Inhibition of monoacylglycerol lipase (MAGL)

Abstract

Provided herein are 1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-ylmethanone compounds, further substituted with aryl and pyrazolyl moieties, for inhibiting monoacylglycerol lipase (MAGL) for use in the treatment of MAGL-mediated diseases or disorders, i.e., neurodegenerative diseases, pain, and inflammatory diseases or conditions, and cancer, as well as related methods for making and using the compounds.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 294,747, filed December 29, 2021, which is hereby incorporated by reference in its entirety.

[0002] Technical Field The present disclosure relates to compounds and methods for inhibiting monoacylglycerol lipase (MAGL), including compounds and methods for the reversible inhibition of MAGL. [Background technology]

[0003] background MAGL is the primary enzyme involved in the in vivo degradation of 2-arachidonoylglycerol (2-AG), an endogenous ligand for cannabinoid receptors (e.g., CB1 and CB2). MAGL inhibition increases the accumulation of 2-arachidonoylglycerol (2-AG), an agonist of CB1 / 2 receptors, and reduces arachidonic acid (AA) and prostaglandin levels in brain and peripheral tissues. Irreversible MAGL inhibitor compounds, such as JZL-184, increase brain and peripheral 2-AG and decrease brain AA. However, chronic, irreversible MAGL inhibition can lead to tolerance. Covalent interactions with MAGL can lead to irreversible enzyme inhibition, potentially resulting in immune-mediated toxicity.

[0004] Thus, there exists a need for reversible MAGL inhibitors useful in the treatment of MAGL-mediated diseases or disorders, including the development of therapeutic compounds with improved dose control and exposure. Such compounds can be developed through clinical trials as pain management treatments and / or analgesic compounds for the treatment of various MAGL-mediated diseases.

[0005] Thus, there is a need in the art for compounds that can potently, selectively, and reversibly inhibit MAGL and for means to treat conditions or disorders associated with or linked to endocannabinoid signaling activity. The present disclosure addresses these and other unmet needs in the art. Summary of the Invention

[0006] overview In particular, the inventors have discovered compounds that inhibit monoacylglycerol lipase (MAGL), including compounds that reversibly inhibit MAGL. Accordingly, in another aspect, the present disclosure provides compounds and methods for inhibiting monoacylglycerol lipase (MAGL).

[0007] In some embodiments, the present disclosure provides a compound of formula (I): TIFF0007777891000001.tif50128In formula, A1 is TIFF0007777891000002.tif39128, R1 is hydrogen, halogen, or cyano; R 3a and R5 are each independently hydrogen, halogen, or lower alkyl; R 52 is lower alkyl, lower cycloalkyl, or lower haloalkyl; R 3b is a halogen, W is a diazole optionally substituted with lower alkyl, lower cycloalkyl, or lower haloalkyl; B1 is TIFF0007777891000003.tif49128, R 20 is hydrogen, halogen, lower alkyl, or lower haloalkyl, and R 26 is hydrogen or halogen, However, the compound in question is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0008] In some embodiments, the present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, fluoro, or cyano; and R 3a and R5 are each independently hydrogen, fluoro, or methyl. In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is fluoro and R 3a and R5 are each independently hydrogen. In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, fluoro, or cyano; and R 3a is hydrogen, fluoro, or methyl, and R is hydrogen. In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or fluoro, and R 3a is hydrogen, fluoro, or methyl, and R5 is hydrogen.

[0009] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 52 is lower alkyl, cyclopropyl, or lower haloalkyl, and R 3b In some embodiments, the present disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 52 is lower alkyl, and R 3b In some embodiments, the present disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 52 is lower haloalkyl, and R 3bIn some embodiments, the present disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 52 is lower alkyl optionally substituted with one or more fluoro groups, and R 3b In some embodiments, the present disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 52 is cyclopropyl and R 3b is fluoro.

[0010] In some embodiments, the disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein W is: TIFF0007777891000004.tif75132; where * indicates a covalent bond to B1, and R 30 , R 31 , R 32 , and R 33 are each independently hydrogen, lower alkyl, lower haloalkyl, or lower cycloalkyl, with the proviso that R 31 and R 33 At least one of, and R 32 and R 33 At least one of the groups is not hydrogen.

[0011] In some embodiments, the disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein W is: TIFF0007777891000005.tif75132; where * indicates a covalent bond to B1, and R 30 , R 31 , R 32 , and R 33 are each independently hydrogen, lower alkyl, lower haloalkyl, or lower cycloalkyl, with the proviso that R 31 and R 33 At least one of, and R 32 and R 33At least one of the groups is not hydrogen.

[0012] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 30 , R 31 , R 32 , and R 33 are each independently hydrogen, methyl, CF, or cyclopropyl, with the proviso that R 31 and R 33 At least one of, and R 32 and R 33 In some embodiments, the present disclosure provides a compound of formula (I) below, or a pharmaceutically acceptable salt thereof, wherein R 30 In some embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein R 33 is hydrogen, methyl, CF3, or cyclopropyl, with the proviso that R 31 and R 33 At least one of, and R 32 and R 33 In some embodiments, the present disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 32 is hydrogen and R 33 is methyl, CF3, or cyclopropyl, or R 32 is methyl, CF3, or cyclopropyl, and R 33 In some embodiments, the present disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 31 is hydrogen and R 33 is methyl, CF3, or cyclopropyl, or R 31 is methyl, CF3, or cyclopropyl, and R 33 is hydrogen.

[0013] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 20 is hydrogen, fluoro, chloro, methyl, or CF3, and R 26 In some embodiments, the present disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 20 is fluoro, chloro, methyl, or CF3, and R 26 In some embodiments, the present disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 20 is methyl or CF3, and R 26 In some embodiments, the present disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 20 is fluoro or chloro or CF3, and R 26 is hydrogen or fluoro.

[0014] In some embodiments, the disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is not (2-fluoro-5-hydroxyphenyl){6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone.

[0015] In some embodiments, the disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0016] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A1 is: TIFF0007777891000006.tif38128, R1 is hydrogen, F or cyano, and R 3a and R5 are each independently hydrogen, F or methyl; W is TIFF0007777891000007.tif30128, where * indicates a covalent bond to B1, and R 30 is hydrogen, methyl, CF3, or cyclopropyl, and R 20 is hydrogen, F, Cl, methyl or CF3, and R 26 is hydrogen or F, with the proviso that the compound is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0017] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A1 is: TIFF0007777891000008.tif38128, R1 is hydrogen, F, or cyano, and R 3a and R5 are each independently hydrogen, F, or methyl; W is TIFF0007777891000009.tif39128, * indicates covalent bond to B1, R 31 and R 33 are each independently hydrogen, methyl, CF, or cyclopropyl, with the proviso that R 31 and R 33 At least one of R is hydrogen; 20 is hydrogen, F, Cl, methyl, or CF3, and R 26 is hydrogen or F.

[0018] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A1 is: TIFF0007777891000010.tif38128, R1 is hydrogen, F, or cyano, and R 3a and R5 are each independently hydrogen, F, or methyl; W is TIFF0007777891000011.tif40128, * indicates covalent bond to B1, R 32 and R 33are each independently hydrogen, methyl, CF, or cyclopropyl, with the proviso that R 32 and R 33 At least one of R is hydrogen; 20 is hydrogen, F, Cl, methyl, or CF3, and R 26 is hydrogen or F.

[0019] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A1 is: TIFF0007777891000012.tif38128, R 3b is F and R 52 is lower alkyl optionally substituted with one or more F, or cyclopropyl; W is TIFF0007777891000013.tif30128, where * indicates a covalent bond to B1, and R 30 is hydrogen, methyl, CF3, or cyclopropyl, and R 20 is hydrogen, F, Cl, methyl, or CF3, and R 26 is hydrogen or F.

[0020] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A1 is: TIFF0007777891000014.tif38128, R 3b is F and R 52 is lower alkyl optionally substituted with one or more F, or cyclopropyl; W is TIFF0007777891000015.tif39128, where * indicates a covalent bond to B1, and R 31 and R 33 are each independently hydrogen, methyl, CF, or cyclopropyl, with the proviso that R 31 and R 33 At least one of R is hydrogen; 20 is hydrogen, F, Cl, methyl, or CF3, and R 26 is hydrogen or F.

[0021] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A1 is: TIFF0007777891000016.tif38128, R 3b is F and R 52 is lower alkyl optionally substituted with one or more F, or cyclopropyl; W is TIFF0007777891000017.tif40128, * indicates covalent bond to B1, R 32 and R 33 are each independently hydrogen, methyl, CF, or cyclopropyl, with the proviso that R 32 and R 33 At least one of R is hydrogen; 20 is hydrogen, F, Cl, methyl, or CF3, and R 26 is hydrogen or F.

[0022] Generally, the methods disclosed herein include administering a compound described by a formula disclosed herein to inhibit MAGL. In some embodiments, a compound described by a formula disclosed herein can be used by contacting the compound with a cell (e.g., a cell expressing MAGL) to reversibly inhibit MAGL in the cell. In yet another aspect, the disclosure provides a method for treating a monoglycerol lipase-mediated disease or disorder. Without limitation, administration to a cell can be performed in vitro or in vivo. In some embodiments, the method includes administering a therapeutically effective amount of a compound described by a formula disclosed herein to a subject in need thereof. For example, an effective amount of a compound disclosed herein can be administered to a subject to treat a condition responsive to reversible inhibition of MAGL.

[0023] In some embodiments, the present disclosure provides a compound of formula (I): TIFF0007777891000018.tif50128In formula, A1 is TIFF0007777891000019.tif39128, R1 is halogen, hydrogen, or cyano; R 3a and R5 are each independently hydrogen, halogen, or lower alkyl; R 52 is lower alkyl, lower cycloalkyl, or lower haloalkyl; R 3b is a halogen, W is a diazole optionally substituted with lower alkyl, lower cycloalkyl, or lower haloalkyl; B1 is TIFF0007777891000020.tif49128, R 20 is halogen, hydrogen, lower alkyl, or lower haloalkyl, and R 26 is hydrogen or halogen, However, the compound in question is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0024] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, fluoro or cyano; R 3a and R5 are each independently hydrogen, halogen, or methyl; R 52 is lower alkyl, cyclopropyl, or lower haloalkyl; R 3b is fluoro, W is diazole optionally substituted with one of methyl, cyclopropyl, or CF3; R 20is fluoro or chloro, methyl, or CF3, and R 26 is hydrogen, fluoro or chloro.

[0025] In some embodiments, the disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein W is: TIFF0007777891000021.tif75132, where * indicates a covalent bond to B1, and R 30 , R 31 , R 32 , and R 33 are each independently hydrogen, lower alkyl, lower haloalkyl, or lower cycloalkyl, with the proviso that R 31 and R 33 At least one of, and R 32 and R 33 At least one of the groups is not hydrogen.

[0026] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 30 , R 31 , R 32 , and R 33 are each independently hydrogen, methyl, CF, or cyclopropyl, with the proviso that R 31 and R 33 At least one of, and R 32 and R 33 At least one of the groups is not hydrogen.

[0027] In some embodiments, the disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein W is: TIFF0007777891000022.tif42144, wherein * indicates a covalent bond to B1.

[0028] In some embodiments, the disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein W is: TIFF0007777891000023.tif29128, * indicates covalent bond to B1, R 30 is methyl.

[0029] In some embodiments, the disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein W is: TIFF0007777891000024.tif39128, * indicates covalent bond to B1, R 31 and R 33 are each independently hydrogen, methyl, CF, or cyclopropyl, with the proviso that R 31 and R 33 One of the groups is hydrogen.

[0030] In some embodiments, the disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein W is: TIFF0007777891000025.tif40128, * indicates covalent bond to B1, R 32 and R 33 are each independently hydrogen, methyl, CF, or cyclopropyl, with the proviso that R 32 and R 33 One of the groups is hydrogen.

[0031] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A1 is: The file is TIFF0007777891000026.tif37128.

[0032] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen.

[0033] In some embodiments, the present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is fluoro.

[0034] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3a is hydrogen, fluoro, or methyl.

[0035] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3a is hydrogen.

[0036] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 20 is methyl and R 26 is hydrogen or fluoro, or R 20 is chloro, fluoro or CF3, R 26 is hydrogen.

[0037] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A1 is: The file is TIFF0007777891000027.tif38128.

[0038] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 52 is lower alkyl optionally substituted with one or more fluoro and cyclopropyl.

[0039] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3b is fluoro.

[0040] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 20 is methyl and R 26 is hydrogen or fluoro, or R 20is fluoro or CF3, and R 26 is hydrogen.

[0041] In some embodiments, the present disclosure provides a compound of formula (II-B) or a pharmaceutically acceptable salt thereof: TIFF0007777891000028.tif86128In formula, R1 is halogen or cyano; R3 is hydrogen, lower alkyl, or halogen; R5 is hydrogen, halogen, or lower alkyl; R 20 is halogen or lower alkyl optionally substituted with one or more halogens, R 26 is a halogen or hydrogen, and R 30 is hydrogen or lower alkyl optionally substituted with one or more halogens, However, the compound in question is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0042] In some embodiments, the present disclosure provides a compound of formula (II-B) or a pharmaceutically acceptable salt thereof, wherein: R1 is F or cyano; R3 is hydrogen, methyl, or F; R5 is hydrogen, F, or methyl; R 20 is F, methyl, or CF3, R 26 is hydrogen or F, and R 30 is hydrogen, methyl, or CF3, However, the compound in question is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0043] In some embodiments, the present disclosure provides a compound of formula (II-C) or a pharmaceutically acceptable salt thereof: TIFF0007777891000029.tif75133In formula, R1 is halogen or cyano; R3 is hydrogen, lower alkyl, or halogen; R5 is hydrogen, halogen, or lower alkyl; R 20 is halogen or lower alkyl optionally substituted with one or more halogens, R 26 is hydrogen or halogen, and R 31 and R 33 are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 31 and R 33 One of the is hydrogen.

[0044] In some embodiments, the present disclosure provides a compound of formula (II-C) or a pharmaceutically acceptable salt thereof, wherein: R1 is F or cyano; R3 is hydrogen, methyl, or F; R5 is hydrogen, F, or methyl; R 20 is F, methyl, or CF3, R 26 is hydrogen or F, and R 31 and R 33 are each independently hydrogen, methyl, or CF3.

[0045] In some embodiments, the present disclosure provides a compound of formula (II-D) or a pharmaceutically acceptable salt thereof: TIFF0007777891000030.tif78128In formula, R1 is halogen or cyano; R3 is hydrogen, lower alkyl, or halogen; R5 is hydrogen, halogen, or lower alkyl; R6 is hydrogen; R 20 is halogen or lower alkyl optionally substituted with one or more halogens, R 26 is a halogen or hydrogen, and R 32 and R 33 are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 32 and R 33 One of the is hydrogen.

[0046] In some embodiments, the present disclosure provides a compound of formula (II-D) or a pharmaceutically acceptable salt thereof, wherein: R1 is F or cyano; R3 is hydrogen, F, or methyl; R5 is hydrogen, F, or methyl; R 20 is F or methyl or CF3, R 26 is hydrogen or F, and R 32 and R 33 are each independently hydrogen, methyl, or CF3, with the proviso that R 32 and R 33 One of the is hydrogen.

[0047] In some embodiments, the present disclosure provides a compound of formula (III-B) or a pharmaceutically acceptable salt thereof: TIFF0007777891000031.tif87128In formula, R3 is a halogen; R 52 is lower alkyl or lower cycloalkyl, each of which may be substituted with halogen; R 30 is lower alkyl, R 20 is lower alkyl, and R 26 is hydrogen or halogen.

[0048] In some embodiments, the present disclosure provides a compound of formula (III-B) or a pharmaceutically acceptable salt thereof, wherein: R3 is F, R 52 is lower alkyl optionally substituted with one or more F, or cyclopropyl; R 30 is methyl, R 20 is methyl, and R 26 is hydrogen or F.

[0049] In some embodiments, the present disclosure provides a compound of formula (III-C) or a pharmaceutically acceptable salt thereof: TIFF0007777891000032.tif66131In formula, R3 is a halogen; R 52 is lower alkyl or lower cycloalkyl, each of which may be substituted with halogen; R 31 and R 33 are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 31 and R 33 One of them is hydrogen, R 20 is lower alkyl optionally substituted with halogen, and R 26 is hydrogen or halogen.

[0050] In some embodiments, the present disclosure provides a compound of formula (III-C) or a pharmaceutically acceptable salt thereof, wherein: R3 is F, R 52is lower alkyl optionally substituted with one or more F, or cyclopropyl; R 31 and R 33 are each independently hydrogen, methyl, or CF3, with the proviso that R 31 and R 33 One of them is hydrogen, R 20 is methyl or CF3, and R 26 is hydrogen or F.

[0051] In some embodiments, the present disclosure provides a compound of formula (III-D) or a pharmaceutically acceptable salt thereof: TIFF0007777891000033.tif87128In formula, R3 is a halogen; R 52 is lower alkyl or lower cycloalkyl, each of which may be substituted with halogen; R 32 and R 33 are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 32 and R 33 One of the is hydrogen. R 20 is lower alkyl optionally substituted with halogen, and R 26 is hydrogen or halogen.

[0052] In some embodiments, the present disclosure provides a compound of formula (III-D) or a pharmaceutically acceptable salt thereof, wherein: R3 is F, R 52 is lower alkyl optionally substituted with one or more F, or cyclopropyl; R 32 and R 33 are each independently hydrogen, methyl, or CF3, with the proviso that R 32 and R 33 One of them is hydrogen, R 20 is methyl or CF3, and R 26 is hydrogen or F.

[0053] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: TIFF0007777891000034.tif70128In formula, The dashed line represents an optional double bond; R1 is a halogen; R3 is hydrogen; W is A, A is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with R 20 is halogen or lower alkyl optionally substituted with one or more halogens, R 30 is lower alkyl optionally substituted with one or more halogens, and R 26 is a halogen or hydrogen, However, the compound in question is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0054] In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is TIFF0007777891000035.tif33128 or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is TIFF0007777891000036.tif51128 or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is TIFF0007777891000037.tif33128 or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is TIFF0007777891000038.tif41128 or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is TIFF0007777891000039.tif35128 or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is TIFF0007777891000040.tif41128 or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is TIFF0007777891000041.tif30128 or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is TIFF0007777891000042.tif45128 or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is TIFF0007777891000043.tif49128 or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the present disclosure provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), a compound defined herein or a pharmaceutically acceptable salt thereof, provided that the compound is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0064] In some embodiments, the present disclosure provides a method of inhibiting monoacylglycerol lipase (MAGL) in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound defined herein.

[0065] In some embodiments, the disclosure provides a method of reversibly inhibiting monoacylglycerol lipase (MAGL), the method comprising contacting a cell expressing MAGL with a compound as defined herein.

[0066] The present disclosure also provides pharmaceutical compositions comprising compounds, as defined herein as reversible and / or selective MAGL inhibitory compounds disclosed herein, and a pharmaceutically acceptable carrier or excipient.

[0067] BRIEF DESCRIPTION OF THE DRAWINGS This disclosure does not include drawings. DETAILED DESCRIPTION OF THE INVENTION

[0068] Detailed Description Applicant has discovered compounds that are reversible MAGL inhibitory compounds and selective MAGL inhibitory compounds. In some embodiments, the compounds are reversible MAGL inhibitory compounds. In some embodiments, the compounds are selective MAGL inhibitory compounds. In some embodiments, the compounds are both reversible MAGL inhibitory compounds and selective MAGL inhibitory compounds.

[0069] In some embodiments, the compound is a reversible MAGL inhibitory compound that is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone. In some embodiments, the compound is a reversible MAGL inhibitory compound and a selective MAGL inhibitory compound that is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0070] compound In some embodiments, the present disclosure provides certain compounds, or pharmaceutically acceptable salts thereof, that are both selective and reversible MAGL inhibitory compounds, as defined herein.

[0071] In some embodiments, the present disclosure provides certain compounds of formula (IA), or pharmaceutically acceptable salts thereof, that are both selective and reversible MAGL inhibitory compounds as defined herein: TIFF0007777891000044.tif30128In formula, A1 is aryl or heteroaryl optionally substituted with one or more Ra; each Ra is independently halogen, cyano, lower alkyl optionally substituted with one or more halogens, cycloalkyl, aminoalkyl, carboxy, carboxamido, or -OR; R6 is hydrogen, lower alkyl or lower cycloalkyl optionally substituted with one or more halogens; V is Selected from TIFF0007777891000045.tif77136, each p is independently 0, 1, 2, 3, or 4; each R independently represents hydrogen, halogen, or alkyl optionally substituted with one or more halogens; W is -A2-, -C(O)-, C(O)-A2-, -C(O)N(R 10 )-, and -C(O)N(R 10 )-A2-, A2 is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with Each R 30 is lower alkyl, R 10 is hydrogen or lower alkyl, B is one or more R b -OR b is a 5- or 6-membered aryl or heteroaryl optionally substituted with Each R b are independently halogen, cyano, lower alkyl optionally substituted with one or more halogens, cycloalkyl, aminoalkyl, carboxy, or carboxamido; However, the compound of formula (IA) is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0072] In some embodiments, the compound is both a selective MAGL inhibitory compound and a chemical MAGL inhibitory compound of formula (IA) that is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone, wherein A1 is a 6-membered aryl ring or a heteroaryl ring containing at least one nitrogen, A2 is a 5-membered heteroaryl ring containing at least one nitrogen heteroatom, and B is a 5- or 6-membered aryl or B is a 5- or 6-membered heteroaryl ring containing at least one nitrogen atom, and wherein each heteroaryl ring of A1, A2, and B contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0073] In some embodiments, A of formula (IA) may be one or more R a In some embodiments, A1 of formula (IA) is a 6-membered aryl or heteroaryl optionally substituted with one or more R a In some embodiments, A1 of formula (IA) is phenyl optionally substituted with one or more R a In some embodiments, A1 of formula (IA) is pyridine optionally substituted with one or more R a and phenyl optionally substituted with .

[0074] Each R of A1 in formula (IA) a The substitutions may be the same or different. aare independently halogen, cyano, lower alkyl optionally substituted with one or more halogens, cycloalkyl, aminoalkyl, carboxy, carboxamide, or -OR6, and each R6 in formula (IA) is independently hydrogen, lower alkyl, or lower cycloalkyl optionally substituted with one or more halogens. In some embodiments, the halogen in R6 in formula (IA) is F or Cl. In some embodiments, the halogen in R6 in formula (IA) is F. In some embodiments, the halogen in R6 in formula (IA) is F or Cl. In some embodiments, the lower alkyl in R6 in formula (IA) is (C1-C4) alkyl. In some embodiments, the lower alkyl in R6 in formula (IA) is methyl optionally substituted with one or more F. In some embodiments, the R6 in formula (IA) is a is CHF, CHF, CF -cyclopropyl, aminoalkyl (including azuridinyl), carboxy, carboxamido, formamido, and amido. In some embodiments, R of formula (IA) a In some embodiments, the cycloalkyl in R of formula (IA) is cyclopropyl. a is -NRxCORy or -CONRx or NRxCO, where Rx and Ry are each independently hydrogen or lower alkyl. In some embodiments, R of formula (IA) a is -NRxCORy or -CONRx or NRxCO, where Rx and Ry are each independently (C1-C4) alkyl or hydrogen. In some embodiments, R of formula (IA) a is -NRxCORy or -CONRx or NRxCO, where Rx and Ry are each independently methyl. In some embodiments, R of formula (IA) a is —NRxCORy or —CONRx or NRxCO, where Rx and Ry are each independently hydrogen.

[0075] In some embodiments, V in formula (IA) is TIFF0007777891000046.tif32128, wherein n and each Rv are as defined above. In some embodiments, V of formula (IA) is: TIFF0007777891000047.tif32128, wherein n and each R are as defined above. In some embodiments, V of formula (IA) is: TIFF0007777891000048.tif32128. In some embodiments, V of formula (IA) is TIFF0007777891000049.tif31128. In some embodiments, V of formula (IA) is TIFF0007777891000050.tif31128. In some embodiments, V of formula (IA) is TIFF0007777891000051.tif31128. In some embodiments, V of formula (IA) is TIFF0007777891000052.tif32128, where Rv is as defined herein for formula (IA).

[0076] In some embodiments, each Rv in Formula (IA) is independently hydrogen, halogen, or alkyl optionally substituted with one or more halogens. In some embodiments, one or more Rv in Formula (IA) is hydrogen. In some embodiments, one or more Rv in Formula (IA) is F or Cl. In some embodiments, one or more Rv in Formula (IA) is F. In some embodiments, one or more Rv in Formula (IA) is alkyl optionally substituted with one or more F. In some embodiments, one or more Rv in Formula (IA) is lower alkyl optionally substituted with one or more F. In some embodiments, one or more Rv in Formula (IA) is (C1-C4) alkyl optionally substituted with one or more F. In some embodiments, one or more Rv in Formula (IA) is CF3. In some embodiments, each Rv in Formula (IA) is -OR v2 where R v2is hydrogen or alkyl optionally substituted with one or more halogens. In some embodiments, each R of formula (IA) is -OR v2 where R v2 is hydrogen or lower alkyl optionally substituted with one or more halogens. In some embodiments, each R of formula (IA) is -OR v2 where R v2 is hydrogen or lower alkyl optionally substituted with one or more F. In some embodiments, each R of formula (IA) is -OR v2 where R v2 In some embodiments, each R in formula (IA) is —OR v2 where R v2 is lower alkyl optionally substituted with one or more halogens. In some embodiments, each Rv of Formula (IA) is F. In some embodiments, each Rv of Formula (IA) is methyl optionally substituted with one or more F. In some embodiments, each Rv of Formula (IA) is methyl.

[0077] In some embodiments, each R of formula (IA) is —OR v2 where R v2 is (C1-C4) alkyl optionally substituted with one or more halogens. In some embodiments, each Rv of formula (IA) is -OR v2 where R v2 is (C1-C4) alkyl optionally substituted with one or more F. In some embodiments, each Rv of formula (IA) is -OR v2 where R v2 is methyl optionally substituted with one or more F.

[0078] In some embodiments, each n for Rv of formula (IA) is 0, 1, 2, 3, or 4. In some embodiments, each n for Rv of formula (IA) is 0. In some embodiments, each n for Rv of formula (IA) is 1. In some embodiments, each n for Rv of formula (IA) is 2. In some embodiments, each n for Rv of formula (IA) is 3. In some embodiments, each n for Rv of formula (IA) is 4.

[0079] In some embodiments, V in formula (IA) is TIFF0007777891000053.tif32128, wherein Rv is halogen, lower alkyl optionally substituted with one or more halogens, or -OR v2 where R v2 is (C1-C4) alkyl optionally substituted with one or more halogens. In some embodiments, V in formula (IA) is TIFF0007777891000054.tif32128, wherein Rv is F, (C1-C4) alkyl optionally substituted with one or more F, or -OR v2 where R v2 is methyl optionally substituted with one or more halogens. In some embodiments, V in formula (IA) is TIFF0007777891000055.tif32128, wherein Rv is F, methyl optionally substituted with one or more F, or -OR v2 where R v2 is methyl optionally substituted with one or more halogens. In some embodiments, V in formula (IA) is TIFF0007777891000056.tif32128, wherein Rv is F, methyl, ethyl, -CF3, or -OR v2 where R v2 is methyl optionally substituted with one or more halogens.

[0080] In some embodiments, W in formula (IA) is A2, where A2 is as defined above. In some embodiments, W in formula (IA) is -C(O)- or -C(O)N(R 10 )-, wherein R 10 is as defined above with respect to formula (IA). In some embodiments, W in formula (IA) is -C(O)-. In some embodiments, W in formula (IA) is -C(O)N(R 10 )-, wherein R 10 is as defined above for formula (IA).

[0081] In some embodiments, W of formula (IA) is A2 and W of formula (IB) is A, wherein A or A2 is a 5-membered heteroaryl containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and one or more R 30 In some embodiments, W of formula (IA) or formula (IB) is a 5-membered heteroaryl containing one or more nitrogen heteroatoms, and optionally one or more additional heteroatoms selected from nitrogen, oxygen, and sulfur, and one or more R 30 In some embodiments, W of formula (IA) or formula (IB) is a 5-membered heteroaryl containing one or more nitrogen heteroatoms and optionally one or two additional heteroatoms selected from nitrogen, oxygen, and sulfur, and is optionally substituted with one or more R 30 In some embodiments, W in formula (IA) or formula (IB) is TIFF0007777891000057.tif18128, wherein R 30 is as defined herein.

[0082] In some embodiments, A2 of formula (IA) is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with 30is (C1-C4) alkyl. In some embodiments, A2 of formula (IA) is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with 30 is methyl.

[0083] In some embodiments, each R of formula (IA) 10 In some embodiments, each R of formula IA 10 is hydrogen or (C-C) alkyl. In some embodiments, one or more R 10 is hydrogen. In some embodiments, one or more R 10 is (C1-C4) alkyl. In some embodiments, one or more R 10 is methyl.

[0084] In some embodiments, B in formula (IA) is one or more R b and each R is a 5- or 6-membered aryl or heteroaryl optionally substituted with b are independently halogen, cyano, lower alkyl optionally substituted with one or more halogens, cycloalkyl, aminoalkyl, carboxy, carboxamide, or -OR6, and R6 is hydrogen optionally substituted with one or more halogens, lower alkyl, or lower cycloalkyl.

[0085] In some embodiments, B of formula (IA) is phenyl or a 5- or 6-membered heteroaryl containing one or more heteroatoms selected from N, O, and S, wherein the B group is selected from one or more R b and each R bare independently halogen, cyano, (C1-C4) alkyl optionally substituted with one or more halogens, (C3-C6) cycloalkyl, 3- to 6-membered heterocycloalkyl, aminoalkyl, carboxy, carboxamido, or -OR6, where R6 is hydrogen optionally substituted with one or more halogens, (C1-C4) alkyl, or (C3-C6) cycloalkyl. In some embodiments, any one or more halogens in the B group of formula (IA) is F.

[0086] In some embodiments, B in formula (IA) is one or more R b and each R b are independently F, Cl, cyano, (C1-C4) alkyl optionally substituted with one or more F or Cl, (C3-C6) cycloalkyl, 3- to 6-membered heterocycloalkyl, aminoalkyl, carboxy, carboxamido, or -OR6, where R6 is hydrogen optionally substituted with one or more F or Cl, (C1-C4) alkyl, or (C3-C6) cycloalkyl.

[0087] In some embodiments, B of formula (IA) is a 5-membered heteroaryl containing one or more heteroatoms selected from N, O, and S, and one or more R b and each R b are independently F, Cl, cyano, (C1-C4) alkyl optionally substituted with one or more F or Cl, (C3-C6) cycloalkyl, 3- to 6-membered heterocycloalkyl, aminoalkyl, carboxy, carboxamido, or -OR6, where R6 is hydrogen optionally substituted with one or more F or Cl, (C1-C4) alkyl, or (C3-C6) cycloalkyl. In some embodiments, B of formula (IA) is a 5-membered heteroaryl containing nitrogen and 0, 1, or 2 additional heteroatoms selected from N, O, and S, and one or more R b and each R bare independently F, Cl, cyano, (C1-C4) alkyl optionally substituted with one or more F or Cl, (C3-C6) cycloalkyl, 3- to 6-membered heterocycloalkyl, aminoalkyl, carboxy, carboxamido, or -OR6, where R6 is hydrogen optionally substituted with one or more F or Cl, (C1-C4) alkyl, or (C3-C6) cycloalkyl.

[0088] In some embodiments, B of formula (IA) is a 6-membered heteroaryl containing one or more heteroatoms selected from N, O, and S, and one or more R b and each R b are independently F, Cl, cyano, (C1-C4) alkyl optionally substituted with one or more F or Cl, (C3-C6) cycloalkyl, 3- to 6-membered heterocycloalkyl, aminoalkyl, carboxy, carboxamido, or -OR6, where R6 is hydrogen optionally substituted with one or more F or Cl, (C1-C4) alkyl, or (C3-C6) cycloalkyl. In some embodiments, B of formula (IA) is a 6-membered heteroaryl containing nitrogen and 0, 1, or 2 additional heteroatoms selected from N, O, and S, and one or more R b and each R b are independently F, Cl, cyano, (C1-C4) alkyl optionally substituted with one or more F or Cl, (C3-C6) cycloalkyl, 3- to 6-membered heterocycloalkyl, aminoalkyl, carboxy, carboxamido, or -OR6, where R6 is hydrogen optionally substituted with one or more F or Cl, (C1-C4) alkyl, or (C3-C6) cycloalkyl.

[0089] In some embodiments, B in formula (IA) is 0, 1, 2, 3, 4, or 4 R b In some embodiments, one or more R of formula (IA) is substituted with b is F. In some embodiments, one or more R bIn some embodiments, one or more R b In some embodiments, one or more R b is (C1-C4) alkyl optionally substituted with one or more F or Cl. In some embodiments, one or more R b is (C1-C4) alkyl optionally substituted with one or more F. In some embodiments, one or more R b is methyl optionally substituted with one or more F or Cl. In some embodiments, one or more R b is methyl optionally substituted with one or more F. In some embodiments, one or more R b is (C-C)cycloalkyl. In some embodiments, one or more R b In some embodiments, one or more R b In some embodiments, one or more R b is cyclohexyl. In some embodiments, one or more R b is a 3-membered heterocycloalkyl group containing an O, N, or S heteroatom. In some embodiments, one or more R b is a 4-membered heterocycloalkyl group containing one or more O, N, or S heteroatoms. In some embodiments, one or more R b is a 5-membered heterocycloalkyl group containing one or more O, N, or S heteroatoms. In some embodiments, one or more R b is a 6-membered heterocycloalkyl group containing one or more O, N, or S heteroatoms. In some embodiments, one or more R b is aminoalkyl. In some embodiments, one or more R b is a carboxy group. In some embodiments, one or more R bis OR6, where R6 is hydrogen, (C1-C4) alkyl or (C3-C6) cycloalkyl optionally substituted with one or more F or Cl.

[0090] In some embodiments, the disclosure provides a compound of formula (IB) or a pharmaceutically acceptable salt thereof: TIFF0007777891000058.tif77128In formula, n is 1, 2, 3, 4 or 5; Each R a are independently halogen, cyano, lower alkyl optionally substituted with one or more halogens, —OR6, amine, amide, or ester; R6 is hydrogen, lower alkyl or cycloalkyl optionally substituted with one or more halogens; W is A, -C(O)-, or -C(O)N(R 10 )- and A is aryl or heteroaryl, each of which contains one or more R 30 may be substituted with Each R 30 is independently lower alkyl optionally substituted with one or more halogens; R 10 is hydrogen or lower alkyl, m is 1, 2, 3, 4, or 5, and Each R b are independently halogen or lower alkyl optionally substituted with one or more halogens.

[0091] In some embodiments, the compound may be a compound of formula (IB), where n is 1, 2, or 3, and each Ra is independently halogen, cyano, lower alkyl optionally substituted with one or more halogens, or -OR6, where R6 is hydrogen optionally substituted with one or more halogens, lower alkyl, or cycloalkyl. In the compound of formula (IB), n is 1, 2, or 3, and each Ra is independently F or Cl, cyano, (C1-C4)alkyl optionally substituted with one or more F, or -OR6, where R6 is hydrogen optionally substituted with one or more F, (C1-C4)alkyl, or cyclopropyl.

[0092] In some embodiments, the disclosure provides a compound of formula (IB) or a pharmaceutically acceptable salt thereof: TIFF0007777891000059.tif114128In formula, n is 1, 2, or 3; each Ra is independently halogen, cyano, lower alkyl optionally substituted with one or more halogens, or -OR6; R6 is hydrogen, lower alkyl or lower cycloalkyl optionally substituted with one or more halogens; W is A, -C(O)-, -C(O)-A-, or -C(O)N(R 10 )- and R 10 is hydrogen or lower alkyl, A is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with R 30 is lower alkyl, m is 1 or 2, and Each R b are independently halogen or lower alkyl optionally substituted with one or more halogens; However, the compound of formula (IB) is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0093] In compounds of formula (IB), W is a 5-membered heteroaryl ring containing at least one nitrogen, such as, for example, triazole, imidazole, pyrazole, or oxadiazole. In some embodiments, Ra, Rv, R6, R 10 , R 30 and R b In some embodiments, the compound is of formula (IB), wherein each Ra is independently Cl, F, CN, cyano, methyl, or -OR6, R6 is hydrogen, (C1-C4) alkyl optionally substituted with one or more F, or cyclopropyl, and W is -A-, -C(O)-, or -C(O)N(R 10 )- and R 10 is hydrogen or methyl, and A is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with R 30 is (C-C) alkyl, m is 1 or 2, and each R b are independently halogen, or (C1-C4) alkyl optionally substituted with one or more F. In some embodiments, the compound is of formula (IB), wherein R 30 is methyl, and each R bare independently halogen, or methyl optionally substituted with one or more F. In some embodiments, the compound is of formula (IB), where A is pyrazole, imidazole, or triazole, each optionally substituted with one methyl. In some embodiments, the compound is of formula (IB), where A is oxadiazole. In some embodiments, the compound is of formula (IB), where A is pyrazole substituted with one methyl. In some embodiments, the compound is of formula (IB), where one Ra is -OR.

[0094] In some embodiments, the compound of formula (IA) of formula (IB) may be a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof: TIFF0007777891000060.tif85128In formula, R1 is hydrogen or halogen; R3 is hydrogen, halogen, or lower alkyl optionally substituted with one or more halogens; R5 is hydrogen, halogen, lower alkoxy or lower alkyl, each of which may be substituted with one or more halogens; R6 is hydrogen, lower alkyl or cycloalkyl optionally substituted with one or more halogens, and W is A, -C(O)-, or -C(O)N(R 10 )- and A is aryl or heteroaryl, each of which contains one or more R 30 may be substituted with Each R 30 is independently lower alkyl optionally substituted with one or more halogens; R 10 is hydrogen or lower alkyl, and m is 1, 2, 3, 4, or 5, and Each R b are independently halogen or lower alkyl optionally substituted with one or more halogens; However, the compound of formula (IB-1) is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0095] In some embodiments, the compound is of formula (IB-1), where R is hydrogen, —CN, Cl, or F. In some embodiments, R is hydrogen, (C-C) alkyl, or cyclopropyl, optionally substituted with one or more F. In some embodiments, the compound is of formula (IB-1), where R is hydrogen, —CN, Cl, or F, and R is hydrogen, (C-C) alkyl, or cyclopropyl, optionally substituted with one or more F. In some embodiments, R is hydrogen, F, or methyl, optionally substituted with one or more halogens. In some embodiments, the compound is of formula (IB-1), where R is hydrogen, —CN, Cl, or F, and R is hydrogen, (C-C) alkyl, or cyclopropyl, optionally substituted with one or more F, and R is hydrogen, F, or methyl, optionally substituted with one or more halogens. In some embodiments, the compound is of formula (IB-1), wherein R1 is hydrogen, -CN, Cl, or F; R6 is hydrogen, (C1-C4) alkyl, or cyclopropyl, optionally substituted with one or more F; R3 is hydrogen, F, or methyl, optionally substituted with one or more halogens; and R5 is hydrogen.

[0096] In some embodiments, the compound is a compound of formula (IB-1), where R1 is Cl, F, or -CN, and R6 is hydrogen. In some embodiments, the compound is a compound of formula (IB-1), where R1 is F. In some embodiments, the compound is a compound of formula (IB-1), where R1 is Cl, F, or -CN, and R3, R5, and R6 are each hydrogen. In some embodiments, the compound is a compound of formula (IB-1), where R1 is Cl, F, or -CN, R3 is hydrogen, methyl, or F, R5 is hydrogen, methyl, or F, and R6 is hydrogen. In some embodiments, the compound is a compound of formula (IB-1), where R1 is F, R3 is hydrogen, methyl, or F, R5 is hydrogen, and R6 is hydrogen. In some embodiments, the compound is a compound of formula (IB-1), wherein R1 is F, R3 is hydrogen, R5 is hydrogen or F, and R6 is hydrogen. In some embodiments, the compound is a compound of formula (IB-1), wherein R1 is hydrogen, R3 is hydrogen or F, R5 is hydrogen, and R6 is hydrogen. In some embodiments, the compound is a compound of formula (IB-1), wherein R1 is F or —CN, R3 is hydrogen or F, R5 is hydrogen, and R6 is hydrogen. In some embodiments, the compound is a compound of formula (IB-1), wherein R1 and R6 are each hydrogen.

[0097] In some embodiments, the compound is a compound of formula (IB-1), where R1 is F and R6 is hydrogen. In some embodiments, the compound is a compound of formula (IB-1), where R1 is F, R6 is hydrogen, and at least one of R3 and R5 is hydrogen. In some embodiments, the compound is a compound of formula (IB-1), where R1 is F, R6 is hydrogen, and R3 and R5 are each hydrogen. In some embodiments, the compound is a compound of formula (IB-1), where R1 is F, R6 is hydrogen, and at least one of R3 and R5 is hydrogen, and at least one of R3 and R5 is F or methyl.

[0098] In some embodiments, the compound is of formula (IB-1), wherein W is A and A is a 5-membered aryl or 5-membered heteroaryl, wherein each A is selected from one or more R 30 and each R 30 are independently lower alkyl optionally substituted with one or more halogens. In some embodiments, the compound is of formula (IB-1), wherein W is A and A is a 5-membered heteroaryl containing at least one nitrogen heteroatom, wherein each A is selected from the group consisting of one or more R 30 and each R 30 are independently (C1-C4) alkyl optionally substituted with one or more halogens. In some embodiments, the compound is of formula (IB-1), wherein W is A and A is a 5-membered heteroaryl containing at least one nitrogen heteroatom, wherein each A is selected from the group consisting of one or more R 30 and each R 30 are independently F or methyl optionally substituted with one or more F.

[0099] In some embodiments, the compound of Formula (IA) or Formula (IB) can be a compound of Formula (IB-2), or a pharmaceutically acceptable salt thereof: TIFF0007777891000061.tif86128In formula, R3 is hydrogen or halogen; R5 is -OR 52 and R 52 is lower alkyl or cycloalkyl, each of which may be substituted with halogen; W is A, —C(O)—, or —C(O)N(R 10 )- and A is aryl or heteroaryl, each of which contains one or more R 30 may be substituted with Each R 30is independently lower alkyl optionally substituted with one or more halogens; R 10 is hydrogen or lower alkyl, and m is 1, 2, 3, 4, or 5, and Each R b are independently halogen or lower alkyl optionally substituted with one or more halogens.

[0100] In some embodiments, the compound is a compound of formula (IB-2), where R3 is hydrogen, Cl, or F. In some embodiments, the compound is a compound of formula (IB-2), where R3 is F. In some embodiments, the compound is a compound of formula (IB-2), where R 52 is (C1-C4) alkyl optionally substituted with one or more halogens, or cyclopropyl. In some embodiments, the compound is of formula (IB-2), wherein R3 is F and R 52 is (C1-C4) alkyl optionally substituted with one or more halogens, or cyclopropyl. In some embodiments, the compound is of formula (IB-2), wherein R 52 is (C1-C4) alkyl optionally substituted with one or more F, or cyclopropyl. In some embodiments, the compound is of formula (IB-2), wherein R3 is F and R 52 is (C1-C4) alkyl optionally substituted with one or more F, or cyclopropyl.

[0101] In some embodiments, the compound is a compound of formula (IB-2), wherein R 52 is selected from the group consisting of methyl, ethyl, and propyl, optionally substituted with one or more F. In some embodiments, the compound is of formula (IB-2), wherein R is F and R 52 is selected from the group consisting of methyl, ethyl, and propyl, optionally substituted with one or more F. In some embodiments, the compound is of formula (IB-2), wherein R 52is selected from the group consisting of methyl, ethyl, isopropyl, —CH—CF, and cyclopropyl. In some embodiments, the compound is of formula (IB-2), wherein R is F and R 52 is selected from the group consisting of methyl, ethyl, isopropyl, —CH2—CF3, and cyclopropyl.

[0102] In some embodiments, the compound is of formula (IB-2), wherein W is A and A is a 5-membered aryl or 5-membered heteroaryl, wherein each A is selected from one or more R 30 and each R 30 are independently lower alkyl optionally substituted with one or more halogens. In some embodiments, the compound is of formula (IB-2), wherein W is A and A is a 5-membered heteroaryl containing at least one nitrogen heteroatom, wherein each A is selected from the group consisting of one or more R 30 and each R 30 are independently (C1-C4) alkyl optionally substituted with one or more halogens. In some embodiments, the compound is of formula (IB-2), wherein W is A and A is a 5-membered heteroaryl containing at least one nitrogen heteroatom, wherein each A is selected from the group consisting of one or more R 30 and each R 30 are independently F or methyl optionally substituted with one or more F.

[0103] In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A and A is one or more R 30 is an aryl or heteroaryl optionally substituted with R 30is (C1-C4)alkyl optionally substituted with one or more halogens. In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), where A is a 5-membered heteroaryl optionally substituted with one or more (C1-C4)alkyl optionally substituted with one or more halogens. In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), where A is a 5-membered heteroaryl containing one or more nitrogen heteroatoms and optionally substituted with one or more methyls.

[0104] In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), where W is selected from the group consisting of imidazole, pyrazole, triazole, and oxadiazole, each optionally substituted with one or more lower alkyl. In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), where W is selected from the group consisting of imidazole, pyrazole, triazole, and oxadiazole, each optionally substituted with one or more methyl. In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), where W is selected from the group consisting of A1, A2, A3, A4, A5, A6, and A7, as shown below, where R 30 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , and R 39 are each independently hydrogen or lower alkyl: TIFF0007777891000062.tif107159.

[0105] In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is selected from the group consisting of A1, A2, A3, A4, A5, and A6, as shown above, and wherein R 30 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , and R 39 are each independently hydrogen or methyl. In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is selected from the group consisting of A1, A2, A3, A4, A5, and A6, as shown above, and wherein R 30 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , and R 39 are each independently hydrogen or methyl.

[0106] In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A1 and R 30 is hydrogen or methyl. In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A1 and R 30 In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A1 and R 30 In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A2 and R 32 and R 33 is hydrogen or methyl.

[0107] In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A2 and R 32 and R 33 One of the groups is hydrogen, and R 32 and R 33 In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A2 and R 32 is methyl and R 33 In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A2 and R 32 is hydrogen and R 33 In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A2 and R 32 is hydrogen and R 33 is hydrogen.

[0108] In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A3 and R 34 is hydrogen or methyl. In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A3 and R 34 In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A1 and R 34 is methyl.

[0109] In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A4 and R 36 and R 37 One of the groups is hydrogen, and R 36 and R37 In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A4 and R 36 is methyl and R 37 In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A4 and R 36 is hydrogen and R 37 In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A4 and R 36 is hydrogen and R 37 is hydrogen.

[0110] In some embodiments, the compound is of formula (IA), formula (IB), formula (IB-1), or formula (IB-2), wherein W is A5.

[0111] In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A6 and R 38 and R 39 One of the groups is hydrogen, and R 38 and R 39 In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A6 and R 38 is methyl and R 39 is hydrogen. In some embodiments, the compound is of formula (IA), formula (IB), formula (IB-1), or formula (IB-2), wherein W is A6 and R 38 is hydrogen and R 39 In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is A6 and R 38 is hydrogen and R39 is hydrogen.

[0112] In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), where at least one of Ra is hydroxyl or (C1-C4)alkoxy optionally substituted with one or more halogens, and n is 1, 2, or 3. In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), where at least one of Ra is hydroxyl or (C1-C4)alkoxy optionally substituted with one or more F, and n is 1, 2, or 3. In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein at least one of Ra is hydroxyl, (C1-C4)alkoxy, or —O—(C1-C6)cycloalkyl, each optionally substituted with one or more F; the remaining Ra are selected from the group consisting of halogen, methyl, and cyano; and n is 1, 2, or 3. In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein at least one of Ra is hydroxyl, (C1-C4)alkoxy, or —O-(cyclopropyl), each optionally substituted with one or more F; the remaining Ra are selected from the group consisting of halogen, methyl, and cyano; and n is 1, 2, or 3. In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein at least one of Ra is hydroxyl, (C1-C4)alkoxy, or —O-(cyclopropyl), each optionally substituted with one or more F; the remaining Ra are selected from the group consisting of Cl, F, methyl, and cyano; and n is 1, 2, or 3.

[0113] In some embodiments, the compound is of formula (IA), formula (IB), formula (IB-1), or formula (IB-2), where W is A7.

[0114] In some embodiments, the compound is of formula (IA), formula (IB), formula (IB-1), or formula (IB-2), where W is —C(O)—.

[0115] In some embodiments, the compound is a compound of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is —C(O)N(R 10 )- and -R 10 is hydrogen. In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is —C(O)N(R 10 )- and -R 10 In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is —C(O)N(R 10 )- and -R 10 is (C1-C4) alkyl optionally substituted with F. In some embodiments, the compound is of Formula (IA), Formula (IB), Formula (IB-1), or Formula (IB-2), wherein W is —C(O)N(R 10 )- and -R 10 is lower alkyl optionally substituted with halogen.

[0116] In some embodiments, the compound of formula (IA) or formula (IB) may be a compound of formula (IC) or a pharmaceutically acceptable salt thereof: TIFF0007777891000063.tif87128In formula, R 20 is lower alkyl, n is 1, 2, or 3; Each R a are independently halogen, cyano, lower alkyl optionally substituted with one or more halogens, or -OR6, and R6 is hydrogen, lower alkyl, or lower cycloalkyl optionally substituted with one or more halogens, and W is as defined above for formula (IA) or formula (IB).

[0117] In some embodiments, the compound is a compound of formula (IC), wherein R 20 is (C1-C4) alkyl. In some embodiments, the compound is of formula (IC), wherein R 20 In some embodiments, the compound is of formula (IC), wherein W is A7 TIFF0007777891000064.tif37128, R 20 is methyl, each Ra is independently F, Cl, -CN, (C1-C4) alkyl optionally substituted with one or more F or Cl, or -OR6, and R6 is hydrogen optionally substituted with one or more F or Cl, (C1-C4) alkyl, or cyclopropyl. In some embodiments, the compound is of formula (IC), where n is 1, 2, or 3, W is A7, and R 20 is methyl and each Ra is independently F, Cl, —CN, methyl, or —OH. In some embodiments, the compound is of formula (IC), where n is 2, W is A7, and R 20 is methyl, and each Ra is independently F or —OH.

[0118] In some embodiments, the compound is a compound of formula (IC), where at least one of Ra is hydroxyl or (C1-C4)alkoxy optionally substituted with one or more halogens, and n is 1, 2, or 3. In some embodiments, the compound is a compound of formula (IC), where at least one of Ra is hydroxyl or (C1-C4)alkoxy optionally substituted with one or more F, and n is 1, 2, or 3. In some embodiments, the compound is a compound of formula (IC), where at least one of Ra is hydroxyl, (C1-C4)alkoxy, or —O—(C1-C6)cycloalkyl, each optionally substituted with one or more F, and the remaining Ra are selected from the group consisting of halogen, methyl, and cyano, and n is 1, 2, or 3. In some embodiments, the compound is of formula (IC), where at least one of Ra is hydroxyl, (C-C)alkoxy, or —O-(cyclopropyl), each optionally substituted with one or more F, and the remaining Ra are selected from the group consisting of halogen, methyl, and cyano, and n is 1, 2, or 3. In some embodiments, the compound is of formula (IC), where at least one of Ra is hydroxyl, (C-C)alkoxy, or —O-(cyclopropyl), each optionally substituted with one or more F, and the remaining Ra are selected from the group consisting of Cl, F, methyl, and cyano, and n is 2 or 3. In some embodiments, the compound is of formula (IC), where at least one of Ra is hydroxyl, and the remaining Ra are selected from the group consisting of F, methyl, and cyano, and n is 2 or 3.

[0119] In some embodiments, the present disclosure provides a compound of Formula (IA) or Formula (IB), or a pharmaceutically acceptable salt thereof, which is also a compound of Formula (II): TIFF0007777891000065.tif70128In formula, R1 is halogen or cyano; R3 is hydrogen, lower alkyl, or halogen; W is -C(O)-A, -C(O)N(R 10 )-A, and A, R 10 is hydrogen or lower alkyl, A is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with R 20 is halogen or lower alkyl optionally substituted with one or more halogens, R 30 is lower alkyl optionally substituted with one or more halogens, and R 26 is a halogen or hydrogen.

[0120] In some embodiments, the compound of Formula (IA) or Formula (IB) may be a compound of Formula (II), wherein R is Cl, F, or cyano; R is hydrogen, F, or methyl; and R 10 is hydrogen or methyl, and R 20 and R 30 are each independently methyl; 26 is F or hydrogen. In some embodiments, the compound of Formula (I) may be a compound of Formula (II), wherein R is Cl, F, or cyano, R is hydrogen, F, or methyl, and R 10 is hydrogen or methyl, and R 20 and R 30 are each independently methyl; 26 is hydrogen. In some embodiments, the compound of formula (I) may be a compound of formula (II), wherein W is —C(O)N(R 10 )-A, wherein R 10 is hydrogen or methyl; A is a 5-membered heteroaryl ring containing at least one nitrogen atom, which may be substituted with one or more lower alkyl groups, which may be substituted with one or more halogen atoms; R 26is hydrogen. In some embodiments, the compound of formula (I) may be a compound of formula (II), wherein R 20 and R 30 are each independently lower alkyl optionally substituted with one or more F, and R 26 is hydrogen. In some embodiments, the compound of formula (I) may be a compound of formula (II), wherein R 20 is lower alkyl optionally substituted with halogen or one or more F, and R 30 is lower alkyl optionally substituted with one or more F, and R 26 is hydrogen. In some embodiments, the compound of formula (I) may be a compound of formula (II), wherein R 20 is Cl, F, or methyl optionally substituted with one or more F, and R 30 is methyl optionally substituted with one or more F, and R 26 is hydrogen.

[0121] In some embodiments, the compound of Formula (IA) or Formula (IB) may be a compound of Formula (II), wherein W is an amide optionally substituted with lower alkyl, a carboxyl, or a 5-membered heteroaryl ring containing at least one nitrogen, such as pyrazole, imidazole, triazole, or oxadiazole, each optionally substituted with lower alkyl. In some embodiments, R is Cl, F, or CN in Formula (II), and R 26 is hydrogen. In some embodiments, R is methyl and R 26 is hydrogen. In some embodiments, R is hydrogen and R 26 is hydrogen. In some embodiments, R is F and R 26 In some embodiments, the compound may be a compound of formula (II), where W is pyrazole, imidazole, triazole, or oxadiazole, each optionally substituted with methyl, R is Cl, F, or CN, R is hydrogen, methyl, or F, and R 26 is hydrogen.

[0122] In some embodiments, the compound of Formula (IA) or Formula (IB) may be a compound of Formula (II), wherein R, R, and R 20 The lower alkyl in R is methyl, 26 is hydrogen. In some embodiments, the compound of formula (I) may be a compound of formula (II), wherein R 10 is methyl; A is pyrazole, imidazole, triazole, or oxadiazole, each of which may be substituted with methyl; R 20 is methyl and R 26 is hydrogen. In some embodiments, the compound of Formula (I) can be a compound of Formula (II), wherein W is pyrazole optionally substituted with one or more methyl, R is F, R is H or F, and R 20 is methyl and R 26 is hydrogen. In some embodiments, the compound of Formula (I) can be a compound of Formula (II), wherein W is pyrazole optionally substituted with one or more methyl, R is F, R is H, and R 20 is methyl and R 26 is hydrogen.

[0123] In some embodiments, the compound of Formula (IA) or Formula (IB) may be a compound of Formula (II), wherein R, R, and R 20 The lower alkyl in R is methyl, 26 is F. In some embodiments, the compound of formula (I) may be a compound of formula (II), wherein R 10 is methyl, A is pyrazole, imidazole, triazole, or oxadiazole, each of which may be substituted with methyl, and R 20 is methyl and R 26 is F. In some embodiments, the compound of Formula (I) can be a compound of Formula (II), wherein W is pyrazole optionally substituted with one or more methyl, R is F, R is H or F, and R 20 is methyl and R26 is F. In some embodiments, the compound of Formula (I) can be a compound of Formula (II), wherein W is pyrazole optionally substituted with one or more methyl, R is F, R is H, and R 20 is methyl and R 26 is F.

[0124] In some embodiments, the present disclosure provides a compound of Formula (IA) or Formula (IB), or a pharmaceutically acceptable salt thereof, which is also a compound of Formula (II): TIFF0007777891000066.tif70128In formula, R1 is halogen or cyano; R3 is hydrogen or halogen; W is A, -C(O)-, or -C(O)N(R 10 )- and R 10 is hydrogen or lower alkyl, A is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with R 20 and R 30 are each independently lower alkyl; and R 26 is as defined herein for formula (IA) or formula (IB), However, the compound of formula (II) is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0125] In compounds of formula (II), W is a 5-membered heteroaryl ring containing at least one nitrogen, such as, for example, pyrazole. In some embodiments, R is Cl, F, or CN. In some embodiments, R is H. In some embodiments, R is F. In some embodiments, Ra, R, R 10 , R 30 and Rb In some embodiments, W is pyrazole optionally substituted with one or more methyls, R is F, R is H or F, and R, R, R are independently methyl. 10 , R 30 In some embodiments, W is pyrazole optionally substituted with one or more methyls, R is F, R is H, and R, R, R are each methyl in the compound of formula (II). 10 , R 30 and Rb are each methyl in the compound of formula (II).

[0126] In some embodiments, the compound of formula (II) is TIFF0007777891000067.tif166158TIFF0007777891000068.tif155158 or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the compound of formula (II) is TIFF0007777891000069.tif213158 or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the present disclosure provides a compound of formula (II-B) or a pharmaceutically acceptable salt thereof: TIFF0007777891000070.tif86128In formula, R1 is halogen or cyano; R3 is hydrogen, lower alkyl, or halogen; R5 is hydrogen, halogen, or lower alkyl; R 20 is halogen or lower alkyl optionally substituted with one or more halogens, R 26 is a halogen or hydrogen, and R 30is hydrogen or lower alkyl optionally substituted with one or more halogens.

[0129] In some embodiments, the disclosure provides a compound of Formula (II-B) or a pharmaceutically acceptable salt thereof, wherein the compound is not (2-fluoro-5-hydroxyphenyl){6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone.

[0130] In some embodiments, the disclosure provides a compound of Formula (II-B) or a pharmaceutically acceptable salt thereof, wherein the compound is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0131] In some embodiments, the present disclosure provides compounds of Formula (II-B) or a pharmaceutically acceptable salt thereof, wherein R is fluoro, R and R are both hydrogen, and R 30 is methyl, R 26 is not hydrogen.

[0132] General Procedure for Acid-Amine Coupling to Prepare Compounds of Formula (II-B) In general, analogs of Formula II-B can be prepared by following a modified version of the synthetic scheme for PSY05-00367 (compound 367). 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid Int-1 was treated with methoxyamine hydrochloride to produce the Weinreb amide Int-2, which underwent Grignard addition with methylmagnesium bromide (CHMgBr) to give the methyl ketone intermediate Int-3. Treatment of Int-3 with N,N-dimethylacetamide dimethyl acetal (DMA-DMA) afforded the spirocyclic-substituted 3-(dimethyamino)but-2-en-1-one intermediate Int-4. 1,3-Dipolar cycloaddition of Int-4 with various phenylhydrazines afforded variations of the desired 3-methylpyrazole intermediate Int-5. N-Boc deprotection of Int-5 using trifluoroacetic acid affords the corresponding trifluoroacetate salt of Int-5, Int-6, which is then coupled with various substituted benzoic acids to afford the final analogs.

[0133] To a stirred solution of 6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate (1 eq.) and 2-fluorobenzoic acid (1.5 eq.) in DMF (10 V) at 0° C., DIPEA (5 eq.) was added and stirred for 15 minutes. To this reaction mixture, T3P (50% solution in ethyl acetate) (1.5 eq.) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of ice-cold water (10 mL) and extracted with ethyl acetate (3×25 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography using 5% MeOH in DCM.

[0134] (Table 1) TIFF0007777891000071.tif65161TIFF0007777891000072.tif248161TIFF0007777891000073.tif194161TIFF0007777891000074.tif68161

[0135] In some embodiments, the present disclosure provides a compound of formula (II-C) or a pharmaceutically acceptable salt thereof: TIFF0007777891000075.tif75132In formula, R1 is halogen or cyano; R3 is hydrogen, lower alkyl, or halogen; R5 is hydrogen, halogen, or lower alkyl; R 20 is halogen or lower alkyl optionally substituted with one or more halogens, R 26 is a halogen or hydrogen, and R 31 and R 33 are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 31 and R 33 One of the is hydrogen.

[0136] General Procedure for Making Compounds of Formula (II-C) Analogs bearing a 1-(4-methyl)pyrazolyl reactive group (W: warhead) can be prepared according to the synthetic scheme of PSY-05-00519-001 (compound 519). The substituted propiophenone intermediate (Int-1) is treated with N,N-dimethylformamide dimethyl acetal (DMF-DMA) to give the phenyl-substituted 3-(dimethylamino)prop-2-en-1-one intermediate Int-2, followed by 1,3-dipolar cycloaddition with hydrazine (NH2NH2) to give the 5-aryl-4-methylpyrazole intermediate Int-3. Concomitant synthesis of tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate Int-C is achieved by reacting tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate with methanesulfonyl chloride. N-Alkylation of Int-3 with Int-C affords a mixture of two regioisomers: the 1,4,5-trisubstituted pyrazole product Int-4, and the 1,3,4-trisubstituted pyrazole product Int-4A. Both Int-4 and Int-4A undergo N-Boc deprotection with trifluoroacetic acid to give the corresponding trifluoroacetate salts Int-5 and Int-5A, respectively. Amidation of 2,fluoro-5-hydroxybenzoic acid with Int-5 or Int-5A affords either the 1-(5-aryl-4-methyl)pyrazolyl or 1-(3-aryl-4-methyl)pyrazolyl analogs, respectively.

[0137] Analogs bearing the 1-(4-trifluoromethyl)pyrazole reactive group can be prepared according to the synthetic scheme of PSY-05-00475-001 (compound 475). Substituted iodobenzene Int-A undergoes Sonogashira coupling with ethyl propiolate to generate the phenyl-substituted propiolate intermediate Int-B. Sodium hydroxide-catalyzed ester hydrolysis of Int-B gives the propiolic acid intermediate Int-1, which then undergoes unique copper-mediated decarboxylation trifluoromethylation with Togni reagent to give the α-trifluoromethyl ketone intermediate Int-2. Treatment of Int-2 with N,N-dimethylformamide dimethyl acetal (DMF-DMA) gives the 3-(dimethylamino)-2-(trifluoromethyl)prop-2-en-1-one intermediate Int-3, which undergoes 1,3-dipolar cycloaddition with hydrazine to give the 2-aryl-4-(trifluoromethyl)pyrazole intermediate Int-4. Treatment of Int-4 with the previously described spirocyclic mesylate intermediate Int-C affords a mixture of two regioisomers: the 1,4,5-trisubstituted pyrazole product Int-5, and the 1,3,4-trisubstituted pyrazole product Int-5A. Both Int-5 and Int-5A undergo N-Boc deprotection with trifluoroacetic acid to afford the corresponding trifluoroacetates Int-6 and Int-6A, respectively. Amidation of 2,fluoro-5-hydroxybenzoic acid with Int-6 or Int-6A affords either the 1-(5-aryl-4-trifluoromethyl)pyrazolyl or 1-(3-aryl-4-trifluoromethyl)pyrazolyl analogs, respectively.

[0138] Similar to the synthesis of compound 525, the synthesis of 1-(4-cyclopropyl)pyrazole reactive group analogs begins with the treatment of substituted acetophenone Int-1 with N,N-dimethylformamide dimethyl acetal (DMF-DMA) to form the 3-(dimethylamino)prop-2-en-1-one intermediate Int-2, which then undergoes 1,3-dipolar cycloaddition with hydrazine to give the 2-arylpyrazole intermediate Int-3. 4-Iodination of Int-3 forms Int-4, which is then N-PMB-protected to form Int-5. Suzuki coupling of Int-5 with cyclopropylboronic acid gives the 2-aryl-4-cyclopropylpyrazole intermediate Int-6, which undergoes PMB-deprotection to liberate the free NH-pyrazole intermediate Int-7. Treatment of Int-7 with the previously described spirocyclic mesylate intermediate Int-C affords a mixture of two regioisomers: the 1,4,5-trisubstituted pyrazole product Int-8, and the 1,3,4-trisubstituted pyrazole product Int-8A. Both Int-8 and Int-8A undergo N-Boc deprotection with trifluoroacetic acid to afford the corresponding trifluoroacetates Int-9 and Int-9A, respectively. Amidation of 2,fluoro-5-hydroxybenzoic acid with Int-9 or Int-9A affords either the 1-(5-aryl-4-cyclopropyl)pyrazolyl or 1-(3-aryl-4-cyclopropyl)pyrazolyl analogs, respectively.

[0139] For analogs bearing a 5-(1-aryl-3-methyl)pyrazolyl reactive group, the first two steps are identical to those presented for the synthesis of analogs of formula (II-B). Starting with Int-3 of formula (II-B), a Claisen condensation is carried out with ethyl acetate to give the 1,3-dicarbonyl intermediate Int-4.

[0140] For analogs bearing 1-(5-aryl-3-cyclopropyl)pyrazolyl or 1-(3-aryl-5-cyclopropyl)pyrazolyl reactive groups, the substituted acetophenone Int-1 undergoes Claisen condensation with ethyl cyclopropanecarboxylate to give the 1,3-dicarbonyl intermediate Int-2. Cyclization of Int-2 with substituted hydrazine hydrate gives the 5-aryl-3-cyclopropylpyrazole intermediate Int-3, which undergoes N-alkylation with the spirocyclic mesylate intermediate Int-C to form two trisubstituted regioisomers: the 1-(5-aryl-3-cyclopropyl)pyrazolyl intermediate Int-4 and the 1-(3-aryl-5-cyclopropyl)pyrazolyl intermediate Int-4a. Both Int-4 and Int-4A undergo N-Boc deprotection with trifluoroacetic acid to give the corresponding trifluoroacetates Int-5 and Int-5A, respectively. Amidation of 2,fluoro-5-hydroxybenzoic acid with Int-5 or Int-5A provides either the 1-(5-aryl-3-cyclopropyl)pyrazolyl or 1-(3-aryl-5-cyclopropyl)pyrazolyl analogs, respectively.

[0141] The synthesis of 1-(5-aryl-3-cyclopropyl)pyrazolyl and 1-(3-aryl-5-cyclopropyl)pyrazolyl reactive group analogs is related to the synthesis of the following analogs: 1-(5-aryl-3-methyl)pyrazolyl reactive group analogs, and 1-(3-aryl-5-methyl)pyrazolyl reactive group analogs. For these two analogs, ethyl cyclopropanecarboxylate is substituted with ethyl acetate in step 1. For the 1-(5-aryl-3-trifluoromethyl)pyrazolyl reactive group analogs and 1-(3-aryl-5-trifluoromethyl)pyrazolyl reactive group analogs, ethyl cyclopropanecarboxylate is substituted with ethyl 2,2,2-trifluoroacetate.

[0142] (Table 2) TIFF0007777891000076.tif178161TIFF0007777891000077.tif213161TIFF0007777891000078.tif172161

[0143] In some embodiments, the present disclosure provides a compound of formula (II-D) or a pharmaceutically acceptable salt thereof: TIFF0007777891000079.tif87128In formula, R1 is halogen or cyano; R3 is hydrogen, lower alkyl, or halogen; R5 is hydrogen, halogen, or lower alkyl; R6 is hydrogen; R 20 is halogen or lower alkyl optionally substituted with one or more halogens, R 26 is a halogen or hydrogen, and R 32 and R 33 are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 32 and R 33 One of the is hydrogen.

[0144] General Procedure for Making Compounds of Formula (II-D) The synthesis of the analogs can be carried out according to the method presented in formula (II-C).

[0145] (Table 3) TIFF0007777891000080.tif60161TIFF0007777891000081.tif191161TIFF0007777891000082.tif230161TIFF0007777891000083.tif48161

[0146] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof: TIFF0007777891000084.tif98128In formula, R3 is a halogen; R5 is -OR 52 and R 52 is lower alkyl or cycloalkyl, each of which may be substituted with halogen; W is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with R 30 is lower alkyl, R 20 is lower alkyl, and R 26 is hydrogen or halogen.

[0147] In some embodiments, in the compound of Formula (III), R 20 is methyl and R 26 is hydrogen or F. In some embodiments, in the compound of formula (III), R 20 is methyl and R 26 is hydrogen. In some embodiments, R 20 is methyl and R 26 is F.

[0148] In compounds of formula (III), W is a 5-membered heteroaryl ring containing at least one nitrogen, such as, for example, pyrazole. In some embodiments, R is F. In some embodiments, R 62 is lower alkyl or cycloalkyl. In some embodiments, R 20 , R 30 , and R 62 The lower alkyl in may be methyl. In some embodiments, W is pyrazole optionally substituted with one or more methyls, and R is F. In some embodiments, in the compound of formula (III), W is pyrazole optionally substituted with one or more methyls, R is F, and R 62 is methyl, ethyl, propyl, or cyclopropyl, each of which may be substituted with one or more F; R20 is methyl.

[0149] In some embodiments, the compound of formula (III) is TIFF0007777891000085.tif100159.

[0150] In some embodiments, the compound of formula (III) is TIFF0007777891000086.tif47156.

[0151] In some embodiments, the compound is TIFF0007777891000087.tif84163.

[0152] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof: TIFF0007777891000088.tif65128In formula, R3 is a halogen; R 62 is lower alkyl or cycloalkyl, each of which may be substituted with halogen; W is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with R 30 is lower alkyl, and R 20 is lower alkyl.

[0153] In compounds of formula (III-A), W is a 5-membered heteroaryl ring containing at least one nitrogen, such as, for example, pyrazole. In some embodiments, R is F. In some embodiments, R 62 is lower alkyl or cycloalkyl. In some embodiments, R 20 , R 30 , and R 62The lower alkyl in may be methyl. In some embodiments, W is pyrazole optionally substituted with one or more methyls, and R is F. In some embodiments, in the compound of Formula (III-A), W is pyrazole optionally substituted with one or more methyls, R is F, and R 62 is methyl, ethyl, propyl, or cyclopropyl, each of which may be substituted with one or more F; R 20 is methyl.

[0154] In some embodiments, the present disclosure provides a compound of formula (III-B) or a pharmaceutically acceptable salt thereof: TIFF0007777891000089.tif87128In formula, R3 is a halogen; R 52 is lower alkyl or lower cycloalkyl, each of which may be substituted with halogen; R 30 is lower alkyl, R 20 is lower alkyl, and R 26 is hydrogen or halogen.

[0155] General Procedure for Making Compounds of Formula (III-B) The synthesis of the analogs is carried out according to the methods presented in formulas (II-B) and (II-C).

[0156] (Table 4) TIFF0007777891000090.tif185161TIFF0007777891000091.tif160161

[0157] In some embodiments, the present disclosure provides a compound of formula (III-C) or a pharmaceutically acceptable salt thereof: TIFF0007777891000092.tif75132In formula, R3 is a halogen; R 52is lower alkyl or lower cycloalkyl, each of which may be substituted with halogen; R 31 and R 33 are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 31 and R 33 One of them is hydrogen, R 20 is lower alkyl optionally substituted with halogen, and R 26 is hydrogen or halogen.

[0158] In some embodiments, the present disclosure provides a compound of formula (III-D) or a pharmaceutically acceptable salt thereof: TIFF0007777891000093.tif66128In formula, R3 is a halogen; R 52 is lower alkyl or lower cycloalkyl, each of which may be substituted with halogen; R 32 and R 33 are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 32 and R 33 One of them is hydrogen, R 20 is lower alkyl optionally substituted with halogen, and R 26 is hydrogen or halogen.

[0159] General Procedure for Making Compounds of Formula (III-D) (Table 5) TIFF0007777891000094.tif222161

[0160] In some embodiments, V in formula (IA) is TIFF0007777891000095.tif32128, wherein n and each Rv are as defined above, and the dashed line represents an optional double bond. In some embodiments, in Formula (IB), the dashed line represents an optional double bond. In some embodiments, in Formula (IB-1), the dashed line represents an optional double bond. In some embodiments, in Formula (IB-2), the dashed line represents an optional double bond. In some embodiments, in Formula (II), the dashed line represents an optional double bond.

[0161] The compounds described herein may exist as salts, such as salts with pharmaceutically acceptable acids. Therefore, such salts of the compounds described herein are also included. The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents present on the compounds described herein. When the compounds of the present invention contain a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of any desired base, either directly or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds of the present invention contain a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of any desired acid, either directly or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monoaqueous, phosphoric, monohydrogen phosphate, dihydrogen phosphate, sulfuric, monohydrogen sulphuric, hydroiodic or phosphorous, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, etc. Also included are salts of amino acids such as alginate, and salts of organic acids such as glucuronic and galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0162] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as, for example, solubility in polar solvents.

[0163] Pharmaceutical Composition In certain embodiments, the present application is directed to pharmaceutical compositions comprising an active pharmaceutical ingredient. In certain embodiments, the pharmaceutical composition comprises a compound disclosed herein as an active pharmaceutical ingredient (API) and a pharmaceutically acceptable carrier comprising one or more excipients. In some embodiments, the pharmaceutical composition optionally further comprises an additional therapeutic compound (i.e., agent) along with a pharmaceutically acceptable carrier. The pharmaceutical composition may be a drug product.

[0164] Pharmaceutically acceptable carriers include carriers known in the art.The choice of pharmaceutically acceptable carriers can depend, for example, on the desired route of administration of the composition.Pharmaceutical compositions (pharmaceutical preparations) can be administered to subjects by any of many routes, including, for example, parenteral administration (for example, intravenous, subcutaneous or intramuscular), oral administration (for example, tablets and capsules), absorption through oral mucosa (for example, sublingual), or transdermal (for example, as a patch that is applied to the skin) or topically (for example, as a cream, ointment or spray that is applied to the skin).

[0165] In some embodiments, pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be formulated for oral administration. For example, the compounds provided herein may be combined with suitable excipients to form an oral unit dosage form, such as a capsule or tablet, containing a target dose of the compound of Formula (I). The pharmaceutical product may be prepared by first preparing the compound of Formula (I) as the active pharmaceutical ingredient (API), followed by roller compaction / milling with intragranular excipients and blending with extragranular excipients. The pharmaceutical product may contain the selected compound of Formula (I) as the API and excipient components in a tablet at the desired dose strength of Compound 1. The blended material may be compressed to form a tablet and then film-coated. The excipients may be selected from materials suitable for inclusion in a pharmaceutical composition for the intended purpose and delivery route, including those that provide the pharmaceutical composition with desired manufacturability and stability, and / or desired in vivo or other properties. In some embodiments, the pharmaceutical composition may include a compound of formula (I) as the API in combination with a filler (e.g., in the form of microcrystalline cellulose), a dry binder or disintegrant (e.g., a cross-linked polymer), a glidant (e.g., colloidal silicon dioxide), and / or a lubricant (e.g., magnesium stearate). In some embodiments, the pharmaceutical composition may include substances to control absorption of the API in the gastrointestinal tract as desired, for example, substances such as sustained-release agents or disintegrants that are involved in carrying or transporting the API drug from one organ or part of the subject's body to another organ or part of the subject's body.

[0166] The formulations may be conveniently presented in unit dosage form and may be prepared by any method known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the target entity and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of compound that produces a therapeutic effect. For use in the methods of the present invention, the active compound may be provided per se, or may be provided as a pharmaceutical composition containing 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient, for example, combined with a pharmaceutically acceptable carrier.

[0167] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0168] To prepare solid dosage forms for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents, (2) binders, (3) humectants, (4) disintegrants, (5) solution retarding agents, (6) absorption enhancers, (7) wetting agents, (8) absorbents, (9) lubricants, (10) complexing agents, and (11) coloring agents. In the case of capsules (including spring and gelatin capsules), tablets, and pills, the pharmaceutical composition may also contain buffering agents. Similar types of solid compositions may also be employed as fillers in soft- and hard-filled gelatin capsules, using appropriate excipients. The pharmaceutical compositions according to the present invention may contain conventional pharmaceutical carriers and / or adjuvants. In some embodiments, pharmaceutical compositions according to the invention may contain conventional carrier agents, including binders, lubricants, and / or glidants selected from products and materials commonly used in the pharmaceutical industry for the preparation of pharmaceutical compositions for the intended route of administration.

[0169] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface-active agents, or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0170] Liquid dosage forms useful for oral administration comprise a pharmaceutically acceptable carrier and the active ingredient provided in a solid form for reconstitution before administration, or in a liquid form (e.g., solution, suspension, or emulsion).In addition to the active ingredient, the liquid dosage form may contain an inert diluent commonly used in the art.For example, the formulation of a pharmaceutically acceptable composition for injection may contain an aqueous solution, such as water or physiological buffered saline, or other solvent or vehicle suitable for the intended route of administration.In some embodiments, the pharmaceutical composition is formulated for parenteral administration.

[0171] The therapeutically effective amount of the pharmaceutical composition can be determined by human clinical trials to determine a safe and effective dose for patients with relevant diagnoses.It is generally understood that the effective amount of the compound can vary depending on the subject's weight, sex, age, and medical history.Other factors that affect the effective amount include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and other types of therapeutic agents administered together with the compound of the present invention, if necessary.If the total dose is large, it can be delivered by multiple administrations of the pharmaceutical composition at doses and administration intervals determined to be safe and effective for patients.

[0172] The present disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts. The acid added to the compound to form the acid addition salt can be an organic acid or an inorganic acid. The base added to the compound to form the base addition salt can be an organic base or an inorganic base. In some embodiments, the pharmaceutically acceptable salt is a metal salt, and in some embodiments, the pharmaceutically acceptable salt is an ammonium salt. For example, the pharmaceutically acceptable acid addition salt can exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of these solvates can also be prepared. The source of such solvates can be derived from solvent crystallization, solvent preparation or crystallization, or solvents inherent in the solvent.

[0173] How to use The compounds described herein can regulate the activity of monoacylglycerol lipase. For example, the compounds described herein can inhibit MAGL. Thus, in one aspect, the present disclosure provides a method for inhibiting MAGL, for example, in cells expressing MAGL. Generally, the method includes administering a compound of formula (I) described herein to cells. Note that the inhibition can be reversible or irreversible. In some embodiments, the compound can reversibly inhibit MAGL. As used herein, "reversible inhibition" means that MAGL retains its activity once the compound is removed or MAGL is no longer in contact with the compound. In other words, the activity of MAGL returns to the same level as before the use of the compound.

[0174] A compound can be administered to a cell, for example, a cell expressing MAGL, in vitro or in vivo. As used herein, administering a compound to a cell means contacting the compound with the cell so that the compound is taken up by the cell. Generally, a cell can be contacted with a compound in a cell culture, for example, in vitro or ex vivo, or the compound can be administered to a subject, for example, in vivo. When used herein in connection with contacting a cell, the term "contacting" or "contacting" includes providing the cell with an appropriate culture medium containing a compound of formula (I). When the cell is in vivo, "contacting" or "contacting" includes administering the compound, for example, in a pharmaceutical composition, to a subject via a suitable administration route for contacting the compound with the cell in vivo.

[0175] As described herein, the compound of formula (I) can be administered to cells in vivo to regulate MAGL, for example, to inhibit MAGL. Thus, in some embodiments, a therapeutically effective amount of a compound of formula (I) can be administered to a subject to inhibit monoacylglycerol lipase. For example, a therapeutically effective amount of a compound of formula (I) can be administered to a subject to treat a monoglycerol lipase-mediated disease or disorder.

[0176] A MAGL-mediated disease or disorder refers to a disease or disorder in which the activity of MAGL is the cause of the disease or disorder. Non-limiting examples of MAGL-mediated diseases or disorders include neurodegenerative diseases, neuropsychiatric disorders, pain and chronic inflammatory diseases, cancer, and other conditions that can be treated with a reversible MAGL inhibitor of formula (I).

[0177] In some embodiments, compounds of Formula (I) are useful for evaluation as drug candidates for the treatment of neurodegenerative diseases such as, for example, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, or Huntington's disease. In some embodiments, compounds of Formula (I) are useful for evaluation as drug candidates for the treatment of neuropsychiatric disorders such as, for example, head trauma, epilepsy, cerebral ischemia, and anxiety and / or depression. In some embodiments, compounds of Formula (I) are useful for evaluation as drug candidates for the treatment of pain and inflammatory diseases or conditions. In some embodiments, compounds of Formula (I) are useful for evaluation as drug candidates for the treatment of cancer types treatable by increasing 2-AG. In some embodiments, compounds of Formula (I) are useful for evaluation as drug candidates for the treatment of obesity, fibrosis, emesis, asthma, fever, and osteoporosis. In some embodiments, compounds of Formula (I) are useful for evaluation as drug candidates for increasing 2-AG levels in subjects in need thereof.

[0178] A subject may be a subject who has been previously diagnosed or identified as suffering from a MAGL-mediated disease or disorder, or one or more complications associated with such a condition, or as having a condition in need of treatment, and optionally has already been treated for such a disease or disorder. Alternatively, a subject may be a subject who has not previously been diagnosed with a MAGL-mediated disease or disorder, or as having one or more complications associated with such a disease or disorder. A "subject in need" of treatment for a particular condition may be a subject who has the condition, a subject who has been diagnosed with the condition, or a subject who is at risk of developing the condition.

[0179] In one embodiment, the subject is a human, hi another embodiment, the subject is an experimental animal or an animal used as a surrogate disease model.

[0180] It should be noted that the terms "administered" and "subject" are used interchangeably in the context of treating a disease or disorder. In jurisdictions that prohibit the patenting of methods performed on the human body, "administering" a composition to a human subject shall mean the formulation of a controlled substance that the human subject administers to themselves by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation consistent with the statute or regulation defining patentable subject matter is intended. In jurisdictions that do not prohibit the patenting of methods performed on the human body, "administering" a composition includes both the method performed on the human body and the aforementioned activities.

[0181] As used herein, the term "administering" refers to placing a composition within a subject by a method or route that results in at least partial localization of the composition at a desired site so that a desired effect occurs. The compounds or compositions described herein can be administered by any suitable route known in the art, including oral or parenteral routes, including, but not limited to, intravenous, intramuscular, subcutaneous, transdermal, respiratory (aerosol), pulmonary, nasal, rectal, and topical (including buccal and sublingual) administration.

[0182] Exemplary methods of administration include, but are not limited to, injection, infusion, infusion, inhalation, or ingestion. "Injection" includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracerebrospinal, and substernal injection and infusion. In some embodiments, administration is generally local rather than systemic.

[0183] In a preferred embodiment, the composition is administered orally, which may be in the form of, but is not limited to, a solution, suspension, tablet, pill, capsule, sustained release formulation, mouthwash, powder, or the like.

[0184] As used herein, the phrase "therapeutically effective amount" refers to an amount of a compound effective to produce some desired therapeutic effect in at least a subpopulation of cells, e.g., an amount of a compound effective to modulate or inhibit the activity of MAGL in a subject at a reasonable benefit / risk ratio applicable to any treatment. Thus, a "therapeutically effective amount" refers to an amount that, when administered to a subject for treating a disease, is sufficient to affect such treatment for the disease.

[0185] Depending on the route of administration, the effective dose can be calculated according to the body weight, body surface area, or organ size of the subject to be treated. Optimization of the appropriate dose can be easily performed by those skilled in the art, taking into account the pharmacokinetic data observed in human clinical trials. Alternatively, or additionally, the administered dose can be determined from studies using animal models of the specific type of condition to be treated, and / or from animal or human data obtained from agents known to exhibit similar pharmacological activity. The final dosing regimen will be determined by the attending physician or doctor, taking into account various factors that modify the action of the active agent, such as, for example, the specific activity of the agent, the specific in vivo half-life of the agent, the severity and responsiveness of the patient's condition, the patient's age, condition, weight, sex, and diet, the severity of any current infection, administration time, the use (or non-use) of other concomitant treatments, and other clinical factors.

[0186] The data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. Such a compound can be administered at an IC50 dose that produces little or no toxicity. 50 Preferably, the circulating concentration range includes the IC (IC ) of the active ingredient. The dosage can vary within this range depending on the dosage form employed and the route of use or administration utilized. The effective dose can be estimated initially from cell culture assays. Doses can be formulated in animal models and determined in cell culture. 50A circulating plasma concentration range (i.e., the concentration of the therapeutic agent that achieves half-maximal inhibition of symptoms) can be obtained. Plasma levels can be measured, for example, by high performance liquid chromatography. The effect of any particular dose can be monitored by a suitable bioassay.

[0187] It will be appreciated that the therapeutic methods of the present invention can be used in combination with additional therapies. For example, a treatment according to the present disclosure can be co-administered with one or more desired therapies or medical procedures for treating a MAGL-mediated disease or disorder.

[0188] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those skilled in the art.

[0189] For convenience, certain terms employed herein, examples, and the appended claims are collected here. Unless otherwise stated or implied from context, the following terms and phrases include the meanings provided below. Unless otherwise expressly stated or apparent from context, the following terms and phrases do not exclude the meaning that such term or phrase has acquired in the art to which it pertains. Definitions are provided to aid in the description of particular embodiments and are not intended to limit the invention as claimed, the scope of which is limited only by the claims. Further, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular.

[0190] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Because any known methods, devices, and materials can be used in the practice or testing of the present invention, methods, devices, and materials related thereto are described herein.

[0191] As used herein, the term "selective MAGL inhibitory compound" refers to a compound that exhibits an IC50 or IC60 inhibitory activity against fatty acid amide hydrolase (FAAH). 50 At least 10 times the IC 50 Selectively inhibits MAGL with an IC of 100 nM or less for MAGL inhibition 50 (according to the MAGL potency assay of Example 22 and the FAAH potency assay of Example 15).

[0192] As used herein, IC 50 The term percent inhibition of a "reversible MAGL inhibitory compound" after dilution to a concentration is 50 + 15% in the assay described in Example 16 below under the heading "Determination of MAGL reversible inhibition."

[0193] As used herein, the term "reversible selective MAGL inhibitory compound" refers to compounds that are both selective and reversible MAGL inhibitory compounds, or pharmaceutically acceptable salts thereof.

[0194] As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group that can be straight-chained or branched and has 1 to about 10 carbon atoms in the chain, preferably about 1 to about 6 carbon atoms in the chain. "Lower alkyl" refers to an alkyl group having 1 to about 4 carbon atoms. "Higher alkyl" refers to an alkyl group having about 5 to about 10 carbon atoms. Alkyl groups can be optionally substituted with one or more alkyl group substituents, which can be the same or different, where "alkyl group substituents" include halo, amino, aryl, hydroxy, alkoxy, aryloxy, alkyloxy, alkylthio, arylthio, aralkyloxy, aralkylthio, carboxy, alkoxycarbonyl, oxo, and cycloalkyl. "Branched" refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl, or propyl, is attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, i-propyl, n-butyl, t-butyl, n-pentyl, heptyl, octyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl, and hexadecyl. Useful alkyl groups include branched or straight chain alkyl groups containing 6 to 50 carbon atoms, including lower alkyl groups containing 1 to about 4 carbon atoms, and higher alkyl groups containing about 12 to about 16 carbon atoms.

[0195] As used herein, the term "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring system containing from about 3 to about 12 carbon atoms. Representative monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, and cyclohexyl. Useful polycyclic cycloalkyl rings include adamantyl. "Lower cycloalkyl" refers to an alkyl group having from 3 to about 6 carbon atoms in the cycloalkyl ring, which may be substituted with halogen, alkyl, alkoxy, or other substituents disclosed herein. "Higher alkyl" refers to an alkyl group having from about 5 to about 10 carbon atoms.

[0196] "Aryl" refers to an aromatic carbocyclic radical containing about 3 to about 10 carbon atoms. An aryl group may be optionally substituted with one or more substituents, which may be the same or different, where "aryl group substituents" include alkyl, alkenyl, alkynyl, hydroxy, alkoxy, carboxy, halo, nitro, trihalomethyl, cyano, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxy, acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylthio, alkylthio, and alkylene. Exemplary aryl groups include substituted or unsubstituted phenyl.

[0197] "Heterocyclyl" refers to a non-aromatic 3- to 8-membered monocyclic or 8- to 12-membered bicyclic ring system having 1 to 3 heteroatoms in the monocyclic ring system, or 1 to 6 heteroatoms in the bicyclic ring system, selected from O, N, or S (e.g., carbon atoms and 1 to 3 or 1 to 6 N, O, or S heteroatoms in the monocyclic or bicyclic ring system, respectively). Typically, C x Heterocyclyl and C x -C y Heterocyclyl is used, where X and Y indicate the number of carbon atoms in the ring system. In some embodiments, 1, 2, or 3 hydrogen atoms in each ring can be replaced by substituents. Exemplary heterocyclyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,4-diazaperhydroepynyl, 1,3-dioxanyl, 1,4-dioxanyl, and the like.

[0198] "Heteroaryl" refers to an aromatic 3- to 8-membered monocyclic or 8- to 12-membered fused bicyclic ring system having 1 to 3 heteroatoms in the monocyclic ring system, or 1 to 6 heteroatoms in the bicyclic ring system, selected from O, N, or S (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms in the monocyclic, bicyclic, or tricyclic ring system, respectively).

[0199] Exemplary aryl and heteroaryl include, but are not limited to, phenyl, pyridinyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrazolyl, pyridazinyl, pyrazinyl, triazinyl, tetrazolyl, indolyl, benzyl, naphthyl, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, tetrahydronaphthyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzo benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazol aryl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pyrimidinyl, Perazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,Examples include 5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, and xanthenyl, each of which may be substituted.

[0200] As used herein, the term "halogen" refers to an atom selected from fluorine, chlorine, bromine, and iodine. The term "halogen radioisotope" or "haloisotope" refers to a radionuclide of an atom selected from fluorine, chlorine, bromine, and iodine.

[0201] A "halogen-substituted moiety" or "halo-substituted moiety," as an isolated group or part of a larger group, refers to an aliphatic, alicyclic, or aromatic moiety, as described herein, that is substituted with one or more "halo" atoms, as such terms are defined in this application.

[0202] As used herein, the term "haloalkyl" refers to an alkyl structure having at least one substituent of fluorine, chlorine, bromine, or iodine, or a combination thereof. Exemplary halo-substituted alkyls include haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, etc. (e.g., halo-substituted (C1-C3) alkyls include chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl (CF3), perfluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoro-l,l-dichloroethyl, etc.).

[0203] As used herein, the term "amino" refers to -NH2 or -NH3 +wherein one or more hydrogen atoms are optionally replaced with alkyl, which may be further substituted with one or more halogen atoms or other substituents disclosed herein. The term "alkylamino" refers to a nitrogen moiety having one straight- or branched-chain unsaturated aliphatic, cyclyl, or heterocyclyl radical attached to the nitrogen, e.g., -NH(alkyl). The term "dialkylamino" refers to a nitrogen moiety having two straight- or branched-chain unsaturated aliphatic, cyclyl, or heterocyclyl radicals attached to the nitrogen, e.g., -N(alkyl)(alkyl). The term "alkylamino" includes "alkenylamino," "alkynylamino," "cyclylamino," and "heterocyclylamino." The term "arylamino" refers to a nitrogen moiety having at least one aryl radical attached to the nitrogen, e.g., -NHaryl and -N(aryl). The term "heteroarylamino" refers to a nitrogen moiety having at least one heteroaryl radical attached to the nitrogen, e.g., -NHheteroaryl and -N(heteroaryl). Optionally, the two substituents together with the nitrogen can also form a ring. Unless otherwise indicated, compounds described herein containing an amino moiety may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tertbutoxycarbonyl, benzyloxycarbonyl, and the like. Exemplary alkylaminos include, but are not limited to, NH(C-C 10 alkyl), for example, -NHCH, -NHCHCH, -NHCHCHCH, and -NHCH(CH). Exemplary dialkylaminos include, but are not limited to, -N(C-C 10 alkyl)2, for example, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, and —N(CH(CH3)2)2.

[0204] The term "aminoalkyl" refers to alkyl, alkenyl, and alkynyl as defined above, except that one or more substituted or unsubstituted nitrogen atoms (-N-) are positioned between the carbon atoms of the alkyl, alkenyl, or alkynyl. For example, a (C2-C6)aminoalkyl refers to a chain containing 2 to 6 carbon atoms and one or more nitrogen atoms positioned between the carbon atoms.

[0205] The terms "hydroxy" and "hydroxyl" refer to the radical --OH.

[0206] As used herein, the term "alkoxyl" or "alkoxy" refers to an alkyl group, as defined above, having an oxygen radical attached thereto and may be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl. Aroxy may be represented by -O-aryl or -O-heteroaryl, where aryl and heteroaryl are as defined herein. Alkoxy and aroxy groups may be substituted as described above for alkyl. Exemplary alkoxy groups include, but are not limited to, O-methyl, O-ethyl, O-propyl, O-isopropyl, O-butyl, O-isobutyl, O-sec-butyl, O-tert-butyl, O-pentyl, O-hexyl, O-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, and the like.

[0207] As used herein, the term "carbonyl" refers to the radical -C(O)-. It is noted that the carbonyl radical can be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, amides, esters, ketones, and the like.

[0208] The term "carboxy" refers to the radical -C(O)O-. It is noted that compounds described herein containing a carboxy moiety may include protected derivatives thereof, i.e., derivatives in which the oxygen is replaced with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like. As used herein, a carboxy group includes -COOH, i.e., a carboxyl group.

[0209] The term "cyano" refers to the radical --CN.

[0210] The term "nitro" refers to the radical -NO2.

[0211] The term "heteroatom" refers to an atom that is not a carbon atom. Specific examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and the halogens. A "heteroatom moiety" includes a moiety where the atom to which the moiety is attached is not a carbon. Examples of heteroatom moieties include -N=, -NR N -, -N + (O - )=, -O-, -S- or -S(O)2-, -OS(O)2-, and -SS-, wherein R N is H or a further substituent.

[0212] "Acyl" refers to the group alkyl-CO-, where alkyl is as defined above. Exemplary acyl groups include alkyls of 1 to about 30 carbon atoms. Exemplary acyl groups also include acetyl, propanoyl, 2-methylpropanoyl, butanoyl, and palmitoyl.

[0213] "Alkoxycarbonyl" refers to an alkyl-O-CO- group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and t-butyloxycarbonyl.

[0214] "Carbamoyl" refers to the group H2N-CO-.

[0215] "Alkylcarbamoyl" refers to the group R'RN-CO- where one of R and R' is hydrogen and the other of R and R' is alkyl as defined above.

[0216] "Dialkylcarbamoyl" refers to the group R'RN-CO-, where each R and R' is independently alkyl as defined above.

[0217] The term "optionally substituted" means that the specified group or moiety is unsubstituted or substituted with one or more (typically 1, 2, 3, 4, 5, or 6 substituents) independently selected from the group of substituents listed below in the definition of "substituent" or as otherwise specified. The term "substituent" refers to a group "substituted with" at any atom of the substituted group or on the substituted group. Suitable substituents include, but are not limited to, halogen, hydroxy, carboxy, oxo, nitro, haloalkyl, alkyl, alkenyl, alkynyl, alkaryl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbanoyl, arylcarbanoyl, aminoalkyl, alkoxycarbonyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, or ureido. In some cases, two substituents, together with the carbons to which they are attached, may form a ring.

[0218] For example, any alkyl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl can be selected from the group consisting of OH, CN, SH, SO2NH2, SO2(C1-C4)alkyl, SO2NH(C1-C4)alkyl, halogen, carbonyl, thiol, cyano, NH2, NH(C1-C4)alkyl, N[(C1-C4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-C8)alkyl, O(C1-C8) alkyl, O(C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, aryl, heteroaryl, substituted aryl, NH2-C(O)-alkylene, NH(Me)-C(O)-alkylene, CH2-C(O)-alkyl, C(O)-alkyl, alkylcarbonylaminyl, CH2-[CH(OH)] m -(CH2) p -OH, CH2-[CH(OH)] m -(CH2) p It may be substituted with 1, 2, 3, 4, or 5 groups selected from -NH2 or CH2-aryl-alkoxy, or any alkyl, cycloalkyl, or heterocyclyl may be substituted with oxo, and "m" and "p" are independently 1, 2, 3, 4, 5, or 6.

[0219] In some embodiments, the optionally substituted group is substituted with one substituent. In some other embodiments, the optionally substituted group is substituted with two independently selected substituents, which may be the same or different. In some other embodiments, the optionally substituted group is substituted with three independently selected substituents, which may be the same, different, or any combination of the same and different. In yet some other embodiments, the optionally substituted group is substituted with four independently selected substituents, which may be the same, different, or any combination of the same and different. In yet some other embodiments, the optionally substituted group is substituted with five independently selected substituents, which may be the same, different, or any combination of the same and different.

[0220] As used herein, the compound designations "Compound Number (#)," "PSY-#," and "PSY-05-#" (where # represents any number equal to or greater than one digit) are synonymous with each other unless otherwise indicated (e.g., "Compound 1" refers to the compound alternatively designated "PSY-05-0001" or "PSY-1").

[0221] As used herein, compound (PSY-05-00074) (alternatively designated Compound 74) is TIFF0007777891000096.tif38128. The compound (PSY-05-00074) is referred to as (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone or (2-fluoro-5-hydroxyphenyl){6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone. Both names are used interchangeably herein to refer to the compound (PSY-05-00074).

[0222] In some embodiments, the compound is TIFF0007777891000097.tif149163.

[0223] In some embodiments, the compound is TIFF0007777891000098.tif47155.

[0224] In some embodiments, the compound is TIFF0007777891000099.tif36128.

[0225] Other compounds include those shown below, which are selective and reversible MAGL inhibitors. TIFF0007777891000100.tif208159

[0226] Other compounds include the compounds shown below. TIFF0007777891000101.tif179156

[0227] Additional Embodiments Furthermore, while preferred embodiments have been shown and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention, and therefore are deemed to be within the scope of the invention as defined in the following claims. Moreover, to the extent not already indicated, it will be understood by those skilled in the art that any one of the various embodiments described and shown herein may be further modified to incorporate features shown in any of the other embodiments disclosed herein.

[0228] Additional embodiments include those listed below. 1. A reversible and selective MAGL inhibitory compound of formula (I) or a pharmaceutically acceptable salt thereof: TIFF0007777891000102.tif77128In formula, n is 1, 2, or 3; each Ra is independently halogen, cyano, lower alkyl optionally substituted with one or more halogens, or -OR6; R6 is hydrogen, lower alkyl or lower cycloalkyl optionally substituted with one or more halogens; W is A, -C(O)-, or -C(O)N(R 10 )- and R 10 is hydrogen or lower alkyl, A is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with R 30 is lower alkyl, m is 1 or 2, and Each R b are independently halogen or lower alkyl optionally substituted with one or more halogens; However, the compound is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone. The compound or a pharmaceutically acceptable salt thereof. 2. a. Each Ra is independently Cl, F, CN, cyano, methyl, or -OR6; b. R6 is hydrogen, (C1-C4) alkyl optionally substituted with one or more F, or cyclopropyl; cW is A, dR 10 is hydrogen or methyl, eA is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with fR 30 is (C1-C4) alkyl, gm is 1 or 2, and h.Each R bare independently halogen or (C1-C4) alkyl optionally substituted with one or more F; The compound of embodiment 1. 3.R 30 is methyl, and each R b The compound of embodiment 2, wherein is independently halogen, or methyl optionally substituted with one or more F. 4.A is a. pyrazole, imidazole, or triazole, each optionally substituted with one methyl; and b. Oxadiazole The compound of embodiment 3, selected from the group consisting of: 5. The compound of embodiment 4, wherein A is a pyrazole substituted with one methyl. 6. The compound of any one of embodiments 1-5, wherein one Ra is —OR6. 7. The compound of embodiment 6, wherein one Rb is methyl. 8. The compound of embodiment 1, which is of formula (IB-1): TIFF0007777891000103.tif85128In formula, R1 is hydrogen or halogen; R3 is hydrogen, halogen, or lower alkyl optionally substituted with one or more halogens; R5 is hydrogen, halogen, lower alkoxy or lower alkyl, each of which may be substituted with one or more halogens; and R6 is hydrogen, lower alkyl or cycloalkyl optionally substituted with one or more halogens. 9. The compound of embodiment 1, which is of formula (IB-2): TIFF0007777891000104.tif86128In formula, R3 is hydrogen or halogen; R5 is -OR 52 and R 52 is lower alkyl or cycloalkyl, each optionally substituted with halogen. 10.W is A1, A2, A3, A4, A5, A6, and A7 TIFF0007777891000105.tif107159, and R 30 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 and R 39 The compound of any one of embodiments 1, 8, or 9, wherein each is independently hydrogen or lower alkyl. 11.R 30 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , and R 39 11. The compound of embodiment 10, wherein each is independently hydrogen or methyl. 12.W is A1 and R 30 The compound of embodiment 10, wherein is methyl. 13.W is A2 and R 32 is hydrogen and R 33 The compound of embodiment 10, wherein is methyl. 14. The compound of embodiment 10, wherein W is A7 and Rb is methyl. 15. The compound of embodiment 1, which is of formula (IC): TIFF0007777891000106.tif87128In formula, R 20 is lower alkyl, and Ra, n, and W are as defined above for formula (I). 16.R 20 16. The compound of embodiment 15, wherein is methyl optionally substituted with one or more F. 17. A reversible and selective MAGL inhibitory compound of formula (II) or a pharmaceutically acceptable salt thereof: TIFF0007777891000107.tif70128In formula, R1 is halogen or cyano; R3 is hydrogen or halogen; W is A, -C(O)-, -C(O)N(R 10 )- and R 10 is hydrogen or lower alkyl, A is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with R 20 and R 30 are each independently lower alkyl; However, the compound is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone. The compound or a pharmaceutically acceptable salt thereof. 18. A reversible and selective MAGL inhibitory compound of formula (III) or a pharmaceutically acceptable salt thereof: TIFF0007777891000108.tif74128In formula, R3 is a halogen; R5 is -OR 52 and R 52 is lower alkyl or cycloalkyl, each of which may be substituted with halogen; W is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with R 30 is lower alkyl, R 20 is lower alkyl, and R 26 is hydrogen or halogen; The compound or a pharmaceutically acceptable salt thereof. 19. R3 is F, R 52 is methyl optionally substituted with halogen or cyclopropyl, W contains at least one nitrogen atom and one or more R 30 is a 5-membered heteroaryl ring optionally substituted with R30 is methyl, R 20 is methyl, and R 26 is hydrogen or F, The compound of embodiment 18. 20. TIFF0007777891000109.tif166158TIFF0007777891000110.tif155158 or a pharmaceutically acceptable salt thereof. twenty one. TIFF0007777891000111.tif213158 or a pharmaceutically acceptable salt thereof. twenty two. A compound selected from the group consisting of TIFF0007777891000112.tif144158. twenty three. A compound selected from the group consisting of TIFF0007777891000113.tif42128. 24. Compound TIFF0007777891000114.tif34128 or a pharmaceutically acceptable salt thereof. 25. Compound TIFF0007777891000115.tif35128 or a pharmaceutically acceptable salt thereof. 26. Compound TIFF0007777891000116.tif39128 or a pharmaceutically acceptable salt thereof. 27. Compound TIFF0007777891000117.tif40128 or a pharmaceutically acceptable salt thereof. 28. Compound TIFF0007777891000118.tif38128 or a pharmaceutically acceptable salt thereof. 29. Compound TIFF0007777891000119.tif38128 or a pharmaceutically acceptable salt thereof. 30. Compound TIFF0007777891000120.tif38128 or a pharmaceutically acceptable salt thereof. 31. Compound TIFF0007777891000121.tif33128 or a pharmaceutically acceptable salt thereof. 32.W is -C(O)N(R 10 )- and R 10 is methyl and R 20 The compound of embodiment 17, wherein is methyl. 33.R 26 33. The compound of embodiment 32, wherein is hydrogen. 34. The compound of any one of embodiments 32-33, wherein R1 is F. 35. The compound of embodiment 34, wherein R3 is hydrogen. 36.W is -C(O)N(R 10 )- and R 10 is methyl and R 20 The compound of embodiment 18, wherein is methyl. 37.R 26 37. The compound of embodiment 36, wherein is hydrogen. 38.R5 is -OR 52 and R 52 The compound of any one of embodiments 36-37, wherein is (C1-C4) alkyl. 39. The compound of embodiment 34, wherein R3 is F. 40. The compound of any one of embodiments 1, 8, 9, 15, or 17, wherein W is A. 41. A compound of formula (II-A) or a pharmaceutically acceptable salt thereof: TIFF0007777891000122.tif61128In formula, R3 is hydrogen, methyl optionally substituted with one or more F, or F; W is a 5-membered heteroaryl ring containing at least one nitrogen heteroatom, optionally substituted with one methyl, optionally substituted with one or more F, or cyclopropyl; R 20 is methyl, Cl or F optionally substituted with one or more F, R 26 is hydrogen or F, However, the compound of formula (II) is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone. 42. A compound of formula (III-A) or a pharmaceutically acceptable salt thereof: TIFF0007777891000123.tif69128In formula, R 52 is cyclopropyl or (C1-C4) alkyl optionally substituted with one or more F; W is C(O)N(R 10 )- and R 10 is methyl, or W is a 5-membered heteroaryl ring containing at least one nitrogen heteroatom and optionally substituted with one methyl; R 20 is (C1-C4) alkyl, and R 26 is hydrogen or F. 43.R 52 43. The compound of embodiment 42, wherein is ethyl or methyl. 44.R 52 The compound of embodiment 42, wherein is cyclopropyl. 45.R 20 The compound of any one of embodiments 42-44, wherein is methyl. 46.R 20 The compound of any one of embodiments 42-44, wherein is —CF 3 . 47.R 26 The compound of any one of embodiments 42-46, wherein is hydrogen. 48.W is A1, A2, A3, A4, A5, and A6, TIFF0007777891000124.tif107159, and R 30 , R 32 , R 33 , R 34 , R 36 , R37 , R 38 and R 39 The compound of any one of embodiments 1, 2, 3, 6-11, 15-19, or 41-47, wherein each is independently hydrogen or methyl. 49.R 30 , R 32 , R 33 , and R 34 and n is independently 1 or 2. The compound of embodiment 48, wherein each is independently methyl. 50. aR 36 and R 37 is methyl and the other is hydrogen, and bR 38 and R 39 one of which is methyl and the other is hydrogen; The compound of embodiment 49. 51. The compound of any one of embodiments 48-50, wherein W is selected from the group consisting of A1, A2, A3, A4 and A5. 52.W is The compound of any one of embodiments 1-19 or 32-52, selected from the group consisting of: TIFF0007777891000125.tif51128. 53.W is The compound of any one of embodiments 1-19 or 32-52, selected from the group consisting of TIFF0007777891000126.tif82135. 54.W is The compound of any one of embodiments 1-19 or 32-52, wherein TIFF0007777891000127.tif19128. 55.W is The compound of any one of embodiments 1-19 or 32-52, wherein TIFF0007777891000128.tif21128. 56.W is The compound of any one of embodiments 1-19 or 32-52, wherein the compound is TIFF0007777891000129.tif28128. 57.W is The compound of any one of embodiments 1-19 or 32-52, wherein TIFF0007777891000130.tif18128. 58.W is The compound of any one of embodiments 1-19 or 32-52, wherein the compound is TIFF0007777891000131.tif21128. 59.W is The compound of any one of embodiments 1-19 or 32-52, wherein the compound is TIFF0007777891000132.tif18128. 60.W is The compound of any one of embodiments 1-19 or 32-52, wherein the compound is TIFF0007777891000133.tif26128. 61. A reversible, selective MAGL inhibitor that is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0229] Additional embodiments include those listed below. 1. A compound selected from the group consisting of: (2,4-Difluoro-5-hydroxyphenyl){6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 126), 4-hydroxy-2-({6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}carbonyl)benzonitrile (compound 128), (2-Fluoro-5-hydroxyphenyl){6-[1-(5-fluoro-2-tolyl)-3-methyl-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 365), (2-Fluoro-5-hydroxyphenyl)(6-{3-methyl-1-[o-(trifluoromethyl)phenyl]-5-pyrazolyl}-2-aza-2-spiro[3.3]heptyl)methanone (compound 366), (2-Fluoro-5-hydroxyphenyl)(6-{5-(trifluoromethyl)-3-[o-(trifluoromethyl)phenyl]-1-pyrazolyl}-2-aza-2-spiro[3.3]heptyl)methanone (compound 414), (2-Fluoro-5-hydroxyphenyl){6-[3-(o-fluorophenyl)-4-methyl-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 417), (2-Fluoro-5-hydroxyphenyl){6-[4-methyl-3-(o-tolyl)-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 440), (2-Fluoro-5-hydroxyphenyl)(6-{4-methyl-3-[o-(trifluoromethyl)phenyl]-1-pyrazolyl}-2-aza-2-spiro[3.3]heptyl)methanone (compound 444), (2-Fluoro-5-hydroxyphenyl){6-[3-(5-fluoro-2-tolyl)-5-methyl-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 446), (2-Fluoro-5-hydroxyphenyl){6-[3-(o-fluorophenyl)-4-(trifluoromethyl)-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 473), (2-Fluoro-5-hydroxyphenyl){6-[3-(2-fluoro-5-tolyl)-4-(trifluoromethyl)-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 475), {6-[3-(2,5-difluorophenyl)-4-methyl-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}(2-fluoro-5-hydroxyphenyl)methanone (compound 477), (6-{4-cyclopropyl-3-[o-(trifluoromethyl)phenyl]-1-pyrazolyl}-2-aza-2-spiro[3.3]heptyl)(2-fluoro-5-hydroxyphenyl)methanone (compound 488), {6-[5-cyclopropyl-3-(5-fluoro-2-tolyl)-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}(2-fluoro-5-hydroxyphenyl)methanone (compound 491), {6-[4-cyclopropyl-3-(o-fluorophenyl)-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}(2-fluoro-5-hydroxyphenyl)methanone (compound 493), {6-[3-(2-chloro-5-fluorophenyl)-4-methyl-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}(2-fluoro-5-hydroxyphenyl)methanone (compound 520), (2-fluoro-5-hydroxyphenyl)(6-{3-[o-(trifluoromethyl)phenyl]-1-pyrazolyl}-2-aza-2-spiro[3.3]heptyl)methanone (compound 525), (2-ethoxy-4-fluorophenyl){6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 146), and [4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]{6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 178), or a pharmaceutically acceptable salt thereof. 2. The compound of embodiment 1, which is (2,4-difluoro-5-hydroxyphenyl){6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 126) or a pharmaceutically acceptable salt thereof. The compound of embodiment 1, which is 3.4-hydroxy-2-({6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}carbonyl)benzonitrile (Compound 128) or a pharmaceutically acceptable salt thereof. 4. The compound of embodiment 1, which is (2-fluoro-5-hydroxyphenyl){6-[1-(5-fluoro-2-tolyl)-3-methyl-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 365) or a pharmaceutically acceptable salt thereof. 5. The compound of embodiment 1, which is (2-fluoro-5-hydroxyphenyl)(6-{3-methyl-1-[o-(trifluoromethyl)phenyl]-5-pyrazolyl}-2-aza-2-spiro[3.3]heptyl)methanone (compound 366) or a pharmaceutically acceptable salt thereof. 6. The compound of embodiment 1, which is (2-fluoro-5-hydroxyphenyl)(6-{5-(trifluoromethyl)-3-[o-(trifluoromethyl)phenyl]-1-pyrazolyl}-2-aza-2-spiro[3.3]heptyl)methanone (compound 414) or a pharmaceutically acceptable salt thereof. 7. The compound of embodiment 1, which is (2-fluoro-5-hydroxyphenyl){6-[3-(o-fluorophenyl)-4-methyl-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 417) or a pharmaceutically acceptable salt thereof. 8. The compound of embodiment 1, which is (2-fluoro-5-hydroxyphenyl){6-[4-methyl-3-(o-tolyl)-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 440) or a pharmaceutically acceptable salt thereof. 9. The compound of embodiment 1, which is (2-fluoro-5-hydroxyphenyl)(6-{4-methyl-3-[o-(trifluoromethyl)phenyl]-1-pyrazolyl}-2-aza-2-spiro[3.3]heptyl)methanone (compound 444) or a pharmaceutically acceptable salt thereof. 10. The compound of embodiment 1, which is (2-fluoro-5-hydroxyphenyl){6-[3-(5-fluoro-2-tolyl)-5-methyl-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 446) or a pharmaceutically acceptable salt thereof. 11. The compound of embodiment 1, which is (2-fluoro-5-hydroxyphenyl){6-[3-(o-fluorophenyl)-4-(trifluoromethyl)-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 473) or a pharmaceutically acceptable salt thereof. 12. The compound of embodiment 1, which is (2-fluoro-5-hydroxyphenyl){6-[3-(2-fluoro-5-tolyl)-4-(trifluoromethyl)-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 475) or a pharmaceutically acceptable salt thereof. 13. The compound of embodiment 1, which is {6-[3-(2,5-difluorophenyl)-4-methyl-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}(2-fluoro-5-hydroxyphenyl)methanone (compound 477) or a pharmaceutically acceptable salt thereof. 14. The compound of embodiment 1, which is (6-{4-cyclopropyl-3-[o-(trifluoromethyl)phenyl]-1-pyrazolyl}-2-aza-2-spiro[3.3]heptyl)(2-fluoro-5-hydroxyphenyl)methanone (compound 488) or a pharmaceutically acceptable salt thereof. 15. The compound of embodiment 1, which is {6-[5-cyclopropyl-3-(5-fluoro-2-tolyl)-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}(2-fluoro-5-hydroxyphenyl)methanone (compound 491) or a pharmaceutically acceptable salt thereof. 16. The compound of embodiment 1, which is {6-[4-cyclopropyl-3-(o-fluorophenyl)-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}(2-fluoro-5-hydroxyphenyl)methanone (compound 493) or a pharmaceutically acceptable salt thereof. 17. The compound of embodiment 1, which is {6-[3-(2-chloro-5-fluorophenyl)-4-methyl-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}(2-fluoro-5-hydroxyphenyl)methanone (compound 520) or a pharmaceutically acceptable salt thereof. 18. The compound of embodiment 1, which is (2-fluoro-5-hydroxyphenyl)(6-{3-[o-(trifluoromethyl)phenyl]-1-pyrazolyl}-2-aza-2-spiro[3.3]heptyl)methanone (compound 525) or a pharmaceutically acceptable salt thereof. 19. The compound of embodiment 1, which is (2-ethoxy-4-fluorophenyl){6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 146) or a pharmaceutically acceptable salt thereof. 20. The compound of embodiment 1, which is [4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]{6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl}methanone (compound 178) or a pharmaceutically acceptable salt thereof.

[0230] Additional embodiments include those listed below. 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: TIFF0007777891000134.tif50128In formula, A1 is TIFF0007777891000135.tif39128, R1 is hydrogen, halogen, or cyano; R 3a and R5 are each independently hydrogen, halogen, or lower alkyl; R 52 is lower alkyl, lower cycloalkyl, or lower haloalkyl; R 3b is a halogen, W is a diazole optionally substituted with lower alkyl, lower cycloalkyl, or lower haloalkyl; B1 is TIFF0007777891000136.tif49128, R 20 is hydrogen, halogen, lower alkyl, or lower haloalkyl, and R26 is hydrogen or halogen, However, the compound in question is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone. 2. R1 is hydrogen, fluoro or cyano; R 3a and R5 are each independently hydrogen, halogen, or methyl; R 52 is lower alkyl, cyclopropyl, or lower haloalkyl; R 3b is fluoro, W is diazole optionally substituted with one of methyl, cyclopropyl, or CF3; R 20 is fluoro or chloro, methyl, or CF3, and R 26 is hydrogen, fluoro or chloro; The compound of embodiment 1. 3.W is TIFF0007777891000137.tif75132; where * indicates a covalent bond to B1, and R 30 , R 31 , R 32 , and R 33 are each independently hydrogen, lower alkyl, lower haloalkyl, or lower cycloalkyl, with the proviso that R 31 and R 33 At least one of, and R 32 and R 33 At least one of the is not hydrogen, The compound of embodiment 2. 4.R 30 , R 31 , R 32 , and R 33 are each independently hydrogen, methyl, CF, or cyclopropyl, with the proviso that R 31and R 33 At least one of, and R 32 and R 33 The compound of embodiment 3, wherein at least one of is not hydrogen. 5.W is TIFF0007777891000138.tif42142, wherein * indicates a covalent bond to B1. 6.W is TIFF0007777891000139.tif30128, where * indicates a covalent bond to B1, and R 30 The compound of embodiment 5, wherein is methyl. 7.W is TIFF0007777891000140.tif39128, * indicates covalent bond to B1, R 31 and R 33 are each independently hydrogen, methyl, CF, or cyclopropyl, with the proviso that R 31 and R 33 The compound of embodiment 5, wherein one of is hydrogen. 8.W is TIFF0007777891000141.tif40128, * indicates covalent bond to B1, R 32 and R 33 are each independently hydrogen, methyl, CF, or cyclopropyl, with the proviso that R 32 and R 33 The compound of embodiment 5, wherein one of is hydrogen. 9.A1 is The compound of any one of embodiments 4 to 8, wherein the compound is TIFF0007777891000142.tif37128. 10. The compound of embodiment 9, wherein R5 is hydrogen. 11. The compound of embodiment 10, wherein R1 is fluoro. 12.R 3a 12. The compound of embodiment 11, wherein is hydrogen, fluoro, or methyl. 13.R 3a 13. The compound of embodiment 12, wherein is hydrogen. 14.R 20 is methyl and R 26 is hydrogen or fluoro, or R 20 is chloro, fluoro or CF3, R 26 14. The compound of embodiment 13, wherein is hydrogen. 15.A1 is The compound of any one of embodiments 4 to 8, wherein the compound is TIFF0007777891000143.tif37128. 16.R 52 16. The compound of embodiment 15, wherein is lower alkyl optionally substituted with one or more fluoro and cyclopropyl. 17.R 3b The compound of embodiment 16, wherein is fluoro. 18. R 20 is methyl and R 26 is hydrogen or fluoro, or R 20 is fluoro or CF3, and R 26 is hydrogen, The compound of embodiment 17. 19. 2. The compound of embodiment 1, which is TIFF0007777891000144.tif34128 or a pharmaceutically acceptable salt thereof. 20. 2. The compound of embodiment 1, which is TIFF0007777891000145.tif35128 or a pharmaceutically acceptable salt thereof. twenty one. 2. The compound of embodiment 1, which is TIFF0007777891000146.tif38128 or a pharmaceutically acceptable salt thereof. twenty two. 2. The compound of embodiment 1, which is TIFF0007777891000147.tif38128 or a pharmaceutically acceptable salt thereof. twenty three. 2. The compound of embodiment 1, which is TIFF0007777891000148.tif33128 or a pharmaceutically acceptable salt thereof. twenty four. 2. The compound of embodiment 1, which is TIFF0007777891000149.tif32128 or a pharmaceutically acceptable salt thereof. twenty five. 2. The compound of embodiment 1, which is TIFF0007777891000150.tif35128 or a pharmaceutically acceptable salt thereof. 26. 2. The compound of embodiment 1, which is TIFF0007777891000151.tif43128 or a pharmaceutically acceptable salt thereof. 27. 2. The compound of embodiment 1, which is TIFF0007777891000152.tif50128 or a pharmaceutically acceptable salt thereof. 28. 2. The compound of embodiment 1, which is TIFF0007777891000153.tif50128 or a pharmaceutically acceptable salt thereof. 29. 2. The compound of embodiment 1, which is TIFF0007777891000154.tif43128 or a pharmaceutically acceptable salt thereof. 30. 2. The compound of embodiment 1, which is TIFF0007777891000155.tif36128 or a pharmaceutically acceptable salt thereof. 31. 2. The compound of embodiment 1, which is TIFF0007777891000156.tif35128 or a pharmaceutically acceptable salt thereof. 32. 2. The compound of embodiment 1, which is TIFF0007777891000157.tif35128 or a pharmaceutically acceptable salt thereof. 33. 2. The compound of embodiment 1, which is TIFF0007777891000158.tif31128 or a pharmaceutically acceptable salt thereof. 34. 2. The compound of embodiment 1, which is TIFF0007777891000159.tif34128 or a pharmaceutically acceptable salt thereof. 35. 2. The compound of embodiment 1, which is TIFF0007777891000160.tif32128 or a pharmaceutically acceptable salt thereof. 36. 2. The compound of embodiment 1, which is TIFF0007777891000161.tif28128 or a pharmaceutically acceptable salt thereof. 37. 2. The compound of embodiment 1, which is TIFF0007777891000162.tif45128 or a pharmaceutically acceptable salt thereof. 38. 2. The compound of embodiment 1, which is TIFF0007777891000163.tif39128 or a pharmaceutically acceptable salt thereof. 39. 2. The compound of embodiment 1, which is TIFF0007777891000164.tif41128 or a pharmaceutically acceptable salt thereof. 40. 2. The compound of embodiment 1, which is TIFF0007777891000165.tif51128 or a pharmaceutically acceptable salt thereof. 41. 2. The compound of embodiment 1, which is TIFF0007777891000166.tif50128 or a pharmaceutically acceptable salt thereof. 42. 2. The compound of embodiment 1, which is TIFF0007777891000167.tif44128 or a pharmaceutically acceptable salt thereof. 43. 2. The compound of embodiment 1, which is TIFF0007777891000168.tif39128 or a pharmaceutically acceptable salt thereof. 44. A compound of formula (II-B) or a pharmaceutically acceptable salt thereof: TIFF0007777891000169.tif86128In formula, R1 is halogen or cyano; R3 is hydrogen, lower alkyl, or halogen; R5 is hydrogen, halogen, or lower alkyl; R 20is halogen or lower alkyl optionally substituted with one or more halogens, R 26 is a halogen or hydrogen, and R 30 is hydrogen or lower alkyl optionally substituted with one or more halogens, However, the compound in question is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone. 45. R1 is F or cyano; R3 is hydrogen, methyl, or F; R5 is hydrogen, F, or methyl; R 20 is F, methyl, or CF3, R 26 is hydrogen or F, and R 30 is hydrogen, methyl, or CF3, However, the compound is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone. The compound of embodiment 44. 46. ​​A compound of formula (II-C) or a pharmaceutically acceptable salt thereof: TIFF0007777891000170.tif75132In formula, R1 is halogen or cyano; R3 is hydrogen, lower alkyl, or halogen; R5 is hydrogen, halogen, or lower alkyl; R 20 is halogen or lower alkyl optionally substituted with one or more halogens, R 26 is hydrogen or halogen, and R 31 and R 33are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 31 and R 33 One of them is hydrogen. 47. R1 is F or cyano; R3 is hydrogen, methyl, or F; R5 is hydrogen, F, or methyl; R 20 is F, methyl, or CF3, R 26 is hydrogen or F, and R 31 and R 33 are each independently hydrogen, methyl, or CF3; The compound of embodiment 46. 48. A compound of formula (II-D) or a pharmaceutically acceptable salt thereof: TIFF0007777891000171.tif78128In formula, R1 is halogen or cyano; R3 is hydrogen, lower alkyl, or halogen; R5 is hydrogen, halogen, or lower alkyl; R6 is hydrogen; R 20 is halogen or lower alkyl optionally substituted with one or more halogens, R 26 is a halogen or hydrogen, and R 32 and R 33 are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 32 and R 33 One of them is hydrogen. 49. R1 is F or cyano; R3 is hydrogen, F, or methyl; R5 is hydrogen, F, or methyl; R 20 is F or methyl or CF3, R 26 is hydrogen or F, and R 32 and R 33 are each independently hydrogen, methyl, or CF3, with the proviso that R 32 and R 33 One of them is hydrogen, The compound of embodiment 48. 50. A compound of formula (III-B) or a pharmaceutically acceptable salt thereof: TIFF0007777891000172.tif87128In formula, R3 is a halogen; R 52 is lower alkyl or lower cycloalkyl, each of which may be substituted with halogen; R 30 is lower alkyl, R 20 is lower alkyl, and R 26 is hydrogen or halogen. 51. R3 is F, R 52 is lower alkyl optionally substituted with one or more F, or cyclopropyl; R 30 is methyl, R 20 is methyl, and R 26 is hydrogen or F, The compound of embodiment 50. 52. A compound of formula (III-C) or a pharmaceutically acceptable salt thereof: TIFF0007777891000173.tif67131In formula, R3 is a halogen; R 52 is lower alkyl or lower cycloalkyl, each of which may be substituted with halogen; R 31 and R 33are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 31 and R 33 One of them is hydrogen, R 20 is lower alkyl optionally substituted with halogen, and R 26 is hydrogen or halogen. 53. R3 is F, R 52 is lower alkyl optionally substituted with one or more F, or cyclopropyl; R 31 and R 33 are each independently hydrogen, methyl, or CF3, with the proviso that R 31 and R 33 One of them is hydrogen, R 20 is methyl or CF3, and R 26 is hydrogen or F, The compound of embodiment 52. 54. A compound of formula (III-D) or a pharmaceutically acceptable salt thereof: TIFF0007777891000174.tif87128In formula, R3 is a halogen; R 52 is lower alkyl or lower cycloalkyl, each of which may be substituted with halogen; R 32 and R 33 are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 32 and R 33 One of them is hydrogen, R 20 is lower alkyl optionally substituted with halogen, and R 26 is hydrogen or halogen. 55. R3 is F, R 52is lower alkyl optionally substituted with one or more F, or cyclopropyl; R 32 and R 33 are each independently hydrogen, methyl, or CF3, with the proviso that R 32 and R 33 One of them is hydrogen, R 20 is methyl or CF3, and R 26 is hydrogen or F, The compound of embodiment 54. 56. A compound of formula (II) or a pharmaceutically acceptable salt thereof: TIFF0007777891000175.tif70128In formula, The dashed line represents an optional double bond; R1 is a halogen; R3 is hydrogen; W is A, A is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with R 20 is halogen or lower alkyl optionally substituted with one or more halogens, R 30 is lower alkyl optionally substituted with one or more halogens, and R 26 is a halogen or hydrogen, However, the compound in question is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone. 57. A pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), a compound of any one of embodiments 1-56 or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone. 58. A method of inhibiting monoacylglycerol lipase (MAGL) in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-56. 59. A method of reversibly inhibiting monoacylglycerol lipase (MAGL), comprising contacting a compound of any one of embodiments 1-56 with a cell expressing MAGL.

[0231] Additional embodiments include those listed below. 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: TIFF0007777891000176.tif50128In formula, A1 is TIFF0007777891000177.tif39128, R1 is halogen, hydrogen, or cyano; R 3a and R5 are each independently hydrogen, halogen, or lower alkyl; R 52 is lower alkyl, lower cycloalkyl, or lower haloalkyl; R 3b is a halogen, W is a diazole optionally substituted with lower alkyl, lower cycloalkyl, or lower haloalkyl; B1 is TIFF0007777891000178.tif49128, R 20 is halogen, hydrogen, lower alkyl, or lower haloalkyl, and R 26 is hydrogen or halogen, However, the compound in question is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone. 2. R1 is hydrogen, fluoro or cyano; R3a and R5 are each independently hydrogen, halogen, or methyl; R 52 is lower alkyl, cyclopropyl, or lower haloalkyl; R 3b is fluoro, W is diazole optionally substituted with one of methyl, cyclopropyl, or CF3; R 20 is fluoro or chloro, methyl, or CF3, and R 26 is hydrogen, fluoro or chloro; The compound of embodiment 1. 3.W is TIFF0007777891000179.tif84132, where * indicates a covalent bond to B1, and R 30 , R 31 , R 32 , and R 33 are each independently hydrogen, lower alkyl, lower haloalkyl, or lower cycloalkyl, with the proviso that R 31 and R 33 At least one of, and R 32 and R 33 At least one of the is not hydrogen, The compound of embodiment 2. 4.R 30 , R 31 , R 32 , and R 33 are each independently hydrogen, methyl, CF, or cyclopropyl, with the proviso that R 31 and R 33 At least one of, and R 32 and R 33 The compound of embodiment 3, wherein at least one of is not hydrogen. 5.W is TIFF0007777891000180.tif42143, wherein * indicates a covalent bond to B1. 6.W is TIFF0007777891000181.tif30128, where * indicates a covalent bond to B1, and R 30 The compound of embodiment 5, wherein is methyl. 7.W is TIFF0007777891000182.tif39128, * indicates covalent bond to B1, R 31 and R 33 are each independently hydrogen, methyl, CF, or cyclopropyl, with the proviso that R 31 and R 33 The compound of embodiment 5, wherein one of is hydrogen. 8.W is TIFF0007777891000183.tif40128, * indicates covalent bond to B1, R 32 and R 33 are each independently hydrogen, methyl, CF, or cyclopropyl, with the proviso that R 32 and R 33 The compound of embodiment 5, wherein one of is hydrogen. 9.A1 is The compound of any one of embodiments 4 to 8, wherein the compound is TIFF0007777891000184.tif37128. 10. The compound of embodiment 9, wherein R5 is hydrogen. 11. The compound of embodiment 10, wherein R1 is fluoro. 12.R 3a 12. The compound of embodiment 11, wherein is hydrogen, fluoro, or methyl. 13.R 3a 13. The compound of embodiment 12, wherein is hydrogen. 14.R 20 is methyl and R 26 is hydrogen or fluoro, or R 20 is chloro, fluoro or CF3, R 26 14. The compound of embodiment 13, wherein is hydrogen. 15.A1 is The compound of any one of embodiments 4 to 8, wherein the compound is TIFF0007777891000185.tif37128. 16.R 52 16. The compound of embodiment 15, wherein is lower alkyl optionally substituted with one or more fluoro and cyclopropyl. 17.R 3b The compound of embodiment 16, wherein is fluoro. 18. R 20 is methyl and R 26 is hydrogen or fluoro, or R 20 is fluoro or CF3, and R 26 is hydrogen, The compound of embodiment 17. 19. A compound of formula (II-B) or a pharmaceutically acceptable salt thereof: TIFF0007777891000186.tif86128In formula, R1 is halogen or cyano; R3 is hydrogen, lower alkyl, or halogen; R5 is hydrogen, halogen, or lower alkyl; R 20 is halogen or lower alkyl optionally substituted with one or more halogens, R 26 is a halogen or hydrogen, and R 30 is hydrogen or lower alkyl optionally substituted with one or more halogens, However, the compound in question is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone. 20. R1 is F or cyano; R3 is hydrogen, methyl, or F; R5 is hydrogen, F, or methyl; R 20 is F, methyl, or CF3, R 26 is hydrogen or F, and R 30 is hydrogen, methyl, or CF3, However, the compound is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone. The compound of embodiment 19. 21. A compound of formula (II-C) or a pharmaceutically acceptable salt thereof: TIFF0007777891000187.tif75132In formula, R1 is halogen or cyano; R3 is hydrogen, lower alkyl, or halogen; R5 is hydrogen, halogen, or lower alkyl; R 20 is halogen or lower alkyl optionally substituted with one or more halogens, R 26 is hydrogen or halogen, and R 31 and R 33 are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 31 and R 33 One of them is hydrogen. twenty two. R1 is F or cyano; R3 is hydrogen, methyl, or F; R5 is hydrogen, F, or methyl; R 20 is F, methyl, or CF3, R 26 is hydrogen or F, and R 31 and R 33 are each independently hydrogen, methyl, or CF3; The compound of embodiment 21. 23. A compound of formula (II-D) or a pharmaceutically acceptable salt thereof: TIFF0007777891000188.tif78128In formula, R1 is halogen or cyano; R3 is hydrogen, lower alkyl, or halogen; R5 is hydrogen, halogen, or lower alkyl; R6 is hydrogen; R 20 is halogen or lower alkyl optionally substituted with one or more halogens, R 26 is a halogen or hydrogen, and R 32 and R 33 are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 32 and R 33 One of them is hydrogen. twenty four. R1 is F or cyano; R3 is hydrogen, F, or methyl; R5 is hydrogen, F, or methyl; R 20 is F or methyl or CF3, R 26 is hydrogen or F, and R 32 and R 33 are each independently hydrogen, methyl, or CF3, with the proviso that R 32 and R 33 One of them is hydrogen, The compound of embodiment 23. 25. A compound of formula (III-B) or a pharmaceutically acceptable salt thereof: TIFF0007777891000189.tif87128In formula, R3 is a halogen; R 52 is lower alkyl or lower cycloalkyl, each of which may be substituted with halogen; R 30 is lower alkyl, R20 is lower alkyl, and R 26 is hydrogen or halogen. 26. R3 is F, R 52 is lower alkyl optionally substituted with one or more F, or cyclopropyl; R 30 is methyl, R 20 is methyl, and R 26 is hydrogen or F, The compound of embodiment 25. 27. A compound of formula (III-C) or a pharmaceutically acceptable salt thereof: TIFF0007777891000190.tif67131In formula, R3 is a halogen; R 52 is lower alkyl or lower cycloalkyl, each of which may be substituted with halogen; R 31 and R 33 are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 31 and R 33 One of them is hydrogen, R 20 is lower alkyl optionally substituted with halogen, and R 26 is hydrogen or halogen. 28. R3 is F, R 52 is lower alkyl optionally substituted with one or more F, or cyclopropyl; R 31 and R 33 are each independently hydrogen, methyl, or CF3, with the proviso that R 31 and R 33 One of them is hydrogen, R 20 is methyl or CF3, and R 26 is hydrogen or F, The compound of embodiment 27. 29. A compound of formula (III-D) or a pharmaceutically acceptable salt thereof: TIFF0007777891000191.tif87128In formula, R3 is a halogen; R 52 is lower alkyl or lower cycloalkyl, each of which may be substituted with halogen; R 32 and R 33 are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R 32 and R 33 One of them is hydrogen, R 20 is lower alkyl optionally substituted with halogen, and R 26 is hydrogen or halogen. 30. R3 is F, R 52 is lower alkyl optionally substituted with one or more F, or cyclopropyl; R 32 and R 33 are each independently hydrogen, methyl, or CF3, with the proviso that R 32 and R 33 One of them is hydrogen, R 20 is methyl or CF3, and R 26 is hydrogen or F, The compound of embodiment 29. 31. A compound of formula (II) or a pharmaceutically acceptable salt thereof: TIFF0007777891000192.tif70128In formula, The dashed line represents an optional double bond; R1 is a halogen; R3 is hydrogen; W is A, A is one or more R 30 is a 5-membered heteroaryl ring optionally substituted with R 20 is halogen or lower alkyl optionally substituted with one or more halogens, R 30 is lower alkyl optionally substituted with one or more halogens, and R 26 is a halogen or hydrogen, However, the compound in question is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone. 32. 2. The compound of embodiment 1, which is TIFF0007777891000193.tif33128 or a pharmaceutically acceptable salt thereof. 33. 2. The compound of embodiment 1, which is TIFF0007777891000194.tif51128 or a pharmaceutically acceptable salt thereof. 34. 2. The compound of embodiment 1, which is TIFF0007777891000195.tif32128 or a pharmaceutically acceptable salt thereof. 35. 2. The compound of embodiment 1, which is TIFF0007777891000196.tif41128 or a pharmaceutically acceptable salt thereof. 36. 2. The compound of embodiment 1, which is TIFF0007777891000197.tif35128 or a pharmaceutically acceptable salt thereof. 37. 2. The compound of embodiment 1, which is TIFF0007777891000198.tif41128 or a pharmaceutically acceptable salt thereof. 38. 2. The compound of embodiment 1, which is TIFF0007777891000199.tif30128 or a pharmaceutically acceptable salt thereof. 39. 2. The compound of embodiment 1, which is TIFF0007777891000200.tif45128 or a pharmaceutically acceptable salt thereof. 40. 2. The compound of embodiment 1, which is TIFF0007777891000201.tif49128 or a pharmaceutically acceptable salt thereof. 41. A pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), a compound of any one of embodiments 1-40 or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone. 42. A method of inhibiting monoacylglycerol lipase (MAGL) in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-40. 43. A method of reversibly inhibiting monoacylglycerol lipase (MAGL), comprising contacting a compound of any one of embodiments 1-40 with a cell expressing MAGL. [Example]

[0232] The following examples illustrate some embodiments and aspects of the present invention. It will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like may be made without altering the spirit or scope of the present invention, and that such modifications and variations are encompassed within the scope of the present invention as defined in the following claims. The following examples are not intended to limit the present invention in any way.

[0233] LC / MS... Abbreviation table

[0234] Example 1: Preparation of synthetic intermediates Intermediate-5: 2-(2-ethoxy-4-fluorobenzoyl)-2-azaspiro[3.3]heptane-6-carboxylic acid Synthesis scheme: TIFF0007777891000202.tif58165

[0235] Step-1: Synthesis of 2-(tert-butyl)6-methyl 2-azaspiro[3.3]heptane-2,6-dicarboxylate (Int-2) To a stirred solution of 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (3.0 gm, 12.44 mmol, 1.0 equiv.) in N,N-dimethylformamide (30 mL) was added potassium carbonate (2.061 gm, 14.93 mmol, 1.2 equiv.) at 0° C. The reaction was stirred at 0° C. for 10 minutes. Methyl iodide (2.12 gm, 14.93 mmol, 1.2 equiv.) was added dropwise, and the reaction was stirred at room temperature for 12 hours. After the reaction was complete, as monitored by TLC, the reaction mixture was diluted with ice-cold water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated to give the crude product. This was purified by Combiflash using 30% ethyl acetate in hexane as the eluent to give 3.10 gm of 2-(tert-butyl) 6-methyl 2-azaspiro[3.3]heptane-2,6-dicarboxylate (Int-2) (97.79% yield). LCMS: 200.2 / z [M-56] + .

[0236] Step-2: Synthesis of methyl 2-azaspiro[3.3]heptane-6-carboxylate (Int-3) To a stirred solution of 2-(tert-butyl)6-methyl 2-azaspiro[3.3]heptane-2,6-dicarboxylate (Int-2) (3.0 gm, 8.0 mmol, 1.0 equiv.) in dichloromethane (30 mL), trifluoroacetic acid (3.0 mL) was added at 0 °C, and the reaction was allowed to stir at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under vacuum, basified with bicarbonate solution (15 mL), and extracted with ethyl acetate (3 x 30 mL). The ethyl acetate phase was separated, dried over sodium sulfate, and concentrated to give 2.50 gm of crude methyl 2-azaspiro[3.3]heptane-6-carboxylate (Int-3) (yield: quantitative). LCMS: 155.90 / z [M+1]+ .

[0237] Step-3: Synthesis of methyl 2-(2-ethoxy-4-fluorobenzoyl)-2-azaspiro[3.3]heptane-6-carboxylate (Int-4) To a stirred solution of 2-ethoxy-4-fluorobenzoic acid (2.0 gm, 10.86 mmol, 1 equiv.) in N,N-dimethylformamide (20 mL) was added HATU (6.19 gm, 16.30 mmol, 1.5 equiv.) and DIPEA (4.20 gm, 32.6 mmol, 3.0 equiv.), followed by methyl 2-azaspiro[3.3]heptane-6-carboxylate (Int-3) (1.33 gm, 10.86 mmol, 1.0 equiv.) at 0 °C. The reaction was allowed to stir at room temperature for 12 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (3 × 30 mL), and washed with brine. The organic phase was dried over sodium sulfate and concentrated under vacuum to obtain crude material. This was purified by CombiFlash using 70% ethyl acetate in n-hexane as the mobile phase to obtain 2.4 gm of the desired product, 2-(2-ethoxy-4-fluorobenzoyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (Int-4) (yield: 73.52%). LCMS: 322.3 m / z [M+1] + .

[0238] Step-4: Synthesis of 2-(2-ethoxy-4-fluorobenzoyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (Int-5) To a stirred solution of methyl 2-(2-ethoxy-4-fluorobenzoyl)-2-azaspiro[3.3]heptane-6-carboxylate (Int-4) (1.0 gm, 3.11 mmol, 1.0 equiv.) in tetrahydrofuran (10 mL), methanol (5 mL), and water (10 mL) was added sodium hydroxide [NaOH] (0.13 gm, 6.23 mmol, 2.0 equiv.) at 0° C. The reaction mixture was then stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under vacuum. The crude product was acidified with 2N HCl (pH ∼4). A white solid precipitated, which was filtered through a Buchner funnel and dried under vacuum to give 2-(2-ethoxy-4-fluorobenzoyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (Int-5), 0.75 gm (yield: 72.11%). LCMS: 308.3 m / z [M+1] + .

[0239] Example 2: Synthesis of (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]hept-5-en-2-yl)methanone [Compound 120] Synthesis scheme: TIFF0007777891000207.tif44158

[0240] Step-1: 6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]hept-5-ene 2,2,2-trifluoroacetate To a stirred solution of tert-butyl 6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (100 mg) in DCM (0.5 ml) was added trifluoroacetic acid (0.5 mL) at 0° C. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, monitored by TLC, the reaction mixture was concentrated to give the crude material. The crude material was triturated with a mixture of diethyl ether and hexane (1:1, 10 mL*3) to give the pure desired compound (0.11 g, quantitative) as a white solid. LCMS: 266.3 m / z [M+H]+; 1H NMR (400 MHz, methanol-d₄) δ: 7.51-7.47 (m, 1H), 7.44-7.36 (m, 2H), 7.28 (d, J = 7.6 Hz, 1H), 6.38 (s, 1H), 5.36 (s, 1H), 4.19-4.13 (m, 4H), 2.88-2.86 (m, 2H), 2.31 (s, 3H), 2.01 (s, 3H).

[0241] Step-2: (2-Fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]hept-5-en-2-yl)methanone To a stirred solution of 6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]hept-5-ene 2,2,2-trifluoroacetate (0.11 g, 0.421 mmol) in DMF (1 mL) was added 2-fluoro-5-hydroxybenzoic acid (0.054 g, 0.506 mmol), TEA (0.088 g, 1.26 mmol), and T3P (0.111 g, 0.506 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as monitored by TLC, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with brine (3×25 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude material. This was purified by Combiflash using 3% MeOH in DCM as eluent to give ((2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]hept-5-en-2-yl)methanone)PSY-05-00120 (0.03 g, 27%) as a white solid. LCMS: 473.7 m / z [M+H]+; 1 H NMR (400MHz, methanol-d4) δ7.51-7.33(m,3H),7.28(d,J=7.9Hz,1H),7.00(t,J=9.2Hz,1H),6.92-6.78( m,2H),6.35(s,1H),5.39(s,1H),4.29-4.09(m,4H),2.78(d,J=5.6Hz,2H),2.30(s,3H),2.00(s,3H).

[0242] Example 3: Synthesis of (4-fluoro-2-isopropoxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone. [Compound 177] Synthesis scheme: TIFF0007777891000208.tif37154

[0243] Step-1: Isopropyl 4-fluoro-2-isopropoxybenzoate (Int-2) To a stirred solution of 284-fluoro-2-hydroxybenzoic acid (2.0 gm, 12.820 mmol, 1 eq.) in N,N-dimethylformamide (20 mL) was added potassium carbonate (17.07 gm, 51.282 mmol, 4.0 eq.), followed by dropwise addition of isopropyl iodide (8.88 gm, 51.282 mmol, 4.0 eq.) at 0° C. The reaction was allowed to stir at room temperature for 12 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (3×50 mL), and washed with brine. The organic phase was dried over sodium sulfate and concentrated under vacuum to give the crude material. This was purified by Combiflash using 20% ​​ethyl acetate in hexane as the mobile phase to give the desired product 4-fluoro-2-isopropoxybenzoic acid, 2.0 gm (yield: 65.14%). 1 H NMR(400MHz,DMSO-d6)δ7.65(dd,J=8.7,7.0Hz,1H),7.08(dd,J=11.8,2.4Hz,1H),6.82(td,J=8.4,2.4Hz, 1H),5.09(hept,J=6.2Hz,1H),4.72(p,J=6.0Hz,1H),3.18(d,J=5.2Hz,1H),1.29(dd,J=6.1,2.7Hz,12H).

[0244] Step-2: Synthesis of 4-fluoro-2-isopropoxybenzoic acid carbonate (Int-3) To a stirred solution of isopropyl 4-fluoro-2-isopropoxybenzoate (Int-2) (1.60 gm, 6.66 mmol, 1.0 equiv.) in tetrahydrofuran (10 mL), methanol (10 mL), and water (10 mL) was added sodium hydroxide [NaOH] (0.53 gm, 13.33 mmol, 2.0 equiv.) at 0° C. The reaction mixture was then stirred for 12 hours at 50° C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under vacuum. The crude product was acidified with 2N HCl (pH ∼4). A white solid precipitated which was filtered through a Buchner funnel and dried under vacuum to give isopropyl 4-fluoro-2-isopropoxybenzoate (Int-3), 1.20 gm (yield: 91%). 1 H NMR(400MHz,DMSO-d6)δ12.53(s,1H),7.69(t,J=7.9Hz,1H),7.05(dd,J=11.9,2.5H z,1H),6.80(td,J=8.4,2.5Hz,1H),4.69(hept,J=6.0Hz,1H),1.27(d,J=6.0Hz,6H).

[0245] Step-3: Synthesis of (4-fluoro-2-isopropoxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Compound-00177) To a stirred solution of 6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate (0.150 gm, 0.56 mmol, 1.0 equiv.) in N,N-dimethylformamide (3 mL) was added 4-fluoro-2-isopropoxybenzoic acid (0.133 gm, 0.674 mmol, 1.2 equiv.), TEA (0.170 gm, 1.68 mmol, 3.0 equiv.), and T3P (50% solution in acetic acid) (0.214 gm, 0.674 mmol, 1.2 equiv.) at 0° C. The resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed as monitored by TLC, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with brine (10 ml), dried over sodium sulfate, and concentrated under vacuum to give the crude material. This was purified by CombiFlash using 50% ethyl acetate in hexane as the eluent to give PSY-05-00177 (0.040 g, yield: 16%) as a white solid. LCMS: 448.5 m / z [M+H] + .HPLC:98.35%; 1 H NMR(400MHz,DMSO-d6)δ7.38(t,J=8.3Hz,2H),7.33-7.22(m,2H),7.15(dd,J=7.9,4.2 Hz,1H),6.97(dd,J=11.6,8.5Hz,1H),6.75(q,J=7.6Hz,1H),6.13(d,J=17.6Hz,1H),4 .70-4.60(m,1H),3.93(s,1H),3.85(d,J=15.1Hz,2H),3.78(s,1H),3.00(dt,J=18.8, 8.5Hz, 1H), 2.34-2.16 (m, 4H), 2.16 (s, 3H), 1.93 (s, 3H), 1.24 (dd, J=11.5, 6.1Hz, 6H).

[0246] Example 4: Synthesis of (2,4-difluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone [Compound 126] Synthesis scheme: TIFF0007777891000212.tif59154

[0247] Step-1: Synthesis of benzyl 5-(benzyloxy)-2,4-difluorobenzoate (Int-2) To a stirred solution of 2,4-difluoro-5-hydroxybenzoic acid (0.40 gm, 2.13 mmol, 1.0 equiv.) in N,N-dimethylformamide (5.0 mL) was added potassium carbonate (0.88 gm, 6.38 mmol, 3.0 equiv.) and benzyl bromide (1.09 gm, 6.38 mmol, 3.0 equiv.) at 0° C. The reaction was stirred at room temperature for 12 hours, and the reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3×20 mL), and washed with brine. The organic phase was dried over sodium sulfate and concentrated under vacuum to give the crude material. This was purified by Combiflash using 35% ethyl acetate in n-hexane as the mobile phase to give the desired product benzyl 5-(benzyloxy)-2,4-difluorobenzoate (Int-2), 0.560 gm (yield: 69.13%). 1 H NMR (400MHz, DMSO-d6) δ7.68(dd,J=9.4,6.8Hz,1H),7.52(t,J=10.9Hz,1H),7.47(d,J=1.9Hz,2H),7.47-7.31(m,8H),5.36(s,2H),5.24(s,2H).

[0248] Step-2: 5-(benzyloxy)-2,4-difluorobenzoic acid (Int-3) To a stirred solution of benzyl 5-(benzyloxy)-2,4-difluorobenzoate (Int-2) (0.50 gm, 1.44 mmol, 1.0 equiv.) in tetrahydrofuran (5.0 mL), methanol (5.0 mL), and water (5.0 mL) was added sodium hydroxide [NaOH] (0.11 gm, 2.89 mmol, 2.0 equiv.) at 0° C. The reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under vacuum. The crude product was acidified with 2N HCl (pH ∼4). A white solid precipitated which was filtered through a Buchner funnel and dried under vacuum to give 5-(benzyloxy)-2,4-difluorobenzoic acid (Int-3), 0.35 gm (yield: 94.59%). 1 H NMR (400MHz, DMSO-d6) δ13.42 (s, 1H), 7.65 (dd, J=9.5, 6.9Hz, 1H), 7.52-7.29 (m, 5H), 5.23 (s, 2H).

[0249] Step-3: Synthesis of (5-(benzyloxy)-2,4-difluorophenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Int-4) To a stirred solution of 2-(5-(benzyloxy)-2-fluorobenzoyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (0.25 gm, 0.677 mmol, 1.0 equiv) in N,N-dimethylformamide (10.0 mL) was added TBTU (0.326 gm, 1.01 mmol, 1.5 equiv), pyridine (0.15 gm, 2.03 mmol, 3.0 equiv), followed by 5-(benzyloxy)-2,4-difluorobenzoic acid (Int-3) (0.16 gm, 0.677 mmol, 1.0 equiv) at 0° C. The reaction was stirred at room temperature for 12 hours and the reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 x 20 mL), and washed with brine. The organic phase was dried over sodium sulfate and concentrated under vacuum to give the crude material, which was purified by Combiflash using 80% ethyl acetate in hexane as the mobile phase to give the desired product (5-(benzyloxy)-2,4-difluorophenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Int-4), 0.25 gm (yield: 52.08%). LCMS: 514.05 m / z [M + ].

[0250] Step-4: Synthesis of (2,4-difluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Compound-00126) A stirred solution of (5-(benzyloxy)-2,4-difluorophenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Int-4) (0.20 gm, 0.400 mmol, 1.0 equiv) was dissolved in methanol (10 mL). 0.050 gm of 10% Pd / C (50% wet) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a bed of celite, washed with methanol (50 mL), and concentrated to give the crude compound. This was purified by column chromatography using 60-120 mesh silica gel and 80% ethyl acetate in hexane as the mobile phase to give the desired product (2,4-difluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00126), 0.080 gm (yield: 48.78%) as a white solid. LCMS: 424.4 m / z [M+1] + 1 H NMR(400MHz,DMSO-d6)δ10.30(s,1H),7.38(t,J=7.7Hz,3H),7.33-7.23(m,1H),7.15(t,J=6.7Hz,1H),7.02-6.93(m,1H),6.14(d,J=18.3Hz ,1H),3.97(d,J=3.4Hz,2H),3.91(s,2H),2.98(dt,J=18.5,8.8Hz,1H),2.45(s,1H),2.34-2.22(m,1H),2.19(t,J=11.7Hz,3H),1.93(s,3H).

[0251] Example 5: Synthesis of 4-hydroxy-2-(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane-2-carbonyl)benzonitrile [Compound 128] TIFF0007777891000217.tif39162

[0252] Step-1: Methyl 2-bromo-5-hydroxybenzoate (2): To a stirred solution of 2-bromo-5-hydroxybenzoic acid (0.5 g, 2.325 mmol) in MeOH, concentrated H2SO4 (2 mL) was added dropwise. The reaction mixture was heated to 90 °C and stirred at the same temperature for 2 h. After completion of the reaction, the RM was concentrated, diluted with ethyl acetate, washed with aqueous NaHCO3 (3 x 15 mL), dried over Na2SO4, and evaporated. The crude material was purified by Combiflash using 30% ethyl acetate in hexane to give methyl 2-bromo-5-hydroxybenzoate (300 mg, 56%) as a colorless liquid. LCMS: 229.9 m / z [M+H] + .

[0253] Step-2: Methyl 2-cyano-5-hydroxybenzoate (3): To a stirred solution of methyl 2-bromo-5-hydroxybenzoate (0.3 g, 1.31 mmol) in DMA, CuCN (0.174 g, 1.89 mmol) was added and stirred at 135 °C for 2 h. The reaction was quenched by the addition of cold water (50 mL) and extracted with ethyl acetate (3 × 25 mL). The organic phase was concentrated and purified by CombiFlash using 30% ethyl acetate in hexane to give methyl 2-cyano-5-hydroxybenzoate (140 mg, 61%) as a white solid. 1 H NMR (400MHz, CDCl) δ7.71(d,J=8.4Hz,1H),7.60(d,J=2Hz,1H),7.13-7.10(m,1H),6.31(s,1H),4.01(s,3H).

[0254] Step-3: (4-hydroxy-2-(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane-2-carbonyl)benzonitrile) (Compound-00128) To a stirred solution of 6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate (0.120 g, 0.449 mmol) and methyl 2-cyano-5-hydroxybenzoate (0.0795 g, 0.449 mmol) in THF at −78° C., LiHMDS (1.35 mL, 1.347 mmol, 1 M solution in THF) was added over 15 min and then stirred at room temperature for 3 h. The reaction was quenched by the addition of water (50 mL) and extracted with ethyl acetate (3×30 mL). The organic phase was concentrated under reduced pressure and purified by Combiflash using 5% MeOH in DCM to give (4-hydroxy-2-(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane-2-carbonyl)benzonitrile) (60 mg, 21%) as a white solid. LCMS: 413.4 m / z [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.68(t,J=7.8Hz,1H),7.43-7.26(m,3H),7.15(dd,J=7.8,3.9Hz,1H),6.98-6.85(m,2H),6.13(d,J=19.6Hz,1H),3.9 9(dd,J=24.0,13.9Hz,4H),2.99(dt,J=22.2,8.4Hz,1H),2.39-2.28(m,2H),2.23(dd,J=12.7,9.0Hz,2H),2.17(d,J=8.5Hz,3H),1.92(s,3H).

[0255] Example 6: Synthesis of 2-(2-fluoro-5-hydroxybenzoyl)-N-methyl-N-(o-tolyl)-2-azaspiro[3.3]heptane-6-carboxamide [Compound 185] and 2-(2-ethoxy-4-fluorobenzoyl)-N-methyl-N-(o-tolyl)-2-azaspiro[3.3]heptane-6-carboxamide [Compound 187] Reaction scheme: TIFF0007777891000218.tif69150

[0256] Step-1: Synthesis of Tert-butyl 6-(methyl(o-tolyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-D) TIFF0007777891000219.tif36128 Tert-butyl 6-(o-tolylcarbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (0.5 g, 1.5151 mmol, 1 equiv.) was dissolved in 5 mL of dimethylformamide. 0.08 g (1.9696 mmol, 1.3 equiv.) of sodium hydride was added, and the reaction mixture was stirred at room temperature for 15 minutes. Subsequently, 0.25 g (1.818 mmol, 1.2 equiv.) of methyl iodide was added, and the reaction mixture was stirred at 60 °C for 6 hours. The reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water. The product was extracted with ethyl acetate (3 × 25 mL), and the combined organics were concentrated to give the crude product. The crude product was purified by column chromatography using ethyl acetate:hexane as a solvent system to give the desired product. Tert-Butyl 6-(methyl(o-tolyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate. 0.51 g (solid) (98% yield). m / z 345.4 [M+1] +1H. NMR (400 MHz, chloroform-d) δ 7.35-7.20 (m, 3H), 7.05 (d, J = 7.6 Hz, 1H), 3.91-3.76 (m, 4H), 3.20 (s, 3H), 2.70 (q, J = 8.3 Hz, 1H), 2.57-2.47 (m, 1H), 2.49-2.39 (m, 1H), 2.22 (s, 3H), 2.05-1.95 (m, 2H), 1.43 (s, 9H).

[0257] Step-2: Synthesis of N-methyl-N-(o-tolyl)-2-azaspiro[3.3]heptane-6-carboxamide (Int-E) TIFF0007777891000220.tif29128 Tert-butyl 6-(methyl(o-tolyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate, 0.5 g, was dissolved in 50 mL of dichloromethane and cooled to 0 °C. 0.8 mL of trifluoroacetic acid was added, and the reaction mixture was stirred at room temperature for 5 h. The reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated and triturated with diethyl ether to give the desired product as N-methyl-N-(o-tolyl)-2-azaspiro[3.3]heptane-6-carboxamide, 0.5 g (solid, 92% yield). m / z 245.4 [M+1] +

[0258] Step-3: Synthesis of 2-(2-fluoro-5-hydroxybenzoyl)-N-methyl-N-(o-tolyl)-2-azaspiro[3.3]heptane-6-carboxamide (Compound-00185) To a solution of 0.1 g (0.676 mmol, 1.1 equiv.) of 2-fluoro-4-hydroxybenzoic acid in 2 mL of dimethylformamide, 0.15 g (0.6147 mmol, 1 equiv.) of the TFA salt of N-methyl-N-(o-tolyl)-2-azaspiro[3.3]heptane-6-carboxamide was added and stirred for 10 minutes. 0.4 mL (2.459 mmol, 4 equiv.) of DIPEA was added and the reaction mixture was stirred for 10 minutes. 0.4 mL (0.7377 mmol, 1.2 equiv.) of T3P was added and the reaction mixture was stirred at room temperature for 10 hours. The reaction was monitored by TLC. After completion, the mixture was diluted with water. The product was extracted with ethyl acetate (3 x 15 mL), and the combined organics were washed with water and dried over anhydrous sodium sulfate. The organic phase was concentrated to give the crude compound. The crude gum was purified by column chromatography using ethyl acetate:hexane as the solvent system. The desired product was obtained as 2-(2-fluoro-5-hydroxybenzoyl)-N-methyl-N-(o-tolyl)-2-azaspiro[3.3]heptane-6-carboxamide 0.05 g (solid) (yield - 22.22%). m / z 383.35[M+1]+ 1H NMR(400MHz,DMSO-d6)δ9.62(d,J=13.5Hz,1H),7.40-7.23(m,3H),7.16(s,1H),7.17-6.98(m,1H),6.83(ddt,J=12.9,8.7,3.7Hz,1H),6.78- 6.69(m,1H),3.97-3.80(m,4H),3.05(d,J=6.1Hz,3H),2.62(td,J=15. 6,7.7Hz,1H),2.39-2.23(m,2H),2.22-2.05(m,3H),2.00-1.90(m,2H).

[0259] Step-4: Synthesis of 2-(2-ethoxy-4-fluorobenzoyl)-N-methyl-N-(o-tolyl)-2-azaspiro[3.3]heptane-6-carboxamide (Compound-00187) To a solution of 0.15 g (0.676 mmol, 1.1 equiv.) of 2-ethoxy-4-fluorobenzoic acid in 2 mL of dimethylformamide was added 0.15 g (0.6147 mmol, 1 equiv.) of the TFA salt of N-methyl-N-(o-tolyl)-2-azaspiro[3.3]heptane-6-carboxamide, followed by 0.4 mL (2.459 mmol, 4 equiv.) of diisopropylethylamine. The reaction mixture was stirred for 10 min. 0.4 mL (0.7377 mmol, 1.2 equiv.) of T3P was added, and the reaction mixture was stirred at room temperature for 10 h. The reaction was monitored by TLC. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 15 mL). The organic phases were combined and concentrated to give the crude product. The crude compound as a gum was purified by column chromatography using EtOAC:Hexane as the solvent system to give the desired product: 2-(2-ethoxy-4-fluorobenzoyl)-N-methyl-N-(o-tolyl)-2-azaspiro[3.3]heptane-6-carboxamide 0.05 g (solid) (yield—21.22%). m / z 411.4[M+1]+ 1H NMR (400MHz, methanol-d4) δ7.42-7.22(dq,J=27.9,7.8Hz,4H),7.14(d,J=7.5Hz,1H),6.91-6.66(m,2H),4.18-3.89(m,5H),3.87(s,1H),3.17(d, J=5.4Hz,3H),2.79(dp,J=24.3,8.0Hz,1H),2.43(ddt,J=27.5,19.5,9.9Hz,2H),2.20(s,3H),2.17-1.98(m,2H),1.41(dt,J=18.6,7.0Hz,3H).

[0260] Example 7: Synthesis of (2-fluoro-5-hydroxyphenyl)(6-(1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone [Compound 367] Synthesis scheme: TIFF0007777891000223.tif57169

[0261] Step-1: Synthesis of tert-butyl 6-(methoxy(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-2) To a stirred solution of 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (2.0 gm, 8.298 mmol, 1.0 equiv.) in N,N-dimethylformamide (20 mL) was added HATU (3.15 gm, 8.29 mmol, 1.5 equiv.), DIPEA (3.21 gm, 24.89 mmol, 3.0 equiv.), followed by N,O-dimethylhydroxylamine hydrochloride (1.00 gm, 10.37 mmol, 1.25 equiv.) at 0 °C, and the reaction was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (25 mL), extracted with ethyl acetate (3 × 30 mL), and washed with brine. The organic phase was dried over sodium sulfate and concentrated under vacuum to give the crude material. This was purified by CombiFlash using 100% ethyl acetate as the mobile phase to give the desired product, tert-butyl 6-(methoxy(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-2), 1.50 gm (63.82% yield). 1H NMR (400 MHz, DMSO-d6) δ 3.89 (s, 2H), 3.73 (s, 2H), 3.62 (s, 3H), 3.08 (s, 3H), 2.30 (dt, J = 8.1, 2.1 Hz, 4H), 1.37 (s, 9H).

[0262] Step-2: Synthesis of tert-butyl 6-acetyl-2-azaspiro[3.3]heptane-2-carboxylate (Int-3) To a stirred solution of tert-butyl 6-(methoxy(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-2) (1.7 gm, 5.98 mmol, 1.0 equiv.) in THF was added methylmagnesium bromide (3 M in THF) (5.98 mL, 17.95 mmol, 3.0 equiv.) under an inert atmosphere at -30°C. The reaction mixture was then stirred at room temperature for 12 hours. The reaction progress was monitored by TLC, and after completion, the reaction mixture was cooled to 0°C, quenched with saturated ammonium chloride solution (10 mL), further diluted with water (30 mL), extracted with ethyl acetate (3 x 30 mL), and washed with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to give the crude material. This was purified by CombiFlash using 80% ethyl acetate in hexane as the mobile phase to give the desired product, tert-butyl 6-acetyl-2-azaspiro[3.3]heptane-2-carboxylate (Int-3), 1.30 gm (90.90% yield). 1H NMR (400 MHz, chloroform-d) δ 3.98 (s, 2H), 3.85 (s, 2H), 3.16 (p, J = 8.3 Hz, 1H), 2.46-2.32 (m, 4H), 2.14 (s, 3H), 1.47 (s, 9H).

[0263] Step-3: Synthesis of tert-butyl (E)-6-(3-(dimethylamino)acryloyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-4) To a stirred solution of tert-butyl 6-acetyl-2-azaspiro[3.3]heptane-2-carboxylate (Int-3) (0.050 gm, 0.209 mmol, 1.0 equiv.) in toluene (1 mL), DMF-DMA (0.074 gm, 0.627 mmol, 3.0 equiv.) was added and stirred at 100° C. for 12 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (3 mL), extracted with ethyl acetate (3×5 mL), and washed with brine. The organic phase was dried over sodium sulfate and concentrated under vacuum to give the crude material. This was purified by Combiflash using 90% ethyl acetate in hexane as the mobile phase to give the desired product tert-butyl (E)-6-(3(dimethylamino)acryloyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-4) 0.040 gm (yield: 65.04%). LCMS: 295.3 m / z [M+1]+.

[0264] Step-4: Synthesis of tert-butyl 6-(1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5) To a stirred solution of tert-butyl (E)-6-(3(dimethylamino)acryloyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-4) (0.30 gm, 0.020 mmol, 1.0 equiv.) in ethanol (9 mL), o-tolylhydrazine (0.177 gm, 1.122 mmol, 1.1 equiv.) was added and the reaction was stirred at 90° C. for 12 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under vacuum to give the crude compound. This was absorbed onto silica gel and purified by Combiflash using 100% ethyl acetate as the mobile phase to give the desired product tert-butyl 6-(1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5) 0.340 gm (yield: 94.44%). LCMS: 354.3 m / z [M+1]+.

[0265] Step-5: Synthesis of 6-(1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane (Int-6) To a stirred solution of tert-butyl 6-(1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5) (0.30 gm, 0.84 mmol, 1.0 equiv.) in dichloromethane (10 mL), trifluoroacetic acid (1.0 mL) was added at 0° C., and the reaction was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under vacuum and triturated with pentane to give 0.30 gm of crude compound 6-(1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane (Int-6) (yield: quantitative). LCMS: 254.2 m / z [M+1]+.

[0266] Step-6: Synthesis of (5-(benzyloxy)-2-fluorophenyl)(6-(1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Int-7) TIFF0007777891000229.tif331285-(Benzyloxy)-2-fluorobenzoic acid To a stirred solution of 6-(1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane (Int-6A) (0.25 gm, 1.016 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) was added TBTU (0.58 gm, 1.52 mmol, 1.5 equiv), pyridine (0.24 gm, 3.04 mmol, 3.0 equiv), followed by 6-(1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane (Int-6) (0.30 gm, 1.21 mmol, 1.2 equiv) at 0° C. and the reaction was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (3 x 20 mL), and washed with brine. The organic phase was dried over sodium sulfate and concentrated under vacuum to give the crude material, which was purified by Combiflash using 90% ethyl acetate in hexane as the mobile phase to give the desired product (5-(benzyloxy)-2-fluorophenyl)(6-(1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Int-7), 0.250 gm (yield: 51.22%). LCMS: 482.3 m / z [M+1]+.

[0267] Step-7: Synthesis of (2-fluoro-5-hydroxyphenyl)(6-(1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Compound-00367) A stirred solution of TIFF0007777891000230.tif34128 (5-(benzyloxy)-2-fluorophenyl)(6-(1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Int-7) (0.20 gm, 0.415 mmol, 1.0 equiv) was dissolved in methanol (10 mL). 0.050 gm of 10% Pd / C (50% wet) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a bed of celite, washed with methanol (50 mL), and concentrated to give the crude compound. This was purified by column chromatography using 60-120 mesh silica gel and 80% ethyl acetate in hexane as the mobile phase to give the desired product (2-fluoro-5-hydroxyphenyl)(6-(1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00367), 0.120 gm as a white solid (yield: 74.07%). LCMS: 392.1 m / z [M+] 1H NMR(400MHz,DMSO-d6)δ9.63(dd,J=8.3,2.5Hz,1H),7.56(d,J=9.5Hz,1H),7.41(t,J=8.5Hz,2 H),7.32(d,J=8.7Hz,1H),7.19(t,J=7.4Hz,1H),7.05(tt,J=9.2,5.3Hz,1H),6.83(s,1H),6.74 (dd,J=5.5,2.7Hz,1H),6.36(d,J=18.6Hz,1H),3.94(dd,J=25.2,10.5Hz,3H),3.05(dt,J=18. 8,8.4Hz,1H),2.34(q,J=12.2,11.5Hz,2H),2.24(q,J=10.5,9.9Hz,2H),1.91(d,J=2.4Hz,3H).

[0268] Example 8: Synthesis of [(2-chloro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone] [Compound 140] Synthesis scheme: TIFF0007777891000231.tif59134

[0269] Step-1: Synthesis of [(2-chloro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone][Compound-00140] To a stirred solution of 6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]hept-5-ene 2,2,2-trifluoroacetate (0.100 gm, 0.2624 mmol) in DMF (5.0 mL) was added 2-chloro-5-hydroxybenzoic acid (0.054 gm, 0.314 mmol), triethylamine (0.106 gm, 1.049 mmol), and propanephosphonic anhydride [T3P, 50 wt% in ethyl acetate] (0.125 gm, 0.393 mmol) at 0° C. The resulting reaction mixture was then stirred for 12 hours at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum to obtain crude material, which was purified by preparative HPLC using 0.1% aqueous formic acid to 100% acetonitrile as the mobile phase to obtain the desired compound as [(2-chloro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone] (PSY-05-0140) 0.028 gm (yield: 26%). m / z 422.6 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),7.43-7.1(m,4H),7.15(t,J=7.7Hz,1H),6.80(t,1H),6.67(d,J=2.8Hz,1H),6.16-6.10(s,1H),3.98(s,1H),3 .92(s,1H),3.82(s,1H),3.76(s,1H),2.99(dt,J=20.8,8.4Hz,1H),2.32 -2.19(m,2H),2.17(d,J=10.7Hz,2H),2.09(s,3H),1.93(d,J=2.2Hz,3H).

[0270] Example 9 Synthesis of (2-fluoro-5-hydroxyphenyl)(6-(5-(2-fluorophenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone [Compound 472] and (2-fluoro-5-hydroxyphenyl)(6-(3-(2-fluorophenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone [Compound 473] Synthesis scheme: TIFF0007777891000232.tif112139

[0271] Step A: Ethyl 3-(2-fluoro-phenyl)propiolate (Int-B) A mixture of 1-fluoro-2-iodo-benzene (Int-A) (11.3 g, 56.06 mmol, 1.1 equiv.), tetrakis(triphenylphosphine)palladium(0) (5.8 g, 5.096 mmol, 0.1 equiv.), and CuI (copper(I) iodide) (1.0 g, 5.096 mmol, 0.1 equiv.) in triethylamine (50 mL) was purged with nitrogen and treated with ethyl propiolate (5.0 g, 50.96 mmol, 1.0 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, decanted, concentrated and purified by flash chromatography (0-20% ethyl acetate in n-hexane) to give the desired product, ethyl 3-(2-fluoro-phenyl)propiolate (Int-B) (2.0 g, 20.44%) as a clear oil.

[0272] Step-B: 3-(2-fluoro-phenyl)propiolic acid (Int-1) To a solution of 3-(2-fluoro-phenyl)propiolic acid salt (Int-B) (2.0 g, 10.42 mmol, 1.0 equiv.) in methanol (5 mL) and HO (15 mL) was added NaOH (0.916 g, 22.91 mmol, 2.2 equiv.). The mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The crude product was diluted with water (100 mL) and acidified with 2 M aqueous HCl. The aqueous mixture was extracted with ethyl acetate (2 × 200 mL), and the combined organic extracts were washed with brine (400 mL), dried over sodium sulfate, and concentrated in vacuo to give 3-(2-fluoro-phenyl)propiolic acid (Int-1) (1.6 g, 93.63%) as a solid.

[0273] Step-1: 3,3,3-trifluoro-1-(2-fluoro-phenyl)propan-1-one (Int-2) TIFF0007777891000235.tif36128 In a sealed test tube equipped with a magnetic stir bar, 3-(2-fluorophenyl)propiolic acid (1.6 g, 9.816 mmol, 1.0 equiv.), Togni-(II) (6.4 g, 19.632 mmol, 2.0 equiv.), Cu(OAc)2·HO (3.56 g, 19.632 mmol, 2.0 equiv.), TMEDA (3.6 mL, 24.54 mmol, 2.5 equiv.), followed by dichloromethane (16 mL) and HO (24 mL) were added. The reaction mixture was stirred at room temperature. After stirring for 24 h, the reaction mixture was extracted with dichloromethane (15 mL × 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to give the pure product, 3,3,3-trifluoro-1-(2-fluoro-phenyl)propan-1-one (Int-2) (0.200 g, 9.95%) as a solid.

[0274] Step-2: (Z)-3-(dimethylamino)-1-(2-fluorophenyl)-2-(trifluoromethyl)prop-2-en-1-one (Int-3) To a stirred solution of 3,3,3-trifluoro-1-(2-fluoro-phenyl)propan-1-one (Int-2) (1.5 g, 7.28 mmol, 1.0 equiv.) in toluene (10 mL), N,N-dimethylformamide dimethylacetal (2.6 g, 21.84 mmol, 3.0 equiv.) was added, and the reaction was heated at 60 °C for 16 h. After completion of the reaction, as monitored by TLC, the reaction mixture was poured into ice-cold water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 15–20% ethyl acetate in n-hexane as the eluent to give (Z)-3-(dimethylamino)-1-(2-fluorophenyl)-2-(trifluoromethyl)prop-2-en-1-one (Int-3) (1.5 g, 78.91%).

[0275] Step-3: 5-(2-fluorophenyl)-4-(trifluoromethyl)-1H-pyrazole (Int-4) To a stirred solution of (Z)-3-(dimethylamino)-1-(2-fluorophenyl)-2-(trifluoromethyl)prop-2-en-1-one (1.5 g, 6.95 mmol, 1.0 equiv.) in isopropyl alcohol (10 mL), hydrazine hydrate (0.38 g, 7.65 mmol, 1.1 equiv.) was added, and the reaction was heated at 80 °C for 16 h. After completion of the reaction, as monitored by TLC, the reaction mixture was concentrated to give a residue. The residue was purified by Combiflash using 15–20% ethyl acetate in n-hexane as the eluent to give 5-(2-fluorophenyl)-4-(trifluoromethyl)-1H-pyrazole (Int-4) (0.90 g, 68.01%).

[0276] Step-4: Tert-butyl 6-(5-(2-fluoro-phenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5) and tert-Butyl 6-(3-(2-fluoro-phenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5A) To a solution of 5-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazole (Int-4) (0.900 g, 3.9121 mmol, 1.0 equiv.) in N,N-dimethylformamide (10 mL) was added tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (Int-C) (1.37 g, 4.694 mmol, 1.2 equiv.) and cesium carbonate (2.54 g, 7.824 mmol, 2.0 equiv.), and the reaction mixture was heated at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was poured into water (20 mL), and the solution was extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with ethyl acetate and n-hexane to give two regioisomers: tert-butyl 6-(5-(2-fluoro-phenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5) and tert-butyl 6-(3-(2-fluoro-phenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5A) (1.0 g, 60.11%).

[0277] Step-5: 6-(5-(2-fluoro-phenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-6) and 6-(3-(2-fluoro-5-phenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-6A) To a stirred solution of tert-butyl 6-(5-(2-fluoro-phenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5) and tert-butyl 6-(3-(2-fluoro-phenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5A) (1.0 g, 0.6605 mmol, 1.0 equiv) in dichloromethane (10 mL) was added trifluoroacetic acid (2.5 mL, 2.5 v) at 0° C. The reaction was stirred at room temperature for 16 h. After the reaction was complete by TLC, the reaction mixture was concentrated and triturated with a mixture of diethyl ether and hexane (1:1, 10 ml*3) to give two regioisomers: 6-(5-(5-fluoro-phenyl)-3-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-6) and 6-(3-(5-fluoro-phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane) (Int-6A) (1.5 g (TFA salt).

[0278] Step-6: 2-fluoro-5-hydroxyphenyl)(6-(5-(2-fluorophenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00474-001) and 2-Fluoro-5-hydroxyphenyl)(6-(3-(2-fluorophenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00475-001) To a stirred solution of 16-(5-(5-fluoro-phenyl)-3-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (INT-5) and 6-(3-(5-fluoro-phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane) (Int-5A) (0.500 g, 1.537 mmol, 1.0 equiv) in N,N-dimethylformamide (5.0 mL) was added pyridine (1.07 g, 15.37 mmol, 10.0 equiv), TBTU (0.740 g, 0.2306 mmol, 1.5 equiv) at 0° C. The reaction was stirred for 15 minutes. Then, 2-fluoro-5-hydroxybenzoic acid (0.359 g, 2.306 mmol, 1.5 equiv.) was added at 0° C. The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed as monitored by TLC, the reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (3×20 mL), and washed again with saturated NaHCO3 solution. The organic phase was dried over sodium sulfate and concentrated under vacuum to give the crude material, which was purified using reverse-phase preparative HPLC. Two fractions were obtained.

[0279] Fraction-1: (2-fluoro-5-hydroxyphenyl)(6-(3-(2-fluorophenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00473-001) (0.012 g, 1.68%). LCMS: m / z 464.01 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.12(d,J=9.7Hz,1H),7.63-7.43(dq,J=19.3,9.9,7.4Hz,4H),7.08(q,J =9.5Hz,1H),6.85(s,1H),6.77(s,1H),4.50(dt,J=14.3,7.5Hz,1H),4.03(d,J=9.0Hz,4H),2.79-2.63(m,4H).

[0280] Fraction-2: 2-Fluoro-5-hydroxyphenyl)(6-(5-(2-fluorophenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00472-001) (0.031 g, 4.35%). LCMS: m / z 464.41 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.69(d,J=5.5Hz,1H),8.62(d,J=9.6Hz,1H),7.53(s,1H),7.51-7.42(m,1H),7.39-7.25(m,2H),7.10(q,J=9.0Hz,1H) ),6.89-6.84(m,1H),6.81(s,1H),4.90(dt,J=23.7,7.9Hz,1H),4.16(d,J=10.3Hz,2H),4.06(d,J=8.1Hz,2H),2.74(dd,J=24.9,10.1Hz,4H).

[0281] Example 10: Synthesis of (2-fluoro-5-hydroxyphenyl)(6-(3-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone [Compound 474] and (2-fluoro-5-hydroxyphenyl)(6-(5-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone [Compound 475] Synthesis scheme: TIFF0007777891000241.tif126155

[0282] Step A: Ethyl 3-(2-fluoro-5-methylphenyl)propiolate (Int-A) A mixture of 1-fluoro-2-iodo-4-methylbenzene (Int-A) (5.0 g, 21.19 mmol, 1.0 equiv.), tetrakis(triphenylphosphine)palladium(0) (2.4 g, 2.119 mmol, 0.1 equiv.), and CuI (0.403 g, 2.119 mmol, 0.1 equiv.) in triethylamine (30 mL) was purged with nitrogen and treated with ethyl propiolate (2.28 g, 23.30 mmol, 1.1 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous NaHCO3 (sodium bicarbonate) and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, concentrated, and purified by flash chromatography (0–20% ethyl acetate / hexanes) to give the desired product, ethyl 3-(2-fluoro-5-methylphenyl)propiolate (Int-B) (1.0 g, 22.89%) as a clear oil.

[0283] Step B: 3-(2-fluoro-5-methylphenyl)propiolic acid (Int-1) To a solution of ethyl 3-(2-fluoro-5-methylphenyl)propiolate (1.0 g, 4.854 mmol, 1.0 equiv.) in methanol (5 mL) and HO (15 mL) was added NaOH (sodium hydroxide) (0.388 g, 9.7086 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The crude product was diluted with HO (100 mL) and acidified with 2 M aqueous HCl (hydrochloric acid). The aqueous mixture was extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with brine (400 mL), dried (MgSO), and concentrated in vacuo to give 3-(2-fluoro-5-methylphenyl)propiolic acid (Int-1) (0.500 g, 57.87%) as a solid.

[0284] Step-1: 3,3,3-trifluoro-1-(2-fluoro-5-methylphenyl)propan-1-one (Int-2) TIFF0007777891000244.tif31128 In a sealed test tube equipped with a magnetic stir bar, 3-(2-fluoro-5-methylphenyl)propiolic acid (1.0 g, 5.6179 mmol, 1.0 equiv.), Togni(II) (1.77 g, 5.6179 mmol, 1.0 equiv.), Cu(OAc)2·HO (copper acetate hydrate) (2.04 g, 11.24 mmol, 2.0 equiv.), TMEDA (1,2-bis(dimethylamino)ethane) (1.306 g, 11.24 mmol, 2.0 equiv.), followed by dichloromethane (10 mL) and HO (10.5 mL) were added. The reaction mixture was stirred at room temperature. After stirring for 24 h, the reaction mixture was extracted with dichloromethane (15 mL × 3), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography to give 3,3,3-trifluoro-1-(2-fluoro-5-methylphenyl)propan-1-one (Int-2) (0.350 g, 28.32%) as a solid.

[0285] Step-2: (Z)-3-(dimethylamino)-1-(2-fluoro-5-methylphenyl)-2-(trifluoromethyl)prop-2-en-1-one (Int-3) To a stirred solution of 3,3,3-trifluoro-1-(2-fluoro-5-methylphenyl)propan-1-one (0.90 g, 4.12 mmol, 1.0 equiv.) in toluene (10 mL) was added N,N-dimethylformamide dimethyl acetal (1.47 g, 12.38 mmol, 3.0 equiv.). The reaction was heated at 60 °C for 16 h. After completion of the reaction, as monitored by TLC, the reaction mixture was poured into ice-cold water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine (100 mL), dried over Na SO , and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 15–20% ethyl acetate in hexane as the eluent to give (Z)-3-(dimethylamino)-1-(2-fluoro-5-methylphenyl)-2-(trifluoromethyl)prop-2-en-1-one (Int-3) (0.47 g, 41.77%).

[0286] Step-3: 5-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazole (Int-4) To a stirred solution of (Z)-3-(dimethylamino)-1-(2-fluoro-5-methylphenyl)-2-(trifluoromethyl)prop-2-en-1-one (0.47 g, 1.70 mmol, 1.0 equiv.) in isopropyl alcohol (5 mL) was added hydrazine hydrate (0.128 g, 2.56 mmol, 1.5 equiv.). The reaction was heated at 80 °C for 16 h. After completion of the reaction, as monitored by TLC, the reaction mixture was concentrated to give a residue. The residue was purified by CombiFlash using 15-20% ethyl acetate in n-hexane as the eluent to give 5-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazole (Int-4) (0.290 g, 69.55%).

[0287] Step-4: Tert-butyl 6-(5-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5) and tert-Butyl 6-(3-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5A) To a solution of 5-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazole (Int-4) (0.270 g, 1.1065 mmol, 1.0 equiv.) in N,N-dimethylformamide (4.8 mL) was added tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (Int-C) (0.386 g, 1.328 mmol, 1.2 equiv.) and cesium carbonate (0.719 g, 2.213 mmol, 2.0 equiv.). The reaction mixture was heated at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and the solution was extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using n-hexane and ethyl acetate to give two regioisomers: tert-butyl 6-(5-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5) and tert-butyl 6-(3-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5A) (0.450 g, 92.61%).

[0288] Step-5: 6-(5-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-6) and 6-(3-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-6A) To a stirred solution of tert-butyl 6-(5-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5) and tert-butyl 6-(3-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5A) (0.290 g, 0.6605 mmol, 1.0 equiv) in dichloromethane (3.0 mL) was added trifluoroacetic acid (0.725 mL, 2.5 v) at 0 °C. The reaction was stirred at room temperature for 16 h. After the reaction was completed as monitored by TLC, the reaction mixture was concentrated and triturated with a mixture of diethyl ether and n-hexane (1:1, 10 mL*3) to give the two regioisomers as TFA salts (0.210 g, crude). 6-(5-(5-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-6) 6-(3-(5-fluoro-2-methylphenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane) (Int-6A) obtained.

[0289] Step-6: 2-fluoro-5-hydroxyphenyl)(6-(5-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00474-001) and 2-Fluoro-5-hydroxyphenyl)(6-(3-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00475-001) TIFF0007777891000249.tif391496-(5-(5-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-6) 6-(3-(5-fluoro-2-methylphenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane) (Int-6A) (0.210 g, To a stirred solution of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) (0.298 g, 0.9288 mmol, 1.5 equiv.) in N,N-dimethylformamide (2.0 mL) was added pyridine (0.247 g, 6.192 mmol, 10.0 equiv.) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) (0.298 g, 0.9288 mmol, 1.5 equiv.) at 0° C. and stirred for 15 minutes. 2-Fluoro-5-hydroxybenzoic acid (0.144 g, 0.9288 mmol, 1.5 equiv.) was then added at 0° C. The resulting reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction as monitored by TLC, the reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (3×20 mL), and washed with saturated sodium carbonate (NaHCO3) solution. The organic phase was dried over sodium sulfate and concentrated in vacuo to give the crude material which was purified using preparative HPLC using 1% formic acid in water:acetonitrile. Two fractions were obtained.

[0290] Fraction-1: (2-fluoro-5-hydroxyphenyl)(6-(3-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00475-001) (0.023 g, 8.2%). LCMS: 478.41 m / z [M+1] + . 1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.11(d,J=9.9Hz,1H),7.45(s,1H),7.39-7.18(m,2H),7.08(q,J=9.6Hz,1H),6.85(s,1H),6.77 (s,1H),4.49(dt,J=14.5,7.7Hz,1H),4.03(d,J=8.7Hz,4H),2.68(ddt,J=51.2,19.7,8.6Hz,2H),2.47(m,2H),2.35(d,J=9.5Hz,3H).

[0291] Fraction-2: (2-fluoro-5-hydroxyphenyl)(6-(5-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00474-001) (0.011 g, 3.9%). LCMS: m / z 478.40 [M+1] + 1 H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.1(d,J=9.9Hz,1H),7.29-7.20(m,3H),7.09(q,J=9.6Hz,1H),6.84(s,1H),6.79( s,1H),4.88(dt,J=14.5,7.7Hz,1H),4.03(d,J=8.7Hz,4H),2.74(ddt,J=51.2,19.7,8.6Hz,4H),2.35(d,J=9.5Hz,3H).

[0292] Example 11: (6-(5-(2,5-difluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone [Compound 476] and Synthesis of (6-(3-(2,5-difluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone [Compound 477] Synthesis scheme: TIFF0007777891000250.tif54162

[0293] Step-1: Synthesis of (Z)-1-(2,5-difluorophenyl)-3-(dimethylamino)-2-methylprop-2-en-1-one (Int-2) To a stirred solution of 1-(2,5-difluorophenyl)propan-1-one (1.0 g, 5.8768 mmol, 1.0 equiv.) in toluene (10 mL) was added N,N-dimethylformamide dimethyl acetal (3.0 mL, 29.384 mmol, 5.0 equiv.). The reaction was heated at 100° C. for 16 hours. After completion, the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was poured into ice-cold water (50 mL) and extracted with ethyl acetate (20 mL×3). The organic phase was washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 30–40% ethyl acetate in hexane as the eluent to give (Z)-1-(2,5-difluorophenyl)-3-(dimethylamino)-2-methylprop-2-en-1-one (Int-2) (1.1 g, 84.61%).

[0294] Step-2: Synthesis of 5-(2,5-difluorophenyl)-4-methyl-1H-pyrazole (Int-3) To a stirred solution of (Z)-1-(2,5-difluorophenyl)-3-(dimethylamino)-2-methylprop-2-en-1-one (1.1 g, 4.88 mmol, 1.0 equiv.) in isopropyl alcohol (20 mL) was added hydrazine hydrate (0.36 mL, 7.33 mmol, 1.5 equiv.). The reaction was heated at 80 °C for 16 h. After completion of the reaction, as monitored by TLC and LCMS, the reaction mixture was concentrated to give a residue. The residue was purified by Combiflash using 20–30% ethyl acetate in hexanes as the eluent to give 5-(2,5-difluorophenyl)-4-methyl-1H-pyrazole (Int-3) (0.80 g, 84.38%).

[0295] Step-3: Synthesis of Tert-butyl 6-(5-(pyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate and Tert-butyl 6-(3-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Mixture of Int-4 and Int-4A) To a well-stirred reaction mixture of 3-(3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridine (0.800 g, 4.12 mmol, 1.0 equiv.), CS2CO3 (2.01 g, 6.18 mmol, 1.5 equiv.) in N,N-dimethylformamide (10 mL) was added tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (1.44 g, 4.94 mmol, 1.2 equiv.). The reaction was heated at 100 °C for 12 h. After completion of the reaction as monitored by TLC, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue that was purified by Combiflash using 30–50% ethyl acetate in hexanes as the eluent to give a mixture of Int-4 and Int-4A (1.0 g, 62.5%).

[0296] Step-4: Synthesis of 6-(5-(2,5-difluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane TFA salt (Int-5) and 6-(3-(2,5-difluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane TFA salt (Int-5A) To a well-stirred reaction mixture of Int-4 and Int-4A (1.0 g, 2.5706 mmol, 1.0 equiv) in dichloromethane (10 mL) was added TFA (2.0 mL) dropwise at 0° C. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was concentrated to give the TFA salts of Int-5 and Int-5A (1.1 g).

[0297] Step-5: Synthesis of (6-(5-(2,5-difluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone and (6-(3-(2,5-difluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00476-001 and PSY-05-00477-001) To a well-stirred reaction mixture of Int-5 and Int-5A (1.13 g, 2.9230 mmol, 1.2 equiv.), pyridine (0.98 mL, 12.1794 mmol, 5.0 equiv.), and 2-fluoro-5-hydroxybenzoic acid (0.38 g, 2.4358 mmol, 1.0 equiv.) in N,N-dimethylformamide (5 mL) was added TBTU (0.321 g, 3.6538 mmol, 1.5 equiv.) at 0 °C. The reaction was stirred at room temperature for 3–4 h. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium carbonate solution (50 mL) and brine (100 mL), dried over sodium sulfate (NaSO), and concentrated under reduced pressure to give a residue. The residue was purified by CombiFlash using 40-50% ethyl acetate in hexane as the eluent. The crude product was purified by preparative HPLC. (PSY-05-00476-001-FR-2: 0.308 g, 20.95%) (PSY-05-00477-001-FR-1: 0.096 g, 6.53%)

[0298] Fraction-1: (6-(3-(2,5-difluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-0477-001 Fr-1). LCMS: m / z 428.03 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ7.52-7.40(m,3H),7.30(dd,J=5.4,2.8Hz,1H),7.08(q,J=8.9Hz,1H),6.85(d,J=3.9Hz,1H),6. 81-6.75(m,1H),4.47(dt,J=15.6,7.8Hz,1H),4.07(dd,J=24.5,5.0Hz,4H),2.60(dd,J=20.2,8.3Hz,4H),1.90(s,3H).

[0299] Fraction-2: (6-(5-(2,5-difluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00476-001 Fr-2) LCMS: m / z 428.3 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ9.69(s,1H),7.72(d,J=5.9Hz,1H),7.39-7.26(m,3H),7.10(q,J=9.1Hz,1H),6.82-6.87(q,J=9.1Hz,1H),6.7 4-6.79(q,J=9.1Hz,1H),4.76(dt,J=23.3,7.9Hz,1H),4.15(d,J=11.2Hz,2H),4.05(d,J=8.7Hz,2H),2.76-2.60(m,4H),1.99(s,3H).

[0300] Example 12: (6-(4-cyclopropyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00488-001), (6-(4-cyclopropyl-3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05- Synthesis of (2-fluoro-5-hydroxyphenyl)(6-(3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00489-001), (2-fluoro-5-hydroxyphenyl)(6-(3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00525-001), and (2-fluoro-5-hydroxyphenyl)(6-(5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00526-001) Synthesis scheme: TIFF0007777891000256.tif80155

[0301] Step-1: Synthesis of (E)-3-(dimethylamino)-1-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (Int-2) To a stirred solution of 1-(2-(trifluoromethyl)phenyl)ethan-1-one (10.0 g, 53.19 mmol, 1.0 equiv.) in toluene (100 mL) was added N,N-dimethylformamide dimethyl acetal (20.56 mL, 265.95 mmol, 5.0 equiv.). The reaction was heated at 100° C. for 16 h. After completion of the reaction, as monitored by TLC and LCMS, the reaction mixture was poured into ice-cold water (50 mL) and extracted with ethyl acetate (75 mL×3). The organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 30–40% ethyl acetate in n-hexane as the eluent to give (E)-3-(dimethylamino)-1-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (Int-2) (11.12 g, 86.06%).

[0302] Step-2: Synthesis of 5-(2-(trifluoromethyl)phenyl)-1H-pyrazole (Int-3) To a stirred solution of (E)-3-(dimethylamino)-1-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (11.12 g, 45.7613 mmol, 1.0 equiv.) in isopropanol (100 mL) was added hydrazine hydrate (2.19 mL, 68.64 mmol, 1.5 equiv.). The reaction was heated at 80 °C for 16 h. After completion of the reaction, as monitored by TLC and LCMS, the reaction mixture was concentrated to give a residue. The residue was purified by Combiflash using 20–30% ethyl acetate in n-hexane as the eluent to give 5-(2-(trifluoromethyl)phenyl)-1H-pyrazole (Int-3) (8.67 g, 89.38%).

[0303] Step-3: Synthesis of 4-iodo-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole (Int-4) To a well-stirred solution of 5-(2-(trifluoromethyl)phenyl)-1H-pyrazole (8.67 g, 40.86 mmol, 1.0 equiv.) in N,N-dimethylformamide (90 mL), N-iodosuccinamide (10.11 g, 44.94 mmol, 1.1 equiv.) was added in a reaction mixture. The reaction was heated at 80 °C for 16 h. After completion of the reaction as monitored by TLC, the reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with brine (100 mL), dried over Na SO , and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 30–50% ethyl acetate in n-hexane as the eluent to give 4-iodo-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole (Int-4) (9.2 g, 66.6%).

[0304] Step-4: Synthesis of 4-iodo-1-(4-methoxybenzyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole (Int-5) To a well-stirred solution of 4-iodo-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole (9.2 g, 27.21 mmol, 1.0 equiv.) and CsCO (13.26 g, 40.82 mmol, 1.5 equiv.) in N,N-dimethylformamide (100 mL) was added 4-methoxybenzyl chloride (4.44 mL, 32.66 mmol, 1.2 equiv.). The reaction was stirred at room temperature for 2–3 h. After completion of the reaction, as monitored by TLC and LCMS, the reaction mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with brine (100 mL), dried over NaSO, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 30–50% ethyl acetate in n-hexane as the eluent to give 4-iodo-1-(4-methoxybenzyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole (Int-5) (10.10 g, 81.0%).

[0305] Step-5: Synthesis of 4-cyclopropyl-1-(4-methoxybenzyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole (Int-6) To a well-stirred reaction mixture of 4-iodo-1-(4-methoxybenzyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole (10.10 g, 22.05 mmol, 1.0 equiv.), cyclopropylboronic acid (3.78 g, 44.10 mmol, 2.0 equiv.), potassium phosphate (K3PO4) (14.04 g, 66.15 mmol, 3.0 equiv.) in toluene (100 mL) was added N 2(g) The mixture was purged for 20 minutes, after which tetrakisPd(0) (1.27 g, 1.102 mmol, 1.2 equiv) was added, and the reaction mixture was heated at 80 °C for 48 hours. After the reaction was complete, as monitored by TLC and LCMS, the reaction mixture was filtered through a bed of Celite and extracted with ethyl acetate (3 × 15 mL). The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with brine (100 mL), dried over NaSO, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 0–50% ethyl acetate in n-hexane as the eluent to give 4-cyclopropyl-1-(4-methoxybenzyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole (Int-6) (4.5 g, 54.82%).

[0306] Step-6: Synthesis of 4-cyclopropyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole (Int-7) To a well-stirred reaction mixture of 4-cyclopropyl-5-(2-fluorophenyl)-1-(4-methoxybenzyl)-1H-pyrazole (4.5 g, 12.06 mmol, 1.0 equiv.) in 40 mL of anisole was added 4.5 mL of trifluoroacetic acid (TFA). The reaction mixture was heated at 120 °C for 12 h. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 30–80% ethyl acetate in n-hexane as the eluent to give 4-cyclopropyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole (Int-7) (1.67 g, 54.79%).

[0307] Step-7: tert-butyl 6-(4-cyclopropyl-3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-8) and Synthesis of tert-butyl 6-(4-cyclopropyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-8A) To a well-stirred reaction mixture of 4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrazole (1.67 g, 6.62 mmol, 1.0 equiv.), CsCO (3.2 g, 9.94 mmol, 1.5 equiv.) in N,N-dimethylformamide (15 mL) was added tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (1.92 g, 6.62 mmol, 1.0 equiv.). The reaction was heated at 80 °C for 12 h. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue that was purified by Combiflash using 30–50% ethyl acetate in n-hexane as the eluent to give a mixture of two regioisomers: tert-butyl 6-(4-cyclopropyl-3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-8) and tert-butyl 6-(4-cyclopropyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-8A) (1.5 g, 50.63%).

[0308] Step-8: Synthesis of 6-(4-cyclopropyl-3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-9) and 6-(4-cyclopropyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-9A) To a well-stirred reaction mixture of tert-butyl 6-(4-cyclopropyl-3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-8) and tert-butyl 6-(4-cyclopropyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-8A) (1.5 g, 2.57 mmol, 1.0 equiv.) in dichloromethane (10 mL), trifluoroacetic acid (TFA) (2.0 mL) was added dropwise at 0°C and stirred for 2–3 h. The reaction mixture was monitored by TLC and LCMS. After visual confirmation of completion of the reaction, the reaction mixture was concentrated to give the TFA salts of 6-(4-cyclopropyl-3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-9) and 6-(4-cyclopropyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-9A) (1.7 g).

[0309] Step-9: (6-(4-cyclopropyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00488-001) and (6-(4-cyclopropyl-3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00489-001), Synthesis of (2-fluoro-5-hydroxyphenyl)(6-(3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00525-001) and (2-fluoro-5-hydroxyphenyl)(6-(5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00526-001) TIFF0007777891000265.tif541546-(4-cyclopropyl-3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-9) and 6-(4-cyclopropyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-9A) TFA salts (1.7 g, 4.92 mmol, 1.2 equiv.), pyridine (1.65 mL, 20.51 mmol, 5.0 equiv.), 2-fluoro-5-hydroxybenzoic acid (0.640 g, 4.10 mmol, 1.0 equiv.) To the well-stirred reaction mixture in dimethylformamide (5 mL) was added TBTU (1.97 g, 6.1538 mmol, 1.5 equiv.) at 0 °C. The reaction was stirred at room temperature for 16 h. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium carbonate solution (50 mL) and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 0-100% ethyl acetate in n-hexane as the eluent to give the crude product. This was purified by preparative HPLC to give two fractions.

[0310] Fraction-1: (6-(4-cyclopropyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00488-001) (0.026 g, 1.11%). LCMS: m / z 486.33 [M+H] + NMR: 1 H NMR(400MHz,DMSO-d6)δ9.73(s,1H),7.91(dd,J=12.6,8.1Hz,1H),7.83-7. 69(m,2H),7.40(t,J=8.0Hz,1H),7.26(d,J=10.1Hz,1H),7.04(dt,J=17.3, 9.2Hz,1H),6.74(s,2H),4.09(dd,J=14.2,6.8Hz,1H),4.01-3.91(m,4H),2 .63(s,2H),2.54(s,2H),1.18(m,1H),0.59(s,2H),0.39(d,J=15.1Hz,2H).

[0311] Fraction-2: (6-(4-cyclopropyl-3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00489-001) (0.07613 g, 3.20%). LCMS: m / z 486.33 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.67(s,1H),7.83(s,1H),7.72(d,J=5.2Hz,1H),7.63(s,1H),7.53(s,2H),7.09(d,J=8.9Hz,1H),6.85(s,2H),4.70(d ,J=7.4Hz,1H),4.12(d,J=10.2Hz,2H),4.00(d,J=8.5Hz,2H),2.65(dd,J=19.9,11.1Hz,4H),1.29(m,1H),0.67(d,J=6.9Hz,2H),0.41(s,2H). (Note: In the Suzuki coupling reaction, the dess-iodo of Int-5 is observed along with the Int-6 product. It was not separated by TLC or LCMS. We used this mixture for the next few steps. In the final preparative HPLC purification, we isolated the product as the dess-CF3 product of PSY-05-00488-001.)

[0312] Fraction-3: (2-fluoro-5-hydroxyphenyl)(6-(3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00525-001) (0.028 g, 1.18%). LCMS: m / z 446.30 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.64(s,1H),7.89(s,1H),7.78-7.71(m,2H),7.58(d,J=9.1Hz,1H),7.42(s,1H) ,7.03(s,1H),6.82(s,1H),6.75(s,1H),6.28(s,1H),4.26(s,1H),3.99(d,J=19.2Hz,4H),2.78(s,4H).

[0313] Fraction-4: (2-fluoro-5-hydroxyphenyl)(6-(5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00526-001) (0.19 g, 8.25%). LCMS: m / z 446.20 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.66(d,J=7.4Hz,1H),7.82(dd,J=16.3,9.0Hz,2H),7.73-7.54(m,3H),7.08(q,J=8.8Hz,1H),6.88-6.82(m,1H) ),6.79(s,1H),6.42(s,1H),4.82(dt,J=23.6,7.9Hz,1H),4.14(d,J=10.1Hz,2H),4.04(d,J=7.9Hz,2H),2.71(dt,J=17.5,10.4Hz,4H).

[0314] Example 13 Synthesis of (6-(3-cyclopropyl-5-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone [Compound 490] and (6-(5-cyclopropyl-3-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone [Compound 491] Synthesis scheme: TIFF0007777891000266.tif61157

[0315] Step-1: 1-Cyclopropyl-3-(5-fluoro-2-methylphenyl)propane-1,3-dione (Int-2): To a stirred solution of 1-(5-fluoro-2-methylphenyl)ethan-1-one (2.0 g, 13.15 mmol, 1.0 equiv.) in diethyl ether (10 mL), NaH 60% (2.1 g, 52.63 mmol, 4.0 equiv.) was added at 0 °C, followed by the dropwise addition of ethyl cyclopropanecarboxylate (7.5 g, 65.78 mmol, 5.0 equiv.). The reaction was stirred at room temperature for 4–5 h. After completion, the reaction was monitored by TLC. The reaction mixture was poured into water (100 mL), acidified with 10% dilute HCl, and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 2–5% ethyl acetate in n-hexane as the eluent to give cyclopropyl-3-(5-fluoro-2-methylphenyl)propane-1,3-dione (Int-2) (2.7 g, 93.27%).

[0316] PSY-05-00490 Int-3 3-cyclopropyl-5-(5-fluoro-2-methylphenyl)-1H-pyrazole: To a stirred solution of the resulting 1-cyclopropyl-3-(5-fluoro-2-methylphenyl)propane-1,3-dione (Int-2) (2.7 g, 12.44 mmol, 1.0 equiv.) in isopropyl alcohol (30 mL), hydrazine hydrate (0.93 g, 18.66 mmol, 1.5 equiv.) was added, and the reaction was heated at 80 °C for 16 h. After completion of the reaction, as monitored by TLC, the reaction mixture was concentrated to give a residue. The residue was purified by CombiFlash using 15–20% ethyl acetate in n-hexane as the eluent to give 3-cyclopropyl-5-(5-fluoro-2-methylphenyl)-1H-pyrazole (2.4 g, 90.53%).

[0317] Step-3: Tert-butyl 6-(3-cyclopropyl-5-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-4) and Tert-butyl 6-(5-cyclopropyl-3-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-4A) To a well-stirred reaction mixture of 3-cyclopropyl-5-(5-fluoro-2-methylphenyl)-1H-pyrazole (Int-3) (1.3 g, 5.99 mmol, 1.0 equiv.) and CS2CO3 (2.9 g, 8.98 mmol, 1.5 equiv.) in N,N-dimethylformamide (10 mL) was added tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (1.74 g, 5.99 mmol, 1.0 equiv.). The reaction was heated at 100 °C for 12 h. After completion of the reaction as monitored by TLC, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 30–35% ethyl acetate in n-hexane as the eluent to give a mixture of tert-butyl 6-(3-cyclopropyl-5-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (int-4) and tert-butyl 6-(5-cyclopropyl-3-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (int-4A) (0.80 g, 32.34%).

[0318] Step-4: 6-(3-cyclopropyl-5-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-5) and 6-(5-cyclopropyl-3-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-5A) To a well-stirred reaction mixture of tert-butyl 6-(3-cyclopropyl-5-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (int-4) and tert-butyl 6-(5-cyclopropyl-3-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (int-4A) (0.8 g, 1.94 mmol, 1.0 equiv) in dichloromethane (5 mL) was added trifluoroacetic acid (1.2 mL) dropwise at 0°C. After completion of the reaction as monitored by TLC, the reaction mixture was concentrated to give a mixture of 6-(3-cyclopropyl-5-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (int-5) and 6-(5-cyclopropyl-3-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (int-5A) (0.98 g, crude).

[0319] Step-5: (6-(3-cyclopropyl-5-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00490-001 Fr-2) and (6-(5-cyclopropyl-3-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00491-001 Fr-1) To a well-stirred reaction mixture of 6-(3-cyclopropyl-5-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (int-5) and 6-(5-cyclopropyl-3-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (int-5A) (1.0 g, 3.52 mmol, 1.0 equiv), pyridine (1.23 g, 17.62 mmol, 5.0 equiv), and carboxylic acid (0.66 g, 4.23 mmol, 1.2 equiv) in N,N-dimethylformamide (5 mL) was added TBTU (1.7 g, 5.28 mmol, 1.5 equiv) at 0 °C. The reaction was stirred at room temperature for 3-4 hours. After the reaction was completed as monitored by TLC, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium carbonate solution (50 mL) and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by CombiFlash using 30-35% ethyl acetate in n-hexane as the eluent. The crude product was purified by preparative HPLC. Two fractions were collected.

[0320] Fraction-1: (6-(5-cyclopropyl-3-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00491-001 Fr-1) (0.075 g, 1.64%). LCMS: m / z 449.5 [M+1] + NMR: 1H NMR(400MHz,DMSO-d6)δ9.65(d,J=7.5Hz,1H),7.36(d,J=5.7Hz,1H),7.21(d,J=9.3Hz,0H),7.10-7.00(m,1H),6.99(d,J=9.0Hz,1H),6.84(s,1H) ,6.76(s,1H),5.93(s,1H),4.28-4.19(m,1H),4.01(d,J=9.4Hz,4H),2.6 7(s,4H),2.01(s,3H),1.90(s,1H),0.87(s,2H),0.66(d,J=14.9Hz,2H).

[0321] Fraction-2: (6-(3-cyclopropyl-5-(5-fluoro-2-methylphenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00490-001 Fr-2) (0.041 g, 0.89%). LCMS: m / z 449.5 [M+1] + NMR: 1 H NMR(400MHz,DMSO-d6)δ9.67(d,J=8.4Hz,1H),7.37-7.26(m,2H),7.13-6.98(m,2H),6.85(s,1H),6.80(s,1H),6.24(s ,1H),4.16(d,J=9.1Hz,2H),4.07(s,2H),2.75(s,4H),2.41(d,J=17.2Hz,3H),1.85(s,1H),0.94(s,2H),0.65(s,2H).

[0322] Example 14 Synthesis of (6-(4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone [Compound 492] and (6-(4-cyclopropyl-3-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone [Compound 493] Synthesis scheme: TIFF0007777891000272.tif74146

[0323] Step-1: Synthesis of (E)-3-(dimethylamino)-1-(2-fluorophenyl)prop-2-en-1-one (Int-2) To a stirred solution of 1-(2-fluorophenyl)ethan-1-one (10.0 g, 5.8768 mmol, 1.0 equiv.) in toluene (10 mL) was added N,N-dimethylformamide dimethyl acetal (3.0 mL, 29.3841 mmol, 5.0 equiv.). The reaction was heated at 100° C. for 16 hours. After completion, the reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water (50 mL) and extracted with ethyl acetate (20 mL×3). The organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 30–40% ethyl acetate in n-hexane as the eluent to give (Z)-1-(2,5-difluorophenyl)-3-(dimethylamino)-2-methylprop-2-en-1-one (Int-2) (10.5 g, 75.0%).

[0324] Step-2: Synthesis of 5-(2-fluorophenyl)-1H-pyrazole (Int-3) To a stirred solution of (E)-3-(dimethylamino)-1-(2-fluorophenyl)prop-2-en-1-one (10.0 g, 51.81 mmol, 1.0 equiv.) in isopropyl alcohol (100 mL) was added hydrazine hydrate (2.49 mL, 77.72 mmol, 1.5 equiv.). The reaction was heated at 80 °C for 16 h. After completion of the reaction, as monitored by TLC and LCMS, the reaction mixture was concentrated to give a residue. The residue was purified by CombiFlash using 20–30% ethyl acetate in n-hexane as the eluent to give 5-(2-fluorophenyl)-1H-pyrazole (Int-3) (7.0 g, 83.40%).

[0325] Step-3: Synthesis of 5-(2-fluorophenyl)-4-iodo-1H-pyrazole (Int-4) To a well-stirred solution of 5-(2-fluorophenyl)-1H-pyrazole (7.0 g, 43.15 mmol, 1.0 equiv.) in N,N-dimethylformamide (10 mL) was added N-iodosuccinamide (10.68 g, 47.4722 mmol, 1.1 equiv.). The reaction was heated at 80° C. for 16 h. After completion of the reaction, as monitored by TLC, the reaction mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 30-50% ethyl acetate in n-hexane as the eluent to give 5-(2-fluorophenyl)-4-iodo-1H-pyrazole (Int-4) (7.56 g, 60.80%).

[0326] Step-4: Synthesis of 5-(2-fluorophenyl)-4-iodo-1-(4-methoxybenzyl)-1H-pyrazole (Int-5) To a well-stirred solution of 5-(2-fluorophenyl)-4-iodo-1H-pyrazole (7.56 g, 26.25 mmol, 1.0 equiv.) and CsCO (12.79 g, 39.37 mmol, 1.5 equiv.) in N,N-dimethylformamide (75 mL) was added 4-methoxybenzyl chloride (4.28 mL, 31.500 mmol, 1.2 equiv.). The reaction was stirred at room temperature for 2–3 h. After completion of the reaction as monitored by TLC, the reaction mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine (50 mL), dried over NaSO, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 30-50% ethyl acetate in hexane as the eluent to give 5-(2-fluorophenyl)-4-iodo-1-(4-methoxybenzyl)-1H-pyrazole (Int-5) (8.25 g, 77.01%).

[0327] Step-5: Synthesis of 4-cyclopropyl-5-(2-fluorophenyl)-1-(4-methoxybenzyl)-1H-spirazole (Int-6) To a well-stirred reaction mixture of 5-(2-fluorophenyl)-4-iodo-1-(4-methoxybenzyl)-1H-pyrazole (8.0 g, 19.60 mmol, 1.0 equiv.), cyclopropylboronic acid (3.36 g, 39.21 mmol, 2.0 equiv.), potassium phosphate (12.48 g, 58.80 mmol, 3.0 equiv.) in toluene (80 mL) was added N 2(g) The mixture was purged for 20 minutes, after which tetrakis (1.13 g, 0.98 mmol, 0.05 equiv.) was added, and the reaction mixture was heated at 80 °C for 48 hours. After the reaction was complete as monitored by TLC, the reaction mixture was filtered through a bed of Celite, and the Celite bed was washed with ethyl acetate. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine (100 mL), dried over NaSO, and concentrated under reduced pressure to give a residue. The residue was purified by CombiFlash using 0–50% ethyl acetate in n-hexane as the eluent to give 4-cyclopropyl-5-(2-fluorophenyl)-1-(4-methoxybenzyl)-1H-pyrazole (Int-6) (1.2 g, 18.99%).

[0328] Step-6: Synthesis of 4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrazole (Int-7) To a well-stirred reaction mixture of 4-cyclopropyl-5-(2-fluorophenyl)-1-(4-methoxybenzyl)-1H-pyrazole (1.2 g, 3.7267 mmol, 1.0 equiv.) in 10 mL of anisole, 1 mL of trifluoroacetic acid was added. The reaction mixture was heated at 120 °C for 12 h. After completion of the reaction as monitored by TLC, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by CombiFlash using 30–50% ethyl acetate in n-hexane as the eluent to give 4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrazole (Int-7) (0.680 g, 90.33%).

[0329] Step-7: Synthesis of tert-butyl 6-(4-cyclopropyl-3-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-8) and tert-butyl 6-(4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-8A) To a well-stirred reaction mixture of 14-cyclopropyl-5-(2-fluorophenyl)-1H-pyrazole (0.80 g, 3.96 mmol, 1.0 equiv.), CsCO (1.93 g, 5.94 mmol, 1.5 equiv.) in N,N-dimethylformamide (10 mL) was added tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (1.15 g, 3.96 mmol, 1.0 equiv.). The reaction was heated at 80 °C for 12 h. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue that was purified by Combiflash using 30–50% ethyl acetate in n-hexane as the eluent to give a mixture of two regioisomers: tert-butyl 6-(4-cyclopropyl-3-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-8) and tert-butyl 6-(4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-8A) (1.0 g, 63.60%).

[0330] Step-8: Synthesis of 6-(4-cyclopropyl-3-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-9) and 6-(4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-9A) TIFF0007777891000280.tif39158tert-Butyl 6-(4-cyclopropyl-3-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-8) and tert-butyl To a well-stirred reaction mixture of 6-(4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-8A) (1.0 g, 2.5706 mmol, 1.0 equiv.) in dichloromethane (10 mL) was added trifluoroacetic acid (2.0 mL) dropwise at 0 °C for 6 h. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was concentrated to give the TFA salt of 6-(4-cyclopropyl-3-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-9) and 6-(4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-9A) (1.13 g).

[0331] Step-9: Synthesis of (6-(4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00492-001) and (6-(4-cyclopropyl-3-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00493-001) TIFF0007777891000281.tif381606-(4-cyclopropyl-3-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-9) and 6-(4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (Int-9A) To a well-stirred reaction mixture of TFA salt (0.868 g, 2.92 mmol, 1.2 equiv.), pyridine (0.98 mL, 12.17 mmol, 5.0 equiv.), and 2-fluoro-5-hydroxybenzoic acid (0.38 g, 2.43 mmol, 1.0 equiv.) in N,N-dimethylformamide (5 mL) was added TBTU (1.17 g, 3.65 mmol, 1.5 equiv.) at 0 °C. The reaction was stirred at room temperature for 16 h. After completion of the reaction, as monitored by TLC and LCMS, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium carbonate solution (50 mL) and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 0-100% ethyl acetate in n-hexane as the eluent to give a mixture of two regioisomers, which was purified by preparative HPLC purification to give two fractions.

[0332] Fraction-1: (6-(4-cyclopropyl-3-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00493-001) (0.027 g, 1.61%). LCMS: m / z 436.22 [M+H] +。1 H NMR(400MHz,DMSO-d6)δ9.64(s,1H),7.36(dd,J=26.7,8.4Hz,4H),7.08(d,J=9.0Hz,1H),6 .77(s,2H),4.41(s,1H),4.02(s,4H),2.70(s,4H),1.40(s,1H),0.69(s,2H),0.46(s,2H).

[0333] Fraction-2: (6-(4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00492-001) (0.087 gm, 5.15%). LCMS: m / z 436.20 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.69(s,1H),7.56(dd,J=20.5,7.4Hz,3H),7.33-7.24(m,2H),6.81(s,2H),4.76-4.66( m,1H),4.15(d,J=10.4Hz,2H),4.04(d,J=8.4Hz,2H),2.72-2.62(m,4H),1.56(s,1H),0.76(s,2H),0.44(s,2H).

[0334] Example 15 Synthesis of (6-(5-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone [Compound 519] and (6-(3-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone [Compound 520] Synthesis scheme: TIFF0007777891000282.tif54170

[0335] Step A: 2-chloro-5-fluoro-N-methoxy-N-methylbenzamide (Int-B) To a stirred solution of 2-chloro-5-fluorobenzoic acid (10.0 g, 57.27 mmol, 1.0 equiv.), N,N-diisopropylethylamine (29.4 mL, 171.82 mmol, 3.0 equiv.), and N,O-dimethylhydroxylamine hydrochloride (6.142 g, 63.0 mmol, 1.1 equiv.) in N,N-dimethylformamide (50 mL) was added HATU (32.66 g, 85.91 mmol, 1.5 equiv.) at 0 °C. The reaction was stirred at room temperature for 16 h. After completion of the reaction as monitored by TLC, the reaction mixture was poured into ice-cold water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 25% ethyl acetate in n-hexane as the eluent to give 2-chloro-5-fluoro-N-methoxy-N-methylbenzamide (Int-B) (10.9 g, 87.3%).

[0336] Step B: 1-(2-chloro-5-fluorophenyl)propan-1-one (Int-1) To a stirred solution of 2-chloro-5-fluoro-N-methoxy-N-methylbenzamide (10.9 g, 50.25 mmol, 1.0 equiv.) in tetrahydrofuran (50 mL) was slowly added a solution of 3 M ethylmagnesium bromide in tetrahydrofuran (25.13 mL, 75.38 mmol, 1.5 equiv.) at −78° C. The reaction was stirred at room temperature for 6 hours. After completion of the reaction as monitored by TLC, the reaction mixture was poured into ice-cold water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 20-25% ethyl acetate in n-hexane as the eluent to give 1-(2-chloro-5-fluorophenyl)propan-1-one (Int-1) (5.28 g, 56.49%).

[0337] Step-1: (E)-1-(2-chloro-5-fluorophenyl)-3-(dimethylamino)-2-methylprop-2-en-1-one (Int-2) To a stirred solution of 1-(2-chloro-5-fluorophenyl)propan-1-one (5.28 g, 28.29 mmol, 1.0 equiv.) in toluene (15 mL) was added N,N-dimethylformamide dimethyl acetal (23.60 g, 198.06 mmol, 7.0 equiv.). The reaction was heated at 100° C. for 16 hours. After completion of the reaction, as monitored by TLC, the reaction mixture was poured into ice-cold water (100 mL) and extracted with ethyl acetate (50 mL×3). The organic phase was washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 25–30% ethyl acetate in hexane as the eluent to give (E)-1-(2-chloro-5-fluorophenyl)-3-(dimethylamino)-2-methylprop-2-en-1-one (Int-2) (5.65 g, 82.62%).

[0338] Step-2: 5-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazole (Int-3) To a stirred solution of (E)-1-(2-chloro-5-fluorophenyl)-3-(dimethylamino)-2-methylprop-2-en-1-one (5.65 g, 23.44 mmol, 1.0 equiv.) in isopropyl alcohol (30 mL) was added hydrazine hydrate (2.0 g, 35.16 mmol, 1.5 equiv.). The reaction was heated at 80 °C for 16 h. After completion of the reaction, as monitored by TLC, the reaction mixture was concentrated to give a residue. The residue was purified by Combiflash using 15–20% ethyl acetate in hexanes as the eluent to give 5-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazole (Int-3) (4.3 g, 87.33%).

[0339] Step-3: (5-(benzyloxy)-2-fluorophenyl)(6-(5-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Int-4) and (5-(benzyloxy)-2-fluorophenyl)(6-(3-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Int-4A) To a well-stirred reaction mixture of 5-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazole (0.2 g, 0.094 mmol, 1.0 equiv.), cesium carbonate (0.46 g, 1.42 mmol, 1.5 equiv.) in N,N-dimethylformamide (5 mL) was added 2-(5-(benzyloxy)-2-fluorobenzoyl)-2-azaspiro[3.3]heptan-6-yl methanesulfonate (0.43 g, 1.04 mmol, 1.3 equiv.). The reaction was heated at 50° C. for 12 h. After completion of the reaction, as monitored by TLC, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue that was purified by Combiflash using 35–40% ethyl acetate in n-hexane as the eluent to give a mixture of two regioisomers: (5-(benzyloxy)-2-fluorophenyl)(6-(5-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Int-4) and (5-(benzyloxy)-2-fluorophenyl)(6-(3-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Int-4A) (0.9 g, 97.63%).

[0340] Step-4: (6-(5-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00519-001), and (6-(3-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00520-001) TIFF0007777891000288.tif30161(5-(benzyloxy)-2-fluorophenyl)(6-(5-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone and (5-(benzyloxy)-2-fluorophenyl)(6-(3-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone A stirred solution of (4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (0.5 g, 0.93 mmol, 1.0 equiv.) in dichloromethane (5 mL) was cooled to -78 °C, and a solution of 1.0 M BCl3 in dichloromethane (2.8 mL, 2.80 mmol, 3.0 equiv.) was added. The resulting reaction mixture was then stirred at -78 °C for 2-3 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with triethylamine (2 mL) and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give two fractions.

[0341] Fraction-1: (6-(5-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00519-001) (0.062 g, 15.01%). LCMS: m / z 444.40 [M+1] + NMR: 1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),7.68(d,J=5.0Hz,1H),7.58(dt,J=8.8,5.6Hz,2H),7.35-7.17(m,1H),7.08(q,J=9.1Hz,1H) ),6.85-6.71(m,2H),4.32(dq,J=24.0,7.9Hz,1H),4.03(d,J=10.7Hz,4H),2.68(q,J=15.2,13.3Hz,4H),1.81(d,J=2.6Hz,3H).

[0342] Fraction-2: (6-(3-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-fluoro-5-hydroxyphenyl)methanone (PSY-05-00520-001) (0.019 g, 4.76%). LCMS: m / z 444.40 [M+1] + NMR: 1 H NMR(400MHz,DMSO-d6)δ9.80(s,1H),7.68(d,J=5.0Hz,1H),7.58(dt,J=8.8,5.6Hz,1H),7.35-7.17(m,2H),7.08(q,J=9.1Hz,1H),6.87-6. 74(m,2H),4.72(dq,J=24.0,7.9Hz,1H),4.13(d,J=10.7Hz,2H),4.02(d,J=9.4Hz,2H),2.68(q,J=15.2,13.3Hz,4H),1.91(d,J=2.6Hz,3H).

[0343] Example 16: Synthesis of 2-(2-ethoxy-4-fluorobenzoyl)-N-(2-isopropylphenyl)-N-methyl-2-azaspiro[3.3]heptane-6-carboxamide [Compound 205] Synthesis scheme: TIFF0007777891000289.tif66140

[0344] Step-1: Synthesis of tert-butyl 6-((2-isopropylphenyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-2) To a stirred solution of 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (0.30 gm, 1.24 mmol, 1 equiv.) in N,N-dimethylformamide (5 mL) was added HATU (0.70 gm, 1.86 mmol, 1.5 equiv.), DIPEA (0.802 gm, 6.22 mmol, 5.0 equiv.), followed by 2-isopropylaniline (Int-1A) (0.21 gm, 1.24 mmol, 1.0 equiv.) at 0° C. The reaction was stirred at room temperature for 12 hours and the reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3×20 mL), and washed with brine. The organic phase was dried over sodium sulfate and concentrated under vacuum to obtain crude material. This was purified by Combiflash using 30% ethyl acetate in n-hexane as the mobile phase to obtain the desired product, tert-butyl 6-((2-isopropylphenyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-2), 0.280 gm (yield: 63.63%). LCMS: 359.6 m / z [M+1]+.

[0345] Step-2: Synthesis of tert-butyl 6-((2-isopropylphenyl)(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate hydrochloride (Int-3) TIFF0007777891000291.tif34128 To a stirred solution of tert-butyl 6-((2-isopropylphenyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (0.4 gm, 1.11 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) was added sodium hydride (0.031 gm, 1.33 mmol, 1.2 equiv) at 0° C. The reaction was stirred at 0° C. for 10 minutes. Methyl iodide (0.187 gm, 1.33 mmol, 1.2 equiv) was added dropwise and the reaction was stirred at room temperature for 12 hours. After the reaction was complete, as monitored by TLC, the reaction mixture was diluted with ice-cold water (10 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated to give the crude product. This was purified by Combiflash using 30% ethyl acetate in hexane as the eluent to give 0.31 gm (75.60% yield) of tert-butyl 6-((2-isopropylphenyl)(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-3). LCMS: 373.4 m / z [M + ].

[0346] Step-3: Synthesis of N-(2-isopropylphenyl)-N-methyl-2-azaspiro[3.3]heptane-6-carboxamide (Int-4) To a stirred solution of tert-butyl 6-((2-isopropylphenyl)(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-3) (0.50 gm, 1.33 mmol, 1.0 equiv.) in dichloromethane (10 mL) was added trifluoroacetic acid (1.0 mL) at 0° C. and the reaction was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated in vacuo, basified with bicarbonate solution (5 mL), and extracted with ethyl acetate. The ethyl acetate layer was separated, dried over sodium sulfate, and concentrated to give crude product N-(2-isopropylphenyl)-N-methyl-2-azaspiro[3.3]heptane-6-carboxamide (Int-4) 0.350 gm (yield: quantitative). LCMS: 273.4 m / z [M+1]+.

[0347] Step-4: Synthesis of 2-(2-ethoxy-4-fluorobenzoyl)-N-(2-isopropylphenyl)-N-methyl-2-azaspiro[3.3]heptane-6-carboxamide (Compound-00205) To a stirred solution of 2-ethoxy-4-fluorobenzoic acid (Int-4A) (0.150 gm, 0.815 mmol, 1.0 equiv.) in N,N-dimethylformamide (3 mL) was added N-(2-isopropylphenyl)-N-methyl-2-azaspiro[3.3]heptane-6-carboxamide (0.221 gm, 0.815 mmol, 1 equiv.), DIPEA (0.31 gm, 2.445 mmol, 3.0 equiv.), and HATU (0.10 gm, 1.222 mmol, 1.5 equiv.) at 0° C. The resulting reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, as monitored by TLC, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The organic phase was washed with brine (10 ml), dried over sodium sulfate and concentrated under vacuum to give crude material which was purified by Combiflash using 10% methanol in dichloromethane as eluent to give 2-(2-ethoxy-4-fluorobenzoyl)-N-(2-isopropylphenyl)-N-methyl-2-azaspiro[3.3]heptane-6-carboxamide (PSY-05-00205), 0.070 gm (yield: 20%) as a white solid. LCMS: 439.7 m / z 1H NMR(400MHz,DMSO-d6)δ7.51-7.38(m,1H),7.42-7.25(m,1H),7.26(dd,J=7.9,4.7Hz,1H),6.95(dd d,J=19.4,11.6,2.4Hz,1H),6.84-6.71(m,1H),4.08(dq,J=21.4,6.8Hz,2H),3.82(t,J=4.8Hz,3H), 3.75(dq,J=14.6,8.9,6.8Hz,1H),3.16-3.01(m,3H),2.83(p,J=6.8Hz,1H),2.68-2.53(m,1H),2.35 -2.20(m,2H),2.00(ddd,J=30.9,12.2,8.7Hz,2H),1.31(dt,J=21.4,7.0Hz,3H),1.21-1.09(m,6H).

[0348] Example 17: Synthesis of 2-(2-ethoxy-4-fluorobenzoyl)-N-ethyl-N-(o-tolyl)-2-azaspiro[3.3]heptane-6-carboxamide [Compound 203] Synthesis scheme: TIFF0007777891000294.tif38156

[0349] Step-1: Synthesis of tert-butyl o-tolylcarbamate (Int-2) To a stirred solution of o-toluidine (1.0 gm, 9.34 mmol, 1.0 equiv.) in N,N-dimethylformamide (10 mL) was added TEA (1.88 gm, 18.69 mmol, 2.0 equiv.), followed by Boc anhydride (2.24 gm, 10.288 mmol, 1.0 equiv.) at 0° C. and stirred at room temperature for 12 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3×20 mL), and washed with brine. The organic phase was dried over sodium sulfate and concentrated under vacuum to give the crude material. This was purified by Combiflash using 30% ethyl acetate in n-hexane as the mobile phase to give the desired product tert-butyl o-tolylcarbamate (Int-2) 1.1 gm (yield: 56.99%). LCMS: 208.2 m / z [M+1]+.

[0350] Step-2: Synthesis of tert-butyl ethyl(o-tolyl)carbamate (Int-3) To a stirred solution of tert-butyl o-tolylcarbamate (0.5 gm, 2.415 mmol, 1.0 equiv.) in N,N-dimethylformamide (8 mL) was added sodium hydride (0.069 gm, 2.898 mmol, 1.2 equiv.) at 0° C. The reaction was stirred at 0° C. for 10 minutes. Ethyl iodide (0.741 gm, 2.898 mmol, 1.2 equiv.) was added dropwise, and the reaction was stirred at room temperature for 12 hours. After the reaction was complete, as monitored by TLC, the reaction mixture was diluted with ice-cold water (10 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated to give the crude product. This was purified by Combiflash using 30% ethyl acetate in hexane as eluent to give 0.45 gm (yield - 80.35%) of tert-butyl ethyl(o-tolyl)carbamate (Int-3). LCMS: 180.1 m / z [M-56]+.

[0351] Step-3: Synthesis of N-ethyl-2-methylaniline (Int-4) To a stirred solution of tert-butyl ethyl(o-tolyl)carbamate (Int-3) (0.50 gm, 2.127 mmol, 1.0 equiv.) in dichloromethane (10 mL) was added trifluoroacetic acid (1.0 mL) at 0° C., and the reaction was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under vacuum, basified with bicarbonate solution (5 mL), and extracted with ethyl acetate. The ethyl acetate layer was separated, dried over sodium sulfate, and concentrated to give crude N-ethyl-2-methylaniline (Int-4) 0.350 gm (yield: quantitative). LCMS: 136.1 m / z [M+1]+.

[0352] Step-4: Synthesis of 2-(2-ethoxy-4-fluorobenzoyl)-N-ethyl-N-(o-tolyl)-2-azaspiro[3.3]heptane-6-carboxamide (Compound-00203) To a stirred solution of 2-(2-ethoxy-4-fluorobenzoyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (Int-5) (0.20 gm, 0.651 mmol, 1 equiv.) in N,N-dimethylformamide (5 mL) was added N-ethyl-2-methylaniline (0.096 gm, 0.651 mmol, 1.0 equiv.), DIPEA (0.25 gm, 1.954 mmol, 3.0 equiv.), and HATU (0.371 gm, 0.977 mmol, 1.5 equiv.) at 0 °C. The resulting reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, as monitored by TLC, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phase was washed with brine (10 ml), dried over sodium sulfate and concentrated under vacuum to give the crude material, which was purified by Combiflash using 10% methanol in dichloromethane as eluent to give 2-(2-ethoxy-4-fluorobenzoyl)-N-ethyl-N-(o-tolyl)-2-azaspiro[3.3]heptane-6-carboxamide (PSY-05-00203), 0.10 gm (yield: 37.03%) as a white solid. LCMS: 425.7 m / z 1H NMR(400MHz,DMSO-d6)δ7.33(s,2H),7.33-7.20(m,2H),7.09(d,J=7.6Hz,1H),6.94(ddd,J=17.5, 11.7,2.4Hz,1H),6.76(dtd,J=10.8,8.4,2.5Hz,1H),4.08(dt,J=13.8,6.9Hz,3H),4.06-3.88(m,1 H),3.86-3.73(m,2H),3.71(s,2H),3.10(dt,J=13.6,6.8Hz,1H),2.33-2.19(m,2H),2.12(d,J=1.9 Hz,3H),1.92(s,1H),1.93-1.82(m,1H),1.30(dt,J=21.2,7.0Hz,3H),0.98(td,J=7.1,5.2Hz,3H).

[0353] Example 18: Synthesis of N-(2-chlorophenyl)-2-(2-ethoxy-4-fluorobenzoyl)-N-methyl-2-azaspiro[3.3]heptane-6-carboxamide [Compound 206] Synthesis scheme: TIFF0007777891000299.tif35144

[0354] Step-1: Synthesis of N-(2-chlorophenyl)-2-(2-ethoxy-4-fluorobenzoyl)-2-azaspiro[3.3]heptane-6-carboxamide (Int-6) To a stirred solution of 2-(2-ethoxy-4-fluorobenzoyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (0.150 gm, 0.488 mmol, 1.0 equiv.) in N,N-dimethylformamide (5 mL) was added TBTU (0.326 gm, 0.879 mmol, 1.8 equiv.). Pyridine (0.154 gm, 1.954 mmol, 5.0 equiv.) was added, followed by 2-chloroaniline (Int-5A) (0.082 gm, 0.586 mmol, 1.2 equiv.) at 0° C. The reaction was stirred at room temperature for 12 hours, and reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 x 20 mL), and washed with brine. The organic phase was dried over sodium sulfate and concentrated under vacuum to obtain a crude material. This was purified by Combiflash using 5% methanol in dichloromethane as the mobile phase to obtain the desired product, N-(2-chlorophenyl)-2-(2-ethoxy-4-fluorobenzoyl)-2-azaspiro[3.3]heptane-6-carboxamide (Int-6) 0.150 gm (yield: 75%). LCMS: 417.7 m / z [M+].

[0355] Step-2: Synthesis of N-(2-chlorophenyl)-2-(2-ethoxy-4-fluorobenzoyl)-N-methyl-2-azaspiro[3.3]heptane-6-carboxamide (Compound-00206) To a stirred solution of N-(2-chlorophenyl)-2-(2-ethoxy-4-fluorobenzoyl)-2-azaspiro[3.3]heptane-6-carboxamide (0.175 gm, 0.420 mmol, 1 equiv.) in N,N-dimethylformamide (3 mL) was added sodium hydride (0.012 gm, 0.504 mmol, 1.2 equiv.) at 0°C. The reaction was stirred at 0°C for 10 minutes. Methyl iodide (0.071 gm, 0.504 mmol, 1.2 equiv.) was added dropwise, and the reaction was stirred at room temperature for 12 hours. After the reaction was complete, as monitored by TLC, the reaction mixture was diluted with ice-cold water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic phase was washed with brine solution, dried over sodium sulfate and concentrated to give the crude product which was purified by Combiflash using 5% methanol in dichloromethane as the mobile phase to give the desired product N-(2-chlorophenyl)-2-(2-ethoxy-4-fluorobenzoyl)-N-methyl-2-azaspiro[3.3]heptane-6-carboxamide (PSY-05-00206) 0.10 gm (yield - 55.55%). LCMS: 431.4 m / z [M+] 1H NMR(400MHz,DMSO-d6)δ7.64(ddd,J=9.3,6.6,3.9Hz,1H),7.46(ddd,J=13.8,6.0,3.3Hz,3H),7.3 8-7.22(m,1H),6.95(ddd,J=15.6,11.6,2.4Hz,1H),6.77(dtd,J=10.6,8.4,2.4Hz,1H),4.11(q,J= 5.9,5.1Hz,1H),4.06(q,J=6.9,5.9Hz,1H),3.84(d,J=7.1Hz,2H),3.76(d,J=14.2Hz,2H),3.07(d ,J=6.4Hz,3H),2.68(hept,J=8.2Hz,1H),2.34-2.24(m,2H),2.08-1.85(m,2H),1.42-1.22(m,3H).

[0356] Example 19: Synthesis of (4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone [Compound 178] Synthesis scheme: TIFF0007777891000302.tif79128

[0357] Step-1: Synthesis of methyl 4-fluoro-2-(2,2,2-trifluoroethoxy)benzoate (Int-2) To a stirred solution of methyl 2,4-difluorobenzoate (0.10 gm, 0.58 mmol, 1.0 equiv.) in N,N-dimethylformamide (2 mL) was added sodium hydride (0.016 gm, 0.679 mmol, 1.2 equiv.) at 0°C. The reaction was stirred at 0°C for 10 minutes. 2,2,2-Trifluoroethan-1-ol (0.081 gm, 0.813 mmol) was added dropwise, and the reaction was stirred at room temperature for 12 hours. After the reaction was complete, as monitored by TLC, the reaction mixture was diluted with ice-cold water (5 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated to give the crude product. This was purified by Combiflash using 10% ethyl acetate in hexane as the eluent to give methyl 4-fluoro-2-(2,2,2-trifluoroethoxy)benzoate (Int-2), 0.10 gm (yield-68%). The compound contained a disubstituted product that was inseparable by column chromatography and was carried forward to the next step as a mixture.

[0358] Step-2: Synthesis of 4-fluoro-2-(2,2,2-trifluoroethoxy)benzoic acid (Int-3) To a stirred solution of methyl 4-fluoro-2-(2,2,2-trifluoroethoxy)benzoate (Int-2) (1.0 gm, 3.96 mmol, 1 equiv.) in THF (10 mL), MeOH (5 mL), and water (5 mL) was added sodium hydroxide [NaOH] (0.23 gm, 5.95 mmol, 1.5 equiv.) at 0° C. The reaction mixture was then stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under vacuum. The crude product was acidified with 2N HCl (pH ∼4). A white solid precipitated, which was filtered through a Buchner funnel and dried under vacuum to give 0.50 gm (53% yield) of 4-fluoro-2-(2,2,2-trifluoroethoxy)benzoic acid (Int-3). 1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.77 (dd, J = 8.7, 7.0 Hz, 1H), 7.17 (dd, J = 11.1, 2.4 Hz, 1H), 6.96 (td, J = 8.4, 2.4 Hz, 1H), 4.84 (q, J = 8.8 Hz, 2H).

[0359] Step-3: Synthesis of (4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Compound-00178-001) To a stirred solution of 6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate (0.10 gm, 0.37 mmol, 1 equiv.) in N,N-dimethylformamide (3 mL) was added 4-fluoro-2-(2,2,2-trifluoroethoxy)benzoic acid (0.89 gm, 0.37 mmol, 1 equiv.), TEA (0.11 gm, 1.12 mmol, 3 equiv.), EDC-HCl (0.10 gm, 0.56 mmol, 1.5 equiv.), and HOBT (0.025 gm, 0.18 mmol, 0.5 equiv.) at 0° C. The resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed as monitored by TLC, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with brine (10 ml), dried over sodium sulfate, and concentrated in vacuo to give the crude material, which was purified by CombiFlash using 80% ethyl acetate in hexane as the eluent to give PSY-05-00178 (0.050) (yield: 28%) as a white solid. LCMS:488.5m / z[M+] 1H NMR(400MHz,DMSO-d6)δ7.46-7.36(m,2H),7.40-7.25(m,2H),7.16(s,1H ),7.21-7.10(m,1H),6.98-6.87(m,1H),6.17(s,1H),4.93-4.79(m,2H), 3.95(s,1H),3.86(d,J=19.9Hz,2H),3.78(s,1H),3.03-2.92(m,1H),2.3 3(t,J=10.4Hz,2H),2.21(dd,J=23.9,9.2Hz,5H),1.93(d,J=2.3Hz,3H).

[0360] Example 20: Synthesis of (2-cyclopropoxy-4-fluorophenyl)(6-(1-(5-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone [Compound 418] and (2-cyclopropoxy-4-fluorophenyl)(6-(1-(5-fluoro-2-methylphenyl)-5-methyl-1H-pyrazol-3-yl)-2-azaspiro[3.3]heptan-2-yl)methanone [Compound 482] Synthesis scheme: TIFF0007777891000306.tif99146

[0361] Step-1: Tert-butyl 6-(methoxy(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-2) To a stirred solution of 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (5.0 g, 20.72 mmol, 1.0 equiv.), diisopropylethylamine (11 mL, 62.16 mmol, 3.0 equiv.), and N,O-dimethylhydroxylamine (3.0 g, 31.08 mmol, 1.5 equiv.) in N,N-dimethylformamide (25 mL) was added HATU (11.8 g, 31.08 mmol, 1.5 equiv.) at 0 °C. The reaction was stirred at room temperature for 6 h. After completion of the reaction as monitored by TLC, the reaction mixture was poured into ice-cold water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 4-5% methanol in dichloromethane as the eluent to give tert-butyl 6-(methoxy(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (5.5 g, 93.34%).

[0362] Step-2: tert-Butyl 6-acetyl-2-azaspiro[3.3]heptane-2-carboxylate (Int-3) To a stirred solution of tert-butyl 6-(methoxy(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-2) (5.5 g, 19.34 mmol, 1.0 equiv.) in tetrahydrofuran (30 mL) was slowly added methylmagnesium bromide 3M (11.6 mL, 34.81 mmol, 1.5 equiv.) at −78° C. The reaction was stirred at room temperature for 4 hours. After completion of the reaction as monitored by TLC, the reaction mixture was poured into ice-cold water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 12–15% ethyl acetate in n-hexane as the eluent to give tert-butyl 6-acetyl-2-azaspiro[3.3]heptane-2-carboxylate (Int-3) (3.2 g, 69.13%).

[0363] Step-3: Tert-butyl 6-(3-oxobutanoyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-4) To a stirred solution of tert-butyl 6-acetyl-2-azaspiro[3.3]heptane-2-carboxylate (Int-3) (2.0 g, 8.36 mmol, 1.0 equiv.) in diethyl ether (10 mL), sodium hydride 60% (1.67 g, 41.48 mmol, 5.0 equiv.) was added at 0 °C, followed by dropwise addition of ethyl acetate (4.9 g, 56.06 mmol, 6.7 equiv.). The reaction was stirred at room temperature for 4–5 h. After completion, the reaction was monitored by TLC. The reaction mixture was poured into water (100 mL), acidified with 10% dilute HCl, and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 10–15% ethyl acetate in n-hexane as the eluent to give tert-butyl 6-(3-oxobutanoyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-4) (2.1 g, 89.3%).

[0364] Step-4: Tert-butyl 6-(1-(5-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5) and Tert-butyl 6-(1-(5-fluoro-2-methylphenyl)-5-methyl-1H-pyrazol-3-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5A) To a stirred solution of tert-butyl 6-(3-oxobutanoyl)-2-azaspiro[3.3]heptane-2-carboxylate (1.6 g, 5.69 mmol, 1.0 equiv) in ethanol (15 mL) was added (5-fluoro-2-methylphenyl)hydrazine (1.5 g, 8.54 mmol, 1.5 equiv) and the reaction was heated at 80° C. for 16 hours. After completion of the reaction, as monitored by TLC, the reaction mixture was concentrated to give a residue. The residue was purified by Combiflash using 80% ethyl acetate in n-hexane as the eluent to give a mixture of tert-butyl 6-(1-(5-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5) and tert-butyl 6-(1-(5-fluoro-2-methylphenyl)-5-methyl-1H-pyrazol-3-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5A) (2.0 g, 91.3%).

[0365] Step-5: 6-(1-(5-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane (Int-6) and 6-(1-(5-fluoro-2-methylphenyl)-5-methyl-1H-pyrazol-3-yl)-2-azaspiro[3.3]heptane) (Int-6A) To a well-stirred reaction mixture of tert-butyl 6-(1-(5-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5) and tert-butyl 6-(1-(5-fluoro-2-methylphenyl)-5-methyl-1H-pyrazol-3-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-5A) (2.0 g, 6.99 mmol, 1.0 equiv) in dichloromethane (10 mL) was added trifluoroacetic acid (3.0 mL) dropwise at 0°C. After completion of the reaction as monitored by TLC, the reaction mixture was concentrated to give a mixture of 6-(1-(5-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane (Int-6) and 6-(1-(5-fluoro-2-methylphenyl)-5-methyl-1H-pyrazol-3-yl)-2-azaspiro[3.3]heptane (Int-6A) (0.420 g, 82.58%).

[0366] Step-6: (2-cyclopropoxy-4-fluorophenyl)(6-(1-(5-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00418-001) and (2-Cyclopropoxy-4-fluorophenyl)(6-(1-(5-fluoro-2-methylphenyl)-5-methyl-1H-pyrazol-3-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00482-001) TIFF0007777891000312.tif431376-(1-(5-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane (Int-6) and 6-(1-(5-fluoro-2-methylphenyl)-5-methyl-1H-pyrazol-3-yl)-2-azaspiro[3.3]heptane (Int To a well-stirred reaction mixture of Int-6A (0.42 g, 1.56 mmol, 1.2 equiv.), N,N-diisopropylethylamine (0.45 g, 6.50 mmol, 5.0 equiv.), and Int-D (0.255 g, 1.30 mmol, 1.0 equiv.) in N,N-dimethylformamide (5 mL) was added TBTU (0.63 g, 1.95 mmol, 1.5 equiv.) at 0 °C. The reaction was stirred at room temperature for 3–4 h. After completion of the reaction as monitored by TLC, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium carbonate solution (50 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the residue. The residue was purified by CombiFlash using 80–90% ethyl acetate in n-hexane as the eluent. The crude product was purified by preparative HPLC. Two fractions were collected.

[0367] Fraction-1: (2-cyclopropoxy-4-fluorophenyl)(6-(1-(5-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00418-001) (0.027 g, 3.96%). LCMS: m / z 464.44 [M+1] + NMR: 1H NMR(400MHz,DMSO-d6)δ7.42(q,J=7.8Hz,1H),7.30(t,J=7.6Hz,2H),7.28-7.11(m,2H),6.87-6.81(m,1H),3.98-3.85(m,3H),3.79(s, 1H),3.70(s,1H),3.13-2.99(m,1H),2.35(t,J=10.1Hz,1H),2.22(dd,J=23.5,9.3Hz,6H),1.91(s,3H),0.89-0.81(m,2H),0.67(s,2H).

[0368] Fraction-2: (2-cyclopropoxy-4-fluorophenyl)(6-(1-(5-fluoro-2-methylphenyl)-5-methyl-1H-pyrazol-3-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00482-001) (0.050 g, 7.33%). LCMS: m / z 464.44 [M+1] + NMR: 1 H NMR(400MHz,DMSO-d6)δ7.43(d,J=7.5Hz,1H),7.26(dq,J=27.9,10.5,9.1Hz,4H),6.82(d,J=13.5Hz,1H),6.12(d,J=13.5Hz,1H),4.06(s,1H),3. 91(s,3H),3.73(s,1H),3.41(s,1H),2.58-2.41(d,J=18.7Hz,2H),2.04( d,J=7.3Hz,3H),1.91(d,J=16.1Hz,3H),0.89-0.80(m,2H),0.72(s,2H).

[0369] Example 21 Synthesis of (2-cyclopropoxy-4-fluorophenyl)(6-(3-(trifluoromethyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Compound 424) and (2-cyclopropoxy-4-fluorophenyl)(6-(5-(trifluoromethyl)-3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Compound 451) Synthesis scheme: TIFF0007777891000313.tif73156

[0370] Step-A: 4,4,4-trifluoro-1-(2-(trifluoromethyl)phenyl)butane-1,3-dione (Int-B) To a stirred solution of 1-(2-(trifluoromethyl)phenyl)ethan-1-one (3.0 g, 1.59 mmol, 1.0 equiv.) in N,N-dimethylformamide at 0 °C under a N atmosphere, NaH 60% (0.500 g, 2.393 mmol, 1.5 equiv.) was added and stirred at 0 °C for 30 min. Ethyl trifluoroacetate (3.50 g, 2.388 mmol, 1.5 equiv.) was then added to the reaction, and the reaction was stirred at room temperature for 16 h. After completion of the reaction as monitored by TLC, the reaction mixture was poured into ice-cold water (100 mL). The mixture was acidified to pH 4.0 with dilute HCl and extracted with ethyl acetate (50 mL × 3). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash using 50% ethyl acetate in n-hexane as the eluent to give tert-butyl 6-(methoxy(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-B) (2.0 g, 44.15%).

[0371] Step-5: (2-cyclopropoxy-4-fluorophenyl)(6-(3-(trifluoromethyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00424-001) and (2-Cyclopropoxy-4-fluorophenyl)(6-(5-(trifluoromethyl)-3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00451-001) To a stirred solution of tert-butyl 6-(methoxy(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-B) (0.3 g, 1.05 mmol, 1.0 equiv.) in ethanol (5 mL) was added (2-cyclopropoxy-4-fluorophenyl)(6-hydrazinyl-2-azaspiro[3.3]heptan-2-yl)methanone (Int-6) (0.62 g, 2.10 mmol, 2.0 equiv.), and the reaction was heated at 80° C. for 16 h. After completion of the reaction, as monitored by TLC, the reaction mixture was concentrated to give a residue. The residue was purified by Combiflash using 80% ethyl acetate in n-hexane as the eluent to give a mixture of two regioisomers. The crude product was purified by preparative HPLC. Two fractions were collected.

[0372] Fraction-1: (2-cyclopropoxy-4-fluorophenyl)(6-(5-(trifluoromethyl)-3-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00451-001) (0.027 g, 4.97%). LCMS: m / z 553.91 [M+1] + NMR: 1 H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.05-7.83(m,3H),7.63(d,J=7.5Hz, 1H),7.30(dq,J=27.9,10.5,9.1Hz,1H),7.21-7.28(dq,J=27.9,10.5,9.1H z,1H),6.92(d,J=13.5Hz,2H),4.46(s,1H),4.00-3.95(s,3H),3.80(s,2H) ),2.78-2.70(d,J=18.7Hz,4H),0.87(d,J=16.1Hz,2H),0.79-0.70(m,2H).

[0373] Fraction-2: (2-cyclopropoxy-4-fluorophenyl)(6-(3-(trifluoromethyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00424-001) (0.050 g, 9.20%). LCMS: m / z 553.91 [M+1] + NMR: 1 H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.15-8.37(m,5H),7.63(d,J=7.5Hz,1H) ,7.40(dq,J=27.9,10.5,9.1Hz,1H),6.92(d,J=13.5Hz,1H),5.52(d,J=13.5H z,1H),4.56(s,1H),4.00(s,3H),3.63(s,2H),2.78-2.70(d,J=18.7Hz,2H),2 .24(d,J=7.3Hz,2H),0.87(d,J=16.1Hz,2H),0.79-0.70(m,2H),0.72(s,2H).

[0374] Example 22: MAGL Inhibitory Potency (IC 50 ) measurement The potency of a particular compound to inhibit MAGL was obtained using the following assay.

[0375] The MAGL potency of the compounds in Tables 6 and 7 was determined using Cayman Chemical's Monoacylglycerol Lipase Inhibitor Screening Assay Kit.

[0376] Cayman's Monoacylglycerol Lipase Inhibitor Screening Assay provides a method for screening inhibitors of human MAGL. MAGL hydrolyzes 4-nitrophenyl acetate to produce 4-nitrophenol, a yellow product with an absorbance of 405-412 nm.

[0377] MAGL inhibition was measured by the following assay. Monoacylglycerol lipase (MAGL) inhibition was measured using recombinant MAGL enzyme (aa 2-303 RBC, internal preparation) and the substrate 4-nitrophenyl acetate (4NPA) (Sigma-Aldrich, N8130). Substrate hydrolysis in the presence of enzyme was measured by absorbance at 405 nm. 10 μL of assay buffer (10 mM Tris pH 7.5, 1 mM EDTA, 0.9% DMSO) was added to each reaction in a clear-bottom 384-well black non-binding plate (Greiner, 781906). Compounds were dispensed using an acoustic liquid handler (Echo, Beckman) in 45 nL (0.1% DMSO). Test compounds and MAGL inhibitor control JZL-184 (Caymen Chemical Co., 13158) were tested in a 10-concentration IC50 mode with a starting concentration of 10 μM and 3-fold serial dilutions. DMSO control wells were included as references. A 10.8 nM (1.8x) MAGL mix was prepared in assay buffer, and 25 μL was added to each reaction well for a final assay concentration of 6 nM. Wells without enzyme received 25 μL of buffer. Plates were incubated at room temperature for 30 minutes. A 35 mM 4NPA solution in methanol was prepared daily. A 4.5x 4NPA substrate solution was prepared in assay buffer, and 10 μL was added to each reaction well for a final assay concentration of 0.25 mM. The plate was spun at 1000 rpm for 1 minute, after which absorbance was measured using a CLARIOstar plate reader (BMG Labtech). Kinetic readings at 405 nm were taken every minute for 30 minutes. Data were analyzed using the linear slope of the reaction progress curve, and the average of the no enzyme wells (background) was subtracted from the data. Background-subtracted slope data were converted to % activity using the average of the enzyme and DMSO vehicle wells. IC50s were calculated using GraphPad software (sigmoidal dose-response, variable slope equation).

[0378] Tables 6 and 7 present exemplary compounds of formula (I) and their MAGL inhibitory potencies measured using the potency assay of Example 22 above, with the following modifications described in Table C below. Table 8 presents MAGL inhibitory potency measurements measured using the potency assay of Example 22 above, with the following modifications described in Table C.

[0379] Table C: Method used to measure MAGL inhibition using 4NPA substrate TIFF0007777891000316.tif225158

[0380] The potency results in Tables 6, 7, and 8 are expressed as the following ranges: "A" indicates an IC<50 nM 50 "B" refers to an IC value between 50 nM and 150 nM. 50 "C" refers to an IC greater than 150 nM and less than 500 nM. 50 "D" refers to an IC between 500 nM and 1 micromolar. 50 "E" refers to an IC greater than 1 micromolar and up to 5.1 micromolar 50 The number after each letter of the potency measurement indicates the method in Table C that was used to obtain that measurement (e.g., "A(1)" indicates an IC of less than 50 nM obtained from Method 1 in Example 22 of Table C). 50 (Measurements are shown).

[0381] Example 23: FAAH Inhibitory Potency (IC 50 ) measurement Relative compound potency at FAAH can be obtained using the following assay: A "selective MAGL inhibitory compound" is one that exhibits an IC50 or IC60 or IC70 or IC80 or IC90 or IC1 ... 50 At least 10 times the IC 50 Selectively inhibits MAGL with an IC of 150 nM or less for MAGL inhibition. 50 (according to the MAGL potency assay of Example 22).

[0382] MAGL-inhibitory compounds were also counterscreened for FAAH inhibitory potency using the following assay. FAAH inhibition was assessed using the Fatty Acid Amide Hydrolase Inhibitor Screening Assay Kit (Cayman, product number 10005196) according to the manufacturer's instructions with some modifications. The kit utilizes human recombinant FAAH and the fluorogenic substrate, AMC arachidonoylamide (AAMCA). Five microliters of assay buffer (125 mM Tris, pH 9.0, 1 mM EDTA, i.e., ethylenediaminetetraacetic acid) was added to a 384-well black plate (Corning, 3573). Test compounds and the control inhibitor JZL-195 (Cayman Chemical, 13668) were tested at starting concentrations of 100 μM and 10 μM, respectively, in a 10-concentration IC50 mode with three-fold serial dilutions. 300 nL or 30 nL of test compound was placed into a 384-well black plate (Corning, 3573) using a Labcyte Echo, followed by the addition of 15 μL of FAAH enzyme (Cayman, 700302) in assay buffer. After a 5-minute preincubation at room temperature, 10 μL of AAMCA was added to the assay buffer to initiate the reaction. The final concentration of FAAH enzyme was not specified, and AAMCA substrate was used at 20 μM. After these dilutions, the final test compound concentrations ranged from 100 μM to 5.08 nM or 10 μM to 0.508 nM. The reaction proceeded for 60 minutes, with plates read every minute at 350 / 460 nm Ex / Em on an Envision plate reader. Data were analyzed in Microsoft Excel using a gradient between 30 and 59 minutes. The average of the no-enzyme wells (background) was subtracted from the data. Background-subtracted slope data were converted to % activity using the average of enzyme and DMSO vehicle wells. IC 50 Values ​​were calculated using GraphPad software (sigmoidal dose-response, variable slope equation).

[0383] The compounds listed in Table D2 were tested in the FAAH counterscreen of Example 23.

[0384] Table D1: Methods used to measure FAAH inhibition TIFF0007777891000317.tif22161

[0385] Table D2: FAAH Counterscreening TIFF0007777891000318.tif73161TIFF0007777891000319.tif232161TIFF0007777891000320.tif45161

[0386] Example 24: Reversible MAGL Inhibition (IC 50 ) measurement The reversible mechanism of MAGL inhibition by test compounds of Formula (I) can be determined. Flag-tagged MAGL enzyme is immobilized on anti-Flag beads. The immobilized enzyme is incubated with + / - inhibitor at doses that result in complete inhibition. A colorimetric substrate (4-NPA) is added, and the reaction is monitored on a plate reader for 30 minutes to confirm complete inhibition. The immobilized enzyme is then thoroughly washed to remove the inhibitor, and fresh substrate is added. The reaction is monitored for an additional 30 minutes. Return of enzyme activity indicates reversible inhibition.

[0387] To confirm the assumption of a reversible inhibition mechanism, the effects of dilution and preincubation on the MAGL inhibitory activity of a compound may be evaluated using the method disclosed in J. Med. Chem. 2019, 62, 1932-1958, 1942. An irreversible inhibition mechanism would not result in a decrease in potency after dilution, whereas a reversible inhibition would result in a significant decrease in potency level after dilution. Therefore, the inhibition produced by incubation with a 4000 nM test compound can be measured after a 40-fold dilution and the potency observed with 4000 nM and 100 nM test compounds can be compared. If the inhibition produced by a 100 nM test compound is similar to that obtained after a 40-fold dilution and significantly lower than that produced by the same compound at a 4000 nM concentration, a reversible inhibition mechanism can be identified.

[0388] As a second assay to identify or confirm the reversible MAGL inhibitory activity of a test compound, the inhibitory activity of the test compound can be measured by using different preincubation times with MAGL. Before adding the substrate to initiate the enzymatic reaction, the test compound can be preincubated with the enzyme for 0, 30, and 60 minutes. Irreversible inhibition should result in higher potency with longer incubation times, whereas reversible inhibition should result in consistent inhibitory potency across all incubation times.

[0389] Determine reversible inhibition of MAGL: The MAGL enzyme was incubated for 30 minutes in the presence of inhibitor at 40 times the IC concentration. The enzyme and inhibitor mixture was then diluted 40 times, and the final concentration of inhibitor was adjusted to the IC 50 The substrate was added and the reaction was monitored for 30 minutes. If the inhibitor was reversible, the IC 50 After dilution to the concentration, the inhibition rate should be 50 + 15%.

[0390] The MAGL reversible inhibition assay of Example 24 above was performed to test the reversibility of inhibition by the compounds listed in Table E. Column A shows the degree of MAGL enzyme activity restored after washing with the test compound (compound concentration before washing: 1 μM). This reflects the reversibility of inhibition, compared to the complete lack of MAGL enzyme activity restored after washing with the irreversible inhibitor, comparison compound JZL-184 (compound concentration before washing: 1 μM). Column B shows the % MAGL activity restored after washing. The % activity restored after washing represents the amount of MAGL enzyme activity generated immediately after a 30-minute wash with the test compound, compared to the amount in the control (no inhibitor before washing) reaction. For some test compounds, it may take longer than 30 minutes for the compound to become completely unbound, and the % activity restored after washing may be less than 100%.

[0391] Table E. Reversible MAGL Inhibition TIFF0007777891000321.tif194161

[0392] It is understood that this disclosure is not limited to the particular methodology, protocols, and reagents, etc., provided herein as these may vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the disclosure, which is defined solely by the claims.

[0393] Example 25: Pharmacokinetic study of compounds in mice Healthy male C57BL / 6 mice (8-12 weeks old) weighing 17-35 g were procured from Global, India. Temperature and humidity were maintained at 22 ± 3°C and 30-70%, respectively, and lighting was controlled with a 12-hour light / dark cycle. Temperature and humidity were recorded by an automated data logger system. All animals were fed a laboratory rodent diet and provided UV-treated reverse osmosis water ad libitum.

[0394] Protocol A: Twenty-four male mice were divided into two groups: Group 1: 30 mg / kg / IP; plasma and brain; Animal No. = 12; Animal Nos. 1–12; Group 2: 30 mg / kg / PO; plasma and brain; Animal No. = 12; Animal Nos. 13–24. Animals in Group 1 were intraperitoneally administered a 30 mg / kg solution of PSY-05-00074-001 in 5% NMP, 5% Solutol HS-15, and 90% saline. Animals in Group 2 were orally administered a 30 mg / kg solution of PSY-05-00074-001 in 5% NMP, 5% Solutol HS-15, and 90% saline. Blood samples (approximately 60 μL) were collected from the retroorbital plexus under mild isoflurane anesthesia at 0.25, 0.5, 1, 2, 4, and 8 hours (IP and PO). Plasma samples were separated by centrifugation of the whole blood and stored at <-70°C until biopsy. Immediately after blood collection from the intraperitoneal and oral groups, the animals were euthanized with excessive CO2, and brain samples were collected from two sets of mice per time point. The brain samples were divided into two portions. Half of the brain sample was homogenized using ice-cold phosphate buffer saline (pH -7.4), and the homogenate was stored at <-70°C ± 10°C until analysis. The total volume of the homogenate was three times the brain weight. The other portion of the brain was stored at <-70°C ± 10°C for further analysis. All samples were processed for analysis by protein precipitation using acetonitrile and analyzed by a fit-for-purpose LC / MS / MS method (LLOQ - 2.02 ng / mL for plasma and 6.06 ng / g for brain). Pharmacokinetic parameters were calculated using the non-compartmental analysis tool in Phoenix WinNonlin®.

[0395] Protocol B: Thirty-six mice were included in the study, divided into three groups: Group 1 (n=12), Group 2 (n=12), and Group 3 (n=12), using a design of n=2 mice per time point. Group 1 animals were administered a solution formulation of PSY-05-00414-001 intravenously at a dose of 5 mg / kg. Group 2 animals were administered a solution formulation of PSY-05-00414-001 orally at a dose of 5 mg / kg. Group 3 animals were administered a solution formulation of PSY-05-00414-001 intraperitoneally at a dose of 5 mg / kg. The formulation vehicle for all three groups was 5% NMP, 5% Solutol HS-15, and 90% saline. Blood samples (approximately 60 μL) were collected from two mice under mild isoflurane anesthesia at 0.25, 0.5, 1, 2, 4, and 8 hours. Plasma was collected by centrifugation and stored at -70 ± 10°C until analysis. After blood collection, brains were perfused and isolated at 0.25, 0.5, 1, 2, 4, and 8 hours. Brain samples were immersed three times in ice-cold phosphate-buffered saline, blotted dry, and cut into two equal portions. Half the brain sample from each time point was weighed and homogenized with twice the brain weight in ice-cold phosphate-buffered saline, yielding a total of three volumes of homogenate. These were stored below -70 ± 10°C until analysis. The remaining half of the brain sample was flash-frozen and kept at -70 ± 10°C until further confirmation from the client. Plasma and brain samples were quantified by a fit-for-purpose LC-MS / MS method (LLOQ: 1.01 ng / mL for plasma and 2.02 ng / mL for brain).

[0396] Protocol C: Fifty-four male mice were included in the study and divided into three groups (Group 1 (n = 18), Group 2 (n = 18), and Group 3 (n = 18)) with a three-mouse / time point design. Animals in Groups 1, 2, and 3 were administered a solution formulation of PSY-05-00451-001 at a dose of 5 mg / kg via intravenous, oral, and intraperitoneal routes, respectively. The formulation vehicles used were 5% v / v NMP, 5% v / v Solutol HS-15, and 90% v / v saline. Blood samples (approximately 60 μL) were collected from sets of three mice at 0.25, 0.5, 1, 2, 4, and 8 hours from the retro-orbital plexus under mild isoflurane anesthesia (Surgivet®). Immediately after blood collection, plasma was collected by centrifugation at 4000 rpm for 10 minutes at 4°C. Samples were stored at -70±10°C until bioanalysis. After blood collection, animals were sacrificed, followed by incision of the vena cava and systemic cardiac perfusion with 10 mL of saline. Brain samples were collected from sets of three mice at 0.25, 0.5, 1, 2, 4, and 8 hours. After isolation, brain samples were rinsed three times in ice-cold saline (approximately 5-10 mL of saline in a disposable Petri dish for 5-10 seconds per rinse), dried on blotting paper, and cut into two equal parts. One half of the brain was used for PK estimation, and the other half was flash-frozen and stored below -70±10°C. Half the brain (for PK estimation) was weighed and homogenized with ice-cold phosphate-buffered saline at a volume twice the brain weight, yielding a total of three volumes of homogenate, which were stored below -70±10°C until analysis. All samples were processed for analysis by protein precipitation and analyzed by a fit-for-purpose LC-MS / MS method (LLOQ = 2.03 ng / mL for plasma and 1.02 ng / mL for brain). Pharmacokinetic parameters were estimated using the non-compartmental analysis tool in Phoenix® WinNonlin software.

[0397] Protocol D: Thirty-six male mice were included in the study and divided into two groups, Group 1 (n = 18) and Group 2 (n = 18), with three mice per time point in a low-density design. Animals in Groups 1 and 2 were administered a solution formulation of PSY-05-00473-001 at a dose of 5 mg / kg via the intravenous and oral routes, respectively. The formulation vehicle used was 5% v / v NMP, 5% v / v Solutol HS-15, and 90% v / v saline. Blood samples (approximately 60 μL) were collected from sets of three mice at 0.25, 0.5, 1, 2, 4, and 8 hours from the retro-orbital plexus under mild isoflurane anesthesia (Surgivet®). Immediately after blood collection, plasma was collected by centrifugation at 4000 rpm for 10 minutes at 4°C...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: During the ceremony, A １ teeth, and R １ is halogen, hydrogen, or cyano; R ３ａ and R ５ are each independently hydrogen, halogen, or lower alkyl; R ５２ is lower alkyl, lower cycloalkyl, or lower haloalkyl; R ３ｂ is a halogen, W is a diazole optionally substituted with lower alkyl, lower cycloalkyl, or lower haloalkyl; B １ teeth, and R ２０ is halogen, hydrogen, lower alkyl, or lower haloalkyl, and R ２６ is hydrogen or halogen, where: Lower alkyl means alkyl having 1 to 4 carbon atoms; Lower cycloalkyl means a cycloalkyl having 3 to 6 carbon atoms in the ring; Lower haloalkyl means halo-substituted lower alkyl; However, the compound is (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone, None of the above.

2. R １ is hydrogen, fluoro, or cyano; R ３ａ and R ５ are each independently hydrogen, halogen, or methyl; R ５２ is lower alkyl, cyclopropyl, or lower haloalkyl; R ３ｂ is fluoro, W is methyl, cyclopropyl, or CF ３ is a diazole optionally substituted with one of R ２０ is fluoro, chloro, methyl, or CF ３ and R ２６ is hydrogen, fluoro or chloro; The compound of claim 1.

3. A １ teeth, and R １ is fluoro, R ３ａ is hydrogen, fluoro, or methyl; R ５ is hydrogen, The compound of claim 2.

4. A １ teeth, and R ３ｂ is fluoro, R ５２ is lower alkyl optionally substituted with one or more fluoro, or is cyclopropyl; The compound of claim 2.

5. W is is selected from the group consisting of In the formula, * represents B １ indicates a covalent bond to, and R ３０ , R ３１ , R ３２ , and R ３３ are each independently hydrogen, lower alkyl, lower haloalkyl, or lower cycloalkyl, with the proviso that R ３１ and R ３３ and at least one of R ３２ and R ３３ At least one of the is not hydrogen, The compound of claim 2.

6. R ３０ , R ３１ , R ３２ , and R ３３ are each independently hydrogen, methyl, CF ３ or cyclopropyl, with the proviso that R ３１ and R ３３ and at least one of R ３２ and R ３３ The compound of claim 5 , wherein at least one of is not hydrogen.

7. R ２０ is methyl, and R ２６ is hydrogen or fluoro, or R ２０ is fluoro or CF ３ and R ２６ is hydrogen, The compound of claim 6.

8. 10. The compound of claim 1, which is a compound of formula (II-B), (II-C), (II-D), (III-B), (III-C) or (III-D), or a pharmaceutically acceptable salt thereof: 、 、 、 、 ,or During the ceremony, R １ is halogen or cyano, R ３ａ is hydrogen, lower alkyl, or halogen; R ３ｂ is a halogen, R ５ is hydrogen, halogen, or lower alkyl; R ２０ is halogen or lower alkyl optionally substituted with one or more halogens, R ２６ is a halogen or hydrogen, R ３０ is hydrogen or lower alkyl optionally substituted with one or more halogens, R ３１ , R ３２ , and R ３３ are each independently hydrogen or lower alkyl optionally substituted with one or more halogens, with the proviso that R ３１ and R ３３ one of which is hydrogen, and R ３２ and R ３３ One of them is hydrogen, R ５２ is lower alkyl optionally substituted with halogen, or lower cycloalkyl.

9. R １ is F or cyano, R ３ａ is hydrogen, methyl, or F; R ３ｂ is F, R ５ is hydrogen, F, or methyl; R ２０ is F, methyl, or CF ３ and R ２６ is hydrogen or F, R ３０ is hydrogen, methyl, or CF ３ and R ３１ , R ３２ , and R ３３ are each independently hydrogen, methyl, or CF ３ and R ５２ is lower alkyl optionally substituted with one or more F, or is cyclopropyl; The compound of claim 8.

10. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

20. 20. A pharmaceutical composition for reversibly inhibiting monoacylglycerol lipase (MAGL), for increasing 2-arachidonoylglycerol (2-AG), or for decreasing arachidonic acid (AA) or prostaglandin levels in a subject in need thereof, comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

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