3 was followed, except that the crude material was purified by preparative HPLC (Welch Xtimate C18 150*25mm*5μm, conditions: water (NH 4 HCO 3 )-MeCN, flow rate (mL / min): 25) was purified from 5-chloro-2-methoxy-pyridine-3-sulfonyl chloride and (3aR,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole as HCl salt (Example 34, Step 2) to obtain (3aR,6aS)-2-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (50 mg, 27%) as a white solid. LCMS m / z = 402.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 8.26 (d, J =2.4Hz, 1H), 8.16 (d, J = 2.8 Hz, 1H), 4.05 (s, 3H), 3.97 - 3.94 (m, 2H), 3.47- 3.42 (m, 2H), 3.41 - 3.35 (m, 2H), 3.28 - 3.26 (m, 2H), 2.88 - 2.81 (m,4H), 2.32 - 2.31 (m, 2H), 2.28 - 2.24 (m, 1H), 1.77 - 1.74 (m, 2H), 1.54 -1.52 (m, 2H).

[0640] Example 42: (3aR, 6aS)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0641]

[0642] A procedure similar to that described in Example 34, Step 3 was followed, except that the crude material was purified by preparative HPLC (Welch Xtimate C18 150*25mm*5μm, conditions: water (NH 4 HCO 3 )-MeCN, flow rate (mL / min): 25) was purified from 2-methoxy-5-methyl-pyridine-3-sulfonyl chloride and (3aR,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole as HCl salt (Example 34, Step 2) to obtain (3aR,6aS)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (61 mg, 35%) as a white solid. LCMS m / z = 382.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 8.12 - 8.11(m, 1H), 8.00 - 7.99 (m, 1H), 4.02 (s, 3H), 3.97 - 3.94 (m, 2H), 3.41 - 3.35(m, 4H), 3.26 - 3.23 (m, 2H), 2.92 (m, 2H), 2.78 (m, 2H), 2.31 (s, 3H), 2.29- 2.23 (m, 3H), 1.77 - 1.74 (m, 2H), 1.61 - 1.47 (m, 2H).

[0643] Example 43: (3aR, 6aS)-2-((2,4-dimethylpyrimidin-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0644]

[0645] A procedure similar to that described in Example 34, Step 3 was followed, except that the crude material was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5μm; conditions: (A) water (NH 4 HCO 3 )-(B) MeCN; Start B: 15; End B: 45; Flow rate (mL / min): 25) to obtain (3aR,6aS)-2-((2,4-dimethylpyrimidin-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (55 mg, 41%) as a white solid from 2,4-dimethylpyrimidine-5-sulfonyl chloride and (3aR,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole as HCl salt (Example 34, Step 2). LCMS m / z = 367.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3) δ(ppm): 8.98 (s, 1H), 3.95 (br d, J = 10.4 Hz, 2H), 3.42 - 3.34 (m, 4H), 3.15- 3.13 (m, 2H), 2.89 - 2.83 (m, 2H), 2.83 (s, 3H), 2.82 - 2.78 (m, 2H), 2.78 (s, 3H), 2.34 (br d, J = 5.6 Hz, 2H), 2.25 - 2.15 (m, 1H), 1.73 (br d, J =12.0 Hz, 2H), 1.54 - 1.44 (m, 2H).

[0646] Example 44: (3aR, 6aS)-2-((2,4-dimethylpyrimidin-5-yl)sulfonyl)-5-(tetrahydrofuran-3-yl)octahydropyrrolo[3,4-c]pyrrole

[0647]

[0648] Following a reaction sequence similar to that described in Example 31, (3aR, 6aS)-2-((2,4-dimethylpyrimidin-5-yl)sulfonyl)-5-(tetrahydrofuran-3-yl)octahydropyrrolo[3,4-c]pyrrole (58 mg, 18%) was obtained as a white solid from (3aR, 6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester and 2,4-dimethylpyrimidine-5-sulfonyl chloride in step 1 and tetrahydrofuran-3-one in step 3. The crude material was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm; conditions: (A) water (NH 4 HCO 3 ) - (B) MeCN; Start B: 10; End B: 40; Flow rate (mL / min): 50) purification. LCMS m / z = 353.1 [M+H] + . 1 H-NMR (400 MHz, CDCl 3) δ(ppm): 8.98 (s, 1H), 3.94 - 3.86 (m, 1H), 3.84 - 3.75 (m, 2H), 3.58 - 3.50(m, 1H), 3.43 - 3.34 (m, 2H), 3.14 - 3.10 (m, 2H), 2.85 (s, 3H), 2.82 (s,3H), 2.78 (s, 3H), 2.76 - 2.63 (m, 2H), 2.40 - 2.26 (m, 2H), 2.06 - 1.94 (m,1H), 1.88 - 1.76 (m, 1H).

[0649] Example 45: (3aR, 6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0650]

[0651] 1. Synthesis of tert-butyl (3aR,6aR)-5-(tetrahydro-2H-pyran-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0652]

[0653] To a solution of tetrahydro-4H-pyran-4-one (177 mg, 1.8 mmol) and (3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (250 mg, 1.2 mmol) in MeOH (10 mL) at 16°C was added acetic acid (0.1 mL) and sodium cyanoborohydride (296 mg, 4.7 mmol), and the reaction was stirred at 30°C for 1 h. The mixture was washed with saturated NaHCO 3 (until pH = 8), quenched, diluted with water (150 mL) and extracted with DCM (90 mL × 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried, filtered and concentrated. The residue was purified by Combiflash® (MeOH / DCM, 0% to 10%) to give tert-butyl (3aR,6aR)-5-(tetrahydro-2H-pyran-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (300 mg, 86%) as a light yellow oil. 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 3.97 - 3.95 (m,2H), 3.88 - 3.85 (m, 2H), 3.67 - 3.64 (m, 2H), 3.45 - 3.44 (m, 2H), 3.43 -3.38 (m, 3H), 1.91 - 1.90 (m, 2H), 1.61-1.59 (m, 2H), 1.57-1.55 (m, 4H), 1.46(s, 9H).

[0654] 2. Synthesis of (3aS,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0655]

[0656] A solution of tert-butyl (3aR,6aR)-5-(tetrahydro-2H-pyran-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (100 mg, 0.337 mmol) in HCl / MeOH (30 mL) was stirred for 12 h at 19° C. The mixture was concentrated to give (3aS,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (80 mg, crude, HCl salt) as a brown solid. 1 H-NMR: (400 MHz, MeOH-d 4 ) δ ppm 4.17 - 3.99 (m, 2H), 3.97 - 3.87(m, 1H), 3.84 - 3.70 (m, 2H), 3.62 - 3.55 (m, 2H), 3.48 - 3.43 (m, 2H), 3.22- 3.11 (m, 2H), 2.89 - 2.57 (m, 2H), 2.17 - 1.98 (m, 2H), 1.93 - 1.68 (m,3H), 1.59 - 1.49 (m, 1H)

[0657] 3. Synthesis of (3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0658]

[0659] To a solution of (3aS,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (72 mg, 0.3 mmol, HCl salt) and 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (80 mg, 0.3 mmol) in DCM (5 mL) was added DIPEA (159 mg, 1.2 mmol) and the reaction was stirred at 20° C. for 2 h. The mixture was concentrated to give a residue, which was purified by preparative HPLC (column: Waters xbridge 150*25mm 10 μm; conditions: (A) water (NH 4 HCO 3 )-(B) MeCN; Start B: 31; End B: 61; Gradient time (min): 8; Flow rate (mL / min): 30) to give (3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (59 mg, 42%) as a light yellow solid. LCMS m / z = 420.0 [M+H] + . 1 H-NMR (400 MHz, MeOH-d 4 ) δ (ppm): 8.43 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 3.99 -3.89 (m, 2H), 3.65 (dd, J = 6.3, 8.6 Hz, 2H), 3.46 - 3.34 (m, 2H), 3.09 (dd,J = 8.8, 10.8 Hz, 2H), 3.01 - 2.93 (m, 2H), 2.90 (s, 3H), 2.74 (tt,J = 3.9,11.1 Hz, 1H), 2.59 (dd,J = 9.3, 10.6 Hz, 2H), 2.35 - 2.21 (m, 2H), 1.92 -1.73 (m, 2H), 1.60 - 1.38 (m, 2H).

[0660] Example 46: (3aR, 6aR)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0661]

[0662] To a solution of (3aS,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (90 mg, 0.5 mmol, HCl salt) (Example 45, Step 3) and 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride (114 mg, 0.5 mmol) in DCM (4 mL) was added DIPEA (178 mg, 1.4 mmol) and the reaction was stirred at 20°C for 2 h. The mixture was concentrated to give a residue, which was purified by preparative HPLC (column: Phenomenex C18 150*25mm*10μm; conditions: (A) water (NH 4 HCO 3 )-(B) MeCN; Start B: 24; End B: 54; Gradient time (min): 8; Flow rate (mL / min): 30) and further purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; conditions: (A) water (FA)-(B) MeCN; Start B: 9; End B: 39; Gradient time (min): 10; Flow rate (mL / min): 25) to give (3aR,6aR)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (43 mg, 20%, formate) as an off-white solid. LCMS m / z = 409.1 [M+H] + . 1 H-NMR (400 MHz, MeOH-d 4 ) δ (ppm): 8.47 (s, 1H), 7.17 (s, 1H), 4.18 (s, 3H), 4.07 - 3.96 (m, 2H), 3.79 - 3.69 (m, 2H), 3.49 - 3.36 (m, 4H), 3.29 - 3.17(m, 2H), 3.10 - 2.99 (m, 2H), 2.51 - 2.35 (m, 2H), 2.03 - 1.88 (m, 2H), 1.72- 1.58 (m, 2H).

[0663] Examples 47 and 48: (3aS, 6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole and (3aR, 6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0664]

[0665] Racemic-(3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole was resolved by chiral SFC purification using (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: Neu-ETOH from 15% to 15%; flow rate (mL / min): 150; column temperature: 35°C) to give:

[0666] (3aS,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (150 mg, 33.4%, Rf = 2.024 min). LCMS m / z = 420.1 [M+H-56] + . 1 HNMR (400 MHz, CDCl 3 ): δ ppm 8.35 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.4 Hz,1H), 4.00-3.97 (m, 2H), 3.67-3.63 (m, 2H), 3.41-3.35 (m, 2H), 3.10-3.05 (m,2H), 3.02-2.98 (m, 2H), 2.92 (s, 3H), 2.78-2.71 (m, 1H), 2.65 (t, J=10.0 Hz,2H), 2.35-2.26 (m, 2H), 1.82-1.72 (m, 2H), 1.62-1.50 (m, 2H). The chirality of the compounds is arbitrarily assigned.

[0667] (3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (120 mg, 26.7%, Rf = 2.054 min) LCMS m / z = 420.1 [M+H-56] + . 1 HNMR (400 MHz, CDCl 3 ): δ ppm8.35 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.4 Hz,1H), 4.00-3.98 (m, 2H), 3.67-3.63 (m, 2H), 3.41-3.35 (m, 2H), 3.11-3.06 (m,2H), 3.03-3.00 (m, 2H), 2.92 (s, 3H), 2.79-2.73 (m, 1H), 2.67 (t, J=9.6 Hz,2H), 2.34-2.28 (m, 2H), 1.80-1.74 (m, 2H), 1.64-1.54 (m, 2H). The chirality of the compounds was arbitrarily assigned.

[0668] Example 49: rac-(3aR,6aS)-2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0669]

[0670] Following a similar procedure as described in Example 33 (steps 1-3), except that the crude material was purified by normal phase column (4 g, EtOAc / EtOH 3 / 1 100%), rac-(3aR,6aS)-2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (18 mg, 63% yield) was obtained as a white solid from 1,3-dimethyl-1H-pyrazole-5-sulfonyl chloride and hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester. LCMS m / z = 355.2 [M+H] + . 1 HNMR (400 MHz, MeOH-d 4): δ (ppm) 6.50-6.67 (m, 1H), 4.02(s, 3H), 3.87-3.97 (m, 2H), 3.40 (td, J = 11.8, 2.0 Hz, 2H), 3.19-3.26 (m,2H), 3.11-3.17 (m, 2H), 2.93 (br dd, J = 9.5, 7.5 Hz, 2H), 2.82 (br d, J =3.5 Hz, 2H), 2.18-2.35 (m, 6H), 1.76-1.86 (m, 2H), 1.40-1.57 (m, 2H).

[0671] Example 50: rac-(3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(2-oxaspiro[3.3]hept-6-yl)octahydropyrrolo[3,4-c]pyrrole

[0672]

[0673] 1. Synthesis of tert-butyl (3aR,6aR)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0674]

[0675] To a solution of tert-butyl rac-(3aS,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (300 mg, 1.41 mmol) and DIEA (547.93 mg, 4.24 mmol) in DCM (15 mL) was added 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (366.91 mg, 1.41 mmol) in DCM (5 mL) at 0 °C. The mixture was warmed to 20 °C and stirred for 1 h. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were washed with water (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column (MeOH / DCM = 0% ~6%) to give the desired compound (300 mg, 48.7%) as a white solid. LCMS m / z = 380.0 [M+H-56] + . 1 HNMR (400 MHz, CDCl 3; = 10.0 Hz, 2H), 2.93 (s, 3H), 2.33-2.25 (m, 2H), 1.45 (s, 9H).

[0676] 2. Synthesis of racemic-(3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole

[0677]

[0678] To a solution of rac-(3aR,6aR)-tert-butyl 5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (100 mg, 229.64 umol) in DCM (3 mL) was added HCl / dioxane (1.5 mL) and the mixture was stirred at 25 °C for 5 h. The mixture was concentrated to give the desired compound (85 mg, crude, HCl salt) as a white solid. LCMS m / z = 336.0 [M+H] + . 1 HNMR (400 MHz, MeOH-d 4 ): δppm 8.47 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 3.77-3.72 (m, 2H), 3.53-3.45 (m, 2H), 3.28-3.19 (m, 2H), 3.08-3.00 (m, 2H), 2.91 (s, 3H), 2.68-2.42 (m, 2H).

[0679] 3. Synthesis of racemic-(3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(2-oxaspiro[3.3]hept-6-yl)octahydropyrrolo[3,4-c]pyrrole

[0680]

[0681] 2-Oxaspiro[3.3]heptan-6-one (72.38 mg, 645.50 umol) was added to racemic (3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole (80 mg, 215.17 umol, HCl salt) and Et 3 N (21.77 mg, 215.17 umol) was dissolved in MeOH (2 mL) (72.38 mg, 645.50 umol) and the solution was adjusted to pH = 5-6 by adding acetic acid at 25 °C. The solution was stirred at 25 °C for 1 h. NaBH was added at 25 °C. 3 CN (67.61 mg, 1.08 mmol), and then the mixture was stirred for 6 h. 3 .H 2 O was neutralized to pH = 7, filtered and purified by preparative HPLC (column: C18-1 150*30mm*5um; conditions: water (NH 3 .H 2 O +NH 4 HCO 3 )-ACN; Start B: 30; End B: 60; Flow rate: 25 mL / min) to give the desired compound (30 mg, 32.3%) as a white solid. LCMS m / z = 432.1 [M+H] + . 1 HNMR (400 MHz, CDCl 3 ): δ ppm 8.35 (d,J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 4.68 (s, 2H), 4.61 (s, 2H), 3.66-3.57 (m, 2H), 3.14 (br s, 1H), 3.08-3.01 (m, 2H), 2.92 (s, 3H), 2.87 (br s,2H), 2.52-2.23 (m, 6H), 2.08 (br s, 2H).

[0682] Example 51: rac-(3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-((tetrahydro-2H-pyran-4-yl)methyl)octahydropyrrolo[3,4-c]pyrrole

[0683]

[0684] Tetrahydro-2H-pyran-4-carbaldehyde (73.68 mg, 645.50 umol) was added to a solution of rac-(3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole (80 mg, 215.17 umol, HCl salt) and Et3N (21.77 mg, 215.17 umol) in MeOH (2 mL) and stirred at 25°C for 1 h. NaBH was added. 3 CN (67.61 mg, 1.08 mmol) and the mixture was stirred at 25 °C for 6 h. 3 .H 2 O was neutralized to pH = 7, filtered and purified by preparative HPLC (column: C18-1 150*30mm*5um; conditions: water (NH 3 .H 2 O + NH 4 HCO 3 )-ACN; Start B: 36; End B: 66; Flow rate: 25 mL / min) to give the desired compound (30 mg, 32.1%) as a white solid. LCMS m / z = 434.1 [M+H] + . 1 HNMR (400 MHz, CDCl 3 ): δppm 8.35 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 4.01-3.92 (m, 2H), 3.67-3.58 (m, 2H), 3.41-3.31 (m, 2H), 3.11-3.01 (m, 2H), 2.92 (s, 3H), 2.88(br s, 2H), 2.57 (br s, 4H), 2.34 (br s, 2H), 1.65-1.60 (m, 3H), 1.33-1.19(m, 2H).

[0685] Example 52: rac-(3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(oxetan-3-ylmethyl)octahydropyrrolo[3,4-c]pyrrole

[0686]

[0687] Following a similar procedure as described in Example 51, rac-(3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(oxetan-3-ylmethyl)octahydropyrrolo[3,4-c]pyrrole (20 mg, 23% yield) was obtained as a white solid from rac-(3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole and oxetane-3-carboxylic acid. LCMS m / z = 406.1 [M+H] + . 1 HNMR (400MHz, CDCl 3 ): δ ppm 8.35 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 4.82-4.72 (m, 2H), 4.42-4.34 (m, 2H), 3.66-3.58 (m, 2H), 3.13-2.96 (m, 5H), 2.92(s, 3H), 2.86-2.79 (m, 2H), 2.60-2.52 (m, 2H), 2.37-2.23 (m, 2H).

[0688] Example 53: rac-(3aR,6aR)-2-((1-methyl-2-oxabicyclo[3.1.1]hept-5-yl)methyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole

[0689]

[0690] 1. Synthesis of rac-((3aR,6aR)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(1-methyl-2-oxabicyclo[3.1.1]hept-5-yl)methanone

[0691]

[0692] A mixture of rac-(3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole (150.00 mg, 447.30 umol) and T3P (426.97 mg, 670.95 umol, 399.41 uL, 50% purity) was dissolved in DMF (2 mL) and DIPEA (289.05 mg, 2.24 mmol, 389.55 uL) and heated at 80°C for 10 min. To the above orange mixture was added a solution of 1-methyl-2-oxabicyclo[3.1.1]heptane-5-carboxylic acid (83.83 mg, 536.76 umol) in DMF (2 mL) and the reaction was stirred at 80°C for another 1 h, then cooled to RT and stirred overnight. The reaction mixture was diluted with DCM (5 mL) and saturated with NaHCO 3 The organic phase was washed with Na 2 SO 4 Dry, filter and concentrate.

[0693] The crude material was purified by column chromatography (12 g SiO2, 50-100% EtOH:EtOAc 1:3 in heptane) to give the desired compound (152 mg, 72%). LCMS m / z = 474.0 [M+H] + . 1 HNMR (400 MHz, CDCl 3 ): δ 8.39(br d, 1H, J=8.2 Hz), 7.68 (br d, 1H, J=8.2 Hz), 4.1-4.2 (m, 2H), 3.84 (brdd, 1H, J=6.9, 10.8 Hz), 3.7-3.8 (m, 3H), 3.1-3.2 (m, 4H), 2.9-3.0 (m, 3H), 2.3-2.4 (m, 1H), 2.1-2.3 (m, 6H), 2.0-2.1 (m, 2H), 1.25 (s, 3H).

[0694] 2. Racemic-(3aR,6aR)-2-((1-methyl-2-oxabicyclo[3.1.1]hept-5-yl)methyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole

[0695]

[0696] Racemic-[(3aS,6aS)-5-[[2-methyl-6-(trifluoromethyl)-3-pyridinyl]sulfonyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(1-methyl-2-oxabicyclo[3.1.1]hept-5-yl)methanone (135.28 mg, 285.70 umol) was dissolved in THF (1 mL). 1M borane (1.14 ml, 1.14 mmol) in THF was added dropwise and the solution was heated to 50 °C overnight. The reaction was cooled to RT and quenched by adding 5 ml of MeoH. The reaction was heated back to 50 °C and stirred overnight. The reaction was then cooled to RT and the solvent was removed in vacuo. The crude product was purified by column chromatography (12 g SiO2, 50-100% EtOH:EtOAc 1:3 in heptane) to give the desired compound (102 mg, 78%). LCMS m / z = 474.0 [M+H] + . 1 HNMR (400 MHz, CDCl 3 ): 1 H NMR (chloroform-d, 500 MHz): δ 8.29 (brd, 1H, J=7.9 Hz), 7.58 (d, 1H, J=7.9 Hz), 3.98 (t, 2H, J=6.9 Hz), 3.5-3.6 (m,2H), 2.99 (br t, 2H, J=9.5 Hz), 2.86 (s, 3H), 2.79 (br s, 2H), 2.5-2.7 (m,4H), 2.26 (br s, 2H), 1.87 (br s, 2H), 1.7-1.8 (m, 2H), 1.52 (br dd, 2H, J=7.8, 17.2 Hz), 1.15 (s, 3H).

[0697] Example 54: rac-(3aR,6aR)-3a-methyl-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole

[0698]

[0699] 1. Synthesis of racemic-((3aR,6aR)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methanone

[0700]

[0701] Following a similar procedure as described in Step 1 of Example 53, rac-((3aR,6aR)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methanone was obtained from rac-(3aS,6aS)-5-[[2-methyl-6-(trifluoromethyl)-3-pyridinyl]sulfonyl]-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole (150 mg, 447.30 umol) and 1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid (76.30 mg, 536.76 umol). The crude material was purified by column chromatography (12 g SiO2, 50-100% EtOH:EtOAc 1:3 in heptane) to give the desired material (165 mg, 80%). LCMS m / z = 460.1 [M+H] + . 1 H NMR (Chloroform-d, 500 MHz): 1 H NMR 1 H NMR (chloroform-d, 500 MHz) δ 8.39(br d, 1H, J=7.9 Hz), 7.68 (br d, 1H, J=7.9 Hz), 3.8-4.0 (m, 3H), 3.7-3.8 (m,3H), 3.0-3.3 (m, 4H), 2.93 (s, 3H), 2.2-2.5 (m, 2H), 1.8-2.0 (m, 4H), 1.45(s, 3H).

[0702] 2. Synthesis of racemic-(3aR,6aR)-2-((1-methyl-2-oxabicyclo[2.1.1]hex-4-yl)methyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole

[0703]

[0704] Following a procedure analogous to that described in step 2 of Example 53, rac-(3aR,6aR)-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole (74 mg, 76%) was obtained from rac-((3aR,6aR)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methanone. LCMS m / z = 446.2 [M+H] + . 1 H NMR (chloroform-d, 500 MHz): δ 8.28 (br d, 1H, J=7.9Hz), 7.58 (br d, 1H, J=8.2 Hz), 3.4-3.7 (m, 4H), 2.7-3.1 (m, 7H), 2.2-2.7 (m,4H), 1.4-1.7 (m, 6H), 1.35 (s, 3H).

[0705] Examples 55 and 56: (3aS, 6aS)-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole and (3aR, 6aR)-3a-methyl-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole

[0706]

[0707] Racemic-(3aR,6aR)-3a-methyl-2-((1-methyl-2-oxabicyclo[2.1.1]hex-4-yl)methyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole was resolved by chiral SFC purification using CHIRALPAKOX-H 30x250mm, 5um. Method: 20% IPA in CO2 with 0.1% DEA (flow rate: 100mL / min, ABPR 120 bar, MBPR 60psi, column temperature 40°C) to give:

[0708] (3aS,6aS)-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole (19.7 mg, 31.8%, Rf = 2.33 min.). LCMS m / z = 446.2 [M+H] + The chirality of a compound is arbitrarily assigned.

[0709] (3aR,6aR)-3a-methyl-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole (20.2 mg, 32.6%, Rf = 2.52 min.). LCMS m / z = 446.2 [M+H] + The chirality of a compound is arbitrarily assigned.

[0710] Example 57: rac-(3aR,6aR)-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0711]

[0712] 1. Synthesis of tert-butyl (3aR,6aR)-5-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0713]

[0714] To a solution of 4-methyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride (200 mg, 780.34 umol, 0.5 oxalate) and DIPEA (302.56 mg, 2.34 mmol) in DCM (10 mL) at 0 °C was added tert-butyl rac-(3aS, 6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (350 mg, 1.34 mmol). The mixture was stirred at 20 °C for 2 hours. The mixture was concentrated to give a crude residue, which was purified by silica gel chromatography (petroleum ether / EtOAc, 0% to 30%) to give the desired compound (190 mg, 55.79%) as a yellow solid. LCMS m / z = 381.0 [M+Ht-Bu] + . 1H NMR (chloroform-d, 500 MHz): δ ppm 9.18 (s, 1 H), 3.78-3.61 (m, 4 H), 3.20-3.13 (m, 2H), 3.03 (br t, J=10.4 Hz, 2 H), 2.95 (s, 3 H), 2.37-2.23 (m, 2 H), 1.46 (s, 9 H).

[0715] 2. Synthesis of racemic-(3aR,6aR)-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole

[0716]

[0717] To a solution of tert-butyl rac-(3aR,6aR)-5-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (180 mg, 412.42 umol) in HFIP (5 mL) at 20°C was added TFA (141.08 mg, 1.24 mmol, 94.75 uL). The mixture was stirred at 20°C for 2 hours. The mixture was concentrated to give the desired compound (180 mg, crude, TFA salt) as a light yellow solid. LCMS m / z = 337.0 [M+H] + . 1 H NMR (chloroform-d, 500 MHz): δ ppm 10.04-9.95 (m, 1 H), 9.19 (s, 1 H), 3.85-3.78 (m, 2 H), 3.65-3.54 (m, 2 H), 3.33-3.20 (m, 2 H), 3.13-3.03 (m, 2 H), 2.94 (s, 3 H), 2.64-2.57 (m, 2 H).

[0718] 3. Synthesis of racemic-(3aR,6aR)-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0719]

[0720] Following a similar procedure as described in Example 51, rac-(3aR,6aR)-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (28 mg, 48% yield) was obtained as a white solid from rac-(3aR,6aR)-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole and tetrahydro-4H-pyran-4-one. LCMS m / z = 421.2 [M+H] + . 1 HNMR (400MHz, CDCl 3 ): δ ppm 9.17 (s, 1H), 3.99 (br d, J=11.2 Hz, 2H), 3.72-3.65 (m,2H), 3.43-3.32 (m, 2H), 3.16-3.10 (m, 2H), 3.05-2.98 (m, 2H), 2.95 (s, 3H), 2.81-2.72 (m, 1H), 2.71-2.62 (m, 2H), 2.39-2.26 (m, 2H), 1.82-1.72 (m, 2H), 1.64-1.50 (m, 2H).

[0721] Example 58: rac-(3aR,6aR)-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-(2-oxaspiro[3.3]hept-6-yl)octahydropyrrolo[3,4-c]pyrrole

[0722]

[0723] Following a similar procedure as described in Example 51, rac-(3aR,6aR)-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-(2-oxaspiro[3.3]hept-6-yl)octahydropyrrolo[3,4-c]pyrrole (21.6 mg, 36.7% yield) was obtained as a white solid from rac-(3aR,6aR)-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole and 2-oxaspiro[3.3]heptan-6-one. LCMS m / z = 433.1 [M+H] + . 1 HNMR (400 MHz, CDCl 3): δ ppm 9.18 (s, 1H), 4.71 (s, 2H), 4.63 (s, 2H), 3.74-3.64 (m, 2H), 3.22-3.07 (m, 3H), 2.96 (s, 3H), 2.93-2.82 (m, 2H), 2.56-2.25(m, 6H), 2.21-1.98(m, 2H).

[0724] Example 59: rac-(3aR,6aR)-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-((tetrahydro-2H-pyran-4-yl)methyl)octahydropyrrolo[3,4-c]pyrrole

[0725]

[0726] Following a similar procedure as described in Example 51, (3aR,6aR)-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-((tetrahydro-2H-pyran-4-yl)methyl)octahydropyrrolo[3,4-c]pyrrole (22 mg, 37.5% yield) was obtained as a white solid from rac-(3aR,6aR)-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole and tetrahydro-2H-pyran-4-carbaldehyde. LCMS m / z = 435.1 [M+H] + . 1 HNMR (400MHz, CDCl 3 ): δ ppm 9.16 (s, 1H), 3.98-3.94 (m, 2H), 3.68-3.67 (m, 2H), 3.36(td, J = 12.0 Hz, 1.6Hz, 2H), 3.17-3.06 (m, 2H), 2.95 (s, 3H), 2.93-2.83 (m,2H), 2.69-2.51 (m, 4H), 2.28-2.43 (m, 2H), 1.70-1.62 (m, 3H), 1.31-1.20 (m,2H).

[0727] Example 60: (3aR, 6aR)-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0728]

[0729] 1. Synthesis of tert-butyl (3aR,6aR)-5-(tetrahydro-2H-pyran-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0730]

[0731] Following the analogous procedure described in step 1 of Example 34, tert-butyl (3aR,6aR)-5-(tetrahydro-2H-pyran-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (300 mg, 86.0% yield) was obtained from tert-butyl (3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and tetrahydro-4H-pyran-4-one. 1 HNMR (400 MHz, CDCl 3 ): δppm 3.97-3.95 (m, 2H), 3.88-3.85 (m, 2H), 3.67-3.64 (m, 2H), 3.45-3.44 (m,2H), 3.43-3.38 (m, 3H), 1.91-1.90 (m, 2H), 1.61-1.59 (m, 2H), 1.57-1.55 (m, 4H), 1.46 (s, 9H).

[0732] 2. Synthesis of (3aS,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0733]

[0734] Following a similar procedure as described in step 2 of Example 34, (3aS,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (80 mg, 100%, HCl salt) was obtained from tert-butyl (3aR,6aR)-5-(tetrahydro-2H-pyran-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and HCl in MeoH. 1 HNMR (400 MHz, CDCl 3 ): δppm 4.17-3.99 (m, 2H), 3.97-3.87 (m, 1H), 3.84-3.70 (m, 2H), 3.62-3.55 (m,2H), 3.48-3.43 (m, 2H), 3.22-3.11 (m, 2H), 2.89-2.57 (m, 2H), 2.17-1.98 (m, 2H), 1.93-1.68 (m, 3H), 1.59-1.49 (m, 1H).

[0735] 3. Synthesis of 4,6-dibromo-2-(trifluoromethyl)pyrimidin-5-amine

[0736]

[0737] To a solution of 2-(trifluoromethyl)pyrimidine-5-amine (2.5 g, 15.33 mmol) in MeCN (40 mL) was added NBS (6.00 g, 33.72 mmol) at 20 °C. The mixture was stirred at 40 °C for 12 hours. The mixture was concentrated to give a crude residue, which was purified by silica gel chromatography (petroleum ether / EtOAc, 0% to 30%) to give the desired compound (2.5 g, 50.83% yield) as a yellow solid. LCMS m / z = 321.6 [M+H] + .

[0738] 4. Synthesis of 4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-amine

[0739]

[0740] At 20 ° C, 4,6-dibromo-2-(trifluoromethyl)pyrimidine-5-amine (7.82 g, 31.16 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxa triborane (2.5 g, 7.79 mmol) in dioxane (100 mL) and water (20 mL) were added Pd (dppf) Cl2 (570.05 mg, 779.08 umol) and K2CO3 (2.69 g, 19.48 mmol). The mixture was stirred at 80 ° C and N2 for 12 hours. The mixture was concentrated to give a crude residue, which was purified by silica gel chromatography (EtOAc / petroleum ether, 0% to 30%) to give the desired compound (1.4 g, 94.0% yield) as a yellow solid. LCMSm / z = 192.1 [M+H] + . 1 HNMR (400 MHz, CDCl 3 ): δ ppm 4.04-3.50 (m, 2H), 2.46 (s, 6H).

[0741] 5. Synthesis of 5-bromo-4,6-dimethyl-2-(trifluoromethyl)pyrimidine

[0742]

[0743] To a solution of 4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-amine (1.4 g, 7.32 mmol) in MeCN (5 mL) was added CuBr 2 To the mixture was added 4-(2-nitro-1-yl)-2-nitropropene (2.45 g, 10.99 mmol) and tert-butyl nitrite (1.13 g, 10.99 mmol). The mixture was stirred at 60 °C for 1 hour. The mixture was concentrated to give a crude residue, which was purified by silica gel chromatography (EtOAc / petroleum ether, 0% to 10%) to give the desired compound (1 g, 53% yield) as a colorless oil. LCMS m / z = 254.7 [M+H] + . 1 HNMR (400 MHz, CDCl 3 ): δ ppm 2.74 (s, 6H).

[0744] 6. Synthesis of 5-(benzylthio)-4,6-dimethyl-2-(trifluoromethyl)pyrimidine

[0745]

[0746] To a 20°C solution of BnBr (905.35 mg, 5.29 mmol) and 5-bromo-4,6-dimethyl-2-(trifluoromethyl)pyrimidine (900 mg, 3.53 mmol) in DMF (40 mL) and water (0.2 mL) was added K2CO3 (1.95 g, 14.12 mmol), thiourea (671.56 mg, 8.82 mmol) and CuI (100.81 mg, 529.34 μmol). The mixture was heated to 60°C and stirred for 0.5 h. The mixture was diluted with water (200 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were purified by Na 2 SO 4 Dry, filter and concentrate to give a crude residue, which is purified by silica gel chromatography (EtOAc / petroleum ether, 0% to 10%) to give the desired compound (0.8 g, 76% yield) as a yellow oil. LCMS m / z = 298.9 [M+H] + . 1 HNMR (400 MHz, CDCl 3 ): δ ppm 7.28-7.19 (m, 3H), 7.17-7.15 (m, 2H), 3.82 (s, 2H), 2.53 (s, 6H).

[0747] 7. Synthesis of 4,6-dimethyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride

[0748]

[0749] Sulfuryl chloride (2.00 g, 14.78 mmol) in DCM (2 mL) was added to a 0°C solution of 5-(benzylthio)-4,6-dimethyl-2-(trifluoromethyl)pyrimidine (630 mg, 2.11 mmol) in water (4 mL) and DCM (20 mL). The reaction mixture was stirred at 0-15°C for 12 h. The mixture was diluted with water (100 mL) and extracted with DCM (40 mL x 3). The aqueous phase was washed with NaHCO 3 Neutralized, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired compound (600 mg, crude) as a yellow solid. 1 HNMR (400 MHz, CDCl3) δ ppm 3.07 (s, 6H).

[0750] 8. Synthesis of (3aR,6aR)-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0751]

[0752] 4,6-Dimethyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride (129.80 mg, 472.61 umol) was added to a solution of (3aS,6aS)-2-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole (100 mg, 429.65 umol, HCl salt) and DIEA (166.58 mg, 1.29 mmol, 224.50 uL) in DCM (10 mL). The mixture was stirred at 20 °C for 2 hours. The mixture was filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (column: Welch XtimateC18 150*25mm*5um; condition: water (NH4HCO3)-ACN; start B: 31; end B: 61; flow rate (ml / min): 25) to give the desired compound (50 mg, 27% yield) as a white solid. LCMS m / z = 435.1 [M+H] + . 1HNMR (500MHz, MeOD): δ ppm 4.97-4.93 (m, 2H), 4.67-4.63 (m, 2H), 4.00-3.96 (m, 2H), 3.10-3.08 (m, 2H), 2.99-2.97 (m, 2H), 2.93 (s, 6H), 2.77-2.73 (m, 1H), 2.62-2.58 (m, 2H), 2.30-2.28 (m, 2H), 1.83-1.80 (m, 2H), 1.53-1.48 (m, 2H).

[0753] Example 61: (3aR, 6aR)-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-(2-oxaspiro[3.3]hept-6-yl)octahydropyrrolo[3,4-c]pyrrole

[0754]

[0755] 1. Synthesis of tert-butyl (3aR,6aR)-5-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0756]

[0757] (3aS, 6aS)-hexahydropyrrolo [3, 4-c] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (274.37 mg, 998.98 umol) was added to a solution of 4,6-dimethyl-2- (trifluoromethyl) pyrimidine-5-sulfonyl chloride (200 mg, 665.99 umol, oxalate) and DIEA (258.22 mg, 2.00 mmol, 348.00 uL) in DCM (10 mL). The mixture was stirred at 20 ° C for 2 hours. The mixture was concentrated to give a crude residue, which was purified by silica gel chromatography (petroleum ether / EtOAc = 5 / 1 to 3 / 1) to give the desired product (110 mg, 244.19 umol, 36.7% yield) as a yellow solid. LCMS m / z = 395.1 [M-tBu + H] + . 1HNMR (500 MHz, MeOD): δ ppm 3.74-3.70 (m, 2H), 3.64-3.61 (m, 2H), 3.19-3.15 (m, 2H), 3.07-3.03 (m, 2H), 2.95 (s, 6H), 2.38-2.35 (m, 2H), 1.47(s, 9H).

[0758] 2. Synthesis of (3aR,6aR)-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole

[0759]

[0760] To a solution of tert-butyl (3aR,6aR)-5-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (110 mg, 244.19 umol) in DCM (3 mL) was added HCl / dioxane (4 M, 3 mL). The mixture was stirred at 20 °C for 1 h. The mixture was concentrated to give compound 4 (120 mg, HCl salt) as a yellow solid. LCMS m / z = 351.1 [M+H] + .

[0761] 3. Synthesis of (3aR,6aR)-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-(2-oxaspiro[3.3]hept-6-yl)octahydropyrrolo[3,4-c]pyrrole

[0762]

[0763] 2-Oxaspiro[3.3]heptan-6-one (34.78 mg, 310.22 umol) was added to a solution of (3aR,6aR)-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole (60 mg, 155.11 umol, HCl salt) and TEA (31.39 mg, 310.22 umol, 43.24 uL) in MeOH (2 mL). The pH of the solution was adjusted to pH=5-6 by adding HOAc. The reaction was stirred for 30 min, then NaBH3CN (19.49 mg, 310.22 umol) was added and the mixture was stirred at 20 °C for 2 h. The mixture was filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; condition: water (NH4HCO3)-ACN; start B: 32; end B: 60; flow rate (ml / min): 25) to give the desired compound (25 mg, 36.1% yield) as a white solid. LCMS m / z =447.1 [M-tBu+H] + . 1 HNMR (500 MHz, MeOD): δ ppm 4.70 (s, 2H), 4.60 (s, 2H), 3.64-3.61 (m, 2H), 3.26-3.23 (m, 1H), 3.22-3.20 (m, 2H), 2.92 (s, 6H), 2.91-2.87 (m, 2H), 2.46-2.42 (m, 4H), 2.31-2.28 (m, 2H), 2.09-2.07 (m, 2H).

[0764] Example 62: (3aR, 6aR)-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-((tetrahydro-2H-pyran-4-yl)methyl)octahydropyrrolo[3,4-c]pyrrole

[0765]

[0766] Following a procedure analogous to that described in step 3 of Example 61, (3aR,6aR)-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-((tetrahydro-2H-pyran-4-yl)methyl)octahydropyrrolo[3,4-c]pyrrole (21 mg, 30%) was obtained from (3aR,6aR)-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole and tetrahydro-2H-pyran-4-carbaldehyde. LCMS m / z = 449.1 [M+H] + . 1 HNMR (500 MHz, MeOD): δ ppm 3.94-3.91 (m, 2H), 3.64-3.61 (m, 2H), 3.42-3.37 (m, 2H), 3.10-3.05 (m, 2H), 2.93-2.88 (m, 8H), 2.60-2.55 (m, 4H), 2.36-2.34 (m, 2H), 1.71-1.68 (m, 3H), 1.25 -1.19 (m, 2H).

[0767] Determination

[0768] EBP functional assay

[0769] EBP immunoaffinity (IA) LC-MS assay measures the effectiveness of small molecule inhibitors of EBP by quantifying concentration-dependent changes in enzyme substrates and products using liquid chromatography atmospheric pressure chemical ionization multiple reaction monitoring mass spectrometry (LC-APCI MRM MS). HEK293T cells are used as the source of EBP enzyme. The enzyme is incubated with small molecule inhibitors of varying concentrations for 30 min. The deuterated form of the EBP substrate yeast sterol-d5 (Avanti Polar Lipids, catalog number 700068P-1mg) is then added, and the plate is incubated at 37 ° C for 4 h. Finally, sterol isomers are extracted and injected into LC-APCI MRM MS. The MRM transitions for quantifying yeast sterol and dihydro-7-enecholestanol (substrate or product of EBP enzymatic reaction, respectively) are 372.3-203.2, CE 30 and DP 80 in positive ion mode. The percentage conversion of zymosterol-d5 to dehydro-7-enocholestanol-d5 was used to derive the IC 50 Tasin-1 (1'-[(4-methoxyphenyl)sulfonyl]-4-methyl-1,4'-bipiperidine, CAS 792927-06-1) was used as a reference small molecule inhibitor.

[0770]

[0771] The percent conversion versus compound concentration data were fit to the following 4-parameter logistic model to generate the IC 50 curve:

[0772]

[0773] Data of the Example

[0774] Example No. EBP functional assay 1 +++ 2 ++ 3 +++ 4 ++ 5 +++ 6 ++ 7 +++ 8 ++ 9 ++ 10 + 11 NT 12 ++ 13 + 14 + 15 ++ 16 +++ 17 ++ 18 NT 19 ++ 20 ++ 21 +++ 22 NT 23 +++ 24 NT 25 NT 26 NT 27 +++ 28 +++ 29 +++ 30 ++ 31 ++ 32 +++ 33 + 34 +++ 35 +++ 36 NT 37 NT 38 NT 39 ++ 40 NT 41 NT 42 NT 43 NT 44 NT 45 ++ 46 ++ 47 ++ 48 ++ 49 + 50 +++ 51 +++ 52 + 53 ++ 54 ++ 55 ++ 56 ++ 57 ++ 58 ++ 59 ++ 60 +++ 61 +++ 62 +++

[0775] *+ means >0.5 μM; ++ means 0.1-0.5 μM; +++ means <0.1 μM; NT = not tested

Claims

1. A compound represented by formula (I): (I)， or a pharmaceutically acceptable salt thereof, wherein: X is NR 1 or CR x ; R x For-NR 1 R 2 ; R 1 and R 2 Each independently selected from H, C 1-6 Alkyl, C 4-8 Cycloalkyl, Het or -Z-Het, wherein the C 1-6 Alkyl, C 4-8 Cycloalkyl and Het are each optionally substituted by one or more R 4 Replacement, the prerequisite is 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 it is attached, it forms 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; Z is C 1-4 alkyl; Het is a 4- to 6-membered monocyclic heterocyclic group or a 6- to 8-membered bicyclic heterocyclic group, each of which is optionally substituted by one or more R 4 replace; R 4 C independently at each occurrence 1-6 Alkyl or halide; 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 is independently selected at each occurrence from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Cycloalkyl, -OR 5a and cyano; R 5a Selected from H, C 1-4 Alkyl and C 1-4 Haloalkyl; The prerequisite is that the compound is not the following compound: 。 2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein Het is a 4- to 6-membered oxygen-containing monocyclic saturated heterocyclic group or a 6- to 8-membered oxygen-containing bicyclic saturated heterocyclic group.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, 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.

4. The compound according to any one of claims 1 to 3, wherein the compound is represented by formula (II): (II); or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of phenyl, pyridyl, pyrimidinyl and pyrazolyl.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: ; ; ;or wherein each of the formulae depicted above is optionally replaced by one to three R 5 replace.

7. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: ; ; ; ; ; ; ;or .

8. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: ; ; ; ; ; ;or .

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 5 is independently selected at each occurrence from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 5a and -CN.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 5 is independently selected at each occurrence from -Cl, -F, -CH3, -CF3, -OCH3 and -CN.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 1 It is -CH2-Het or Het.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 1 For Het.

13. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein Het is selected from the group consisting of oxetanyl, 2-oxaspiro[3.3]heptyl, tetrahydropyranyl and 2-oxabicyclo[2.1.1]hexyl, 2-oxabicyclo[3.1.1]heptyl, tetrahydrofuranyl.

14. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein Het is selected from the group consisting of tetrahydropyranyl and tetrahydrofuranyl.

15. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein Het is represented by the following formula: , , , , or wherein each of the formulae depicted above is optionally replaced by one or two R 4 replace.

16. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein Het is represented by the following formula: ;or wherein each of the formulae depicted above is optionally replaced by one or two R 4 replace.

17. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein Het is represented by the following formula: , , , , or .

18. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein Het is represented by the following formula: ;or .

19. The compound according to any one of claims 1 to 18, wherein the compound is represented by formula (III): (III); or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: ;or wherein each of the formulae depicted above is optionally replaced by one to three R 5 replace.

21. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: ;or .

22. A compound as claimed in any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein R 5 In each occurrence, independently selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl.

23. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein R 5 is independently selected at each occurrence from -CH3, -, and -CF3.

24. The compound of any one of claims 1 to 3, wherein the compound is represented by formula (IV): (IV); or a pharmaceutically acceptable salt thereof.

25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of phenyl, pyridyl and pyrazolyl.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: ; ;or wherein each of the formulae depicted above is optionally replaced by one to three R 5 replace.

27. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: ; ; ; ; ;or .

28. A compound as described in any one of claims 1 to 3 and 24 to 27, or a pharmaceutically acceptable salt thereof, wherein R 5 In each occurrence, independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 5a and C 3-8 Cycloalkyl.

29. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R 5 is independently selected at each occurrence from -CH3, -CF3, -OCH3, -OCHF2 and cyclopropyl.

30. A compound as described in any one of claims 1 to 3 and 24 to 29, or a pharmaceutically acceptable salt thereof, wherein R 1 is Het or –Z-Het; and R 2 H or C 1-6 alkyl.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein Het is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, and 2-oxaspiro[3.3]heptyl.

32. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R 1 It is expressed by the following formula: ; ; ; ; ;or wherein each of the formulae depicted above is optionally replaced by one or two R 4 replace.

33. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R 1 It is expressed by the following formula: ; ; ; ; ;or .

34. A compound as described in any one of claims 1 to 3 and 24 to 33, or a pharmaceutically acceptable salt thereof, wherein R 2 is H or –CH3.

35. A compound as described in any one of claims 1 to 3 and 24 to 29, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the N atom to which it is attached, it forms a 4- to 7-membered monocyclic heterocyclic ring, which is optionally replaced by one or more R 4 replace.

36. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the N atom to which it is attached, is selected from the group consisting of piperidinyl and morpholinyl.

37. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the N atom to which it is attached, it is represented by the following formula: ;or wherein each of the formulae depicted above is optionally replaced by one or two R 4 replace.

38. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the N atom to which it is attached, it is represented by the following formula: ;or .

39. A compound as described in any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R 4 is –CH3.

40. The compound of claim 1, wherein the compound is represented by formula (II): (II); or a pharmaceutically acceptable salt thereof, wherein: R 1 Het or -CH2-Het Het is a 4- to 6-membered monocyclic heterocyclic group or a 6- to 8-membered bicyclic heterocyclic group, each of which is optionally substituted by one or more R 4 replace; Each R 4 Independently for C 1-3 alkyl; R 3 For one or more R 5 substituted 5- or 6-membered monocyclic heteroaryl; Each R 5 Independently for C 1-3 Alkyl and C 1-3 Halogenated alkyl.

41. The compound of claim 40 or a pharmaceutically acceptable salt thereof, wherein R 3 is pyridyl, pyrimidinyl or pyrazolyl.

42. The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: ; ;or wherein each of the formulae depicted above is optionally replaced by two or three R 5 replace.

43. The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: ; ; ;or .

44. A compound as described in any one of claims 40 to 43, wherein each R 5 Selected from -CF3 and -CH3.

45. The compound or pharmaceutically acceptable salt thereof according to any one of claims 40 to 44, wherein Het is tetrahydropyranyl or 2-oxabicyclo[2.1.1]hexyl.

46. ​​The compound of claim 45 or a pharmaceutically acceptable salt thereof, wherein Het is represented by the formula: or wherein each of the formulae depicted above is optionally replaced by one or two R 4 replace.

47. The compound of claim 45 or a pharmaceutically acceptable salt thereof, wherein Het is represented by the formula: or .

48. A compound as described in any one of claims 40 to 44, or a pharmaceutically acceptable salt thereof, wherein R 1 It is expressed by the following formula: , or .

49. A compound as described in any one of claims 40 to 48, or a pharmaceutically acceptable salt thereof, wherein R 4 It is -CH3.

50. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (3aR,5r,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole; (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole; (3aR,5r,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole; (3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-5-(4-methylpiperidin-1-yl)octahydrocyclopenta[c]pyrrole; (3aR,5s,6aS)-2-((2,4-dimethylphenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((4,6-dimethylpyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; 4-((3aR,5r,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)morpholine; (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydrofuran-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,6aS)-2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole; 2-(mesitylsulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole; 3-Fluoro-5-(((3aR,6aS)-5-(tetrahydro-2H-pyran-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)benzonitrile; (3aR,6aS)-2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole; (3aR,6aS)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole; (3aR,6aS)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole; (3aR,6aS)-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole; (3aR,6aS)-2-((2-chloro-6-methoxypyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole; (3aR,6aS)-2-((3,5-difluorophenyl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole; (3aR,6aS)-2-((6-methoxypyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole; (3aR,6aS)-2-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole; (3aR,6aS)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole; (3aR,6aS)-2-((2,4-dimethylpyrimidin-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole; (3aR,6aS)-2-((2,4-dimethylpyrimidin-5-yl)sulfonyl)-5-(tetrahydrofuran-3-yl)octahydropyrrolo[3,4-c]pyrrole; (3aR,6aR)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole; (3aR,6aR)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[3,4-c]pyrrole; (3aS,6aS)-5-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2-(oxan-4-ylmethyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; (3aS,6aS)-5-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2-(2-oxaspiro[3.3]hept-6-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; (3aS,6aS)-5-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2-(oxan-4-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; rac-(3aR,6aR)-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-2-(2-oxaspiro[3.3]hept-6-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; rac-(3aR,6aR)-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-2-(oxan-4-ylmethyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; rac-(3aR,6aR)-5-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2-(2-oxaspiro[3.3]hept-6-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; rac-(3aR,6aR)-5-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2-(oxan-4-ylmethyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; rac-(3aR,6aR)-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-2-(oxan-4-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; (3aS,6aS)-2-[(1-methyl-2-oxabicyclo[ 2.1.1]hex-4-yl)methyl]-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; rel-(3aR,6aR)-2-[(1-methyl-2-oxabicyclo[ 3.1.1]hept-5-yl)methyl]-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; (3aR,6aR)-2-[(1-methyl-2-oxabicyclo[ 2.1.1]hex-4-yl)methyl]-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; (3aS,6aS)-2-[(1-methyl-2-oxabicyclo[ 2.1.1]hex-4-yl)methyl]-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; rac-(3aR,6aR)-5-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2-(oxan-4-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; rac-(3aR,6aR)-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-2-(oxan-4-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; (3aR,6aRS)-5-(2,5-dimethylpyrazol-3-yl)sulfonyl-2-(oxan-4-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; and rac-(3aR,6aR)-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl-2-(oxetan-3-ylmethyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole; or a pharmaceutically acceptable salt thereof.

51. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

52. A method for treating a disease mediated by emopamide binding protein, comprising administering to a subject an effective amount of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 50, or the pharmaceutical composition according to claim 51.

53. A method of treating an autoimmune disease in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 50, or a pharmaceutical composition as claimed in claim 51.

54. The method of claim 53, wherein the autoimmune disease is multiple sclerosis.

55. The method of claim 54, wherein the compound or pharmaceutical composition repairs or forms new myelin sheaths in the subject.

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