SPIROCYCLIC MODULATORS OF CHOLESTEROL BIOSYNTHESIS AND THEIR USE TO PROMOTE REMYELINATION - Patent application

Abstract

The subject matter described herein relates to myelin-promoting compounds of formula I and pharmaceutical salts thereof, methods of preparing the compounds, pharmaceutical compositions containing the compounds, and methods of administering the compounds to treat disorders, such as myelin-related disorders. TIFF2024542295000365.tif28119

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 282,354, filed November 23, 2021, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] Field The subject matter described herein relates to myelin-promoting compounds of Formula I, methods for making the compounds, pharmaceutical compositions thereof, and their use in treating myelin-related disorders. [Background technology]

[0003] background Myelin-related disorders are disorders that result in abnormalities of the myelin sheath (e.g., dysmyelination, demyelination, and hypomyelination) in the nerve cells of a subject, e.g., CNS neurons, including their axons. The loss or degradation of the myelin sheath in such disorders results in slowed or halted neuronal conduction. The resulting myelin-related disorders are characterized by deficits in sensory, motor, cognitive, or other physiological functions. Myelin-related disorders include multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, childhood leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis pleuromyelitis (EPL), and central pontine myelinolysis. These include, but are not limited to, chronic myelolysis (CPM), adrenoleukodystrophy, Alexander disease, Pelizabeth-Mersbacher disease (PMD), vanishing white matter disease, Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post-radiation injury, neurological complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barré syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination.

[0004] MS is the most common myelin-related disorder, affecting millions worldwide and resulting in an estimated 18,000 deaths per year. It is a complex neurological disease characterized by the deterioration of central nervous system (CNS) myelin. Myelin, composed largely of lipids (70% lipid, 30% protein), protects axons, enables saltatory conduction, and accelerates axonal electrical impulses. Axonal demyelination in chronic MS can lead to axonal degeneration and neuronal death. Furthermore, MS destroys oligodendrocytes, highly specialized CNS cells that generate and maintain myelin. A repair process called remyelination occurs early in the disease, but over time, oligodendrocytes become unable to completely rebuild and restore the myelin sheath. Repeated attacks result in successively less effective remyelination until scar-like plaques accumulate around damaged axons. These scars are the cause of symptoms.

[0005] Currently, there is no cure for myelin-related disorders, and only a few disease-modifying therapies are available. Thus, there is a need for new therapeutic approaches to the treatment of myelin-related disorders, including promoting remyelination. The subject matter described herein addresses this unmet need. Summary of the Invention [Means for solving the problem]

[0006] overview In certain embodiments, the subject matter described herein relates to a compound of Formula I, or a pharmaceutically acceptable salt thereof:

[0007] In certain embodiments, the subject matter described herein relates to a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0008] In certain embodiments, the subject matter described herein relates to a method of treating a disorder in a subject in need of treatment, wherein the disorder is a myelin-related disorder, comprising administering to the subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] In certain embodiments, the subject matter described herein relates to a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula I or a pharmaceutically acceptable salt thereof, for use in treating a myelin-related disorder.

[0010] In certain embodiments, the subject matter described herein relates to a method of promoting myelination in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] In certain embodiments, the subject matter described herein relates to the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a myelin-related disorder.

[0012] In certain embodiments, the subject matter described herein relates to a method of obtaining a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0013] Other embodiments are also described. DETAILED DESCRIPTION OF THE INVENTION

[0014] Detailed Description Described herein are compounds of Formula I, methods for making the compounds, pharmaceutical compositions thereof, and their use in treating myelin-related disorders. In some embodiments, the compounds provided herein are promyelinating.

[0015] Without wishing to be bound by theory, enhancing and / or inducing the accumulation of Δ8,9-unsaturated sterol intermediates in the cholesterol biosynthesis pathway in oligodendrocyte precursor cells (OPCs) can induce the generation of oligodendrocytes. Enhancement and / or induction of Δ8,9-unsaturated sterol intermediate accumulation can be provided, for example, by inhibiting the accumulation of Δ8,9-unsaturated sterol intermediates and / or modulating and / or inhibiting enzymes in the OPC cholesterol biosynthesis pathway for which Δ8,9-unsaturated sterol intermediates are substrates, and by directly and / or indirectly administering Δ8,9-unsaturated sterol intermediates to OPCs. Enhancement and / or induction of Δ8,9-unsaturated sterol intermediate accumulation can promote the differentiation, survival, proliferation, and / or maturation of OPCs, which is believed to be useful for treating diseases and / or disorders in subjects in which myelination is beneficial to the subject.

[0016] Thus, in some embodiments, an agent capable of enhancing and / or inducing the accumulation of Δ8,9-unsaturated sterol intermediates of the cholesterol biosynthetic pathway in OPCs, such as a compound of Formula I or a pharmaceutically acceptable salt thereof, can be administered to a subject and / or OPCs in an amount effective to promote and / or induce differentiation, proliferation, and / or maturation of OPCs, and oligodendrogenesis. In certain embodiments, the agent, e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof, is a compound that inhibits enzyme-mediated synthesis of one or more sterol intermediates in the cholesterol biosynthetic pathway in OPCs and / or promotes the accumulation of Δ8,9-unsaturated sterol intermediates.

[0017] In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof can regulate and / or inhibit one or more enzyme-mediated conversion steps (e.g., between lanosterol and / or lanosterol) in the cholesterol biosynthetic pathway, such as the lanosterol to cholesterol pathway, and regulating and / or inhibiting these one or more steps in OPCs can promote and / or induce the generation of oligodendrocytes. For example, in some embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof can inhibit CYP51, sterol 14-reductase (TM7SF2 and / or LBR), SC4MOL, NSDHL, and / or emopamil-binding protein (EBP) enzyme-mediated synthesis of sterol intermediates in the cholesterol biosynthetic pathway. In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof can inhibit CYP51, sterol 14-reductase, and / or EBP. In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof can inhibit EBP.

[0018] For example, in certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof used in the methods described herein can inhibit the enzyme-mediated conversion of zymostenol to lathosterol through inhibition of emopamil-binding protein (EBP) isomerase enzyme activity. Alternatively, in certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof used in the methods described herein can inhibit sterol C14 reductase enzyme activity or CYP51 enzyme activity in the cholesterol biosynthetic pathway.

[0019] Emopamil-binding protein (EBP) is an enzyme responsible for one of the final steps in the production of cholesterol. Specifically, EBP converts zymostenol to lathosterol, which is then modified by other enzymes to produce cholesterol. EBP is also known as Δ8-Δ7-sterol isomerase, 3-β-hydroxysteroid-delta(8), delta(7)-isomerase, CDPX2, CHO2, CPX, or CPXD.

[0020] Without being bound by any particular theory, it is believed that the compound of Formula I or a pharmaceutically acceptable salt thereof can inhibit the EBP-mediated conversion of zymostenol to lathosterol in the cholesterol biosynthesis pathway of OPCs, resulting in enhanced and / or induced accumulation of Δ8,9-unsaturated sterol intermediates. In some embodiments, enhanced and / or induced accumulation of Δ8,9-unsaturated sterol intermediates can promote OPC differentiation, survival, proliferation, and / or maturation, and can treat diseases and / or disorders in subjects where myelination or myelin development is beneficial to the subject. This mechanism of promoting myelination is distinct from the primary action of immunomodulatory agents often used to treat myelin-related disorders.

[0021] The presently disclosed subject matter is now more fully described below. However, many modifications and other embodiments of the presently disclosed subject matter described herein will occur to those skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the description herein. Therefore, the presently disclosed subject matter should not be limited to the particular embodiments disclosed, but rather it should be considered that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein encompasses all alternatives, modifications, and equivalents. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the event that one or more of the incorporated documents, patents, and similar materials differs from or conflicts with the present application, including, but not limited to, defined terms, term usage, described technology, etc., the present application shall control.

[0022] I. Definition As used herein, the following words, phrases and symbols are generally intended to have the meanings indicated below, except to the extent that the context in which they are used indicates otherwise.

[0023] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment of a substituent. For example, -C(O)NH2 is attached through a carbon atom. Dashes at the beginning or end of a chemical group are for convenience. Chemical groups may be shown with or without one or more dashes without losing their ordinary meaning. A wavy or dashed line drawn vertically through or across the end of a line in a structure indicates a designated point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which chemical groups are described or named.

[0024] Prefix “C” u -C v " indicates that the following group has u to v carbon atoms. For example, "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0025] Reference herein to a value or parameter preceded by "about" includes (and describes) embodiments directed to that value or parameter itself. In certain embodiments, the term "about" includes the stated amount ± 50%. In certain other embodiments, the term "about" includes the stated amount ± 20%. In certain other embodiments, the term "about" includes the stated amount ± 10%. In other embodiments, the term "about" includes the stated amount ± 5%. In certain other embodiments, the term "about" includes the stated amount ± 1%. In certain other embodiments, the term "about" includes the stated amount ± 0.5%, and in certain other embodiments, 0.1%. Such variations are appropriate for practicing the disclosed methods or using the disclosed compositions. Also, the term "about x" includes the reference to "x." Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0026] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a group having 1 to 20 carbon atoms (i.e., C1 to C6). 20 alkyl), 1 to 12 carbon atoms (i.e., C1 to C 12 alkyl), 1 to 8 carbon atoms (i.e., C1 to C8 alkyl), 1 to 6 carbon atoms (i.e., C1 to C6 alkyl), 1 to 4 carbon atoms (i.e., C1 to C4 alkyl), or 1 to 3 carbon atoms (i.e., C1 to C3 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons can be encompassed; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0027] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" groups, "alkylenyl" groups, "arylene" groups, and "arylenyl" groups, respectively. Also, unless otherwise specified, when a combination of groups is referred to herein as a single moiety, e.g., arylalkyl or aralkyl, the last-mentioned group includes the atom by which that moiety is attached to the remainder of the molecule.

[0028] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and, unless otherwise specified, 2 to 20 carbon atoms (i.e., C2-C6 20alkenyl), 2 to 8 carbon atoms (i.e., C2-C8 alkenyl), 2 to 6 carbon atoms (i.e., C2-C6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-C4 alkenyl). Examples of alkenyl groups include, for example, ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0029] "Alkynyl" refers to an alkyl group having 2 to 20 carbon atoms (i.e., C2-C6), unless otherwise specified. 20 The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond, which may have from 2 to 8 carbon atoms (i.e., C2-C8 alkynyl), from 2 to 6 carbon atoms (i.e., C2-C6 alkynyl), or from 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). The term "alkynyl" also includes groups having one triple bond and one double bond.

[0030] "Alkoxy" refers to the group "alkyl-O-" (e.g., C1-C3 alkoxy or C1-C6 alkoxy). Example alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0031] "Alkylthio" refers to the group "alkyl-S-".

[0032] "Acyl" is the group -C(O)R y In the formula, R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of acyls include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0033] An "amide" is the group -C(O)NRy R z refers to the "C-amido" group, and the group -NR y C(O)R z "N-amido" refers to both a hydroxyl group and a hydroxyl group, y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein, or R y and R z together form a heterocyclyl, which may be optionally substituted as defined herein.

[0034] "Amino" is the group -NR y R z In the formula, R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0035] "Amidino" is -C(NR y )(NR z 2), where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0036] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to a group having 6 to 20 ring carbon atoms (i.e., C6 to C8). 20 aryl), 6 to 12 carbon ring atoms (i.e., C6 to C 12 aryl), or 6 to 10 carbon ring atoms (i.e., C6 to C 10aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl, regardless of the point of attachment. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl, regardless of the point of attachment.

[0037] "Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-", e.g., (C-C 10 A non-limiting example of arylalkyl is benzyl.

[0038] "Carbamoyl" is the group -OC(O)NR y R z refers to the "O-carbamoyl" group and the group -NR y C(O)OR z "N-carbamoyl" refers to both a hydroxyl group and a hydroxyl group, y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0039] "Carboxyl ester" or "ester" is -OC(O)R x and -C(O)OR x In the formula, R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0040] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having single or multiple rings, which may include fused, bridged, and spiro ring systems. The term "cycloalkyl" refers to cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and at least one sp 3 As used herein, cycloalkyl includes carbocyclic fused ring systems (i.e., at least one non-aromatic ring) having 3 to 20 ring carbon atoms (i.e., C3 to C6). 20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3 to C 12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3 to C 10 Cycloalkyl groups include cycloalkyls having 3 to 8 ring carbon atoms (i.e., C-C cycloalkyls), 3 to 7 ring carbon atoms (i.e., C-C cycloalkyls), or 3 to 6 ring carbon atoms (i.e., C-C cycloalkyls). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Furthermore, the term cycloalkyl is intended to encompass any moiety containing a non-aromatic alkyl ring that may be fused to an aryl ring, regardless of attachment to the rest of the molecule. Additionally, cycloalkyl also includes "spirocycloalkyl" when two positions for substitution exist on the same carbon atom (e.g., spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl). As used herein, "halocycloalkyl," e.g., C3-C7 halocycloalkyl, refers to a C3-C7 cycloalkyl group substituted with one or more halogens.

[0041] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-", e.g., (C3-C6 cycloalkyl)-C1-C3 alkyl.

[0042] "Guanidino" is -NR y C(=NR z )(NR y R z ) where each R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0043] "Hydrazino" refers to -NHNH2.

[0044] "Imino" is the group -C(NR y )R z In the formula, R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0045] "Imide" is the group -C(O)NR y C(O)R z In the formula, R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0046] "Halogen" or "halo" refers to atoms occupying Group VIIA of the periodic table, such as fluoro (fluorine), chloro (chlorine), bromo (bromine) or iodo (iodine).

[0047] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms have been replaced with halogen. For example, halo-C1-C3 alkyl refers to an alkyl group of 1 to 3 carbons in which at least one hydrogen atom has been replaced with halogen. Halo-C1-C6 alkyl refers to an alkyl group of 1 to 6 carbons in which at least one hydrogen atom has been replaced with halogen. When a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which are not necessarily the same halogen. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0048] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced with halogen. For example, halo-C1-C3 alkoxy refers to an alkoxy group of 1 to 3 carbons in which at least one hydrogen atom is replaced with halogen. Halo-C1-C6 alkoxy refers to an alkoxy group of 1 to 6 carbons in which at least one hydrogen atom is replaced with halogen. Non-limiting examples of haloalkoxy are -OCH2CF3, -OCF2H, and -OCF3.

[0049] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms have been replaced with hydroxy groups (e.g., hydroxy-C1-C3-alkyl, hydroxy-C1-C6-alkyl). The term "hydroxy-C1-C3 alkyl" refers to a 1 to 3 carbon alkyl chain in which one or more hydrogens on any carbon have been replaced with hydroxy groups, particularly one hydrogen on one carbon of the chain has been replaced with a hydroxy group. The term "hydroxy-C1-C6 alkyl" refers to a 1 to 6 carbon alkyl chain in which one or more hydrogens on any carbon have been replaced with hydroxy groups, particularly one hydrogen on one carbon of the chain has been replaced with a hydroxy group. Non-limiting examples of hydroxyalkyl include -CH2OH, -CH2CH2OH, and -C(CH3)2CH2OH.

[0050] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic groups, provided that the point of attachment to the remainder of the molecule is through a carbon atom. In certain embodiments, a heteroalkyl can have 1 to 3 carbon atoms (e.g., C1-C3 heteroalkyl) or 1 to 6 carbon atoms (e.g., C1-C6 heteroalkyl) and one or more (e.g., 1, 2, or 3) heteroatoms or heteroatomic groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. By way of example, one, two, or three carbon atoms of the alkyl group in a "heteroalkyl" may be independently replaced with the same or different heteroatomic groups. Heteroatomic groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc., in which R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CHOCH, -CH(CH)OCH, -CHCHOCH, -CHCHOCH, -CHCHOCHCHOCH, etc.), thioethers (e.g., -CHSCH, -CH(CH)SCH, -CHCHSCH, -CHCHSCHCHSCH, etc.), sulfones (e.g., -CHS(O)CH, -CH(CH)S(O)CH, -CHCHS(O)CH, -CHCHS(O)CHCHOCH, etc.), and amines (e.g., -CHNR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2CH2NR y CH3, etc.), wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. In certain embodiments, heteroalkyl can have 1 to 20 carbon atoms, 1 to 15 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0051] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to an aromatic group having 1 to 20 ring carbon atoms (i.e., C1 to C6). 20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3 to C 12Heteroaryl), or 3-8 carbon ring atoms (i.e., C3-C8 heteroaryl) and 1-5 ring heteroatoms, 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain cases, heteroaryl includes 9-10 membered ring systems (i.e., 9-10 membered heteroaryl), 5-10 membered ring systems (i.e., 5-10 membered heteroaryl), 5-7 membered ring systems (i.e., 5-7 membered heteroaryl), 5-6 membered ring systems (i.e., 5-6 membered heteroaryl), or 4-6 membered ring systems (i.e., 4-6 membered heteroaryl), each independently selected from 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, benzo[4,6]imidazo[1,2-a]pyridyl ... Azolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenoazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinucinyl Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, and the heteroaryl can be attached via either ring of the fused system.Any aromatic group having single or multiple fused rings containing at least one heteroatom is considered heteroaryl, regardless of attachment to the rest of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl, as defined above.

[0052] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-", e.g., (5- to 10-membered monocyclic heteroaryl)-C1-C3 alkyl.

[0053] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or may have multiple fused, bridged, or spiro rings. Any non-aromatic ring containing at least one heteroatom is considered heterocyclyl (i.e., it can be bonded via a carbon atom or a heteroatom), regardless of the bond. Furthermore, the term heterocyclyl is intended to encompass moieties containing any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the bond to the rest of the molecule. The term heterocyclyl is also intended to encompass moieties containing a cycloalkyl ring fused to a heteroaryl ring, regardless of the bond to the rest of the molecule. Additionally, the term heterocyclyl is intended to encompass moieties containing a cycloalkyl ring fused to a heterocyclyl ring, regardless of attachment to the rest of the molecule. As used herein, heterocyclyl refers to a group of 2 to 20 ring carbon atoms (i.e., C2 to C6). 20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2 to C 12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-C10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2 to C8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3 to C 12Heterocyclyls have 3 to 8 ring carbon atoms (i.e., C-C heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C-C heterocyclyl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. When a heterocyclyl ring contains 4 to 6 ring atoms, it is also referred to herein as a 4- to 6-membered heterocyclyl. Five- or 6-membered heterocyclyls, having 5 or 6 ring atoms, respectively, and 5- to 10-membered heterocyclyls, having 5 to 10 ring atoms, are also disclosed herein. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, and octahydroisoquinolyl. Examples of heterocyclyl include 2-oxoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In certain embodiments, the term "heterocyclyl" can include "spiroheterocyclyl" when two positions for substitution exist on the same carbon atom and at least one ring of the spiro system contains at least one heteroatom.Examples of spiro-heterocyclyl rings include bicyclic and tricyclic systems such as, for example, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be attached via either ring of the fused system.

[0054] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0055] "Oxime" is a group -CR y (=NOH), where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0056] "Oxo" refers to the group (=O).

[0057] "Cyano" refers to the group (-CN).

[0058] "N-oxide" refers to the group (-N + -O - ) refers to

[0059] "Thiol" refers to the group (-SH).

[0060] "Sulfonyl" refers to the group -S(O)R y In the formula, R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. A non-limiting example of a sulfonyl group is -SO(C1-C6 alkyl), referred to herein as alkylsulfonyl. Examples of sulfonyl include methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0061] "Sulfinyl" is the group -S(O)R y In the formula, R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0062] "Sulfonamide" is a group -SO2NR y R z and -NR y SO2R z In the formula, R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0063] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. Also, the term "optionally substituted" refers to any one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms on a specified atom or group that may or may not be replaced with a non-hydrogen moiety.

[0064] As used herein, the term "substituted" means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl) in which at least one (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen moiety. Unless otherwise specified, such non-hydrogen moieties may be alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH, =NNH, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)OH, sulfonamide, thiol, thioxo, N-oxide, or -Si(R y )3(in the formula, each R y are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl).

[0065] In certain embodiments, "substituted" means that one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)ORh , -NR g S(=O) 1-2 R h , -C(=O)R g , -C(=O)OR g , -OC(=O)OR g , -OC(=O)R g , -C(=O)NR g R h , -OC(=O)NR g R h , -OR g , -SR g , -S(=O)R g , -S(=O)2R g , -OS(=O) 1-2 R g , -S(=O) 1-2 OR g , -NR g S(=O) 1-2 NR g R h , =NSO2R g , =NOR g , -S(=O) 1-2 NR g R h , -SF5, -SCF3, or -OCF3. In certain embodiments, "substituted" also means that one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced with -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , or -CH2SO2NR g R h In the above, R g and R hare the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, "substituted" also refers to one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms being replaced by a bond to amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or R g and R h and R i means any of the above groups, wherein two of these, together with the atom to which they are attached, form a heterocyclyl ring optionally substituted with oxo, halo, or alkyl optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy.

[0066] Polymers or similar indefinite structures arrived at by defining a substituent with an infinite number of additional substituents (e.g., a substituted aryl having a substituted alkyl, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl group with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" can refer to other chemical groups as defined herein.

[0067] In certain embodiments, the phrase "one or more / one or more" as used herein refers to 1 to 5. In certain embodiments, the phrase "one or more / one or more" as used herein refers to 1 to 4. In certain embodiments, the phrase "one or more / one or more" as used herein refers to 1 to 3.

[0068] Any compound or structure provided herein is intended to represent unlabeled forms of the compound as well as isotopically labeled forms (isotopologues). These forms of compounds are also referred to as "isotopically enriched analogs," including "isotopically enriched analogs." Isotopically labeled compounds have the structures depicted herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. Various isotopically labeled compounds of the present disclosure include, for example, 3 H, 13 C and 14These include those into which a radioactive isotope such as C has been incorporated. Such isotopically labeled compounds may be useful in metabolism studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or radioactive treatment of patients.

[0069] The term "isotopically enriched analog" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogen atoms have been replaced with deuterium atoms, such as hydrogen atoms on a carbon atom. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced with deuterium atoms.

[0070] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F, 3 H, 11C-labeled compounds can be useful for PET or SPECT or other imaging studies.The isotopically labeled compounds of the present disclosure can generally be prepared by carrying out the procedures disclosed in the following schemes or examples and preparations, by using readily available isotopically labeled reagents instead of non-isotopically labeled reagents.In this context, it is understood that deuterium is considered as a substituent in the compounds described herein.

[0071] The concentration of such heavy isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium. Furthermore, in some embodiments, corresponding deuterated analogs are provided.

[0072] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0073] Pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, isomers (such as stereoisomers), and mixtures of isomers (such as mixtures of stereoisomers) of the compounds described herein are also provided.

[0074] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use. Generally, such materials are not biologically or otherwise undesirable; e.g., the substance can be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious way with any of the other components of the composition in which it is contained.

[0075] The term "pharmaceutically acceptable salts" of a given compound generally includes salts that are safe and not biologically or otherwise undesirable, including those that are acceptable for veterinary and human pharmaceutical use. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and organic acids. Furthermore, when a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.Salts derived from organic bases include salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e. , HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3, mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3) or mixed amines, and the like. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0076] The term "hydrate" refers to a complex formed by combining a compound described herein with water.

[0077] "Solvate" refers to an association or complex of one or more solvent molecules with a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. Solvates include hydrates.

[0078] Some of the compounds described herein may exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that the compound includes both the amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers. Another example of a compound with several tautomers is 1,4-thiazine. Tautomers are 1λ 4 ,4-thiazine, 2H-1,4-thiazine and 4H-1,4-thiazine, 4 Only 4-thiazine is aromatic.

[0079] The compounds described herein, or pharmaceutically acceptable salts thereof, may contain asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids, as (D)- or (L)-. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative), using, for example, chiral high-performance liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0080] "Stereoisomers" refer to compounds made up of the same atoms joined by the same bonds, but with different three-dimensional structures and are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0081] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0082] Relative centers of compounds depicted herein are indicated graphically using a "thick bond" style (bold or parallel lines), and absolute stereochemistry is indicated using wedge bonds (bold or parallel lines).

[0083] "Treatment" or "treating" is an approach to obtaining beneficial or desired results, including, but not limited to, clinical results. Beneficial or desired results can include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition and / or reducing the severity of the disease or condition), b) delaying or halting the onset of one or more clinical symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, preventing or slowing the worsening or progression of a disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of a disease or condition), and / or c) alleviating a disease or condition, i.e., causing a regression of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of a disease or condition, enhancing the effect of another drug, slowing disease progression, improving quality of life, and / or prolonging survival). Reduction of the pathological consequences of demyelination is also encompassed by "treatment" or "treating."

[0084] "Prevention" or "preventing" means any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. In some embodiments, the compounds may be administered to subjects (including humans) at risk for or who have a family history of the disease or condition.

[0085] "Subject" refers to an animal, e.g., a mammal (including a human), that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful for human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0086] The term "therapeutically effective amount" or "effective amount" of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof means an amount sufficient to treat a subject when administered to the subject to provide a therapeutic benefit, such as amelioration of symptoms or delay of disease progression. The therapeutically effective amount may vary depending on the subject and the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the method of administration, and can be readily determined by one of ordinary skill in the art. An effective amount of a compound of the present disclosure in such a treatment method is, for example, from about 0.01 mg / kg / day to about 1000 mg / kg / day, or from about 0.1 mg / kg / day to about 100 mg / kg / day.

[0087] As used herein, the term "excipient" refers to an inert or inactive substance that may be used in the manufacture of a drug or pharmaceutical composition, such as a tablet, containing a compound described herein (or a pharmaceutically acceptable salt) as an active ingredient. A variety of substances may be encompassed by the term excipient, including, but not limited to, a diluent, filler or bulking agent, binder, disintegrant, wetting agent, coating, emulsifier or dispersing agent, compression / encapsulation aid, cream or lotion, lubricant, solution for parenteral administration, material for chewable tablets, sweetener or flavoring agent, suspending / gelling agent, or any substance used as a wet granulator. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coating materials include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coating, etc.; compression / encapsulation materials include, for example, calcium carbonate, glucose, fructose dc (dc - "directly compressible"), honey dc, lactose (anhydrous or monohydrate, optionally combined with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, Examples of suitable additives include maltodextrin, carrageenan, etc.; lubricants include magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable tablet materials include dextrose, fructose dc, lactose (monohydrate, optionally combined with aspartame or cellulose), etc.; suspending / gelling agents include carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulating agents include calcium carbonate, maltodextrin, microcrystalline cellulose, etc. In some cases, the term "excipient" does not include pharmaceutically acceptable carriers.

[0088] Additional definitions may also be provided below as needed.

[0089] II. Compounds In certain embodiments, the subject matter described herein has formula I [ka] or a pharmaceutically acceptable salt thereof, wherein j 1、 j2 and m1 are each independently 1, 2, or 3; m2 is 0, 1, 2 or 3; The sum of j1 and j2 and the sum of m1 and m2 are each 5 or less, and the total sum of j1, j2, m1, and m2 is 9 or less, Ring A is [ka] and [ka] indicates the attachment of the ring to the rest of the molecule, * indicates the attachment of ring A to ring B, X is N or CH and Y is O or CH2, and when X is N, Y is CH2; R z is, if present, independently selected at each occurrence from the group consisting of halogen, hydroxy, C-C alkyl, halo-C-C alkyl, C-C alkoxy, halo-C-C alkoxy, —CN, and —NRR′; The Two R's z may form a bridge together with the atoms on ring A to which they are attached, p is 0, 1, 2, or 3; Ring B is phenyl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, N, and S; R yis, if present, independently selected at each occurrence from the group consisting of halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C7 cycloalkyl, C3-C7 halocycloalkyl, —SO2(C1-C6 alkyl), —CN, and —NRR′; n is 0, 1, 2, 3, or 4; R x is halogen, hydroxy, C1-C 10 Alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, 5-7 membered heterocyclyl, C3-C7 cycloalkyl, C6-C 10 selected from the group consisting of aryl, 5- to 6-membered heteroaryl, -SO2(C1-C6 alkyl), -CN, and -NRR'; The heterocyclyl, cycloalkyl, aryl, or heteroaryl may be (R xA ) q is replaced by q is 0, 1, 2, 3, 4, or 5; R xA is, if present, independently selected at each occurrence from the group consisting of halogen, C-C alkyl, hydroxy, C-C alkoxy, halo-C-C alkoxy, halo-C-C alkyl, —SO(C-C alkyl), —CN, and —NR′R′″; R, R', R'', and R''' are each independently H, C1-C6 alkyl, or halo-C1-C6 alkyl.

[0090] In certain embodiments, the compound comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 N atoms. In certain embodiments, the compound comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridazinyl, and triazinyl. In certain embodiments, the compound comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of phenyl, pyrazolyl, pyridinyl, triazolyl, and imidazolyl. In certain embodiments, the compound comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of pyrazolyl, pyridinyl, triazolyl, and imidazolyl. In certain embodiments, the compound comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-membered heteroaryl containing 2 or 3 N atoms. In certain embodiments, the compound comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of pyrazolyl and triazolyl.

[0091] In certain embodiments, the compound comprises a compound of formula I, or a pharmaceutically acceptable salt thereof: wherein ring B is phenyl or a 5- or 6-membered heteroaryl containing 1 to 3 N; j 1、 j2 and m1 are each independently 1, 2, or 3; m2 is 0, 1, 2 or 3; The sum of j1 and j2 and the sum of m1 and m2 are each 4 or less, and the total sum of j1, j2, m1, and m2 is 7 or less.

[0092] In certain embodiments, the compound comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R x are halogens, C1 to C 10selected from the group consisting of alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, 5- to 7-membered heterocyclyl, C3-C7 cycloalkyl, and 5- to 6-membered heteroaryl; The heterocyclyl, cycloalkyl, or aryl may be (R xA ) q and q is an integer of 0 to 3; R xA When present, each occurrence is independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy.

[0093] In certain embodiments, the compound comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R y When present, R is independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C7 cycloalkyl, and C3-C7 halocycloalkyl. y is selected from the group consisting of halogen, C3-C7 cycloalkyl, and C1-C6 alkyl. y is C3-C7 cycloalkyl. In certain embodiments, R y is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclopentyl. y is C1-C6 alkyl. In certain embodiments, R y is selected from the group consisting of methyl, ethyl, propyl, and butyl. In certain embodiments, R y is propyl. In certain embodiments, R y is isopropyl.

[0094] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, p is 0, 1, or 2. In some embodiments, p is 0. In certain embodiments, R zis, when present, independently selected at each occurrence from the group consisting of halogen, hydroxy, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkoxy, -CN, and -NRR', where each R and R' is independently H, C1-C3 alkyl, or halo-C1-C3 alkyl. z When present, each occurrence is independently halogen, hydroxy, C1-C3 alkyl, or halo-C1-C3 alkyl.

[0095] In certain embodiments, the compound comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the sum of m1 and m2 is 3 or less.

[0096] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, ring A is [ka] where: [ka] indicates a bond between the ring and the rest of the molecule, * indicates a bond between Ring A and Ring B, X is N or CH, Y is O or CH, and when X is N, Y is CH. In certain embodiments, X is N and Y is CH. In other embodiments, X is CH and Y is CH. In still further embodiments, X is CH and Y is O. In some embodiments, m1 and m2 are independently 1 or 2. In some embodiments, one of m1 and m2 is 1 and the other is 2. In other embodiments, both m1 and m2 are 1. In still further embodiments, both m1 and m2 are 2. In further embodiments, one of m1 and m2 is 3 and the other is 1. In certain embodiments, j1 and j2 are independently 1 or 2. In some embodiments, one of j1 and j2 is 1 and the other is 2. In other embodiments, both j1 and j2 are 1. In further embodiments, both j1 and j2 are 2. In still further embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2. In particular embodiments, one of m1 and m2 is 1 and the other is 2, and j1 and j2 are both 1.

[0097] In other embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, ring A is [ka] where: [ka] indicates a bond between the ring and the rest of the molecule, * indicates a bond between Ring A and Ring B, X is N or CH, Y is O or CH, and when X is N, Y is CH. In certain embodiments, X is N and Y is CH. In other embodiments, X is CH and Y is CH. In still further embodiments, X is CH and Y is O. In some embodiments, m1 and m2 are independently 1 or 2. In some embodiments, one of m1 and m2 is 1 and the other is 2. In other embodiments, both m1 and m2 are 1. In still further embodiments, both m1 and m2 are 2. In further embodiments, one of m1 and m2 is 3 and the other is 1. In certain embodiments, j1 and j2 are independently 1 or 2. In some embodiments, one of j1 and j2 is 1 and the other is 2. In other embodiments, both j1 and j2 are 1. In further embodiments, both j1 and j2 are 2. In still further embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2. In particular embodiments, one of m1 and m2 is 1 and the other is 2, and j1 and j2 are both 1.

[0098] In still further embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, m1 and m2 are independently 1 or 2; and j1 and j2 are independently 1 or 2.

[0099] In certain embodiments of a compound of Formula I or a pharmaceutically acceptable salt thereof, one of m1 and m2 is 1 and the other is 2; and j1 and j2 are both 1.

[0100] In other embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, m1 and m2 are both 2 and j1 and j2 are both 1.

[0101] In certain embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, Ring A is [ka] is selected from the group consisting of:

[0102] In some embodiments of Formula I or a pharmaceutically acceptable salt thereof, Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0103] In some embodiments of Formula I or a pharmaceutically acceptable salt thereof, Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0104] In some embodiments of Formula I or a pharmaceutically acceptable salt thereof, Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0105] In some embodiments of Formula I or a pharmaceutically acceptable salt thereof, Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0106] In some embodiments of Formula I or a pharmaceutically acceptable salt thereof, Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0107] In some embodiments of Formula I or a pharmaceutically acceptable salt thereof, Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0108] In a particular embodiment (embodiment A), the compound of formula I is of formula Ia [ka] or a pharmaceutically acceptable salt thereof, wherein Y1, Y2, Y3, Y4, and Y5 are each independently selected from the group consisting of CH, C, N, S, and SH; and C and S are each independently selected from the group consisting of R x or R y and one, two, or three of Y1, Y2, Y3, Y4, and Y5 are N, SH, SR x , or SR y j1, j2, m1, m2, R z , R x , R y , p and n are as defined for Formula I.

[0109] In certain embodiments of embodiment A above, the compound comprises a compound of formula Ia, or a pharmaceutically acceptable salt thereof, wherein Y1-Y5 are each independently selected from the group consisting of CH, C, and N; and C is R y or R x In certain embodiments, the compound is substituted with one of Y1, Y2, Y3, Y4, and Y5 is N and one is CR x and the remainder are each independently CH or CR yIn certain embodiments, the compound includes a compound of formula Ia, wherein one of Y, Y, Y, Y, and Y is CR x and the remainder are each independently CH or CR y In certain embodiments, the compound includes compounds of formula Ia, wherein Y is CR x In certain embodiments, the compound includes a compound of formula Ia, wherein Y, Y, Y, and Y are each CH and Y is CR. x In certain embodiments, the compound includes a compound of formula Ia, wherein Y, Y, and Y are N and Y is CR. x In certain embodiments, the compound includes a compound of formula Ia, wherein Y is N, Y, Y, and Y are CH, and Y is CR. x In certain embodiments, the compound includes compounds of formula Ia, wherein Y is CR y wherein Y2 and Y4 are CH, Y5 is N, and Y3 is CR x In certain embodiments, the compound includes compounds of formula Ia, wherein Y is CR y wherein Y2 and Y5 are CH, Y4 is N, and Y3 is CR x In certain embodiments, the compound includes a compound of formula Ia, wherein Y is CR y Y2 is N, Y4 and Y5 are CH, and Y3 is CR x In certain embodiments, R y is selected from the group consisting of halogen, C3-C7 cycloalkyl, and C1-C6 alkyl. y is C3-C7 cycloalkyl. In certain embodiments, R y is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclopentyl. y is C1-C6 alkyl. In certain embodiments, R y is selected from the group consisting of methyl, ethyl, propyl, and butyl. In certain embodiments, R y is propyl. In certain embodiments, R yis isopropyl.

[0110] In some embodiments of the above Embodiment A, compounds of Formula Ia or pharmaceutically acceptable salts thereof include compounds where p is 0, 1, or 2. In some embodiments, p is 0. In certain embodiments, R z is, when present, independently selected at each occurrence from the group consisting of halogen, hydroxy, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkoxy, -CN, and -NRR', where each R and R' is independently H, C1-C3 alkyl, or halo-C1-C3 alkyl. z When present, each occurrence is independently halogen, hydroxy, C1-C3 alkyl, or halo-C1-C3 alkyl.

[0111] In some embodiments of the above Embodiment A, compounds of Formula Ia or pharmaceutically acceptable salts thereof are those in which Ring A is [ka] (In the formula, [ka] indicates the attachment of the ring to the rest of the molecule, * indicates the connection of ring A to ring B, and X is N or CH, and Y is O or CH; if X is N, then Y is CH. In certain embodiments, X is N and Y is CH. In other embodiments, X is CH and Y is CH. In still further embodiments, X is CH and Y is O. In some embodiments, m1 and m2 are independently 1 or 2. In some embodiments, one of m1 and m2 is 1 and the other is 2. In other embodiments, both m1 and m2 are 1. In still further embodiments, both m1 and m2 are 2. In further embodiments, one of m1 and m2 is 3 and the other is 1. In certain embodiments, j1 and j2 are independently 1 or 2. In some embodiments, one of j1 and j2 is 1 and the other is 2. In other embodiments, both j1 and j2 are 1. In further embodiments, both j1 and j2 are 2. In still further embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2. In particular embodiments, one of m1 and m2 is 1 and the other is 2, and j1 and j2 are both 1.

[0112] In other embodiments of the above embodiment A, the compound of formula Ia or a pharmaceutically acceptable salt thereof is one in which ring A is [ka] (In the formula, [ka] indicates the attachment of the ring to the rest of the molecule, * indicates the attachment of ring A to ring B, X is N or CH, Y is O or CH, and if X is N, Y is CH. In certain embodiments, X is N and Y is CH. In other embodiments, X is CH and Y is CH. In still further embodiments, X is CH and Y is O. In some embodiments, m1 and m2 are independently 1 or 2. In some embodiments, one of m1 and m2 is 1 and the other is 2. In other embodiments, both m1 and m2 are 1. In still further embodiments, both m1 and m2 are 2. In further embodiments, one of m1 and m2 is 3 and the other is 1. In certain embodiments, j1 and j2 are independently 1 or 2. In some embodiments, one of j1 and j2 is 1 and the other is 2. In other embodiments, both j1 and j2 are 1. In further embodiments, both j1 and j2 are 2. In still further embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2. In particular embodiments, one of m1 and m2 is 1 and the other is 2, and j1 and j2 are both 1.

[0113] In still further embodiments of embodiment A above, compounds of formula Ia or pharmaceutically acceptable salts thereof include compounds where m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0114] In certain embodiments of Embodiment A above, compounds of Formula Ia or pharmaceutically acceptable salts thereof include compounds where one of m1 and m2 is 1 and the other is 2, and j1 and j2 are both 1.

[0115] In other embodiments of the above embodiment A, compounds of Formula Ia or pharmaceutically acceptable salts thereof include compounds wherein m1 and m2 are both 2, and j1 and j2 are both 1.

[0116] In certain embodiments of Embodiment A above, compounds of Formula Ia or pharmaceutically acceptable salts thereof are those in which Ring A is [ka] The compound includes a compound selected from the group consisting of:

[0117] In some embodiments of the above Embodiment A, compounds of Formula Ia or pharmaceutically acceptable salts thereof are those in which Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0118] In some embodiments of the above Embodiment A, compounds of Formula Ia or pharmaceutically acceptable salts thereof are those in which Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0119] In some embodiments of the above Embodiment A, compounds of Formula Ia or pharmaceutically acceptable salts thereof are those in which Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0120] In some embodiments of the above Embodiment A, compounds of Formula Ia or pharmaceutically acceptable salts thereof are those in which Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0121] In some embodiments of the above Embodiment A, compounds of Formula Ia or pharmaceutically acceptable salts thereof are those in which Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0122] In some embodiments of the above Embodiment A, compounds of Formula Ia or pharmaceutically acceptable salts thereof are those in which Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0123] In some embodiments of the above embodiment A, the compound of Formula Ia or a pharmaceutically acceptable salt thereof is wherein Y, Y, Y, Y, and Y are each independently N, C, or CH, and one or two of Y, Y, Y, Y, and Y may be N; n is 0 or 1, R y is C3-C5 cycloalkyl, halogen, or C1-C6 alkyl; R x is halo-C1-C6 alkyl, p is 0, Ring A is [ka] is selected from the group consisting of one of m1 and m2 is 2 and the other is 1; Includes compounds where j1 and j2 are each 1.

[0124] In some embodiments of Embodiment A above, including but not limited to, the above embodiments, the compound includes a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein one of Y, Y, Y, Y, and Y is N. In certain embodiments, the compound is x Includes compounds where is trifluoromethyl.

[0125] In a particular embodiment (embodiment B), the compound of formula I is of formula Ib [ka] (Wherein, E1, E2, E3, and E4 are CH, S, SH, CR x , C.R. y , N.R. x , N.R. y , N, O, NH, SR x , and S.R. y and one, two, or three of E1, E2, E3, or E4 are independently selected from the group consisting of S, SH, N, NR x , N.R. y , O, N.H., S.R. x , or SR y and j1, j2, m1, m2, R z , R x , R y , p and n are as defined for Formula I), or a pharmaceutically acceptable salt thereof.

[0126] In certain embodiments of embodiment B above, the compound of formula Ib or a pharmaceutically acceptable salt thereof may be one in which E2 is CR x In certain embodiments, the compound is one in which E3 is N, NR y or CH. In certain embodiments, compounds include compounds of formula Ib where n is 1. In still further embodiments, E2 is CR x and E3 is N, NR y or CH, and n is 1.

[0127] In certain embodiments of the above embodiment B, the compound of formula Ib or a pharmaceutically acceptable salt thereof is R y In certain embodiments, R y is C3-C7 cycloalkyl. In certain embodiments, R y is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclopentyl. y is C1-C6 alkyl. In certain embodiments, R y is selected from the group consisting of methyl, ethyl, propyl, and butyl. In certain embodiments, R y is propyl. In certain embodiments, R y is isopropyl.

[0128] In certain embodiments of the above embodiment B, compounds of formula Ib or pharmaceutically acceptable salts thereof include compounds where p is 0, 1, or 2. In some embodiments, p is 0. In certain embodiments, R z is, when present, independently selected at each occurrence from the group consisting of halogen, hydroxy, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkoxy, -CN, and -NRR', where each R and R' is independently H, C1-C3 alkyl, or halo-C1-C3 alkyl. z When present, each occurrence is independently halogen, hydroxy, C1-C3 alkyl, or halo-C1-C3 alkyl.

[0129] In certain embodiments of the above embodiment B, compounds of formula Ib or pharmaceutically acceptable salts thereof are those in which ring A is [ka] (In the formula, [ka] indicates the attachment of the ring to the rest of the molecule, * indicates the attachment of ring A to ring B, X is N or CH, Y is O or CH, and if X is N, Y is CH. In certain embodiments, X is N and Y is CH. In other embodiments, X is CH and Y is CH. In still further embodiments, X is CH and Y is O. In some embodiments, m1 and m2 are independently 1 or 2. In some embodiments, one of m1 and m2 is 1 and the other is 2. In other embodiments, both m1 and m2 are 1. In still further embodiments, both m1 and m2 are 2. In further embodiments, one of m1 and m2 is 3 and the other is 1. In certain embodiments, j1 and j2 are independently 1 or 2. In some embodiments, one of j1 and j2 is 1 and the other is 2. In other embodiments, both j1 and j2 are 1. In further embodiments, both j1 and j2 are 2. In still further embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2. In particular embodiments, one of m1 and m2 is 1 and the other is 2, and j1 and j2 are both 1.

[0130] In particular embodiments of the above embodiment B, compounds of formula Ib or pharmaceutically acceptable salts thereof are those in which ring A is [ka] (In the formula, [ka] indicates the attachment of the ring to the rest of the molecule, * indicates the attachment of ring A to ring B, X is N or CH, Y is O or CH, and if X is N, Y is CH. In certain embodiments, X is N and Y is CH. In other embodiments, X is CH and Y is CH. In still further embodiments, X is CH and Y is O. In some embodiments, m1 and m2 are independently 1 or 2. In some embodiments, one of m1 and m2 is 1 and the other is 2. In other embodiments, both m1 and m2 are 1. In still further embodiments, both m1 and m2 are 2. In further embodiments, one of m1 and m2 is 3 and the other is 1. In certain embodiments, j1 and j2 are independently 1 or 2. In some embodiments, one of j1 and j2 is 1 and the other is 2. In other embodiments, both j1 and j2 are 1. In further embodiments, both j1 and j2 are 2. In still further embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2. In particular embodiments, one of m1 and m2 is 1 and the other is 2, and j1 and j2 are both 1.

[0131] In still further embodiments of embodiment B above, compounds of formula Ib or pharmaceutically acceptable salts thereof include compounds where m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0132] In certain embodiments of the above embodiment B, compounds of formula Ib or pharmaceutically acceptable salts thereof include compounds where one of m1 and m2 is 1 and the other is 2, and j1 and j2 are both 1.

[0133] In other embodiments of the above embodiment B, compounds of Formula Ib or pharmaceutically acceptable salts thereof include compounds where m1 and m2 are both 2, and j1 and j2 are both 1.

[0134] In certain embodiments of the above embodiment B, compounds of formula Ib or pharmaceutically acceptable salts thereof are those in which ring A is [ka] The compound includes a compound selected from the group consisting of:

[0135] In some embodiments of the above embodiment B, compounds of formula Ib or pharmaceutically acceptable salts thereof are those in which ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0136] In some embodiments of the above embodiment B, compounds of formula Ib or pharmaceutically acceptable salts thereof are those in which ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0137] In some embodiments of the above embodiment B, compounds of formula Ib or pharmaceutically acceptable salts thereof are those in which ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0138] In some embodiments of the above embodiment B, compounds of formula Ib or pharmaceutically acceptable salts thereof are those in which ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0139] In some embodiments of the above embodiment B, compounds of formula Ib or pharmaceutically acceptable salts thereof are those in which ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0140] In some embodiments of the above embodiment B, compounds of formula Ib or pharmaceutically acceptable salts thereof are those in which ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0141] In certain embodiments (embodiment C), the compound of formula I is of formula Ic [ka] (Wherein, E1 is N or CH, j1, j2, m1, m2, R z , R x , R y and p is as defined for formula I), or a pharmaceutically acceptable salt thereof.

[0142] In certain embodiments of the above embodiment C, the compound of formula Ic or a pharmaceutically acceptable salt thereof is R x is selected from the group consisting of halo-C1-C6 alkyl, C3-C5 cycloalkyl, phenyl, and 6-membered heteroaryl, and the cycloalkyl, phenyl, or heteroaryl is selected from the group consisting of (R xA ) qIn certain embodiments, the compound is substituted with R x In certain embodiments, the compound includes compounds where R is selected from the group consisting of trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, and fluoroethyl. x In certain embodiments, the compound includes compounds where R x is cyclopropyl and q is 0. In certain embodiments, R y is selected from the group consisting of halogen, C3-C7 cycloalkyl, and C1-C6 alkyl. y is C3-C7 cycloalkyl. In certain embodiments, R y is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclopentyl. y is C1-C6 alkyl. In certain embodiments, R y is selected from the group consisting of methyl, ethyl, propyl, and butyl. In certain embodiments, R y is propyl. In certain embodiments, R y is isopropyl.

[0143] In certain embodiments of Embodiment C above, compounds of Formula Ic or pharmaceutically acceptable salts thereof include compounds where p is 0, 1, or 2. In some embodiments, p is 0. In certain embodiments, R z is, when present, independently selected at each occurrence from the group consisting of halogen, hydroxy, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkoxy, -CN, and -NRR', where each R and R' is independently H, C1-C3 alkyl, or halo-C1-C3 alkyl. z When present, each occurrence is independently halogen, hydroxy, C1-C3 alkyl, or halo-C1-C3 alkyl.

[0144] In certain embodiments of the above embodiment C, compounds of formula Ic or pharmaceutically acceptable salts thereof are those in which ring A is [ka] (In the formula, [ka] indicates the attachment of the ring to the rest of the molecule, * indicates the attachment of ring A to ring B, X is N or CH, Y is O or CH, and if X is N, Y is CH. In certain embodiments, X is N and Y is CH. In other embodiments, X is CH and Y is CH. In still further embodiments, X is CH and Y is O. In some embodiments, m1 and m2 are independently 1 or 2. In some embodiments, one of m1 and m2 is 1 and the other is 2. In other embodiments, both m1 and m2 are 1. In still further embodiments, both m1 and m2 are 2. In further embodiments, one of m1 and m2 is 3 and the other is 1. In certain embodiments, j1 and j2 are independently 1 or 2. In some embodiments, one of j1 and j2 is 1 and the other is 2. In other embodiments, both j1 and j2 are 1. In further embodiments, both j1 and j2 are 2. In still further embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2. In particular embodiments, one of m1 and m2 is 1 and the other is 2, and j1 and j2 are both 1.

[0145] In certain embodiments of the above embodiment C, compounds of formula Ic or pharmaceutically acceptable salts thereof are those in which ring A is [ka] (In the formula, [ka] indicates the attachment of the ring to the rest of the molecule, * indicates the attachment of ring A to ring B, X is N or CH, Y is O or CH, and if X is N, Y is CH. In certain embodiments, X is N and Y is CH. In other embodiments, X is CH and Y is CH. In still further embodiments, X is CH and Y is O. In some embodiments, m1 and m2 are independently 1 or 2. In some embodiments, one of m1 and m2 is 1 and the other is 2. In other embodiments, both m1 and m2 are 1. In still further embodiments, both m1 and m2 are 2. In further embodiments, one of m1 and m2 is 3 and the other is 1. In certain embodiments, j1 and j2 are independently 1 or 2. In some embodiments, one of j1 and j2 is 1 and the other is 2. In other embodiments, both j1 and j2 are 1. In further embodiments, both j1 and j2 are 2. In still further embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2. In particular embodiments, one of m1 and m2 is 1 and the other is 2, and j1 and j2 are both 1.

[0146] In still further embodiments of embodiment C above, compounds of formula Ic or pharmaceutically acceptable salts thereof include compounds where m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0147] In certain embodiments of the above embodiment C, compounds of formula Ic or pharmaceutically acceptable salts thereof include compounds where one of m1 and m2 is 1 and the other is 2, and j1 and j2 are both 1.

[0148] In other embodiments of embodiment C above, compounds of Formula Ic or pharmaceutically acceptable salts thereof include compounds where m1 and m2 are both 2 and j1 and j2 are both 1.

[0149] In certain embodiments of the above embodiment C, compounds of formula Ic or pharmaceutically acceptable salts thereof are those in which ring A is [ka] The compound includes a compound selected from the group consisting of:

[0150] In some embodiments of the above Embodiment C, compounds of Formula Ic or pharmaceutically acceptable salts thereof are those in which Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0151] In some embodiments of the above Embodiment C, compounds of Formula Ic or pharmaceutically acceptable salts thereof are those in which Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0152] In some embodiments of the above Embodiment C, compounds of Formula Ic or pharmaceutically acceptable salts thereof are those in which Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0153] In some embodiments of the above Embodiment C, compounds of Formula Ic or pharmaceutically acceptable salts thereof are those in which Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0154] In some embodiments of the above Embodiment C, compounds of Formula Ic or pharmaceutically acceptable salts thereof are those in which Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0155] In some embodiments of the above Embodiment C, compounds of Formula Ic or pharmaceutically acceptable salts thereof are those in which Ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0156] In certain further embodiments of embodiment C above, the compound of formula Ic, or a pharmaceutically acceptable salt thereof, is E1 is CH or N; R y is C1-C6 alkyl or C3-C5 cycloalkyl, R x is selected from the group consisting of halo-C1-C6 alkyl, phenyl, C3-C5 cycloalkyl, and 5- or 6-membered heteroaryl, and the cycloalkyl, phenyl, or heteroaryl is (R xA ) q is replaced by q is 0, 1, or 2; R xA is present, and each occurrence is independently selected from the group consisting of halogen, C-C alkyl, hydroxy, C-C alkoxy, halo-C-C alkoxy, and halo-C-C alkyl; p is 0, Ring A is [ka] and one of m1 and m2 is 2 and the other is 1, or m1 and m2 are each 2, or one of m1 and m2 is 3 and the other is 1, or m1 and m2 are each 1; Compounds in which j1 and j2 are each 1, or one of j1 and j2 is 2 and the other is 1, or j1 and j2 are each 2 are included.

[0157] In certain aspects of embodiment C above, compounds of formula Ic, or pharmaceutically acceptable salts thereof, include compounds where one of m1 and m2 is 2 and the other is 1, and j1 and j2 are both 1. In certain embodiments, the compounds are y is selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl, and cyclopentyl. y In certain embodiments, R x is selected from the group consisting of halo-C1-C6 alkyl, phenyl, 6-membered heteroaryl, and cyclopropyl, and the phenyl, 6-membered heteroaryl, or cyclopropyl is selected from the group consisting of (R xA ) q In certain embodiments, the compound is substituted with R x In certain embodiments, the compound includes compounds where R x is cyclopropyl and q is 0. In certain embodiments, compounds include those where R x (R xA ) q and q is 1. In certain embodiments, the compound is pyridinyl substituted with R xA In certain embodiments, the compound includes compounds where R xAis trifluoromethyl or trifluoromethoxy.

[0158] In some embodiments of the compound or pharmaceutically acceptable salt of any of the foregoing Formula I, Ia, Ib, or Ic, R x are halogens, C1 to C 10 selected from the group consisting of alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, 5- to 7-membered heterocyclyl, C3-C7 cycloalkyl, and 5- to 6-membered heteroaryl; The heterocyclyl, cycloalkyl, or aryl may be (R xA ) q and q is an integer of 0 to 3; R xA When present, each occurrence is independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy.

[0159] In a particular embodiment (embodiment D), the compound of formula I is of formula Id [ka] (In the formula, D1, D2, D3, D4, and D5 each independently represent R xA or when bonded to CH, they are N or C, and up to three of D1, D2, D3, D4, and D5 are N, q is 1 or 2, and j1, j2, m1, m2, R z , R y , , and p are as defined for Formula I), or a pharmaceutically acceptable salt thereof.

[0160] In certain embodiments of embodiment D above, the compound of formula Id or a pharmaceutically acceptable salt thereof may be one in which D3 or D4 is CR xA In certain embodiments, the compound is a compound wherein D1 is CH, D2 is CH, and D3 is CR xAand D4 is N and D5 is CH. In certain embodiments, the compound is a compound of formula Id where D1 is CH, D2 is N, D3 is CH, and D4 is CR xA and D5 is CH. In certain embodiments, the compound includes compounds of formula Id where D1, D2, and D3 are CH and D4 is CR xA and D5 is N. In certain embodiments, the compound is xA In certain embodiments, the compound includes compounds of formula Id where R xA In certain embodiments, the compound includes compounds of formula Id where R xA In certain embodiments, the compound includes compounds of formula Id, wherein R is selected from the group consisting of trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, and fluoroethyl. xA Includes compounds of formula Id where is trifluoromethyl.

[0161] In certain embodiments of embodiment D above, the compound of formula Id or a pharmaceutically acceptable salt thereof is R y is selected from the group consisting of halogen, C3-C7 cycloalkyl, and C1-C6 alkyl. y In certain embodiments, the compound includes compounds where R y is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclopentyl. y In certain embodiments, the compound includes compounds where R y In certain embodiments, the compound includes compounds where R y In certain embodiments, the compound includes compounds where R y Includes compounds where is isopropyl.

[0162] In some embodiments of the above embodiment D, compounds of formula Id or pharmaceutically acceptable salts thereof include compounds where p is 0, 1, or 2. In some embodiments, p is 0. In certain embodiments, R z is, when present, independently selected at each occurrence from the group consisting of halogen, hydroxy, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkoxy, -CN, and -NRR', where each R and R' is independently H, C1-C3 alkyl, or halo-C1-C3 alkyl. z When present, each occurrence is independently halogen, hydroxy, C1-C3 alkyl, or halo-C1-C3 alkyl.

[0163] In certain embodiments of the above embodiment D, compounds of formula Id or pharmaceutically acceptable salts thereof include compounds where p is 0.

[0164] In certain embodiments of the above embodiment D, compounds of formula Id or pharmaceutically acceptable salts thereof are those in which ring A is [ka] (In the formula, [ka] indicates the attachment of the ring to the rest of the molecule, * indicates the attachment of ring A to ring B, X is N or CH, Y is O or CH, and if X is N, Y is CH. In certain embodiments, X is N and Y is CH. In other embodiments, X is CH and Y is CH. In still further embodiments, X is CH and Y is O. In some embodiments, m1 and m2 are independently 1 or 2. In some embodiments, one of m1 and m2 is 1 and the other is 2. In other embodiments, both m1 and m2 are 1. In still further embodiments, both m1 and m2 are 2. In further embodiments, one of m1 and m2 is 3 and the other is 1. In certain embodiments, j1 and j2 are independently 1 or 2. In some embodiments, one of j1 and j2 is 1 and the other is 2. In other embodiments, both j1 and j2 are 1. In further embodiments, both j1 and j2 are 2. In still further embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2. In particular embodiments, one of m1 and m2 is 1 and the other is 2, and j1 and j2 are both 1.

[0165] In other embodiments of the above embodiment D, the compound of formula Id or a pharmaceutically acceptable salt thereof is one in which ring A is [ka] (In the formula, [ka] indicates the attachment of the ring to the rest of the molecule, * indicates the attachment of ring A to ring B, X is N or CH, Y is O or CH, and if X is N, Y is CH. In certain embodiments, X is N and Y is CH. In other embodiments, X is CH and Y is CH. In still further embodiments, X is CH and Y is O. In some embodiments, m1 and m2 are independently 1 or 2. In some embodiments, one of m1 and m2 is 1 and the other is 2. In other embodiments, both m1 and m2 are 1. In still further embodiments, both m1 and m2 are 2. In further embodiments, one of m1 and m2 is 3 and the other is 1. In certain embodiments, j1 and j2 are independently 1 or 2. In some embodiments, one of j1 and j2 is 1 and the other is 2. In other embodiments, both j1 and j2 are 1. In further embodiments, both j1 and j2 are 2. In still further embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2. In particular embodiments, one of m1 and m2 is 1 and the other is 2, and j1 and j2 are both 1.

[0166] In still further embodiments of embodiment D above, compounds of formula Id or pharmaceutically acceptable salts thereof include compounds where m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0167] In certain embodiments of the above embodiment D, compounds of formula Id or pharmaceutically acceptable salts thereof include compounds where one of m1 and m2 is 1 and the other is 2, and j1 and j2 are both 1.

[0168] In other embodiments of embodiment D above, compounds of formula Id or pharmaceutically acceptable salts thereof include compounds where m1 and m2 are both 2 and j1 and j2 are both 1.

[0169] In certain embodiments of the above embodiment D, compounds of formula Id or pharmaceutically acceptable salts thereof are those in which ring A is [ka] The compound includes a compound selected from the group consisting of:

[0170] In some embodiments of the above embodiment D, compounds of formula Id or pharmaceutically acceptable salts thereof are those in which ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0171] In some embodiments of the above embodiment D, compounds of formula Id or pharmaceutically acceptable salts thereof are those in which ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0172] In certain embodiments of the above embodiment D, compounds of formula Id or pharmaceutically acceptable salts thereof are those in which ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0173] In some embodiments of the above embodiment D, compounds of formula Id or pharmaceutically acceptable salts thereof are those in which ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0174] In some embodiments of the above embodiment D, compounds of formula Id or pharmaceutically acceptable salts thereof are those in which ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0175] In some embodiments of the above embodiment D, compounds of formula Id or pharmaceutically acceptable salts thereof are those in which ring A is [ka] In certain embodiments, m1 and m2 are independently 1 or 2, and j1 and j2 are independently 1 or 2.

[0176] In certain embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, for example, any of the compounds of Formula Ia, Ib, Ic, or Id above, or pharmaceutically acceptable salts thereof, the compounds are those in which ring A is [ka] is selected from the group consisting of:

[0177] In certain embodiments of a compound of Formula I or a pharmaceutically acceptable salt thereof, for example, a compound or pharmaceutically acceptable salt of any of Formulae Ia, Ib, Ic, or Id above, the compound includes a compound where one of 1 and m2 is 1 and the other is 2. In certain embodiments, the compound includes a compound where m1 and m2 are each 1. In certain embodiments, the compound includes a compound where one of m1 and m2 is 3 and the other is 1. In certain embodiments, the compound includes a compound where m1 and m2 are each 2. In certain embodiments, the compound includes a compound where m1 is 1 and m2 is 0. In certain embodiments, the compound includes a compound where one of j1 and j2 is 1 and the other is 2. In certain embodiments, the compound includes a compound where one of j1 and j2 is 3 and the other is 1. In certain embodiments, the compound includes a compound where j1 and j2 are each 1. In certain embodiments, the compound includes a compound where j1 and j2 are each 2.

[0178] In certain embodiments of a compound of Formula I or a pharmaceutically acceptable salt thereof, e.g., a compound of any of Formulas Ia, Ib, Ic, or Id above, or a pharmaceutically acceptable salt thereof, the compound includes compounds in which j1, j2, m1, and m2 are as shown in Table A. [Table A]

[0179] In certain embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, for example, any of the compounds of Formula Ia, Ib, Ic, or Id above, or pharmaceutically acceptable salts thereof, the compound is one in which ring A is [ka] In some embodiments, ring A is [ka] In other embodiments, ring A is: [ka] is.

[0180] In certain embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, for example, any of the compounds of Formula Ia, Ib, Ic, or Id above, or pharmaceutically acceptable salts thereof, the compound is one in which ring A is [ka] In some embodiments, ring A is [ka] In other embodiments, ring A is: [ka] is.

[0181] The subject matter described herein includes the following compounds in Table 1, or pharmaceutically acceptable salts thereof. In Table 1, an asterisk (*) indicates an isolated isomer or group of isolated isomers, but no stereochemistry has been assigned. Individual enantiomers and diastereomers are included in the table below by compound name, and their corresponding structures can be readily determined therefrom. In some cases, the enantiomers or diastereomers of the present disclosure can be identified by their respective properties, such as retention time by chiral HPLC, NMR peaks, and / or biological activity (e.g., as further described in the Examples), with the absolute configuration of one or more chiral centers being arbitrarily assigned (e.g., the stereochemistry of all chiral centers is arbitrarily assigned, or the stereochemistry of one chiral center is known and the remaining chiral centers are arbitrarily assigned, etc.). [Table 1-1] [Table 1-2] [Table 1-3] Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 [Table 1-21] [Table 1-22]

[0182] III. Pharmaceutical Compositions and Modes of Administration The compounds provided herein are usually administered in the form of pharmaceutical compositions.Therefore, also provided herein are pharmaceutical compositions comprising one or more compounds described herein, or their pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers, and one or more pharmaceutically acceptable additives.Suitable pharmaceutically acceptable additives may include, for example, inert solid diluents and fillers, liquid diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.Such compositions are prepared by methods well known in the pharmaceutical field.See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & C.T. Rhodes, Eds.).

[0183] In some embodiments, the pharmaceutical composition comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula Ib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula Ic, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula Id, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0184] The pharmaceutical composition can be administered in a single dose or multiple doses.The pharmaceutical composition can be administered by various methods, including, for example, rectal, buccal, intranasal and transdermal routes.In certain embodiments, the pharmaceutical composition can be administered by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical or inhalant administration.

[0185] One mode of administration is parenteral, for example, by injection.The form that the pharmaceutical compositions described herein can be incorporated into for injection administration includes, for example, aqueous suspension or oil suspension, or emulsion containing sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixir, mannitol, dextrose or sterile aqueous solution and similar pharmaceutical vehicles.

[0186] Oral administration can be another route for administering the compounds described herein. Administration can be, for example, via capsules or tablets, such as enteric-coated tablets. When preparing pharmaceutical compositions containing at least one compound described herein or its pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers, the active ingredient is usually diluted with an additive and / or enclosed in such a carrier, which can be in the form of a capsule, sachet, paper, or other container. When an additive serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injection solution, and sterile packaged powder.

[0187] Some examples of suitable additives include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations may further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propyl hydroxybenzoates, sweeteners, and flavoring agents.

[0188] Compositions containing at least one compound described herein or its pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject by using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are given in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods disclosed herein uses a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0189] To prepare solid compositions such as tablets, the principal active ingredient can be mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers. When these preformulation compositions are referred to as homogeneous, the active ingredient can be dispersed evenly throughout the composition such that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0190] The tablets or pills of the compounds described herein can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach.For example, the tablets or pills can comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope that covers the former.The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be delayed in release.Various materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0191] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable additives as described herein. In some embodiments, compositions are administered by oral or nasal respiratory routes for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by the use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0192] The specific dose level of the compounds of the present application for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combinations, and the severity of the particular disease in the subject being treated. For example, dosages may be expressed as milligrams of a compound described herein per kilogram of subject body weight (mg / kg). Doses of approximately 0.1 to 150 mg / kg may be appropriate. In some embodiments, doses of approximately 0.1 mg / kg and 100 mg / kg may be appropriate. In other embodiments, doses of 0.5 to 60 mg / kg may be appropriate. Normalizing according to subject body weight is particularly useful when adjusting dosages between subjects of widely differing sizes, such as when using a drug in both children and adults, or when converting an effective dose in a non-human subject, such as a dog, to a dose appropriate for a human subject. Doses may be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties of the particular compound, including absorption, distribution, metabolism, and excretion. In addition, toxicity factors may affect the dosage and administration regimen. When administered orally, pills, capsules, or tablets may be taken orally daily or at more frequent intervals for a specified time period. This regimen can be repeated for a predetermined number of treatment cycles.

[0193] IV. Treatment Methods Described herein are methods for promoting myelination of central nervous system neurons in a subject suffering from a myelin-related disorder, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutical composition comprising the same. In certain embodiments, the subject matter disclosed herein relates to a compound of Formula I, or a pharmaceutically acceptable salt thereof, for promoting myelination of central nervous system neurons in a subject suffering from a myelin-related disorder. In another embodiment, the subject matter described herein relates to the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for promoting myelination of central nervous system neurons in a subject suffering from a myelin-related disorder.

[0194] In certain embodiments, in a method for promoting myelination of central nervous system neurons in a subject suffering from a myelin-related disorder, a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, inhibits enzyme-mediated synthesis of one or more sterol intermediates in the cholesterol biosynthetic pathway.

[0195] In certain embodiments, in a method for promoting myelination of central nervous system neurons in a subject suffering from a myelin-related disorder, a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, promotes the accumulation of a Δ8,9-unsaturated sterol intermediate in the cholesterol biosynthetic pathway.

[0196] In certain embodiments, in a method of promoting myelination of central nervous system neurons in a subject suffering from a myelin-related disorder, the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, inhibits one or more of CYP51, sterol-14-reductase, or EBP enzyme-mediated synthesis of sterol intermediates in the cholesterol biosynthetic pathway.

[0197] In certain embodiments, in a method for promoting myelination of central nervous system neurons in a subject suffering from a myelin-related disorder, a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, induces, promotes, and / or modulates the differentiation, proliferation, and / or maturation of oligodendrocyte precursor cells (OPCs). In certain embodiments, the induction of OPC differentiation is characterized by increased myelin basic protein (MBP) expression.

[0198] In certain embodiments, the subject matter described herein relates to a method of treating a disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to the subject in need thereof. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ic, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Id, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0199] In certain embodiments, the subject matter disclosed herein relates to a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating a disorder in a subject in need thereof. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ic, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Id, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0200] In certain embodiments, the subject matter disclosed herein relates to the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ic, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Id, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0201] In certain embodiments, the presently disclosed subject matter relates to a method of promoting myelination in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to the subject. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ic, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Id, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0202] In certain embodiments, the subject matter disclosed herein relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, for use in promoting myelination in a subject in need thereof. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of Formula I is a compound of Formula Ia or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ic or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Id or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0203] In certain embodiments, the subject matter disclosed herein relates to the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, in the manufacture of a medicament for promoting myelination in a subject in need thereof. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of Formula I is a compound of Formula Ia or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ic or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Id or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0204] In certain embodiments, the presently disclosed subject matter relates to a method of inducing differentiation of endogenous oligodendrocyte precursor cells (OPCs) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In certain embodiments, the subject is suffering from a myelin-related disorder. In certain embodiments, the myelin-related disorder is multiple sclerosis.

[0205] Such myelin-related disorders include multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, childhood leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander disease, Pelizaeum-Mersbacher disease (PMD), vanishing white matter disease, Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, and Alzheimer's disease. These include, but are not limited to, Zheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post-radiation injury, neurological complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barré syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination.

[0206] A compound of Formula I, or a pharmaceutically acceptable salt thereof, can be administered alone or in combination with another agent to a subject suffering from a myelin-related disorder to promote myelination of neurons (e.g., neuronal axons). Myelin-related disorders can include any disease, condition (e.g., those resulting from traumatic spinal cord injury and cerebral infarction), or disorder that results in abnormalities in the myelin sheath. Abnormalities can be caused by loss of myelin, referred to as demyelination, myelin dysfunction, referred to as dysmyelination, or failure to form sufficient myelin, referred to as hypomyelination. The myelin-related disorders described herein can result from genetic disorders or one or more of a variety of neurotoxic insults. In some embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ic, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Id, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0207] As used herein, "demyelination" refers to the activity of demyelination, or damage or loss of some or all of the myelin sheath that insulates nerves, and is a hallmark of myelin-related disorders. In certain embodiments, demyelination refers to damage or loss of some or all of the myelin sheath that insulates a subset of an individual's nerves, such as, for example, one or more nerves localized in a particular region of the body (e.g., the brain or spinal cord, or neurons in both the brain and spinal cord, or the optic nerve).

[0208] Oligodendrocytes are required for myelination of neurons. As used herein, the term "myelination" refers to the production of myelin sheaths for nerves by replacing or restoring the function of myelin-producing cells. Neurons undergoing remyelination can be in the brain, spinal cord, or both the brain and spinal cord. Restoring the function of myelin-producing cells can include, for example, increasing the myelin production rate in a cell or cells that have a lower-than-average production level. Such an increase can include increasing the myelin production rate to or above the average production level, but can also include increasing the myelin production rate to a level that is still lower than average but higher than the previous level.

[0209] As used herein, "promoting myelination" refers to increasing the rate of myelin production, rather than simply a net increase in the amount of myelin, compared to a baseline level of myelin production in a subject. The increase in myelin production rate can be determined using imaging techniques or functional measurements. In some embodiments, myelination is promoted by increasing OPC differentiation, increasing the accumulation of 8,9-unsaturated sterol intermediates in biosynthetic pathways, increasing the formation of OPCs, or any combination thereof. Such activity can be assessed, for example, using one or more in vitro assays, such as those described herein or known to those skilled in the art.

[0210] As used herein, "baseline level of myelin production rate" refers to the myelin production rate in a subject being treated before treatment begins.

[0211] V. Methods of Preparing Compounds of Formula I and Their Pharmaceutically Acceptable Salts The compounds can be synthesized by synthetic routes, including processes similar to those known in the chemical arts, and the processes for other heterocycles described below, particularly in light of the description contained herein. Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, e.g., Volume 3; Liebigs Annalen der Chemie, (9): 1910-16, (1985); Helvetica Chimica Acta, 41: 1052-60, (1958); Arzneimittel-Forschung, 40(12): 1328-31, (1990) (each of which is expressly incorporated by reference). Starting materials are generally available from commercial sources, such as Aldrich Chemicals (Milwaukee, Wis.), or are readily prepared using methods well known to those of skill in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, NY (1967-2006 ed.), or Beilstein's Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

[0212] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful for synthesizing the compounds and the necessary reagents and intermediates are known in the art and can be found, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 3 rdEd., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

[0213] The compounds can be prepared singly or as compound libraries containing at least two, e.g., 5 to 1,000 compounds, or 10 to 100 compounds. Libraries of compounds of Formula I, or pharmaceutically acceptable salts thereof, can be prepared by procedures known to those skilled in the art, by a combinatorial "split and mix" approach, or by multiple parallel synthesis using either solution-phase or solid-phase chemistry. Thus, according to a further aspect, there is provided a compound library containing at least two compounds, or pharmaceutically acceptable salts thereof. [Example]

[0214] Example The examples provide exemplary methods for preparing the compounds. Those skilled in the art will understand that other synthetic routes may be used to synthesize the compounds. While specific starting materials and reagents are shown and discussed in the schemes, general procedures, and examples, other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions. Furthermore, many of the exemplary compounds prepared by the methods described can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. An asterisk (*) indicates an isolated isomer or group of isolated isomers, but no stereochemistry has been assigned.

[0215] Example A: 6-((1S,3R)-3-(4-(trifluoromethyl)phenyl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 1A) and 6-((1R,3R)-3-(4-(trifluoromethyl)phenyl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 1B) [ka] Step 1: (R)-3-(4-(trifluoromethyl)phenyl)cyclopentanone [ka]

[0216] To a solution of (4-(trifluoromethyl)phenyl)boronic acid (500 mg, 2.63 mmol), cyclopent-2-enone (240 mg, 2.92 mmol), and HO (48 mg, 2.66 mmol) in 1,4-dioxane (5 mL), Rh(acac)(C2H4)2 (8 mg, 0.03 mmol) and (R)-BINAP (23 mg, 0.04 mmol) were added. The reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica column chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound (181 mg, 30% yield). LCMS (ESI) [M+H] +. =229.1.

[0217] Step 2: 6-((3R)-3-(4-(trifluoromethyl)phenyl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0218] To a solution of (R)-3-(4-(trifluoromethyl)phenyl)cyclopentanone (68 mg, 0.30 mmol) and 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (50 mg, 0.25 mmol) in anhydrous methanol (3.0 mL) was added two drops of acetic acid. The reaction mixture was stirred at 25 °C for 5 minutes. NaBHCN (80 mg, 1.27 mmol) was added, and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with saturated aqueous NaHCO (50 mL) and extracted with dichloromethane (50 mL × 3). The combined organic layers were concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (10% methanol in dichloromethane) to give the title compound (60 mg, 63% yield). LCMS (ESI) [M+H] + =374.0.

[0219] Step 3A: 6-((1S,3R)-3-(4-(trifluoromethyl)phenyl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 1A) [ka]

[0220] 6-((3R)-3-(4-(trifluoromethyl)phenyl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (90 mg, 0.24 mmol) was separated by chiral SFC (Daicel Chiralpak AD, 0.1% NH3 / EtOH in water 20:80) to give the first eluting peak as a pure single undefined enantiomer of the title compound (40 mg, 42% yield). LCMS (ESI) [M+H] + =374.1. 1H NMR(400MHz,CDCl3)δ 7.55(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),4.09(s,4H),3.20-3.09(m,1H),2.93-2.80(m,2H),2.79 -2.71(m,3H),2.29-2.09(m,4H),2.02-1.91(m,1H),1.86-1.70(m,2H),1.69-1.60(m,1H).The relative cis stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0221] Step 3B: 6-((1R,3R)-3-(4-(trifluoromethyl)phenyl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 1B) [ka]

[0222] 6-((3R)-3-(4-(trifluoromethyl)phenyl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (90 mg, 0.24 mmol) was separated by chiral SFC (Daicel Chiralpak AD, 0.1% NH3 in water / EtOH 20:80) to give the second eluting peak as a pure single undefined enantiomer of the title compound (45 mg, 46% yield). LCMS (ESI) [M+H] + =374.1. 1 H NMR(400MHz,DMSO-d6)δ 7.64(d,J=8.0Hz,2H),7.48(d,J=7.6Hz,2H),4.15(s,4H),3.39-3.21(m,1H),3.32-3.22(m,1 H),2.95-2.56(m,5H),2.19-2.08(m,5H),1.81-1.72(m,1H),1.67-1.62(m,1H). 1 Assignment was based on 1 H NMR analysis.

[0223] Example B: 6-((1R,3S)-3-(4-(trifluoromethyl)phenyl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 1C) and 6-((1S,3S)-3-(4-(trifluoromethyl)phenyl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 1D) [ka] Step 1: (S)-3-(4-(trifluoromethyl)phenyl)cyclopentanone [ka]

[0224] To a solution of (4-(trifluoromethyl)phenyl)boronic acid (500 mg, 2.63 mmol), cyclopent-2-enone (240 mg, 2.92 mmol), and HO (48 mg, 2.66 mmol) in 1,4-dioxane (5 mL), Rh(acac)(C2H4)2 (8 mg, 0.03 mmol) and (S)-BINAP (23 mg, 0.04 mmol) were added. The reaction mixture was stirred at 100 °C for 5 h and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound (150 mg, 25% yield). LCMS (ESI) [M+H] + =229.1

[0225] Step 2: 6-((3S)-3-(4-(trifluoromethyl)phenyl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0226] To a solution of (S)-3-(4-(trifluoromethyl)phenyl)cyclopentanone (67 mg, 0.29 mmol) and 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (50 mg, 0.25 mmol) in anhydrous methanol (3.0 mL), two drops of acetic acid were added, and the mixture was stirred at 25 °C for 5 minutes. NaBHCN (80 mg, 1.27 mmol) was added, and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with saturated aqueous NaHCO (50 mL) and extracted with dichloromethane (50 mL × 3). The combined organic layers were concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (10% methanol in dichloromethane) to give the title compound (75 mg, 72% yield). LCMS (ESI) [M+H] + =374.0.

[0227] Step 3A: 6-((1R,3S)-3-(4-(trifluoromethyl)phenyl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 1C) [ka]

[0228] 6-((3S)-3-(4-(trifluoromethyl)phenyl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (75 mg, 0.201 mmol) was separated by chiral SFC (Daicel Chiralpak AD-H, 0.1% NH3 / MeOH in water 25:75) to give the first eluting peak as a pure single undefined enantiomer of the title compound (30 mg, 39% yield). LCMS (ESI): [M+H] + =374.0. 1H NMR(400MHz,DMSO-d6)δ 7.64(d,J=8.4Hz,2H),7.50(d,J=8.0Hz,2H),4.14(s,4H),3.22-3.09(m,1H),2.78-2.56(m,5H),2.21-2.1 7(m,1H),2.13-2.02(m,3H),1.89-1.82(m,1H),1.72-1.67(m,J=5.6Hz,2H),1.59-1.47(m,1H).The relative cis stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0229] Step 3B: 6-((1S,3S)-3-(4-(trifluoromethyl)phenyl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 1D) [ka]

[0230] 6-((3S)-3-(4-(trifluoromethyl)phenyl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (75 mg, 0.201 mmol) from step 2 of compound 1C was separated by chiral SFC (Daicel Chiralpak AD-H, 0.1% NH3 / MeOH in water 25:75) to give the second eluting peak as a pure single undefined enantiomer of the title compound (23 mg, 29% yield). LCMS (ESI): [M+H] + =374.0. 1 H NMR(400MHz,DMSO-d6)δ 7.66(d,J=8.0Hz,2H),7.49(d,J=8.0Hz,2H),4.21(s,4H),3.52-3.42(m,2H),2.76-2.57(m,3H),2.39-2.03(m,6H),1.89-1.45(m,3H). 1 Assignment was based on 1 H NMR analysis.

[0231] Example C: 6-((1s,4s)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 2A) and 6-((1s,4r)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 2B) [ka] Step 1: 1-methyl-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-3-(trifluoromethyl)-1H-pyrazole [ka]

[0232] A solution of 5-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazole (15.0 g, 65.5 mmol), potassium phosphate (27.8 g, 131 mmol), SPhosPdG (2.56 g, 3.28 mmol), and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (17.4 g, 65.5 mmol) in 1,4-dioxane (300 mL) and water (75.0 mL) was stirred at 70 °C for 18 hours. The reaction mixture was extracted with EtOAc (150 mL, 120 mL, 100 mL). The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure to give the crude title compound (20.0 g, 95.3% yield). LCMS(ESI)[M+H] + =289.0.

[0233] Step 2: 1-methyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-3-(trifluoromethyl)-1H-pyrazole [ka]

[0234] A solution of 1-methyl-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-3-(trifluoromethyl)-1H-pyrazole (20.0 g, 69.3 mmol) and Pd(OH)2 / C (4.00 g, 69.3 mmol, 10% purity) in MeOH (300 mL) was stirred under hydrogen (30 psi) at 50 °C for 18 h. The reaction mixture was filtered through a pad of celite and concentrated to give the crude title compound (20.0 g, 99.3% yield). LCMS (ESI) [M+H] + =291.2.

[0235] Step 3: 4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexan-1-one [ka]

[0236] A solution of 1-methyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-3-(trifluoromethyl)-1H-pyrazole (20.0 g, 68.9 mmol) in AcOH (105 mL) and HO (35.0 mL) was stirred at 50° C. for 8 hours. The pH of the solution was adjusted to 7 with 1N aqueous NaOH. The reaction mixture was extracted with EtOAc (150 mL, 120 mL, 100 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was triturated with isopropyl ether at 25° C. for 20 minutes to give the title compound (10.0 g, 58.4% yield). LCMS (ESI) [M+H] + =247.1. 1 H NMR(400MHz,DMSO-d6)δ 6.57(s,1H),3.85-3.94(m,3H),3.26-3.36(m,1H),2.52-2.66(m,2H),2.23-2.48(m,2H),2.10-2.22(m,2H),1.80(qd,J=12.0,4.00Hz,2H).

[0237] Step 4A: 6-((1s,4s)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 2A) [ka]

[0238] A solution of 4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexan-1-one (59 mg, 0.24 mmol), 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (95 mg, 0.48 mmol), and acetic acid (0.028 mL, 0.48 mmol) in 2-dichloroethane (1.2 mL) was stirred at 25 °C for 1 h. Sodium triacetoxyborohydride (102 mg, 0.48 mmol) was added, and the reaction mixture was stirred at 60 °C for 18 h. The mixture was neutralized with 1 N aqueous NH4Cl (0.5 mL), diluted with DMSO, filtered, and purified by preparative HPLC (acetonitrile / water gradient with 0.1% TFA) to afford the first eluting peak as the pure single stereoisomer of the above-titled compound (3.8 mg, 4% yield). LCMS(ESI)[M+H] + =392.2. 1 H NMR(400MHz,DMSO-d6)δ 6.52(s,1H),4.22-4.08(m,4H),3.84(s,3H),2.87-2.76(m,1H),2.74(s,2H),2.61(t,J=7.3Hz,2H),2.3 7-2.30(m,1H),2.13-2.05(m,2H),1.88-1.80(m,2H),1.79-1.65(m,2H),1.63-1.49(m,4H).The relative cis stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0239] Step 4B: 6-((1s,4r)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 2B) [ka]

[0240] The crude reaction mixture from Step 4A was purified by preparative HPLC (acetonitrile / water gradient + 0.1% TFA) to afford the second eluting peak as a pure single stereoisomer of the above-titled compound (6.7 mg, 6% yield). LCMS (ESI) [M+H] + =392.2. 1 H NMR(400MHz,DMSO-d6)δ 6.49(s,1H),4.18-4.04(m,4H),3.84(s,3H),2.80(s,2H),2.75-2.62(m,3H),2.21-2 .11(m,1H),2.07(t,J=7.2Hz,2H),2.00-1.86(m,4H),1.41-1.22(m,4H). 1 Assignment was based on 1 H NMR analysis.

[0241] Example D: 6-((1r,4r)-4-(4-(trifluoromethyl)phenyl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 3A) and 6-((1s,4s)-4-(4-(trifluoromethyl)phenyl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 3B) [ka] Step 1: 8-[4-(trifluoromethyl)phenyl]-1,4-dioxaspiro[4.5]dec-7-ene [ka]

[0242] To a suspension of 4-bromobenzotrifluoride (1000 mg, 4.44 mmol), 1,4-dioxa-spiro[4,5]dec-7-ene-8-boronic acid pinacol ester (1182.8 mg, 4.44 mmol), and K2CO3 (1843 mg, 13.33 mmol) in 1,4-dioxane (10 mL) and water (2 mL), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (325 mg, 0.44 mmol) was added. The reaction mixture was stirred at 80 °C under a N2 atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (1200 mg, 95% yield). LCMS (ESI) [M+H] + =285.1.

[0243] Step 2: 8-[4-(trifluoromethyl)phenyl]-1,4-dioxaspiro[4.5]decane [ka]

[0244] To a solution of 8-[4-(trifluoromethyl)phenyl]-1,4-dioxaspiro[4.5]dec-7-ene (1200 mg, 4.22 mmol) in ethanol (10 mL) was added platinum(IV) oxide (191.7 mg, 0.84 mmol), and the mixture was stirred under H (15 psi) at 25° C. for 1 h. The mixture was filtered and concentrated to give the title compound (1200 mg, 99.3% yield). 1 H NMR(400MHz,CD3OD)δ 7.54(d,J=8.0Hz,2H),7.39(d,J=8.0Hz,2H),3.97-3.92(m,4H),2.69-2.66(m,1H),1.85-1.81(m,6H),1.77-1.68(m,2H).

[0245] Step 3: 4-[4-(trifluoromethyl)phenyl]cyclohexanone [ka]

[0246] A suspension of 8-[4-(trifluoromethyl)phenyl]-1,4-dioxaspiro[4.5]decane (1200 mg, 4.19 mmol) and hydrochloric acid (4 mL, 24 mmol, 6 M) in water (10 mL) was stirred at 25 °C for 2 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (25 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound (940 mg, 93% yield). LCMS (ESI) [M+H] + =243.1.

[0247] Step 4A: 6-((1r,4r)-4-(4-(trifluoromethyl)phenyl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 3A) [ka]

[0248] To a solution of 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (50.0 mg, 0.25 mmol) in anhydrous dichloromethane (2 mL) was added triethylamine (0.04 mL, 0.25 mmol). The mixture was stirred at 25 °C for 30 min, and then 4-[4-(trifluoromethyl)phenyl]cyclohexanone (61.2 mg, 0.25 mmol) and acetic acid (0.05 mL) were added, and the mixture was stirred at 25 °C for 4 h. NaBH(OAc) (161 mg, 0.76 mmol) was added, and the mixture was stirred at 25 °C for 1.5 h. The reaction mixture was concentrated, and the residue was purified by silica column chromatography (0-50% ethyl acetate in petroleum ether) to give a mixture of cis and trans isomers (60 mg, 61.2% yield). LCMS (ESI) [M+H] += 388.1. The cis and trans mixture of isomers was then separated by chiral SFC (Daicel Chiral, 0.1% NH3 / EtOH in water 45:65) to give the first eluting peak as a pure single stereoisomer of the title compound (7.3 mg, 12% yield). LCMS (ESI) [M+H] + =388.1. 1 H NMR(400MHz,CD3OD)δ 7.57(d,J=8.4Hz,2H),7.42(d,J=8.4Hz,2H),4.18-4.09(m,4H),3.01(s,2H),2.85(t,J=7.2Hz,2H),2.68-2.56(m,1H),2.30(t,J=11 .2Hz,1H),2.21(t,J=7.2Hz,2H),2.15(d,J=11.2Hz,2H),1.95(d,J=13.2Hz,2H),1.64-1.53(m,2H),1.47-1.38(m,2H). 1 Assignment was based on 1 H NMR analysis.

[0249] Step 4B: 6-((1s,4s)-4-(4-(trifluoromethyl)phenyl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 3B) [ka]

[0250] The cis and trans mixture of isomers from Step 4A was separated by chiral SFC (Daicel Chiral, 0.1% NH3 / EtOH in water 45:65) to give the second eluting peak as a pure single stereoisomer of the title compound (38.5 mg, 62.9% yield). LCMS (ESI) [M+H] + =388.1. 1H NMR(400MHz,CD3OD)δ 7.57(d,J=8.4Hz,2H),7.44(d,J=8.4Hz,2H),4.13(s,4H),2.94(s,2H),2.82(t,J=6.8Hz,2H),2.75(s,1H), 2.49(s,1H),2.23-2.19(m,2H),2.08-2.00(m,2H),1.95(s,2H),1.75-1.67(m,2H),1.63(s,2H).The relative cis stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0251] Example E: 6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 4) [ka] Step 1: 8-(4-(trifluoromethyl)phenyl)-1,4-dioxa-8-azaspiro[4.5]decane [ka]

[0252] To a solution of 4-fluorobenzotrifluoride (1.146 g, 6.98 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (1.0 g, 6.98 mmol) in N,N-dimethylacetamide (10 mL) was added K2CO3 (2.41 g, 17.46 mmol) at 0 °C. The mixture was stirred at 120 °C for 19 h. The reaction mixture was concentrated under reduced pressure, and the crude was purified by silica column chromatography (1-10% ethyl acetate in petroleum ether) to give the title compound (200 mg, 10% yield). LCMS (ESI) [M+H] + =288.0.

[0253] Step 2: 1-[4-(trifluoromethyl)phenyl]piperidin-4-one [ka]

[0254] To a suspension of 8-[4-(trifluoromethyl)phenyl]-1,4-dioxa-8-azaspiro[4.5]decane (200 mg, 0.69 mmol) in water (2 mL) was added hydrochloric acid (0.58 mL, 3.48 mmol, 6 M) at 20 °C. The reaction mixture was stirred for 2 h. The pH of the reaction mixture was adjusted to pH 7 with saturated aqueous NaHCO3 (10 mL) at 0 °C, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica column chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (150 mg, 76.2% yield). LCMS (ESI) [M+H] + =244.1.

[0255] Step 3: 6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0256] To a solution of 1-[4-(trifluoromethyl)phenyl]piperidin-4-one (50 mg, 0.21 mmol) and 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (41 mg, 0.21 mmol) in methanol (2 mL) was added NaBHCN (65 mg, 1.03 mmol) and acetic acid (0.01 mL) at 0 °C. The mixture was stirred at 80 °C for 16 h. The reaction mixture was purified by reverse-phase chromatography (gradient of acetonitrile and 0.05% aqueous NH OH) to give the title compound (24.5 mg, 29.1% yield). LCMS (ESI) [M+H] + =389.0. 1H NMR(400MHz,CD3OD)δ 7.45(d,J=8.8Hz,2H),7.07-7.01(m,1H),7.04(d,J=8.8Hz,1H),4.16-4.07(m,4H),3.85(d,J=13.2Hz,2H),2.96(s,2H),2.93-2.8 5(m,2H),2.84-2.78(m,1H),2.82(t,J=7.2Hz,2H),2.44-2.32(m,1H),2.20(t,J=7.2Hz,2H),2.04-1.97(m,2H),1.65-1.54(m,2H).

[0257] Example F: 6-(1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 5) [ka] The title compound was synthesized generally following the procedure for compound 4, using 5-fluoro-2-(trifluoromethyl)pyridine instead of 4-fluorobenzotrifluoride in step 1. LCMS (ESI) [M+H] + =390.2.1H NMR(400MHz,CD3OD)δ 8.33(s,1H),7.74-7.67(m,1H),6.91(d,J=9.2Hz,1H),4.48-4.44(m,2H),4.20-4.12(m,4H),3.20(s,2 H),3.08-2.98(m,4H),2.81-2.79(m,1H),2.28(t,J=7.2Hz,2H),2.07-2.04(m,2H),1.54-1.51(m,2H).

[0258] Example G: 6-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 6) [ka] The title compound was synthesized generally following the procedure for compound 4, using 2-fluoro-5-(trifluoromethyl)pyridine instead of 4-fluorobenzotrifluoride in step 1. LCMS (ESI) [M+H] + =390.1. 1 H NMR(400MHz,CD3OD)δ 8.34(s,1H),7.73(dd,J=9.2,2.4,Hz,1H),6.93(d,J=9.2Hz,1H),4.55-4.52(m,2H),4.27-4.15(m,4H),3.43( s,2H),3.26(t,J=7.2Hz,2H),3.12-2.94(m,3H),2.36(t,J=7.2Hz,2H),2.14-2.11(m,2H),1.60-1.56(m,2H).

[0259] Example H: 6-(1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 7) [ka] Step 1: 1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-ol [ka]

[0260] A solution of 2-chloro-3-methyl-5-(trifluoromethyl)pyridine (196 mg, 1.0 mmol), cesium fluoride (456 mg, 3.0 mmol), N,N-diisopropylethylamine (0.52 mL), and piperidin-4-ol (131 mg, 1.30 mmol) in dimethyl sulfoxide (5.0 mL) was stirred at 100° C. for 18 hours. The mixture was diluted with DMSO, filtered, and purified by preparative reverse-phase HPLC (acetonitrile / water gradient with 0.1% TFA) to give the title compound (254 mg, 98% yield). LCMS (ESI) [M+H] + =261.2. 1H NMR(400MHz,DMSO-d6)δ 8.39(s,1H),7.78(s,1H),4.70(d,J=4.2Hz,1H),3.74-3.62(m,1H),3.56-3.45 (m,2H),2.99-2.88(m,2H),2.28(s,3H),1.89-1.78(m,2H),1.57-1.44(m,2H).

[0261] Step 2: 1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-one [ka]

[0262] To a solution of 1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-ol (250 mg, 0.96 mmol) in dichloromethane (4.8 mL) was slowly added Dess-Martin periodinane (815 mg, 1.92 mmol). The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was diluted with 1 N aqueous NaHCO (2 mL), 1 N aqueous NaSO (2 mL), and dichloromethane (5 mL). The aqueous layer was extracted with dichloromethane (2 × 5 mL). The combined organic layers were concentrated under reduced pressure. The mixture was diluted with DMSO, filtered, and purified by preparative reverse-phase HPLC (acetonitrile / water gradient + 0.1% TFA) to give the title compound (94 mg, 38% yield). LCMS (ESI) [M+H] + =259.2.

[0263] Step 3: 6-(1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0264] A mixture of 1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-one (47 mg, 0.18 mmol), 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrogen chloride (71 mg, 0.36 mmol), and 4A molecular sieves (15 mg) in 1,2-dichloroethane (0.9 mL) was stirred at 25° C. for 4 hours. Acetic acid (0.021 mL, 0.36 mmol) and sodium triacetoxyborohydride (76 mg, 0.36 mmol) were added, and the reaction mixture was stirred at 25° C. for 18 hours. The mixture was neutralized with 1N aqueous NH4Cl (0.5 mL), diluted with DMSO, filtered, and purified by preparative HPLC (acetonitrile / water gradient with 0.1% TFA) to give the title compound (8.2 mg, 11% yield). LCMS(ESI)[M+H] + =404.3. 1 H NMR(400MHz,CD3OD)δ 8.30(s,1H),7.70(s,1H),4.18-4.06(m,4H),3.67(d,J=13.0Hz,2H),2.98(s,2H),2.94-2. 79(m,4H),2.43-2.31(m,4H),2.21(t,J=7.2Hz,2H),2.06-1.97(m,2H),1.72-1.58(m,2H).

[0265] Example I: 6-((1r,4r)-4-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 8A) and 6-((1s,4s)-4-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 8B) [ka] Step 1: 1-Isopropyl-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-3-(trifluoromethyl)-1H-pyrazole [ka]

[0266] To a suspension of 5-bromo-1-isopropyl-3-(trifluoromethyl)pyrazole (2 g, 7.78 mmol), 1,4-dioxa-spiro[4,5]dec-7-ene-8-boronic acid pinacol ester (1035 mg, 3.89 mmol), and CsCO (7605 mg, 23.34 mmol) in 1,4-dioxane (20 mL) and water (5 mL), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (551 mg, 0.78 mmol) was added. The mixture was stirred at 80 °C under a N atmosphere for 2 h. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica column chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (700 mg, 28% yield). LCMS (ESI) [M+H] + =317.2.

[0267] Step 2: 1-Isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-3-(trifluoromethyl)-1H-pyrazole [ka]

[0268] To a solution of 1-isopropyl-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-3-(trifluoromethyl)-1H-pyrazole (700 mg, 2.21 mmol) in methanol (5 mL) was added 10% palladium on carbon (471 mg, 0.44 mmol). The suspension was degassed under vacuum and purged with H2 (15 psi) three times. The mixture was stirred under H2 (15 psi) at 25 °C for 16 h. The resulting mixture was filtered, and the filtrate was concentrated under vacuum to give the title compound (700 mg, 99% yield). LCMS (ESI) [M+H] + =319.2.

[0269] Step 3: 4-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexanone [ka]

[0270] To a solution of 5-(1,4-dioxaspiro[4.5]decan-8-yl)-1-isopropyl-3-(trifluoromethyl)pyrazole (700 mg, 2.2 mmol) in tetrahydrofuran (10 mL) was added hydrochloric acid (5 mL, 30 mmol, 6 M). The mixture was stirred at 25 °C for 30 minutes. The mixture was diluted with water (5 mL) and the pH was adjusted to approximately pH 9 with saturated aqueous NaHCO3. The resulting mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with water (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0-70% ethyl acetate in petroleum ether) to give the title compound (450 mg, 75% yield). LCMS (ESI) [M+H] + =275.2.

[0271] Step 4A: 6-((1r,4r)-4-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 8A) [ka]

[0272] To a solution of 4-[2-isopropyl-5-(trifluoromethyl)pyrazol-3-yl]cyclohexanone (140 mg, 0.51 mmol) in methanol (5 mL) was added 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (115 mg, 0.58 mmol), acetic acid (0.1 mL), and NaBHCN (160 mg, 2.55 mmol). The mixture was stirred at 70 °C for 3 hours. The reaction mixture was diluted with water (5 mL), and the pH was adjusted to approximately pH 9 with saturated aqueous NaHCO solution. The resulting solution was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with water (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile / water gradient containing 0.05% NH3 and 10 mM NH4HCO3) to give the second eluting peak as the title compound as a pure single stereoisomer (49.5 mg, 23% yield). LCMS (ESI) [M+H] + =420.2. 1 H NMR(400MHz,CD3OD)δ 6.33(s,1H),4.69-4.62(m,1H),4.17-4.08(m,4H),2.97(s,2H),2.83(t,J=7.2Hz,2H),2.79-2.71(m,1H),2.31-2.23(m,1H),2.20 (t,J=7.2Hz,2H),2.14-2.11(m,2H),2.01-1.97(m,2H),1.58-1.48(m,2H),1.46(d,J=6.4Hz,6H),1.45-1.36(m,2H). 1 Assignment was based on 1 H NMR analysis.

[0273] Step 4B: 6-((1s,4s)-4-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 8B) [ka]

[0274] The crude reaction mixture from Step 4A was purified by reverse phase chromatography (acetonitrile / water gradient containing 0.05% NH3 and 10 mM NH4HCO3) to give the first eluting peak as the title compound as a pure single stereoisomer (45.8 mg, 21% yield). LCMS (ESI) [M+H] + =420.3. 1 H NMR(400MHz,CD3OD)δ 6.35(s,1H),4.69-4.62(m,1H),4.14-4.08(m,4H),2.93-2.84(m,3H),2.75(t,J=7.2Hz,2H),2.42-2.37(m,1H),2 .19(t,J=7.2Hz,2H),1.99-1.91(m,2H),1.90-1.81(m,2H),1.72-1.63(m,4H),1.46(d,J=6.4Hz,6H).The relative cis stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0275] Example J: (S)-6-(1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compounds 9A* and 9B*) [ka] The title compound was synthesized following a procedure similar to that for the synthesis of compound 4, using 1,4-dioxa-7-azaspiro[4.4]nonane and 5-fluoro-2-(trifluoromethyl)pyridine in step 1. The racemic mixture (130 mg, 0.35 mmol) was separated by chiral SFC (Daicel Chiralcel OJ-H, 0.1% NH3 in water / EtOH 70:30) to give compound 9A* as the second eluting peak as a pure single undefined enantiomer of the title compound (41.8 mg, 32% yield). LCMS (ESI) [M+H] + =376.1. 1H NMR(400MHz,CDCl3)δ 8.00(d,J=2.8Hz,1H),7.49(d,J=8.8Hz,1H),6.81(dd,J=8.8,2.8Hz,1H),4.10(s,4H),3.55-3.50(m,2H),3.43-3.38(m,1H),3.2 6-3.22(m,1H),3.11-3.05(m,1H),2.98-2.94(m,1H),2.89-2.86(m,1H),2.83-2.78(m,2H),2.25-2.19(m,3H),2.08-2.00(m,1H).

[0276] Compound 9B* was obtained as a pure single undefined enantiomer of the title compound (first eluting peak 44.3 mg, 0.1121 mmol, 32.4% yield). LCMS (ESI) [M+H] + =376.1.1H NMR(400MHz,CDCl3)δ 8.00(d,J=2.8Hz,1H),7.49(d,J=8.8Hz,1H),6.81(dd,J=8.8,2.8Hz,1H),4.10(s,4H),3.55-3.50(m,2H),3.43-3.37(m,1H),3.2 6-3.22(m,1H),3.11-3.05(m,1H),2.98-2.94(m,1H),2.89-2.86(m,1H),2.85-2.79(m,2H),2.26-2.19(m,3H),2.09-1.97(m,1H).

[0277] Example K (Compounds 10A*, 10B*, 10C*, and 10D*): 6-((1S,3S)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide; 6-((1R,3S)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3 6-((1S,3R)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide;6-((1R,3R)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka] Step 1: 1-Isopropyl-3-(trifluoromethyl)-1H-pyrazole [ka]

[0278] To a stirred solution of 3-(trifluoromethyl)pyrazole (7.5 g, 55.11 mmol) in N,N-dimethylformamide (80 mL) was added 2-iodopropane (28 g, 165.34 mmol) and CsCO (90 g, 275.57 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered, and the filtrate was diluted with water (100 mL) and extracted with dichloromethane (100 mL × 4). The combined organic layers were washed with brine (50 mL × 5), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (6.57 g, 67% yield). LCMS (ESI) [M+H] + =178.9. 1H NMR(400MHz,CDCl3)δ 7.46(d,J=1.2Hz,1H),6.50(d,J=1.2Hz,1H),4.60-4.53(m,1H),1.54(d,J=6.8Hz,6H).

[0279] Step 2: 5-Bromo-1-isopropyl-3-(trifluoromethyl)-1H-pyrazole [ka]

[0280] To a solution of 1-isopropyl-3-(trifluoromethyl)-1H-pyrazole (2.0 g, 11.23 mmol) in tetrahydrofuran (40 mL) cooled to −78° C., n-butyllithium (9 mL, 22.45 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 15 minutes. Bromine (2 mL, 33.68 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at −30° C. for 1.5 hours and then quenched with saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with tert-butyl methyl ether (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (1.6 g, 55% yield). LCMS (ESI) [M+H+2] + =259.0. 1 H NMR(400MHz,CDCl3)δ 6.54(s,1H),4.78-4.74(m,1H),1.51(d,J=6.4Hz,6H).

[0281] Step 3: 3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclopent-2-en-1-one [ka]

[0282] To a solution of 5-bromo-1-isopropyl-3-(trifluoromethyl)-1H-pyrazole (1 g, 3.89 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one (729 mg, 3.5 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added KCO (1613 mg, 11.67 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (276 mg, 0.39 mmol). The mixture was stirred at 80 °C under a N atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica column chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (400 mg, 40% yield). LCMS(ESI)[M+H] + =259.1. 1 H NMR(400MHz,CDCl3)δ 6.78(s,1H),6.39(t,J=1.6Hz,1H),4.80-4.73(m,1H),3.05-3.02(m,2H),2.61-2.54(m,2H),1.56-1.56(m,6H).

[0283] Step 4: 3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclopentanone [ka]

[0284] To a solution of 3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclopent-2-en-1-one (400 mg, 1.55 mmol) in methanol (5 mL) was added 10% palladium on carbon (248 mg, 0.46 mmol). The reaction mixture was stirred under H2 (15 psi) at 25 °C for 2 h. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-15% ethyl acetate in petroleum ether) to give the title compound (320 mg, 80% yield). LCMS (ESI) [M+H] + =261.2.

[0285] Step 5: 6-(3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0286] Racemic 3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl) (650 mg, 2.5 mmol) was separated by chiral SFC (Phenomenex-Cellulose-2, 0.1% NH3 / IPA in water 20:80) to afford the first eluting peak as a pure single, undefined enantiomer of 3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclopentanone (230 mg, 35% yield). To a solution of this material (110 mg, 0.42 mmol) in methanol (5 mL) was added 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (105 mg, 0.53 mmol), acetic acid (0.02 mL), and NaBH3CN (133 mg, 2.11 mmol). The mixture was stirred at 70 °C for 3 h. The reaction mixture was diluted with water (5 mL) and the pH was adjusted to about pH 9 with saturated aqueous NaHCO3 (1 mL). The resulting solution was extracted with dichloromethane (20 mL x 2). The combined organic layers were washed with water (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.

[0287] Compound 10A*: The residue was purified by preparative TLC (10% methanol in dichloromethane) to afford the second eluting peak as a pure single undefined enantiomer of the title compound (39.8 mg, 22% yield). LCMS (ESI) [M+H] + =406.2. 1H NMR(400MHz,DMSO-d6)δ 6.54(s,1H),4.68-4.61(m,1H),4.17-4.10(m,4H),3.28-3.24(m,1H),2.76-2.52(m,5H),2.22-2.18(m,1H) ),2.12-2.03(m,3H),1.88-1.79(m,1H),1.69-1.61(m,2H),1.59-1.49(m,1H),1.37(dd,J=6.4,2.8Hz,6H).

[0288] Compound 10B*: The residue from the preparation of compound 10A above was purified by preparative TLC (10% methanol in dichloromethane) to afford the first eluting peak as a pure single undefined enantiomer of the title compound (43.1 mg, 24% yield). LCMS (ESI) [M+H] + =406.2. 1 H NMR(400MHz,DMSO-d6)δ 6.50(s,1H),4.68-4.59(m,1H),4.15-4.10(m,4H),3.34-3.33(m,1H),2.88-2.72(m,3H),2.66-2.54(m,2H) ),2.15-2.00(m,4H),1.94-1.91(m,1H),1.79-1.69(m,1H),1.62-1.51(m,2H),1.37(dd,J=6.4,5.2Hz,6H).

[0289] Compound 10C*: Racemic 3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclopentanone from the preparation of compound 10A (650 mg, 2.5 mmol) was separated by chiral SFC (Phenomenex-Cellulose-2, 0.1% NH3 / IPA in water 20:80) to give the second eluting peak as a pure single undefined enantiomer of 3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclopentanone (230 mg, 35% yield). Reductive alkylation of the above material (110 mg, 0.42 mmol) using the conditions described for the preparation of compound 10A, step 5, followed by preparative TLC (10% methanol in dichloromethane) gave the second eluting peak as a pure single undefined enantiomer of the title compound (50 mg, 27% yield). LCMS(ESI)[M+H] + =406.2. 1 H NMR(400MHz,DMSO-d6)δ 6.54(s,1H),4.68-4.62(m,1H),4.14(s,4H),3.28-3.23(m,1H),2.75-2.55(m,5H),2.25-2.16(m, 1H),2.12-2.04(m,3H),1.84(m,1H),1.65(m,2H),1.59-1.50(m,1H),1.37(dd,J=6.4,2.8Hz,6H).

[0290] Compound 10D*: The residue from the preparation of compound 10C was purified by preparative TLC (10% methanol in dichloromethane) to afford the first eluting peak as a pure single undefined enantiomer of the title compound (33.8 mg, 19% yield). LCMS (ESI) [M+H] + =406.2. 1 H NMR(400MHz,DMSO-d6)δ 6.51(s,1H),4.67-4.60(m,1H),4.15(brs,4H),3.30-3.20(m,1H),2.76(m,2H),2.61(m,2H) ),2.18-1.98(m,5H),1.92(m,1H),1.79-1.71(m,1H),1.61-1.53(m,2H),1.39-1.36(m,6H).

[0291] Example L: (cis)-6-(3-(6-(trifluoromethyl)pyridin-3-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 11A) and (trans)-6-(3-(6-(trifluoromethyl)pyridin-3-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 11B) [ka] The title compound was synthesized following a procedure similar to that used in the synthesis of compounds 1A and 1B, using (6-(trifluoromethyl)pyridin-3-yl)boronic acid in step 1.

[0292] (cis)-6-(3-(6-(trifluoromethyl)pyridin-3-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 11A): The racemic mixture was separated by chiral SFC (Daicel Chiralpak AD-H, 0.1% NH3 in water / EtOH 30:70) to give the first eluting peak as a pure single undefined enantiomer of the title compound (30.7 mg, 37% yield). LCMS (ESI) [M+H] + =375.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 4.19-4.12 (m, 4H), 3.30-3.14 (m, 2H), 2.80-2.72 (m, 2H), 2.69-2.69 (m, 2H), 2.28-2.18 (m, 1H), 2.16-2.04 (m, 3H), 1.94-1.81 (m, 1H), 2.16-2.04 (m, 2H), 1.59 (d, J = 10.0 Hz, 1H). The relative stereochemistry of the cis isomer is 1 Assigned based on H NMR analysis, absolute stereochemistry was not assigned.

[0293] (trans)-6-(3-(6-(trifluoromethyl)pyridin-3-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 11B): The racemic mixture was separated by chiral SFC (Daicel Chiralpak AD-H, 0.1% NH3 in water / EtOH 30:70) to give the second eluting peak as a pure single undefined enantiomer of the title compound (36.8 mg, 44% yield). LCMS (ESI) [M+H] + =375.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 4.19-4.12 (m, 4H), 3.03-2.70 (m, 4H), 2.66-2.57 (m, 2H), 2.20-2.05 (m, 4H), 2.03-1.93 (m, 1H), 1.84-1.70 (m, 1H), 1.65-1.56 (m, 2H). The relative stereochemistry of the trans isomer is 1 Assigned based on H NMR analysis, absolute stereochemistry was not assigned.

[0294] Example M: ​​(Compounds 11C* and 11D*): 6-((1R,3S)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and 6-((1S,3S)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka] The title compound was synthesized following a procedure similar to that for the synthesis of compounds 1C and 1D, using (6-(trifluoromethyl)pyridin-3-yl)boronic acid in step 1.

[0295] Compound 11C*: The racemic mixture was separated by chiral SFC (Daicel Chiralpak IG, 0.1% NH3 / MeOH in water 45:55) to give the first eluting peak as a pure single undefined enantiomer of the title compound (34 mg, 28% yield). LCMS (ESI) [M+H] + =375.2. 1 H NMR (400 MHz, CDCl) δ 8.61 (s, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 4.10 (s, 4H), 3.24-3.15 (m, 1H), 2.94-2.69 (m, 5H), 2.34-2.26 (m, 1H), 2.24-2.13 (m, 3H), 2.09-1.92 (m, 1H), 1.86-1.57 (m, 2H), 1.68-1.53 ​​(m, 1H). The stereochemistry at the pyridine ring bond has been assigned, and those at other stereocenters have been arbitrarily assigned.

[0296] Compound 11D*: The racemic mixture was separated by chiral SFC (Daicel Chiralpak IG, 0.1% NH3 / MeOH in water 45:55) to give the second eluting peak as a pure single undefined enantiomer of the title compound (30 mg, 25% yield). LCMS (ESI) [M+H] + =375.2. 1 H NMR (400 MHz, CDCl) δ 8.60 (d, J = 1.6 Hz, 1H), 7.72-7.68 (m, 1H), 7.64-7.60 (m, 1H), 4.09 (s, 4H), 3.41-3.29 (m, 1H), 2.91-2.80 (m, 3H), 2.76-2.71 (m, 2H), 2.27-2.05 (m, 5H), 1.88-1.78 (m, 1H), 1.72-1.63 (m, 2H). Stereochemistry at the pyridine ring bond has been assigned, and those at other stereocenters have been arbitrarily assigned.

[0297] Example N: 6-((1r,4r)-4-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 12A) and 6-((1s,4s)-4-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 12B) [ka] Step 1: 4,4,4-trifluoro-1-(1,4-dioxaspiro[4.5]decan-8-yl)butane-1,3-dione [ka]

[0298] A solution of 1-(1,4-dioxaspiro[4.5]decan-8-yl)ethan-1-one (1.0 g, 5.43 mmol), ethyl 2,2,2-trifluoroacetate (1.93 g, 13.6 mmol), and sodium methoxide (6.20 mL, 27.1 mmol, 25% by weight in methanol) in 1,4-dioxane (36.2 mL) cooled to 0°C was stirred at 0-25°C for 18 h. The reaction mixture was diluted with EtOAc (50 mL) and 1N aqueous NH4Cl (30 mL) and neutralized to pH 6-7 with 2N aqueous HCl. The aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure to give the crude title compound (2.16 g, 100% yield). LCMS (ESI) [M+H] + =281.3.

[0299] Step 2: 4-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexan-1-one [ka]

[0300] A solution of 4,4,4-trifluoro-1-(1,4-dioxaspiro[4.5]decan-8-yl)butane-1,3-dione (638 mg, 2.23 mmol), cyclopropylhydrazine hydrochloride (297 mg, 2.73 mmol), and triethylamine (0.38 mL, 2.73 mmol) in hexafluoro-2-propanol (3.8 mL) was stirred at 25 °C for 18 h. AcOH (0.66 mL, 11.5 mmol) and water (2 mL) were added, and the reaction mixture was stirred at 50 °C for 18 h. The reaction mixture was diluted with dichloromethane (20 mL) and 1 N aqueous NaHCO (14 mL). The aqueous layer was extracted with dichloromethane (2 × 20 mL). The combined organic layers were dried (NaSO) and concentrated under reduced pressure to give the crude title compound (0.72 g, 100% yield). LCMS(ESI)[M+H] + =273.0.

[0301] Step 3A: 6-((1r,4r)-4-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 12A) [ka]

[0302] A solution of 4-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexan-1-one (190 mg, 0.70 mmol), 2-thia-6-azaspiro[3.4]octane 2,2-dioxide trifluoroacetic acid (384 mg, 1.40 mmol), and N,N-diisopropylethylamine (1.22 mL, 6.98 mmol) in dichloromethane (6.98 mL) was stirred for 4 h at 30 °C. Sodium triacetoxyborohydride (444 mg, 2.09 mmol) was added, and the reaction mixture was stirred at 25 °C for 18 h. The mixture was neutralized with 1N aqueous NH4Cl (0.5 mL), diluted with DMSO, filtered, and purified by preparative HPLC (acetonitrile / water gradient + 0.1% TFA) to afford the second eluting peak as a pure single stereoisomer of the above-titled compound (32 mg, 11% yield). LCMS (ESI) [M+H] + =418.2. 1 H NMR(400MHz,DMSO-d6)δ 6.50(s,1H),4.17-4.06(m,4H),3.76-3.67(m,1H),2.96-2.86(m,1H),2.81(s,2H),2.67(t,J=7.2Hz,2H),2. 22-2.13(m,1H),2.07(t,J=7.2Hz,2H),2.02-1.94(m,4H),1.49-1.23(m,4H),1.11-0.99(m,4H). 1 Assignment was based on 1 H NMR analysis.

[0303] Step 3B: 6-((1s,4s)-4-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 12B) [ka]

[0304] The crude mixture from Step 3A was purified by preparative HPLC (acetonitrile / water gradient + 0.1% TFA) to afford the first eluting peak as a pure single stereoisomer of the above-titled compound (55 mg, 19% yield). LCMS (ESI) [M+H] + =418.2. 1 H NMR(400MHz,DMSO-d6)δ 6.53(s,1H),4.21-4.10(m,4H),3.76-3.66(m,1H),3.07-2.97(m,1H),2.74(s,2H),2.61(t,J=7.3Hz,2H),2.36-2.32( m,1H),2.09(t,J=7.4Hz,2H),1.90-1.79(m,2H),1.79-1.62(m,4H),1.62-1.51(m,2H),1.14-0.99(m,4H).The relative cis stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0305] Example O: (Compounds 13A*, 13B*, 13C*, and 13D*): 6-((1R,3S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide; 6-((1S,3R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3 .4]octane 2,2-dioxide;6-((1R,3R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide;6-((1S,3S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka] Step 1: 3-Bromocyclopent-2-enone [ka]

[0306] To a suspension of Ph3PBr2 (4.73 g, 11.2 mmol) in dichloromethane (10 mL) was added cyclopent-4-ene-1,3-dione (1.0 g, 10.2 mmol) and triethylamine (1.56 mL, 11.2 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 18 h. A yellow suspension formed. The reaction mixture was concentrated in vacuo, and 2-methoxy-2-methylpropane (50 mL) was added. The reaction mixture was stirred and filtered. The organic layer was concentrated under reduced pressure and purified by silica column chromatography (10% to 20% ethyl acetate in petroleum ether) to give the title compound (1.10 g, 67% yield). 1 H NMR(400MHz,DMSO-d6)δ 6.66-6.62(m,1H),3.01-2.94(m,2H),2.50-2.47(m,2H).

[0307] Step 2: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-enone [ka]

[0308] A mixture of 4-bromocyclopent-2-enone (1.10 g, 6.83 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2 dioxaborolane) (1.91 g, 7.52 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (500 mg, 0.68 mmol), and KOAc (2.01 g, 20.5 mmol) in 1,4-dioxane (10 mL) was degassed and purged with N2 three times. The reaction mixture was stirred under N2 at 100 °C for 12 h. A brown suspension formed. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica column chromatography (2% to 3% methanol in dichloromethane) to give the title compound (1.30 g, 91% yield). 1 H NMR(400MHz,DMSO-d6)δ 6.45-6.40(m,1H),2.68-2.63(m,2H),2.28-2.23(m,2H),1.27(s,12H).

[0309] Step 3: 3-(3-bromo-1-isopropyl-1H-pyrazol-5-yl)cyclopent-2-enone [ka]

[0310] A suspension of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-enone (1.30 g, 6.25 mmol), 3,5-dibromo-1-isopropyl-1H-pyrazole (1.67 g, 6.25 mmol), CsCO (6.11 g, 18.7 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (457 mg, 0.62 mmol) in 1,4-dioxane (30 mL) and water (6 mL) was degassed and purged with N three times. The reaction mixture was stirred under N at 100 °C for 1.5 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica column chromatography (40-50% ethyl acetate in petroleum ether) to give the title compound (1.0 g, 59% yield). 1 H NMR(400MHz,CDCl3)δ 6.85(s,1H),6.64(d,J=1.6Hz,1H),5.04-4.94(m,1H),3.31-3.28(m,2H),2.90-2.84(m,2H),1.85(d,J=6.4Hz,6H).LCMS(ESI)[M+H] + =269.2.

[0311] Step 4: 3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopent-2-enone [ka]

[0312] A suspension of 3-(3-bromo-1-isopropyl-1H-pyrazol-5-yl)cyclopent-2-enone (1.0 g, 3.7 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine (1.01 g, 3.7 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (270 mg, 0.4 mmol), and CsCO (3630 mg, 11.1 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was degassed and purged with N three times. The reaction mixture was stirred under N at 100 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica column chromatography (30-50% ethyl acetate in petroleum ether) to give the title compound (1000 mg, 80% yield). LCMS (ESI) [M+H] + =336.1.

[0313] Step 5: 3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone [ka]

[0314] To a solution of 3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopent-2-enone (1.0 g, 2.98 mmol) in methanol (20 mL) was added 10% palladium on carbon (0.32 g, 0.30 mmol) at 25 °C. The reaction mixture was stirred under H (15 psi) at 25 °C for 20 h. The reaction mixture was filtered, and the solid was washed with methanol (10 mL × 2). The combined organic layers were concentrated in vacuo. The residue was purified by silica column chromatography (30-50% ethyl acetate in petroleum ether) to give the title compound (700 mg, 69.6% yield). 1H NMR(400MHz,CDCl3)δ 9.47(s,1H),9.09(d,J=1.2Hz,1H),8.64(s,1H),6.72(s,1H),4.88-4.75(m,1H),3.82-3.75(m,1H),3.10- 3.00(m,1H),2.88-2.78(m,2H),2.73-2.61(m,2H),2.47-2.39(m,1H),1.93-1.86(m,6H).LCMS(ESI)[M+H] + =338.1. 800 mg of the above racemic mixture of 3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone was separated by chiral SFC (Chiral Pak AD-3, 0.05% DEA in ethanol / CO 5:95 to 40:60) to give the second eluting peak as a pure single undefined enantiomer of 3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone (370 mg, 46.2% yield).

[0315] Step 6A: 6-((1R,3S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 13A*) [ka]

[0316] To a solution of 3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone (105 mg, 0.31 mmol, single undefined enantiomer from Step 5) and 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (95 mg, 0.48 mmol) in anhydrous methanol (5 mL) was added acetic acid (18.6 mg, 0.31 mmol) and NaBHCN (100 mg, 1.59 mmol). The reaction mixture was quenched with saturated aqueous NaHCO (5 mL). The mixture was extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with brine (25 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The cis and trans mixture of the title product was separated by reverse phase chromatography (acetonitrile / water gradient containing 0.05% NH3 and 10 mM NH4HCO3). The title compound (40 mg, 31% yield) was isolated as the first eluting peak as a pure single undefined enantiomer. LCMS (ESI) [M+H] + =483.2. 1 H NMR(400MHz,CDCl3)δ 9.16(s,1H),8.76(s,1H),8.32(s,1H),6.36(s,1H),4.55-4.44(m,1H),4.10(s,4H),3.37-3.32(m,1H),2.90-2.83(m,3H),2.78-2.71(m ,2H),2.30-2.22(m,1H),2.21-2.17(m,2H),2.14-2.04(m,2H),1.93-1.85(m,1H),1.79-1.65(m,2H),1.54(d,J=6.4Hz,6H).The relative cis stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0317] Step 6B: 6-((1S,3R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 13B*) [ka]

[0318] The title compound (13 mg, 10% yield) was isolated as the second eluting peak of Step 6A as a pure single undefined enantiomer. LCMS (ESI) [M+H] + =483.2. 1 H NMR(400MHz,CDCl3)δ 9.16(s,1H),8.77(s,1H),8.32(s,1H),6.42(s,1H),4.57-4.42(m,1H),4.10(s,4H),3.25-3.17(m,1H),2.92-2.86(m,2H),2.79-2.74(m ,3H),2.34-2.28(m,1H),2.21-2.18(m,3H),2.06-1.90(m,1H),1.84-1.76(m,2H),1.72-1.62(m,1H),1.54(d,J=6.4Hz,6H).The relative cis stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0319] Step 6C: 6-((1R,3R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 13C*) [ka]

[0320] The title compound was synthesized following a procedure similar to that for compound 13A. The racemic mixture of 6-(3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (160.0 mg, 0.33 mmol) was separated by chiral SFC (Daicel Chiralpak IG, 0.1% NH3 in water / EtOH 60:40). The title compound (31.6 mg, 18.6% yield) was isolated as a pure single undefined enantiomer as the first eluting peak. LCMS (ESI) [M+H]+ =483.2. 1 H NMR(400MHz,CDCl3)δ 9.16(s,1H),8.76(s,1H),8.32(s,1H),6.36(s,1H),4.53-4.47(m,1H),4.10(s,4H),3.35-3.31(m,1H),2.87-2.83(m,3H),2.7 5-2.72(m,2H),2.25-2.18(m,3H),2.13-2.02(m,2H),1.93-1.86(m,1H),1.79-1.69(m,2H),1.54(t,J=7.2Hz,6H).The relative trans stereochemistry 1 Assignment was based on 1 H NMR analysis.

[0321] Step 6D: 6-((1S,3S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 13D*) [ka]

[0322] The title compound was synthesized following a procedure similar to that for compound 13A. The title compound (55.9 mg, 34.2% yield) was isolated as the second eluting peak as a pure, single, undefined enantiomer. LCMS (ESI) [M+H] + =483.2. 1 H NMR(400MHz,CDCl3)δ 9.16(d,J=1.6Hz,1H),8.76(d,J=1.2Hz,1H),8.32(s,1H),6.42(s,1H),4.53-4.43(m,1H),4.10(s,4H),3.21-3.12(m,1H),2.90-2.84(m ,2H),2.77-2.73(m,3H),2.33-2.27(m,1H),2.21-2.14(m,3H),2.02-1.96(m,1H),1.84-1.69(m,3H),1.54(d,J=6.4Hz,6H). 1 Assignment was based on 1 H NMR analysis.

[0323] Example P: 6-((1r,4r)-4-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 14A) and 6-((1s,4s)-4-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 14B) [ka] The title compound was synthesized according to a procedure similar to that used to synthesize compounds 3A and 3B, using 5-bromo-2-(trifluoromethyl)pyridine in step 1. The residue was purified by reverse-phase chromatography (acetonitrile / water gradient containing 0.05% NH and 10 mM NHHCO).

[0324] 6-((1r,4r)-4-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (compound 14A) [ka]

[0325] The title compound (77.8 mg, 32.2% yield) was obtained as the first eluting peak as a pure single stereoisomer. LCMS (ESI) [M+H] + =389.2. 1 H NMR(400MHz,CD3OD)δ 8.60(d,J=1.8Hz,1H),7.92(dd,J=8.4,2.0Hz,1H),7.74(d,J=8.0Hz,1H),4.23-4.03(m,4H),2.99(s,2H),2.84(t,J=7.2Hz,2H),2 .74-2.72(m,1H),2.30-2.29(m,1H),2.24-2.13(m,4H),1.98(d,J=12.4Hz,2H),1.66-1.62(m,2H),1.51-1.38(m,2H). 1 Assignment was based on 1 H NMR analysis.

[0326] 6-((1s,4s)-4-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (compound 14B). [ka]

[0327] The title compound (33.8 mg, 14% yield) was obtained as the second eluting peak as a pure single stereoisomer. LCMS (ESI) [M+H] + =389.2. 1 H NMR(400MHz,CD3OD)δ 8.56(d,J=1.6Hz,1H),7.89(dd,J=8.0,1.6Hz,1H),7.71(d,J=8.4Hz,1H),4.09(s,4H),2.86(s,2H),2.83-2 .70(m,3H),2.42(d,J=3.2Hz,1H),2.16(t,J=7.2Hz,2H),1.99-1.89(m,4H),1.70-1.57(m,4H).The relative cis stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0328] Example Q: 6-((1r,4r)-4-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 15) and 6-((1r,4r)-4-(1-ethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 16) [ka] Step 1: 4-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexan-1-one and 4-(1-ethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)cyclohexan-1-one [ka]

[0329] A solution of 4,4,4-trifluoro-1-(1,4-dioxaspiro[4.5]decan-8-yl)butane-1,3-dione (500 mg, 1.78 mmol), ethylhydrazine hydrochloride (207 mg, 2.14 mmol), triethylamine (0.298 mL, 2.14 mmol), and trifluoroacetic acid (0.324 mL, 4.28 mmol) in isopropanol (8.9 mL) was stirred at 60 °C for 18 h. AcOH (1.02 mL, 17.8 mmol) and water (4.5 mL) were added, and the reaction mixture was stirred at 50 °C for 5 h. The reaction mixture was diluted with dichloromethane (20 mL) and 1 N aqueous NaHCO (20 mL). The aqueous layer was extracted with dichloromethane (2 × 20 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a crude mixture of the title compounds (420 mg, 90% yield). LCMS (ESI) [M+H] + =261.2.

[0330] Step 2: 6-((1r,4r)-4-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 15) [ka]

[0331] A solution of crude 4-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexan-1-one and 4-(1-ethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)cyclohexan-1-one (416 mg, 2.40 mmol), 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (474 ​​mg, 2.40 mmol), and 4A molecular sieves (60 mg) in 1,2-dichloroethane (8.0 mL) was stirred at 40 °C for 18 h. Acetic acid (0.183 mL, 3.20 mmol) and sodium triacetoxyborohydride (678 mg, 3.20 mmol) were added, and the reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was diluted with 1N aqueous NH4Cl (1 mL), 1N aqueous NaHCO3 (10 mL), and 10% methanol in dichloromethane (20 mL). The aqueous layer was extracted with 10% methanol in dichloromethane (2 x 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was diluted with DMSO, filtered, and purified by preparative HPLC (acetonitrile / water gradient + 0.1% TFA) to give the first eluting peak as a pure single stereoisomer of the title compound (33 mg, 5% yield). LCMS (ESI) [M+H] + =406.2. 1 H NMR(400MHz,DMSO-d6)δ 6.48(s,1H),4.20-4.03(m,6H),2.80(s,2H),2.77-2.62(m,3H),2.23-2.11(m,1H),2.07 (t,J=7.2Hz,2H),2.00-1.92(m,2H),1.92-1.83(m,2H),1.49-1.21(m,8H). 1 Assignment was based on 1 H NMR analysis.

[0332] 6-((1r,4r)-4-(1-ethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 16) [ka]

[0333] The title compound was synthesized according to a similar procedure to compound 15. The residue was purified by preparative HPLC (acetonitrile / water gradient + 0.1% TFA) to give the second eluting peak as the title compound (4.9 mg, 1% yield) as a pure single stereoisomer. LCMS (ESI) [M+H] + =406.2. 1 H NMR(400MHz,DMSO)δ 6.67(s,1H),4.21-4.03(m,6H),2.79(s,2H),2.65(t,J=7.2Hz,2H),2.59-2.52 (m,1H),2.17-2.02(m,3H),1.99-1.90(m,4H),1.42-1.18(m,7H). 1 Assignment was based on 1 H NMR analysis.

[0334] Example R: (Compounds 17A*, 17B*, 17C* and 17D*): 6-((1S,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide; 6-((1S,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3 6-((1R,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide;6-((1R,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka] 6-(3-(1-Isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide was synthesized following a procedure similar to that performed for compounds 36A-36D, but instead using 3-oxocyclopentanecarboxylic acid and isopropylhydrazine HCl in the triazole-forming reaction (J. Org. Chem. 2011, 76, 1177). The diastereomeric mixture was separated by chiral SFC (Phenomenex Amylose-1, 0.1% ammonium hydroxide / CO2 15:85 in methanol) to give two peaks comprising a cis / trans mixture of 6-(3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide. Peak 1 was then further separated by chiral SFC (Chiralcel OX, 0.1% ammonium hydroxide / CO2 25:75 in methanol) to give the first eluting peak as a pure single undefined enantiomer of the title compound (compound 17A*, 3.8 mg, 1.4% yield). LCMS (ESI) [M+H] + =484.2.

[0335] The diastereomeric mixture was separated by chiral SFC (Phenomenex Amylose-1, 0.1% ammonium hydroxide / CO2 15:85 in methanol) to give two peaks, each constituting a cis / trans mixture of 6-(3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide. Peak 2 was separated by chiral SFC (Chiralcel OX, 0.1% ammonium hydroxide / CO2 25:75 in methanol) to give the first eluting peak as a pure single undefined enantiomer of the title compound (compound 17B*, 3.5 mg, 1.3% yield). LCMS (ESI) [M+H] +=484.2.

[0336] The diastereomeric mixture was separated by chiral SFC (Phenomenex Amylose-1, 0.1% ammonium hydroxide / CO2 15:85 in methanol) to give two peaks comprising a cis / trans mixture of 6-(3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide. Peak 1 was then further separated by chiral SFC (Chiralcel OX, 0.1% ammonium hydroxide / CO2 25:75 in methanol) to give the second eluting peak as a pure single undefined enantiomer of the title compound (compound 17C*) (13 mg, 5% yield). LCMS (ESI) [M+H] + =484.2. 1 H NMR(400MHz,DMSO-d6)δ 9.34-9.20(m,1H),8.59-8.47(m,1H),8.01-7.94(m,1H),4.76(hept,J=6.6Hz,1H),4.18-4.09(m,4H),3.53-3.42 (m,1H),2.81-2.58(m,5H),2.29-2.19(m,1H),2.16-2.02(m,3H),2.01-1.64(m,4H),1.45(dd,J=6.5,2.9Hz,6H).

[0337] The diastereomeric mixture was separated by chiral SFC (Phenomenex Amylose-1, 0.1% ammonium hydroxide / CO2 in methanol 15:85) to give two peaks comprising a cis / trans mixture of 6-(3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide. Peak 2 was then further separated by chiral SFC (Chiralcel OX, 0.1% ammonium hydroxide / CO2 in methanol 25:75) to give the second eluting peak as a pure single undefined enantiomer of the title compound (compound 17D*) (13 mg, 5% yield). LCMS (ESI) [M+H] + =484.2. 1 H NMR δ 9.30-9.24(m,1H),8.58-8.51(m,1H),8.00-7.95(m,1H),4.76(hept,J=6.5Hz,1H),4.19-4.07(m,4H),3.54-3.42 (m,1H),2.83-2.58(m,5H),2.30-2.20(m,1H),2.15-2.02(m,3H),2.01-1.65(m,4H),1.45(dd,J=6.5,2.9Hz,6H).

[0338] Example S: (Compounds 18A*, 18B*, 18C*, and 18D*): 6-((1S,3R)-3-(3-cyclopropyl-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide; 6-((1S,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3 6-((1R,3R)-3-(3-cyclopropyl-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide;6-((1R,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka] 6-(3-(3-cyclopropyl-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide was synthesized following a procedure similar to that of compound 36A, but instead using 3-oxocyclopentanecarboxylic acid, cyclopropylcarbamidine HCl, and isopropylhydrazine HCl in the triazole-forming reaction (J. Org. Chem. 2011, 76, 1177).

[0339] The diastereomeric mixture was separated by chiral SFC (Chiralpak IC, 0.1% ammonium hydroxide in methanol / CO₂ 30:70) to give the first eluting peak as a racemic mixture of 6-(3-(3-cyclopropyl-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide. Peak 1 was then separated by chiral SFC (Chiralpak ID, 0.1% ammonium hydroxide in methanol / CO₂ 25:75) to give the first eluting peak as a pure single enantiomer of the undefined title compound (compound 18A*) (12 mg, 3% yield). LCMS (ESI) [M+H] + =379.2. 1 H NMR(400MHz,DMSO-d6)δ 4.51(hept,J=6.6Hz,1H),4.19-4.08(m,4H),3.47-3.34(m,1H),2.82-2.69(m,3H),2.64-2.56(m,2H),2 .12-1.98(m,3H),1.94-1.83(m,4H),1.75-1.45(m,2H),1.32(dd,J=6.5,3.8Hz,6H),0.85-0.67(m,4H).

[0340] The diastereomeric mixture was separated by chiral SFC (Chiralpak IC, 0.1% ammonium hydroxide in methanol / CO₂ 30:70) to give the first eluting peak as a racemic mixture of 6-(3-(3-cyclopropyl-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide. Peak 1 was then separated by chiral SFC (Chiralpak ID, 0.1% ammonium hydroxide in methanol / CO₂ 25:75) to give the second eluting peak as a pure single enantiomer of the undefined title compound (compound 18B*) (12.2 mg, 3.1% yield). LCMS (ESI) [M+H] + =379.20. 1H NMR(400MHz,DMSO-d6)δ 4.51(hept,J=6.6Hz,1H),4.19-4.08(m,4H),3.47-3.34(m,1H),2.82-2.69(m,3H),2.64-2.56(m,2H),2 .12-1.98(m,3H),1.94-1.83(m,4H),1.75-1.45(m,2H),1.32(dd,J=6.5,3.8Hz,6H),0.85-0.67(m,4H).

[0341] The diastereomeric mixture was separated by chiral SFC (Chiralpak IC, 0.1% ammonium hydroxide in methanol / CO 30:70) to afford the second eluting peak as a pure single undefined enantiomer of 6-(3-(3-cyclopropyl-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (compound 18C*) (6 mg, 1.7% yield). LCMS (ESI) [M+H] + =379.20. 1 H NMR(400MHz,DMSO-d6)δ 4.52(hept,J=6.7Hz,1H),4.18-4.07(m,4H),3.42-3.20(m,2H),2.77-2.54 (m,5H),2.14-1.57(m,8H),1.32(dd,J=6.5,2.5Hz,6H),0.85-0.69(m,4H).

[0342] The diastereomeric mixture was separated by chiral SFC (Chiralpak IC, 0.1% ammonium hydroxide in methanol / CO 30:70) to afford the third eluting peak as a pure single undefined enantiomer of 6-(3-(3-cyclopropyl-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (compound 18D*) (21 mg, 5.6% yield). LCMS (ESI) [M+H] + =379.20. 1H NMR(400MHz,DMSO-d6)δ 4.52(hept,J=6.7Hz,1H),4.18-4.07(m,4H),3.42-3.20(m,2H),2.77-2.54 (m,5H),2.14-1.57(m,8H),1.32(dd,J=6.5,2.5Hz,6H),0.85-0.69(m,4H).

[0343] Example T: (Compounds 19A*, 19B*, 19C*, and 19D*): 6-((3S,5S)-5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 6-((3R,5S)-5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-yl)-2-thia-6-azaspiro[3 .4]octane 2,2-dioxide, 6-((3R,5R)-5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 6-((3S,5R)-5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka] Step 1: 1-(4-(trifluoromethyl)phenyl)but-3-en-1-ol [ka]

[0344] To a stirred solution of 4-(trifluoromethyl)benzaldehyde (2 g, 11.49 mmol) in tetrahydrofuran (20 mL) was added allylmagnesium bromide (13.8 mL, 13.8 mmol, 1 M) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (1500 mg, 60% yield). 1 H NMR(400MHz,CDCl3)δ 7.63(d,J=8.0Hz,2H),7.50(d,J=8.4Hz,2H),5.90-5.75(m,1H),5.26-5.15(m,2H),4.89-4.73(m,1H),2.62-2.43(m,2H),2.26-2.13(m,1H).

[0345] Step 2: 3,4-Dibromo-1-(4-(trifluoromethyl)phenyl)butan-1-ol [ka]

[0346] To a solution of 1-(4-(trifluoromethyl)phenyl)but-3-en-1-ol (2 g, 9.25 mmol) in dichloromethane (10 mL) was added a solution of Br (0.5 mL, 9.76 mmol) in dichloromethane (10 mL) at −30° C. The reaction mixture was stirred at −30° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was used directly in the next step.

[0347] Step 3: 4-Bromo-2-(4-(trifluoromethyl)phenyl)tetrahydrofuran [ka]

[0348] To a solution of 3,4-dibromo-1-(4-(trifluoromethyl)phenyl)butan-1-ol (3.48 g, 9.25 mmol) in anhydrous methanol (20 mL) was added K2CO3 (5.11 g, 37 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 16 h, quenched with saturated aqueous NH4Cl (20 mL), and extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound (1600 mg, 58% yield). 1 H NMR(400MHz,CDCl3)δ 7.62(d,J=8.0Hz,2H),7.47(d,J=8.0Hz,2H),5.42-5.31(m,1H),4.63-4.54(m,2H),4.33-4.28(m,1H),2.76-2.68(m,1H),2.33-2.23(m,1H).

[0349] Step 4: 5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-yl acetate [ka]

[0350] To a solution of 4-bromo-2-(4-(trifluoromethyl)phenyl)tetrahydrofuran (1600 mg, 5.42 mmol) in dimethyl sulfoxide (60 mL) was added potassium acetate (1600 mg, 16.30 mmol). The reaction mixture was stirred at 20 °C for 16 h, quenched with saturated aqueous NH Cl (50 mL), and extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was used directly in the next step.

[0351] Step 5: 5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-ol [ka]

[0352] To a solution of 5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-yl acetate (1486 mg, 5.42 mmol) in anhydrous methanol (60 mL) was added K2CO3 (2.26 g, 16.36 mmol). The reaction mixture was stirred at 20 °C for 16 h, quenched with saturated aqueous NH4Cl (60 mL), and extracted with dichloromethane (50 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was used directly in the next step. 1 H NMR(400MHz,CDCl3)δ 7.63-7.59(m,2H),7.55-7.45(m,2H),5.27-4.93(m,1H),4.70-4.57(m,1H),4.30-4.1 1(m,1H),3.97-3.91(m,1H),2.76-2.37(m,1H),1.95-1.87(m,1H),1.82-1.73(m,1H).

[0353] Step 6: 5-(4-(trifluoromethyl)phenyl)dihydrofuran-3(2H)-one [ka]

[0354] To a solution of 5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-ol (800 mg, 3.45 mmol) in anhydrous dichloromethane (48 mL) was added Dess-Martin periodinane (3.02 g, 7.13 mmol). The reaction mixture was stirred at 25 °C for 5 h, quenched with saturated aqueous NaSO (50 mL), and extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (0–20% ethyl acetate in petroleum ether) to give the racemic mixture of the title compounds (400 mg, 50% yield). The racemic mixture (429 mg, 1.86 mmol) was separated by chiral SFC (Daicel Chiralpak AD-H, 0.1% NH3 / EtOH in water 90:10) to give the first eluting peak as a pure single undefined enantiomer of the title compound (300 mg, 58% yield).

[0355] Step 7: 6-((3R,5R)-5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 6-((3S,5R)-5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0356] The mixture of diastereomers (98.0 mg, 0.26 mmol) was separated by chiral SFC (Daicel Chiralpak AD-H (250 mm × 30 mm, 5 μm); 0.1% NH H O / MeOH = 65:65, 60 mL / min) to give the title compound 19A* (first peak in SFC, 42 mg, 0.11 mmol, 42% yield) and the title compound 19B* (second peak in SFC, 31 mg, 0.08 mmol, 32% yield). LCMS (ESI): [M+H] + =376.2.

[0357] Compound 19A*: 1 H NMR(400MHz,CDCl3)δ 7.61(d,J=8.4Hz,2H),7.47(d,J=8.4Hz,2H),5.00(dd,J=6.8,9.6Hz,1H),4.07-3.94(m,6H),3 .27-3.18(m,1H),2.88-2.70(m,4H),2.54-5.49(m,1H),2.19-2.11(m,2H),1.81-1.78(m,1H).

[0358] Compound 19B*: 1 H NMR(400MHz,CDCl3)δ 7.61(d,J=8.0Hz,2H),7.43(d,J=8.0Hz,2H),5.13(dd,J=7.2,10.4Hz,1H),4.19(dd,J=6.0,8.8Hz,1H),4.09(s,4H),3.83(dd,J=6. 4,8.4Hz,1H),3.12-3.06(m,1H),2.94-2.81(m,2H),2.79-2.72(m,2H),2.47-2.33(m,1H),2.19(t,J=7.2Hz,2H),1.97-1.93(m,1H).

[0359] Step 8: 6-((3S,5S)-5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 6-((3R,5S)-5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0360] To a solution of (S)-5-(4-(trifluoromethyl)phenyl)dihydrofuran-3(2H)-one (peak 2, 50 mg, 0.22 mmol) and 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (66 mg, 0.34 mmol) in anhydrous methanol (4 mL), two drops of acetic acid were added, and the reaction mixture was stirred at 25 °C for 5 min. NaBHCN (70 mg, 1.12 mmol) was then added, and the mixture was stirred at 70 °C for 2 h. The reaction mixture was quenched with saturated NaHCO solution (20 mL) and extracted with dichloromethane (50 mL × 2) and ethyl acetate (50 mL × 2). The combined organic layers were concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (10% methanol in dichloromethane) to give a mixture of diastereoisomers (51 mg, 0.13 mmol, 60% yield). LCMS(ESI)[M+H] + =376.2.

[0361] The mixture of diastereomers (51 mg, 0.13 mmol) was separated by chiral SFC (Daicel Chiralpak AD (250 mm × 30 mm, 10 μm); 0.1% NH / MeOH in HO = 65:65, 70 mL / min) to give the title compound 19C* (first peak in SFC, 17 mg, 0.04 mmol, 33% yield) and the title compound 19D* (second peak in SFC, 21 mg, 0.05 mmol, 41% yield). LCMS (ESI): [M+H] + =376.2.

[0362] Compound 19C*: 1 H NMR(400MHz,CDCl3)δ 7.60(d,J=8.0Hz,2H),7.47(d,J=8.0Hz,2H),5.13-4.85(m,1H),4.11-3.93(m,6H),3.28- 3.17(m,1H),2.93-2.61(m,4H),2.56-2.48(m,1H),2.19-2.12(m,2H),1.91-1.73(m,1H).

[0363] Compound 19D*: 1H NMR(400MHz,CDCl3)δ 7.61(d,J=8.0Hz,2H),7.43(d,J=8.0Hz,2H),5.13(dd,J=7.2,10.4Hz,1H),4.19(dd,J=6.0,8.8Hz,1H),4.09(s,4H),3.83(dd,J=6. 4,8.4Hz,1H),3.12-3.06(m,1H),2.94-2.81(m,2H),2.79-2.72(m,2H),2.47-2.33(m,1H),2.19(t,J=7.2Hz,2H),1.97-1.93(m,1H).

[0364] Example U: (Compounds 20A*, 20B*, 20C*, and 20D*): 6-((1S,3S)-3-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide; 6-((1R,3S)-3-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclopentyl)-2-thia-6-azaspiro[3 6-((1S,3R)-3-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide;6-((1R,3R)-3-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka] Step 1: 1-Isopropyl-4-(trifluoromethyl)imidazole [ka]

[0365] To a stirred solution of 2-iodopropane (3.75 g, 22.05 mmol) and 4-(trifluoromethyl)-1H-imidazole (1.0 g, 7.35 mmol) in N,N-dimethylformamide (10 mL) was added CsCO (11.97 g, 36.74 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica column chromatography (0–50% ethyl acetate in petroleum ether) to give the title compound (1 g, 76.4% yield). 1 H NMR(400MHz,CD3OD)δ 7.86(s,1H),7.74(s,1H),4.60-4.47(m,1H),1.51(d,J=6.4Hz,6H).

[0366] Step 2: 2-Bromo-1-isopropyl-4-(trifluoromethyl)imidazole [ka]

[0367] To a stirred solution of 1-isopropyl-4-(trifluoromethyl)imidazole (5000.0 mg, 28.07 mmol) in anhydrous tetrahydrofuran (50 mL) was added n-butyllithium (13.47 mL, 33.68 mmol) at −75° C. under a nitrogen atmosphere. The reaction was stirred at −76° C. for 30 minutes. NBS (5495 mg, 30.87 mmol) in anhydrous tetrahydrofuran (10 mL) was then added, and the reaction was stirred for 3 hours. The reaction was quenched with saturated aqueous NH4Cl (30 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (100% petroleum ether) to give the title compound (4500 mg, 62.4% yield).

[0368] Step 3: 3-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclopent-2-en-1-one [ka]

[0369] To a stirred solution of 2-bromo-1-isopropyl-4-(trifluoromethyl)imidazole (2.0 g, 7.8 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one (2.43 g, 11.7 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (569 mg, 0.8 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added CsCO (6.34 g, 19.5 mmol). The mixture was stirred at 80 °C under N for 6 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (100% petroleum ether) to give the title compound (1.0 g, 39.8% yield). LCMS (ESI) [M+H] + =259.0.

[0370] Step 4: 3-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclopentan-1-one [ka]

[0371] To a solution of 3-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclopent-2-en-1-one (900.0 mg, 3.49 mmol) in ethanol (10 mL) was added 10% palladium on carbon (742 mg, 0.70 mmol) under N2. The suspension was degassed and purged with H2 (15 psi) three times. The mixture was stirred under H2 (15 psi) at 25 °C for 16 h. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (900 mg, 99% yield). LCMS (ESI) [M+H] + =261.1.

[0372] Step 5: 6-((1S,3S)-3-(1-Isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 20A*): 3-(1-Isopropyl-4-(trifluoromethyl)-H-imidazol-2-yl)cyclopentan-1-one (900.0 mg, 3.46 mmol) was purified by chiral SFC (Daicel Chiralcel OD, 0.1% NH3 in water / EtOH 55:45) to afford the first eluting peak as a pure single undefined enantiomer of 3-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclopentan-1-one (400 mg, 44.4% yield). To a solution of the above material (50.0 mg, 0.19 mmol), 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (42.0 mg, 0.21 mmol) in anhydrous methanol (3 mL) was added NaBHCN (40 mg, 0.63 mmol). The reaction was stirred at 50 °C for 1.5 h. The reaction was concentrated, and the resulting residue was purified by reverse-phase chromatography (acetonitrile / water gradient + 0.05% NHOH) to give a racemic mixture of the title compounds. The racemic mixture was separated by chiral SFC (Daicel Chiralcel OD, 0.1% NH in water / ethanol 55:45) to give the first eluting peak as a pure, single, undefined enantiomer of the title compound (13.6 mg, 17.3% yield, Compound 20A*). LCMS (ESI) [M+H] + =406.2. 1 H NMR(400MHz,CD3OD)δ 7.63(s,1H),4.62-4.54(m,1H),4.20-4.06(m,4H),3.57-3.43(m,1H),3.04-2.88(m,3H),2.79(t,J=7.2Hz,2H ),2.22(t,J=7.2Hz,2H),2.17-1.96(m,4H),1.93-1.85(m,1H),1.68-1.60(m,1H),1.46(dd,J=6.8,2.0Hz,6H).

[0373] Compound 20B* was obtained as the second eluting peak as pure one undefined enantiomer of the title compound (42.8 mg, 54.4% yield). LCMS (ESI) [M+H] + =406.2. 1 H NMR(400MHz,CD3OD)δ 7.59(s,1H),4.58-4.47(m,1H),4.16-4.01(m,4H),3.29-3.25(m,1H),2.90(s,2H),2.86-2.68(m,3H),2.27-2 .15(m,3H),2.11-2.01(m,1H),1.98-1.86(m,3H),1.83-1.75(m,1H),1.41(dd,J=6.8,1.6Hz,6H).The relative cis stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0374] Racemic 3-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclopentan-1-one (900.0 mg, 3.46 mmol) prepared as described above was purified by chiral SFC (Daicel Chiralcel OD, 0.1% NH3 in water / EtOH 55:45) to give the second eluting peak as a pure single undefined enantiomer of 3-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclopentan-1-one (300 mg, 33.3% yield). LCMS (ESI) [M+H] + =261.1. Following a procedure similar to that in Example 44, the above material (50.0 mg, 0.19 mmol) was converted to the racemic mixture of the title compound. The racemic mixture was separated by chiral SFC (Daicel Chiralcel OD, 0.1% NH3 in water / ethanol 55:45) to afford the first eluting peak as a pure single undefined enantiomer of the title compound (59 mg, 37.9% yield, compound 20C*). LCMS (ESI) [M+H] + =406.2. 1H NMR(400MHz,CD3OD)δ 7.65(s,1H),4.59-4.52(m,1H),4.23-4.08(m,4H),3.58-3.46(m,1H),3.05-2.89(m,3H),2.80(t,J=7.2Hz,2H ),2.24(t,J=7.2Hz,2H),2.20-1.95(m,4H),1.94-1.85(m,1H),1.66-1.62(m,1H),1.47(dd,J=6.8,2.0Hz,6H).

[0375] The racemic mixture was separated by chiral SFC (Daicel Chiralcel OD, 0.1% NH3 in water / ethanol 5:45) to give the second eluting peak as a pure single undefined enantiomer of the title compound (35.7 mg, 22.7% yield, compound 20D*). LCMS (ESI) [M+H] + =406.2. 1 H NMR(400MHz,CD3OD)δ 7.63(s,1H),4.56-4.50(m,1H),4.20-4.04(m,4H),3.33-3.29(m,1H),2.92(s,2H),2.88-2.66(m,3H),2 .31-2.16(m,3H),2.15-2.04(m,1H),2.03-1.86(m,3H),1.84-1.73(m,1H),1.45(dd,J=6.8,2.0Hz,6H).

[0376] Example V: 6-((1s,4s)-4-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 21A) and 6-((1r,4r)-4-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 21B) [ka] The title compound was synthesized following a procedure similar to that for compound 3A, using 5-bromo-4-methyl-2-(trifluoromethyl)pyridine in step 1. The mixture of stereoisomers was purified by preparative TLC (10% ethyl acetate in methanol).

[0377] 6-((1s,4s)-4-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (compound 21A): [ka]

[0378] The title compound (30 mg, 9.7% yield) was obtained as the first eluting peak as a pure single stereoisomer. LCMS (ESI) [M+H] + =403.2. 1 H NMR(400MHz,CDCl3)δ 8.50(s,1H),7.45(s,1H),4.08(s,4H),2.93(s,2H),2.82-2.71(m,3H),2.41(s,3H),2.31-2.24 (m,1H),2.19-2.11(m,4H),1.92-1.89(m,2H),1.65-1.54(m,2H),1.44-1.25(m,2H).The relative cis stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0379] 6-((1r,4r)-4-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 21B) [ka]

[0380] The title compound (61 mg, 21.5% yield) was obtained as the second eluting peak as a pure single stereoisomer. LCMS (ESI) [M+H] + =403.2. 1H NMR(400MHz,CDCl3)δ 8.50(s,1H),7.45(s,1H),4.09(s,4H),2.93(s,2H),2.83-2.73(m,3H),2.42(s,3H),2. 19-2.12(m,4H),1.93-1.90(m,2H),1.65-1.55(m,3H),1.41-1.26(m,2H). 1 Assignment was based on 1 H NMR analysis.

[0381] Example W: (Compounds 22A* and 22B*): (R)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (S)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka] 6-(1-(4-(trifluoromethyl)phenyl)azepan-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0382] The title compound was synthesized following a similar procedure to compound 4, using 1,4-dioxa-7-azaspiro[4.5]decane in step 1. The racemic mixture was separated by chiral SFC (Daicel Chiralpak AD-H, 0.1% NH3 in water / IPA 70:30) to afford the first eluting peak as a pure single undefined enantiomer of the title compound (15.6 mg, 19% yield, compound 22A*). LCMS (ESI) [M+H] + =389.0. 1H NMR(400MHz,CD3OD)δ 7.50-7.42(m,2H),7.02(d,J=8.8Hz,2H),4.15-4.05(m,4H),3.90-3.98(m,1H),3.80-3.70(m,1H),3.00-2.95(m,2H),2.92-2.7 5(m,4H),2.47-2.37(m,1H),2.19(t,J=7.2Hz,2H),2.12-2.04(m,1H),1.89-1.80(m,1H),1.72-1.57(m,1H),1.52-1.39(m,1H).

[0383] The same purification conditions provided afforded the second eluting peak as a pure single undefined enantiomer of the title compound (20.0 mg, 24% yield, Compound 22B*). LCMS (ESI) [M+H] + =389.0. 1 H NMR(400MHz,CD3OD)δ7.45(d,J=8.8Hz,2H),7.02(d,J=8.8Hz,2H),4.18-4.04(m,4H),3.95-3.90(m,1H),3.73(d,J=12.8Hz,1H),3.00-2.95(m ,2H),2.92-2.74(m,4H),2.47-2.37(m,1H),2.19(t,J=7.2Hz,2H),2.11 -2.03(m,1H),1.89-1.79(m,1H),1.71-1.58(m,1H),1.53-1.39(m,1H).

[0384] Example X: 6-((1s,4s)-4-(1-cyclobutyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 23A), 6-((1r,4r)-4-(1-cyclobutyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 23B), and 6-((1r,4r)-4-(1-cyclobutyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 24) [ka] The title compound was synthesized following a similar procedure to compound 12A, using cyclobutylhydrazine hydrochloride in step 2. Separation of the isomers by reverse-phase HPLC afforded the purified products compounds 23A, 23B, and 24.

[0385] 6-((1s,4s)-4-(1-cyclobutyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (compound 23A) [ka]

[0386] LCMS(ESI)[M+H] + =432.2. 1 H NMR(400MHz,DMSO-d6)δ 6.50(s,1H),4.97(m,1H),4.21-4.07(m,4H),2.89-2.78(m,1H),2.73(s,2H),2.60(t,J=7.2Hz,2H),2.55-2.51(m ,2H),2.41-2.29(m,3H),2.09(t,J=7.3Hz,2H),1.88-1.77(m,4H),1.76-1.64(m,2H),1.61-1.48(m,4H).cis stereochemistry 1 Assignment was based on 1 H NMR analysis.

[0387] 6-((1r,4r)-4-(1-cyclobutyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (compound 23B) [ka]

[0388] LCMS(ESI)[M+H] + =432.2. 1H NMR(400MHz,DMSO-d6)δ 6.48(s,1H),5.03-4.91(m,1H),4.22-4.01(m,4H),2.85-2.60(m,5H),2.59-2.51(m,2H),2.41-2. 32(m,2H),2.22-2.02(m,3H),2.01-1.91(m,2H),1.88-1.74(m,4H),1.48-1.22(m,4H).Trans stereochemistry 1 Assignment was based on 1 H NMR analysis.

[0389] 6-((1r,4r)-4-(1-cyclobutyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 24) [ka]

[0390] LCMS(ESI)[M+H] + =432.2. 1 H NMR(400MHz,DMSO-d6)δ 6.50(s,1H),4.97(m,1H),4.21-4.07(m,4H),2.89-2.78(m,1H),2.73(s,2H),2.60(t,J=7.2Hz,2H),2.55-2.51(m, 2H),2.41-2.29(m,3H),2.09(t,J=7.3Hz,2H),1.88-1.77(m,4H),1.76-1.64(m,2H),1.61-1.48(m,4H).Trans stereochemistry 1 Assignment was based on 1 H NMR analysis.

[0391] Example Y: 7-((1s,4s)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (Compound 25A) and 7-((1r,4r)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (Compound 25B) [ka] The title compound was synthesized following a similar procedure to compound 15, using methylhydrazine hydrochloride in step 1 and 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride in step 2. The crude mixture was purified by reverse-phase HPLC to give the title compound.

[0392] Compound 25A: 7-((1s,4s)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide. LCMS (ESI) [M+H] + =406.2. 1 H NMR(400MHz,DMSO-d6)δ 6.47(s,1H),3.91(s,4H),3.84(s,3H),2.72-2.63(m,1H),2.49-2.42(m,4H),2.3 9-2.29(m,1H),1.96-1.89(m,2H),1.83-1.70(m,6H),1.47-1.30(m,4H).cis stereochemistry 1 Assignment was based on 1 H NMR analysis.

[0393] Compound 25B: 7-((1r,4r)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide. LCMS (ESI) [M+H] + =406.2. 1 H NMR(400MHz,DMSO-d6)δ 6.49(s,1H),3.91(s,4H),3.84(s,3H),2.97-2.86(m,1H),2.47-2.24(m,4H),2.23-2.17(m,1H),1.93- 1.82(m,2H),1.79(t,J=5.4Hz,4H),1.76-1.67(m,2H),1.66-1.56(m,2H),1.56-1.45(m,2H).Trans stereochemistry 1 Assignment was based on 1 H NMR analysis.

[0394] Example Z: (Compounds 26A* and 26B*): (S)-7-((1r,4S)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide and (R)-7-((1r,4R)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide [ka]

[0395] 7-((1r,4r)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide [ka]

[0396] The racemic mixture of 7-((1r,4r)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide was synthesized following a procedure similar to that for compound 15, using methylhydrazine hydrochloride in step 1 and 2-thia-7-azaspiro[4.5]decane 2,2-dioxide hydrochloride in step 2.

[0397] The mixture was separated by chiral SFC (Chiralpak IC, 0.1% ammonium hydroxide in methanol / CO2 25:75) to give the first eluting peak as a pure single undefined enantiomer of the title compound (4.3 mg, 4% yield, compound 26A*). LCMS (ESI) [M+H] + =420.2. 1H NMR (400 MHz, DMSO) δ 6.48 (s, 1H), 3.84 (s, 3H), 3.20-3.12 (m, 3H), 2.88 (d, J = 13.6 Hz, 1H), 2.73-2.57 (m, 3H), 2.44-2.33 (m, 2H), 2.26-2.19 (m, 1H), 2.09-1.98 (m, 1H), 1.96-1.72 (m, 5H), 1.64-1.49 (m, 2H), 1.49-1.31 (m, 6H). The stereochemistry of the chiral centers in the spiro ring was arbitrarily assigned.

[0398] The second eluting peak was also obtained as a pure single undefined enantiomer of the title compound (4.0 mg, 4% yield, Compound 26B*). LCMS (ESI) [M+H] + =420.2. 1 H NMR (400 MHz, DMSO-d₆) δ 6.48 (s, 1H), 3.84 (s, 3H), 3.20-3.12 (m, 3H), 2.88 (d, J = 13.6 Hz, 1H), 2.72-2.55 (m, 3H), 2.44-2.32 (m, 2H), 2.26-2.19 (m, 1H), 2.10-1.98 (m, 1H), 1.97-1.73 (m, 5H), 1.64-1.50 (m, 2H), 1.49-1.30 (m, 6H). The stereochemistry of the chiral centers in the spiro ring was arbitrarily assigned.

[0399] Example AA: (Compounds 27A* and 27B*): (R)-7-((1r,4R)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[4.4]nonane 2,2-dioxide and (S)-7-((1r,4S)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[4.4]nonane 2,2-dioxide [ka] 7-((1r,4r)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[4.4]nonane 2,2-dioxide [ka]

[0400] The racemic mixture of 7-((1r,4r)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[4.4]nonane 2,2-dioxide was synthesized following a procedure similar to that for compound 15, using methylhydrazine hydrochloride in step 1 and 2-thia-7-azaspiro[4.4]nonane 2,2-dioxide hydrochloride in step 2.

[0401] The mixture was separated by chiral SFC (Chiralpak IA, 0.1% ammonium hydroxide in methanol / CO 15:85) to give the first eluting peak as a pure single undefined enantiomer of the title compound (18.5 mg, 18% yield). Compound 27A*: LCMS (ESI) [M+H] + =406.2. 1 H NMR(400MHz,DMSO-d6)δ 6.49(s,1H),3.84(s,3H),3.20-3.13(m,2H),3.12-3.04(m,2H),2.76-2.65(m,3H),2.64- 2.56(m,1H),2.55-2.51(m,1H),2.19-2.06(m,3H),2.00-1.74(m,6H),1.45-1.22(m,4H).

[0402] The second eluting peak was also obtained as a pure single undefined enantiomer of the title compound (18.3 mg, 18% yield). Compound 27B*: LCMS (ESI) [M+H] + =406.2. 1H NMR (400 MHz, DMSO-d6) δ 6.49 (s, 1H), 3.84 (s, 3H), 3.20-3.13 (m, 2H), 3.13-3.04 (m, 2H), 2.76-2.65 (m, 3H), 2.64-2.52 (m, 2H), 2.21-2.04 (m, 3H), 2.01-1.82 (m, 5H), 1.82-1.72 (m, 1H), 1.45-1.22 (m, 4H). The stereochemistry of the chiral centers in the spiro ring was arbitrarily assigned.

[0403] Example BB: 6-(1-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 28) Step 1: 8-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane [ka]

[0404] A solution of 5-bromo-4-methyl-2-(trifluoromethyl)pyridine (250 mg, 1.04 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (225 mg, 1.58 mmol) in tetrahydrofuran (5 mL) was treated with sodium t-butoxide (300 mg, 3.13 mmol) and Pd-PEPPSI-IHept in a glovebox. Cl -Py (113 mg, 0.11 mmol) was added. The reaction mixture was stirred at 60 °C under N2 atmosphere for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica column chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (280 mg, 89% yield). LCMS (ESI) [M+H] + =303.1.

[0405] Step 2: 1-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)piperidin-4-one [ka]

[0406] 8-(4-Methyl-6-(trifluoromethyl)pyridin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane (280 mg, 0.93 mmol) and hydrochloric acid (12 mL, 72 mmol, 6 M) were stirred at 25 °C for 16 hours. The pH of the reaction mixture was adjusted to pH = 9 using saturated aqueous NaHCO3 (30 mL) at 0 °C. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica column chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (200 mg, 79.4% yield). LCMS (ESI) [M+H] + =259.1.

[0407] Step 3: 6-(1-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, compound 28 [ka]

[0408] To a solution of 1-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)piperidin-4-one (80 mg, 0.31 mmol) and 2-thia-6-azaspiro[3.4]octane 2,2-dioxide (100 mg, 0.62 mmol) in anhydrous methanol (4 mL) was added NaBHCN (100 mg, 1.59 mmol) and acetic acid (0.08 mL) at 20 °C. The reaction mixture was stirred at 50 °C for 15 hours. The reaction was quenched with saturated aqueous NaHCO (6 mL) and extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (10% methanol in dichloromethane) to give the title compound (33.4 mg, 26.2% yield). LCMS(ESI)[M+H] + =404.2. 1 H NMR(400MHz,CDCl3)δ 8.30(s,1H),7.46(s,1H),4.09(s,4H),3.24(d,J=12.0Hz,2H),2.92(s,2H),2.87-2.71(m,4H),2 .36(s,3H),2.35-2.27(m,1H),2.19(t,J=7.2Hz,2H),1.99(d,J=12.8Hz,2H),1.77-1.64(m,2H).

[0409] Example CC: 6-(1-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 29) [ka] The title compound was synthesized following a similar procedure to compound 28, using 3-bromo-2-methyl-6-(trifluoromethyl)pyridine in step 1. The crude mixture was purified by reverse-phase HPLC to give the title compound.

[0410] LCMS(ESI)[M+H] + =404.2. 1H NMR(400MHz,CDCl3)δ 7.46(d,J=8.4Hz,1H),7.31(d,J=8.4Hz,1H),4.09(s,4H),3.21(d,J=12.0Hz,2H),2.93(s,2H),2.80(t,J=7.2Hz,2H),2 .71(t,J=10.8Hz,2H),2.58(s,3H),2.37-2.27(m,1H),2.19(t,J=7.2Hz,2H),1.99(d,J=11.6Hz,2H),1.80-1.65(m,2H).

[0411] Example DD: 6-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 30) [ka] The title compound was synthesized following a similar procedure to compound 28, using 2-bromo-3-chloro-5-(trifluoromethyl)pyridine in step 1. The crude mixture was purified by reverse phase HPLC to give the title compound. LCMS (ESI) [M+H] + =424.0. 1 H NMR(400MHz,DMSO-d6,)δ 8.52(s,1H),8.16(s,1H),4.17-4.09(m,4H),3.93(d,J=12.8Hz,2H),2.99(t,J=11.6Hz,2H),2.90-2.8 0(m,2H),2.75-2.65(m,2H),2.43-2.32(m,1H),2.09(s,2H),1.91(d,J=11.2Hz,2H),1.60-1.45(m,2H).

[0412] Example EE: 6-(1-(5-fluoro-3-methylpyridin-2-yl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 31) [ka] The title compound was synthesized following a similar procedure to compound 28, using 2-bromo-5-fluoro-3-methylpyridine in step 1. The crude mixture was purified by reverse phase HPLC to give the title compound. LCMS (ESI) [M+H] + =353.9. 1 H NMR(400MHz,CD3OD)δ 7.96(d,J=2.8Hz,1H),7.39(dd,J=8.8,2.4Hz,1H),4.28-4.15(m,4H),3.43-3.35(m,4H),3.21 (t,J=7.2Hz,2H),2.88-2.77(m,3H),2.40-2.25(m,5H),2.15-2.05(m,2H),1.95-1.80(m,2H).

[0413] Example FF: 6-(1-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 32) [ka] The title compound was synthesized following a similar procedure to compound 4, using 2,3-difluoro-5-(trifluoromethyl)pyridine in step 1. The crude mixture was purified by reverse-phase HPLC to give the title compound. LCMS (ESI) [M+H] + =408.2. 1 H NMR(400MHz,DMSO-d6)δ 8.32(s,1H),7.92-7.88(m,1H),4.16-4.08(m,6H),3.14-3.08(m,2H),2.79(s,2H),2.67- 2.64(m,2H),2.50-2.39(s,1H),2.09-2.06(m,2H),1.89-1.87(m,2H),1.48-1.42(m,2H).

[0414] Example GG: (trans)-6-(4-(3-(5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (compound 33A) and (cis)-6-(4-(3-(5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (compound 33B) [ka] Step 1: [5-(difluoromethoxy)-3-pyridyl]boronic acid [ka]

[0415] To a solution of 3-bromo-5-(difluoromethoxy)pyridine (1 g, 4.5 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2 dioxaborolane) (2 g, 9 mmol) in 1,4-dioxane (15 mL) was added potassium acetate (1.3 g, 13.4 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (326 mg, 0.5 mmol). The mixture was stirred at 80 °C under N for 16 h. The crude product was used in the next step without further purification. LCMS (ESI) [M+H] + =190.0.

[0416] Step 2: 4-(3-(5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)cyclohexan-1-one [ka]

[0417] To a solution of [5-(difluoromethoxy)-3-pyridyl]boronic acid (662 mg, 3.51 mmol), 4-(5-bromo-2-isopropyl-pyrazol-3-yl)cyclohexanone (500 mg, 1.75 mmol), and K2CO3 (727 mg, 5.3 mmol) in 1,4-dioxane (10 mL) and water (2 mL), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (128 mg, 0.18 mmol) was added. The mixture was stirred at 100 °C under N2 for 16 hours. The mixture was diluted with water (25 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (25 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica chromatography to give the title compound (400 mg, 65% yield). LCMS(ESI)[M+H] + =350.0.

[0418] Step 3A: 6-((1r,4r)-4-(3-(5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 33A) [ka]

[0419] To a solution of 4-(3-(5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)cyclohexan-1-one (100 mg, 0.29 mmol) in methanol (5 mL) was added 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (68 mg, 0.34 mmol), acetic acid (0.02 mL), and NaBHCN (90 mg, 1.43 mmol). The mixture was stirred at 50 °C for 3 hours. The reaction mixture was diluted with water (10 mL), and the pH was adjusted to approximately pH 9 with saturated aqueous NaHCO (10 mL). The mixture was extracted with dichloromethane (20 ml × 3). The combined organic layers were washed with brine (25 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (acetonitrile / water gradient containing 0.05% NH and 10 mM NHHCO) to give the first eluting peak as a pure single stereoisomer of the title compound (58 mg, 40% yield). LCMS (ESI) [M+H] + =495.0. 1 H NMR (400 MHz, CDCl3) δ 8.84(d,J=1.6Hz,1H),8.37(d,J=2.4Hz,1H),7.89(s,1H),6.81-6.21(m ,2H),4.53-4.34(m,1H),4.08(s,4H),2.95-2.76(m,4H),2.60(t,J=11. 2Hz,1H),2.23(d,J=11.2Hz,1H),2.17(t,J=7.2Hz,2H),2.13-2.01(m,4H),1.59(s,2H),1.54(d,J=6.4Hz,6H),1.49-1.29(m,2H).The trans relative stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0420] Step 3B: (cis)-6-(4-(3-(5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (compound 33B) [ka]

[0421] The title compound was synthesized according to a procedure similar to that for Compound 33A. The crude mixture was purified by preparative HPLC (acetonitrile / water gradient containing 0.05% NH3 and 10 mM NH4HCO3) to give the second eluting peak as the pure single stereoisomer of the title compound (32.6 mg, 22% yield). LCMS (ESI) [M+H] + =495.0. 1 H NMR(400MHz,CDCl3)(400MHz,CDCl3)δ 8.87(d,J=1.6Hz,1H),8.37(d,J=2.4Hz,1H),7.89(s,1H),6.96-6.23(m,2H),4.47(td,J=6.4,12.8Hz,1H),4.25-3.88(m,4H),2.85(s,2H),2 .77-2.72(m,2H),2.72-2.65(m,1H),2.44(s,1H),2.20-2.16(m,2H),1.99-1.80(m,4H),1.72-1.60(m,4H),1.54(d,J=6.4Hz,6H).The relative cis stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0422] Example HH: 6-((1r,4r)-4-(3-(3,3-difluoroazetidin-1-yl)-1-isopropyl-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 35) [ka] Step 1: 6-((1r,4r)-4-(3-bromo-1-isopropyl-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0423] To a solution of 2-thia-6-azaspiro[3.4]octane 2,2-dioxide (735 mg, 4.56 mmol) and 4-(3-bromo-1-isopropyl-1H-pyrazol-5-yl)cyclohexanone (1000.0 mg, 3.51 mmol) in methanol (20 mL) was added acetic acid (631 mg, 10.52 mmol) and NaBHCN (661 mg, 10.52 mmol). The mixture was stirred at 50 °C for 16 hours. The reaction mixture was diluted with aqueous NaHCO (50 mL) and extracted with dichloromethane (50 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-2% methanol in dichloromethane) to give the second eluting peak as a pure single stereoisomer of the above-titled compound (1000 mg, 66% yield). 1 H NMR(400MHz,CDCl3)δ 5.95(s,1H),4.46-4.31(m,1H),4.08(s,4H),2.92(s,2H),2.80(t,J=6.8Hz,2H),2.54(t,J= 11.6Hz,1H),2.32-2.16(m,3H),2.11-1.89(m,4H),1.48(d,J=6.4Hz,6H),1.45-1.21(m,4H).

[0424] Step 2: 2-((1s,4s)-4-(3-(5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)cyclohexyl)-7-oxa-2-azaspiro[3.5]nonane [ka]

[0425] To a solution of 6-((1r,4r)-4-(3-bromo-1-isopropyl-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (80 mg, 0.19 mmol) and 3,3-difluoroazetidine hydrochloride (36 mg, 0.28 mmol) in tetrahydrofuran (3 mL) was added sodium tert-butoxide (54 mg, 0.56 mmol) and Pd-PEPPSI-IHeptCl-Py (21 mg, 0.02 mmol) in a glove box. The resulting mixture was stirred at 60 °C under a N atmosphere for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography (acetonitrile / water gradient containing 0.05% NH3 and 10 mM NH4HCO3) to give the title compound (32.6 mg, 38% yield) as a pure single stereoisomer. LCMS (ESI) [M+H] + =443.1. 1 H NMR(400MHz,CD3OD)δ 5.42(s,1H),4.48-4.41(m,1H),4.19-4.16(m,3H),4.13-4.08(m,5H),2.97(s,2H),2.82(t,J=7.2Hz,2H),2.64-2.58(m,1H),2. 27-2.18(m,3H),2.11-2.08(m,2H),1.97-1.94(m,2H),1.53-1.43(m,3H),1.39(d,J=6.4Hz,6H),1.38-1.28(m,1H). 1 Assignment was based on 1 H NMR analysis.

[0426] Example II: (Compounds 36A* and 36B*): 6-((1r,4r)-4-(1-ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and 6-((1s,4s)-4-(1-ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka] Step 1: 4-(1-ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclohexan-1-one [ka]

[0427] The title compound (130 mg, 54% yield) was obtained using silica flash column chromatography (heptane / isopropyl acetate) according to the general procedure in J. Org. Chem. 2011, 76, 1177. LCMS (ESI) [M+H] + =353.2.

[0428] Step 2: 6-(4-(1-ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0429] To a mixture of 4-(1-ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclohexan-1-one (160 mg, 0.47 mmol) and 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (197 mg, 0.95 mmol) in dichloroethane (2.4 mL) was added 4 Å molecular sieves (200 mg). The reaction was stirred at 40° C. for 18 hours, whereupon acetic acid (27 μL, 0.47 mmol) and sodium triacetoxyborohydride (150 mg, 0.71 mmol) were added. The reaction was stirred at 25° C. for an additional 18 hours, then diluted with DCM and the saturated sodium bicarbonate solution was dried over MgSO, filtered, and concentrated in vacuo.

[0430] The mixture of cis and trans isomers was separated by reverse-phase HPLC (acetonitrile / water gradient + 0.1% TFA) to give the first eluting peak as the title compound (41 mg, 14.5%), compound 36A*, as a pure single stereoisomer. LCMS (ESI) [M+H] + =484.2. 1 H NMR(400MHz,DMSO-d6)δ 9.33(d,J=2.0Hz,1H),8.60-8.51(m,1H),8.06-7.98(m,1H),4.45-4.32(m,3H),4.29-4.21(m,3H),4.00-3.5 2(m,3H),3.39-3.25(m,2H),2.49-2.40(m,1H),2.35-2.25(m,1H),2.14-1.75(m,9H),1.43(t,J=7.2Hz,3H).

[0431] The second eluting peak was the title compound (38 mg, 13.4%) as a pure single stereoisomer of Compound 36B*. LCMS (ESI) [M+H] + =484.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.26(d,J=2.1Hz,1H),8.56-8.48(m,1H),8.02-7.97(m,1H),4.45-4.33(m,3H) ,4.32-4.24(m,3H),3.86(dd,J=12.0,5.9Hz,1H),3.68-3.53(m,2H),3.42-3.2 8(m,1H),3.08-2.98(m,1H),2.49-2.37(m,2H),2.35-2.25(m,1H),2.15(dt,J= 22.8,11.5Hz,2H),2.07-2.01(m,2H),1.78-1.49(m,4H),1.43(t,J=7.2Hz,3H).

[0432] Example JJ: (Compounds 38A*, 38B*, 38C* and 38D*) (S)-7-((1s,4R)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[4.4]nonane 2,2-dioxide; (R)-7-((1s,4S)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[4. 4]nonane 2,2-dioxide; (S)-7-((1r,4S)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[4.4]nonane 2,2-dioxide, and (R)-7-((1r,4R)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[4.4]nonane 2,2-dioxide [ka] The title compound was synthesized generally following the procedure for compound 15, using methylhydrazine in step 1. The mixture of isomers was separated by chiral SFC (Chiralpak IA, 0.1% ammonium hydroxide in methanol / CO 15:85) to give the four isomers as pure single undefined enantiomers.

[0433] Compound 38A*:LCMS(ESI)[M+H] + =406.2. 1 H NMR(400MHz,DMSO-d6)δ 6.47(s,1H),3.84(s,3H),3.23-3.07(m,4H),2.84-2.76(m,1H),2.71-2.61(m,2H),2.59-2.52(m,1H) ),2.43(d,J=9.1Hz,1H),2.31-2.27(m,1H),2.24-2.07(m,2H),1.96-1.64(m,6H),1.61-1.48(m,4H).

[0434] Compound 38B*:LCMS(ESI)[M+H] + =406.2.

[0435] Compound 38C*:LCMS(ESI)[M+H] + =406.2. 1 H NMR(400MHz,DMSO-d6)δ 6.49(s,1H),3.84(s,3H),3.20-3.13(m,2H),3.12-3.04(m,2H),2.76-2.65(m,3H),2.64 -2.56(m,1H),2.55-2.51(m,1H),2.19-2.06(m,3H),2.00-1.74(m,6H),1.45-1.22(m,4H)

[0436] Compound 38D*:LCMS(ESI)[M+H] + =406.2. 1 H NMR(400MHz,DMSO-d6)(400MHz,DMSO-d6)δ 6.49(s,1H),3.84(s,3H),3.20-3.13(m,2H),3.13-3.04(m,2H),2.76-2.65(m,3H),2.64- 2.52(m,2H),2.21-2.04(m,3H),2.01-1.82(m,5H),1.82-1.72(m,1H),1.45-1.22(m,4H).

[0437] Example KK: 7-((1r,4r)-4-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (Compound 40A) and 7-((1s,4s)-4-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (Compound 40B) [ka] The title compound was synthesized generally following the procedure for compound 15, using cyclopropylhydrazine in step 1 and 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride in step 2. The crude mixture was purified by reverse-phase HPLC to provide the title compound.

[0438] 7-((1r,4r)-4-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (Compound 40A). LCMS (ESI) [M+H] + =432.2. 1 H NMR(400MHz,DMSO-d6)δ 6.49(s,1H),3.91(s,4H),3.75-3.65(m,1H),3.18-3.07(m,1H),2.46-2.27(m,4H),2.26-2.18(m,1H), 1.92-1.84(m,2H),1.83-1.73(m,6H),1.73-1.62(m,2H),1.58-1.46(m,2H),1.14-0.98(m,4H). 1 Assigned by 1 H NMR analysis.

[0439] 7-((1s,4s)-4-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (Compound 40B). LCMS (ESI) [M+H] + =432.2. 1 H NMR(400MHz,DMSO-d6)δ 6.49(s,1H),3.91(s,4H),3.75-3.65(m,1H),2.93-2.82(m,1H),2.48-2.41(m,4H),2.40-2.30(m,1H),2. 05-1.96(m,2H),1.86-1.79(m,2H),1.76(t,J=5.3Hz,4H),1.47-1.32(m,4H),1.14-0.98(m,4H). 1 Assigned by 1 H NMR analysis.

[0440] Example LL: (Compounds 42A*, 42B*, 42C*, and 42D*): 7-((1S,3R)-3-(1-cyclopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide, 7-((1R,3R)-3-(1-cyclopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3 .5]nonane 2,2-dioxide, 7-((1S,3S)-3-(1-cyclopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide, and 7-((1R,3S)-3-(1-cyclopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka] The title compound was synthesized following a procedure similar to that for compound 36A. The cis / trans mixture was separated by chiral SFC (Chiralpak IH, 0.1% ammonium hydroxide / CO2 15:85 in methanol) to give the second eluting peak as a pure, single, undefined stereoisomer of the title compound (14 mg, 5% yield, compound 42A*). LCMS (ESI) [M+H] + =496.1. 1H NMR(400MHz,DMSO-d6)δ 8.28(d,J=7.9Hz,1H),8.21-8.12(m,1H),7.94-7.88(m,1H),4.00-3.85 (m,4H),3.78-3.68(m,1H),3.61-3.48(m,1H),3.30-3.23(m,1H),2.77-2 .66(m,1H),2.47-2.39(m,2H),2.38-2.27(m,2H),2.17-2.07(m,1H),1.9 7-1.85(m,2H),1.84-1.72(m,5H),1.72-1.61(m,1H),1.24-1.06(m,4H).

[0441] The first eluting peak was also obtained as a pure single undefined stereoisomer of the title compound (44 mg, 17% yield, Compound 42B*). LCMS (ESI) [M+H] + =496.1. 1 H NMR(400MHz,DMSO-d6)δ 8.27(d,J=7.9Hz,1H),8.21-8.12(m,1H),7.94-7.88(m,1H),3.92(s,4H),3.79-3.69(m,1H),3.69-3.56(m,1H),2.82(p,J=7 .6Hz,1H),2.49-2.28(m,4H),2.25-2.14(m,1H),2.14-1.96(m,3H),1.94-1.75(m,5H),1.60-1.48(m,1H),1.24-1.07(m,4H).

[0442] The title compound was synthesized following a procedure similar to that for compound 36A. The cis / trans mixture was separated by chiral SFC (Chiralpak IA, 0.1% ammonium hydroxide / CO2 25:75 in methanol) to afford the second eluting peak as a pure, single, undefined stereoisomer of the title compound (47 mg, 25% yield, compound 42C*). LCMS (ESI) [M+H] + =496.1. 1H NMR(400MHz,DMSO-d6)δ 8.27(d,J=7.9Hz,1H),8.23-8.16(m,1H),7.97-7.90(m,1H),4.19-4.07(m,4H),3.80-3.55(m,5H ),3.06-2.92(m,2H),2.62-2.54(m,1H),2.28-2.14(m,5H),2.08-1.92(m,4H),1.24-1.12(m,4H).

[0443] The first peak was also obtained as a pure single undefined stereoisomer (cis or trans) of the title compound (9.5 mg, 5% yield, Compound 42D*). LCMS (ESI) [M+H] + =496.1. 1 H NMR(400MHz,DMSO-d6)δ δ 8.27(d,J=7.9Hz,1H),8.22-8.12(m,1H),7.95-7.87(m,1H),3.92(s,4H) ),3.79-3.69(m,1H),3.69-3.56(m,1H),2.88-2.75(m,1H),2.42-2.36( m,4H),2.25-2.08(m,1H),2.14-2.02(m,1H),2.06-1.95(m,2H),1.95-1 .79(m,1H),1.79(t,J=5.4Hz,4H),1.61-1.46(m,1H),1.26-1.00(m,4H).

[0444] Example MM: (Compounds 43A* and 43B*): (trans)-7-(-4-(1-ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and (cis)-7-(-4-(1-ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka] 7-(4-(1-ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0445] The title compound was synthesized following a similar procedure to compound 36A. The cis / trans mixture was purified by reverse phase HPLC to give the title compound.

[0446] Compound 43A:LCMS(ESI)[M+H] + =498.2 1 H NMR(400MHz,DMSO-d6)δ 9.30-9.25(m,1H),8.57-8.50(m,1H),8.03-7.96(m,1H),4.24(q,J=7.2Hz,2H),3.94-3.89(m,4H),3.22-3.15(m,1H),2.49-2.35(m ,4H),2.31-2.25(m,1H),2.08-1.88(m,4H),1.84-1.76(m,4H),1.70-1.60(m,2H),1.60-1.50(m,2H),1.41(t,J=7.2Hz,3H). 1 Assigned by 1 H NMR analysis.

[0447] Compound 43B:LCMS(ESI)[M+H] + =498.2 1 H NMR(400MHz,DMSO-d6)δ 9.26(d,J=2.0Hz,1H),8.56-8.49(m,1H),8.01-7.95(m,1H),4.25(q,J=7.2Hz,2H),3.94-3.89(m,4H),2.98-2.8 6(m,1H),2.49-2.37(m,5H),1.98-1.91(m,2H),1.88-1.73(m,6H),1.72-1.58(m,2H),1.50-1.37(m,5H). 1 Assigned by 1 H NMR analysis.

[0448] Example NN: 6-(1-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, compound 44 [ka] Step 1: 8-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane [ka]

[0449] To a solution of 1,4-dioxa-8-azaspiro[4.5]decane (0.42 mL, 5.01 mmol) and 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (1000 mg, 5.01 mmol) in dimethyl sulfoxide (10 mL) was added K2CO3 (2078 mg, 15.04 mmol) at 25 °C. The reaction mixture was stirred at 100 °C for 16 h. The mixture was diluted with ethyl acetate (200 mL) and washed with water (50 mL) and brine (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica column chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (1500 mg, 92.7% yield). LCMS (ESI) [M+H] + =323.1.

[0450] Step 2: 1-[3-chloro-5-(trifluoromethyl)-2-pyridyl]piperidin-4-one [ka]

[0451] To a suspension of 8-[3-chloro-5-(trifluoromethyl)-2-pyridyl]-1,4-dioxa-8-azaspiro[4.5]decane (1500.0 mg, 4.64 mmol) in water (20 mL) was added HCl (1.94 mL, 11.84 mmol, 6 M) at 20 °C. The reaction mixture was stirred at 20 °C for 2 h and then cooled to 0 °C. The pH was adjusted to approximately pH 7 with saturated aqueous NaHCO (10 mL). The mixture was extracted with ethyl acetate (40 mL × 2). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica column chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (1000 mg, 56.4% yield). LCMS (ESI) [M+H] + =279.1.

[0452] Step 3: 1-[3-cyclopropyl-5-(trifluoromethyl)-2-pyridyl]piperidin-4-one [ka]

[0453] To a suspension of 1-[3-chloro-5-(trifluoromethyl)-2-pyridyl]piperidin-4-one (200.0 mg, 0.72 mmol), potassium (cyclopropylmethyl)trifluoroborate (581 mg, 3.59 mmol), and CsCO (701 mg, 2.15 mmol) in dioxane (5 mL) and water (1 mL), [2-(2-aminophenyl)phenyl]-chloro-palladium, bis(1-adamantyl)-butyl-phosphane (48 mg, 0.07 mmol) was added. The reaction mixture was stirred at 90 °C under N for 16 h. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (0–30% ethyl acetate in petroleum ether) to give the title compound (200 mg, 98% yield). LCMS(ESI)[M+H] + =285.1.

[0454] Step 4: 6-(1-(3-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, compound 44 [ka]

[0455] To a solution of 1-[3-cyclopropyl-5-(trifluoromethyl)-2-pyridyl]piperidin-4-one (50.0 mg, 0.18 mmol), 2-thia-6-azaspiro[3.4]octane 2,2-dioxide (34 mg, 0.21 mmol), and acetic acid (0.1 mL) in methanol (2.5 mL) was added NaBHCN (55 mg, 0.88 mmol). The reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (25 mL × 3). The organic layer was washed with brine (25 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (36.9 mg, 46.4% yield). LCMS (ESI) [M+H] + =429.7. 1 H NMR(400MHz,CD3OD)δ 8.26(s,1H),7.40(d,J=2.4Hz,1H),4.14-4.12(m,4H),3.98-3.95(m,2H),3.00(s,2H),2.99-2.91(m,2H),2.86-2.82(m,2 H),2.46-2.38(m,1H),2.21(t,J=7.2Hz,2H),2.10-1.98(m,3H),1.76-1.63(m,2H),1.14-1.10(m,2H),0.79-0.77(m,2H).

[0456] Example 00: 6-(1-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 45) [ka] Step 1: 8-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane [ka]

[0457] To a solution of 2-chloro-5-fluoro-3-(trifluoromethyl)pyridine (200 mg, 1.0 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (215 mg, 1.5 mmol), and sodium tert-butoxide (289 mg, 3 mmol) in tetrahydrofuran (1 mL) was added 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazole, 3-chloropyridine, dichloropalladium (60 mg, 0.06 mmol). The reaction was then stirred under N at 60° C. for 16 hours. The mixture was filtered and concentrated in vacuo. The residue was purified by silica flash chromatography to give the title compound (287 mg, 75% yield). LCMS (ESI) [M+H] + =307.1.

[0458] Step 2: 1-[5-fluoro-3-(trifluoromethyl)-2-pyridyl]piperidin-4-one [ka]

[0459] To a solution of 8-[5-fluoro-3-(trifluoromethyl)-2-pyridyl]-1,4-dioxa-8-azaspiro[4.5]decane (150 mg, 0.49 mmol) was added hydrochloric acid (1.6 mL, 6.4 mmol, 4 M in 1,4-dioxane). The reaction mixture was stirred at 25° C. for 2 hours. The pH of the reaction mixture was then adjusted to 11 with NaOH (2N). The aqueous phase was extracted with ethyl acetate (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography to give the title compound (55 mg, 42.8% yield). LCMS (ESI) [M+H] + =263.

[0460] Step 3: 6-(1-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0461] To a solution of 1-[5-fluoro-3-(trifluoromethyl)-2-pyridyl]piperidin-4-one (50 mg, 0.19 mmol), 2-thia-6-azaspiro[3.4]octane 2,2-dioxide (37 mg, 0.23 mmol), and acetic acid (11 mg, 0.19 mmol) in methyl alcohol (2 mL) was added NaBHCN (59 mg, 0.95 mmol). The mixture was stirred at 50 °C for 3 hours. The reaction mixture was diluted with dichloromethane, the pH was adjusted to approximately 9 with NaHCO, and the resulting solution was extracted with dichloromethane. The combined organics were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC to give the title compound (30 mg, 39% yield). LCMS (ESI) [M+H] + =408.2; 1H NMR(400MHz,CDCl3)δ 8.33(d,J=2.4Hz,1H),7.64(d,J=2.8,8.0Hz,1H),4.09(s,4H),3.43-3.40(m,2H),2.95-2.87(m,4 H),2.83-2.80(m,2H),2.34-2.30(m,1H),2.19-2.16(m,2H),1.94-1.91(m,2H),1.74-1.67(m,2H).

[0462] Example PP: (Compounds 46A*, 46B*, 46C*, and 46D*): 7-((1R,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide, 7-((1S,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3 .5]nonane 2,2-dioxide, 7-((1R,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide, and 7-((1S,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka] Step 1: 3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)cyclopentanone [ka]

[0463] To a solution of 3-(5-bromo-2-isopropyl-pyrazol-3-yl)cyclopentanone (1000 mg, 3.69 mmol), [6-(trifluoromethyl)-2-pyridyl]boronic acid (1408 mg, 7.38 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (261 mg, 0.37 mmol), and K2CO3 (1529 mg, 11.1 mmol) in 1,4-dioxane (40 mL) and water (8 mL). The resulting mixture was stirred at 100 °C under a N2 atmosphere for 3 hours. The reaction mixture was diluted with water (20 mL × 3) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (1 g, 2.96 mmol, 80% yield). LCMS (ESI) [M+H] + =338.2. SFC showed two peaks.

[0464] Step 2: (R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)cyclopentanone and (S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)cyclopentanone [ka]

[0465] 3-[2-Isopropyl-5-[6-(trifluoromethyl)-2-pyridyl]pyrazol-3-yl]cyclopentanone (1000 mg, 2.96 mmol) was purified by SFC (Daicel Chiralcel OD (250 mm × 30 mm, 10 μm); 0.1% NH in HO; EtOH, 45%, 60 mL / min) to give the title compound 46A* (first peak in SFC, 400 mg, 1.19 mmol, 40% yield) and the title compound 46B* (second peak in SFC, 360 mg, 1.067 mmol, 36% yield). Absolute stereochemistry was arbitrarily assigned.

[0466] Step 3: 7-((3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0467] To a solution of (3R)-3-[2-isopropyl-5-[6-(trifluoromethyl)-2-pyridyl]pyrazol-3-yl]cyclopentanone (80 mg, 0.24 mmol) in methanol (8 mL) was added 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (64 mg, 0.30 mmol) and acetic acid (14 mg, 0.24 mmol), followed by NaBHCN (45 mg, 0.71 mmol). The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with NaHCO (10 mL) and extracted with dichloromethane (10 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0-5% methyl alcohol in dichloromethane) to give the title compound (100 mg, 0.20 mmol, 84.9% yield) as a mixture of diastereomers.

[0468] Step 4: 7-((1R,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide, 7-((1S,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide, [ka]

[0469] The mixture of diastereoisomers (120 mg, 0.24 mmol) was purified by SFC (Daicel Chiralcel OD (250 mm × 30 mm, 10 μm), 0.1% NH in water; EtOH, 45%, 60 mL / min) to give title compound 46A (first peak in SFC, 73.1 mg, 0.14 mmol, 58% yield) and title compound 46B (second peak in SFC, 38.2 mg, 0.0722 mmol, 29.9% yield). LCMS (ESI) [M+H] + =497.2.

[0470] Compound 46A*: 1 H NMR(400MHz,CD3OD)δ 8.17(d,J=8.0Hz,1H),7.98(t,J=8.0Hz,1H),7.63(d,J=7.2Hz,1H),6.79(s,1H),4.70-4.61(m,1H),3.93(s,4H),3.28-3.23(m ,1H),2.89-2.83(m,2H),2.74-2.02(m,6H),1.95(t,J=5.2Hz,4H),1.81-1.74(m,2H),1.72-1.64(m,1H),1.52(d,J=6.4Hz,6H).

[0471] Compound 46B*: 1 H NMR(400MHz,CD3OD)δ 8.18(d,J=8.0Hz,1H),7.98(t,J=8.0Hz,1H),7.63(d,J=7.8Hz,1H),6.72(s,1H),4.69-4.61(m,1H),3.93(s,4H),3.45-3.37(m,1H),2.9 6-2.92(m,1H),2.84-2.45(m,3H),2.29-1.99(m,5H),1.96(d,J=5.2Hz,4H),1.79-1.72(m,1H),1.69-1.59(m,1H),1.52(d,J=6.4Hz,6H).

[0472] Step 5: 7-((3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0473] To a solution of (3S)-3-[2-isopropyl-5-[6-(trifluoromethyl)-2-pyridyl]pyrazol-3-yl]cyclopentanone (80 mg, 0.24 mmol) in methyl alcohol (8 mL) was added 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (64 mg, 0.30 mmol) and acetic acid (14 mg, 0.24 mmol), followed by NaBHCN (45 mg, 0.71 mmol). The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was diluted with NaHCO (10 mL) and extracted with dichloromethane (10 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0-5% methyl alcohol in dichloromethane) to give the title compound (110 mg, 0.2215 mmol, 93% yield), which was obtained as a mixture of diastereomers.

[0474] Step 6: 7-((1R,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and 7-((1S,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0475] The mixture of diastereoisomers (120 mg, 0.24 mmol) was purified by SFC (Daicel Chiralcel OD (250 mm × 30 mm, 10 μm), 0.1% NH in water; EtOH, 45%, 60 mL / min) to give title compound 46C* (first peak in SFC, 44.41 mg, 0.0867 mmol, 33.1% yield) and title compound 46D* (second peak in SFC, 81.33 mg, 0.1556 mmol, 59.4% yield). LCMS (ESI) [M+H] + =497.2.

[0476] Compound 46C*: 1 H NMR(400MHz,CD3OD)δ 8.19(d,J=8.0Hz,1H),7.99(t,J=8.0Hz,1H),7.65(d,J=7.6Hz,1H),6.73(s,1H),4.68-4.62(m,1H),3.93(s,4H),3.45-3.37(m,1H),2 .94-2.90(m,1H),2.60(s,3H),2.30-1.99(m,5H),1.96(d,J=5.2Hz,4H),1.83-1.73(m,1H),1.69-1.59(m,1H),1.53(d,J=6.4Hz,6H).

[0477] Compound 46D*: 1 H NMR(400MHz,CD3OD)δ 8.19(d,J=8.0Hz,1H),7.99(t,J=8.0Hz,1H),7.64(d,J=7.6Hz,1H),6.80(s,1H),4.68-4.60(m,1H),3.93(s,4H),3.29-3.24(m ,1H),2.89-2.83(m,2H),2.74-2.02(m,6H),1.95(d,J=5.2Hz,4H),1.85-1.75(m,2H),1.70-1.65(m,1H),1.53(d,J=6.4Hz,6H).

[0478] Example QQ: 6-((1s,4s)-4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 47A) and 6-((1r,4r)-4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 47B) [ka] Step 1: 3-chloro-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-(trifluoromethyl)pyridine [ka]

[0479] To a solution of 2-bromo-3-chloro-5-(trifluoromethyl)pyridine (2.0 g, 7.68 mmol), 1,4-dioxa-spiro[4,5]dec-7-ene-8-boronic acid pinacol ester (2.04 g, 7.68 mmol), and potassium carbonate (3.18 g, 23.0 mmol) in 1,4-dioxane (24 mL) and water (6 mL) was added Pd(dppf)Cl (561 mg, 0.77 mmol). The reaction mixture was stirred at 90 °C under N for 16 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica column chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (2400 mg, 7.51 mmol, 98% yield). LCMS (ESI) [M+H] = 320.1.

[0480] Step 2: 3-methyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-(trifluoromethyl)pyridine [ka]

[0481] To a solution of 3-chloro-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-(trifluoromethyl)pyridine (800.0 mg, 2.5 mmol), potassium methyltrifluoroborate (610 mg, 5 mmol), and sodium carbonate (3.75 mL, 7.50 mmol, 2N) in 1,4-dioxane (16 mL) was added RuPhosPdG2 (389 mg, 0.50 mmol). The reaction mixture was stirred at 110 °C under N2 for 16 h. The reaction mixture was then concentrated in vacuo, and the residue was purified by silica column chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (540 mg, 1.80 mmol, 72% yield). LCMS (ESI), [M+H]+ = 300.2.

[0482] Step 3: 3-methyl-2-(1,4-dioxaspiro[4.5]decan-8-yl)-5-(trifluoromethyl)pyridine [ka]

[0483] To a solution of 2-(1,4-dioxaspiro[4.5]decan-8-yl)-3-methyl-5-(trifluoromethyl)pyridine (500 mg, 1.66 mmol) in THF (10 mL) was added 10% palladium on carbon (150 mg). The reaction mixture was stirred under H (15 psi) at 20° C. for 4 h. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to give the title compound (500 mg, 1.66 mmol, 100% yield), which was used directly without further purification. LCMS (ESI) [M+H] + =302.1.

[0484] Step 4: 4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)cyclohexanone [ka]

[0485] A solution of 8-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]-1,4-dioxa-8-azaspiro[4.5]decane (500 mg, 1.63 mmol) in HCl (2 mL, 12 mmol, 6 M) was stirred at 20 °C for 16 hours. The reaction mixture was adjusted to pH = 9 with saturated NaHCO (10 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate (40 mL × 2). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude title compound (400 mg, 1.526 mmol, 93.4% yield). LCMS (ESI) [M+H] + =258.1.

[0486] Step 5: 6-((cis)-4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (compound 47A) and 6-((trans)-4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (compound 47B) [ka]

[0487] To a solution of 4-[3-methyl-5-(trifluoromethyl)-2-pyridyl]cyclohexanone (100 mg, 0.389 mmol), acetic acid (0.08 mL, 0.97 mmol), and 2-thia-6-azaspiro[3.4]octane 2,2-dioxide (94 mg, 0.583 mmol) in methanol (4 mL) was added sodium cyanoborohydride (73 mg, 1.18 mmol). The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was diluted with ethyl acetate (80 mL). The resulting mixture was washed with NaHCO (10 mL × 3). The organic phase was concentrated and the residue was purified by preparative TLC (10% dichloromethane in methanol) to give title compound 47A (32.07 mg, 0.0796 mmol, 20.5% yield) and title compound 47B (63.48 mg, 0.157 mmol, 40.5% yield). LCMS (ESI), [M+H] + =403.2.

[0488] Compound 47A: 1 H NMR(400MHz,CDCl3)δ 8.66(s,1H),7.62(s,1H),4.10(s,4H),3.03-2.92(m,1H),2.86(s,2H),2.75(t,J=6.8Hz,2H),2.44(br s,1H),2.17(t,J=7.2Hz,2H),1.97-2.12-1.97(m,4H),1.71(brs,3H),1.65-1.47(m,3H),1.26(s,1H).

[0489] Compound 47B: 1 H NMR(400MHz,CDCl3)δ 8.64(s,1H),7.63(s,1H),4.15-4.07(m,4H),2.94(s,2H),2.91-2.85(m,1H),2.81(t,J=6.8Hz,2H),2.40-2 .37(m,1H),2.35-2.22(m,1H),2.20-2.02(m,5H),1.87-1.72(m,4H),1.48-1.35(m,2H),1.30-1.25(m,1H).

[0490] Example RR: 6-((1r,4r)-4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 48A) and 6-((1s,4s)-4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 48B) [ka] The title compound was synthesized following a similar procedure to compound 47A using 2-bromo-3-chloro-5-(trifluoromethyl)pyridine.

[0491] The mixture of diastereomers was purified by silica flash chromatography (0-10% methanol in dichloromethane) to give compound 48A (first peak by HPLC, 55.2 mg, 38.3% yield) and compound 48B (second peak by HPLC, 31.4 mg, 0.0706 mmol, 21.8% yield). LCMS (ESI) [M+H] + =423.0

[0492] Compound 48A: 1 H NMR(400MHz,CD3OD)δ 8.75(s,1H),8.13(d,J=1.6Hz,1H),4.15-4.08(m,4H),3.28-3.27(m,1H),3.03(s,2H),2.87(t,J=7.2H z,2H),2.42-2.30(m,1H),2.24-2.16(m,4H),1.95-1.91(m,2H),1.81-1.71(m,2H),1.49-1.39(m,2H).

[0493] Compound 48B: 1H NMR(400MHz,CD3OD)δ 8.74(s,1H),8.13(d,J=1.6Hz,1H),4.15-4.08(m,4H),3.41-3.39(m,1H),2.87(s,2H),2.76( t,J=7.2Hz,2H),2.45-2.35(m,1H),2.20-2.16(m,2H),2.12-2.04(m,4H),1.67-1.63(m,4H).

[0494] Example SS: 6-((1r,4r)-4-(5-(trifluoromethyl)pyridin-2-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 49) [ka] The title compound was synthesized using the same experimental procedure as for compound 50A, using 2-bromo-5-(trifluoromethyl)pyridine. The relative stereochemistry is as follows: 1 Assigned based on H NMR analysis. Yield 27.4 mg (14%) of the title compound. LCMS (ESI) [M+H] + =389.1; 1 H NMR(400MHz,DMSO-d6)δ 8.86(s,1H),8.10(dd,J=8.3,2.5Hz,1H),7.52(d,J=8.3Hz,1H),4.17-4.08(m,4H),2.81(s,2H),2.80-2.72(m,1H),2.67(t,J=7 .2Hz,2H),2.23-2.11(m,1H),2.07(t,J=7.2Hz,2H),2.04-1.96(m,2H),1.95-1.86(m,2H),1.66-1.51(m,2H),1.35-1.22(m,2H).

[0495] Example TT: 7-((1r,4r)-4-(5-(trifluoromethyl)pyridin-2-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (Compound 50A) and 7-((1s,4s)-4-(5-(trifluoromethyl)pyridin-2-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (Compound 50B) [ka] Step 1: 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-(trifluoromethyl)pyridine [ka]

[0496] A solution of 2-bromo-5-(trifluoromethyl)pyridine (2260 mg, 10.0 mmol), potassium phosphate (4245 mg, 20.0 mmol), cataCXiumPdG (259.8 mg, 0.35 mmol), and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (3193 mg, 12.0 mmol) in 1,4-dioxane (25.0 mL) and water (8.33 mL) was stirred at 70 °C for 18 h. The mixture was diluted with 1 N NH Cl (20 mL) and dichloromethane (60 mL). The aqueous layer was extracted with dichloromethane (2 × 10 mL). The combined organic layers were dried over anhydrous Na SO and concentrated in vacuo to give the crude title compound (4.8 g, approximately 100% yield). LCMS(ESI)[M+H] + =286.0. 1 H NMR(400MHz,DMSO-d6)δ 8.89(s,1H),8.13(dd,J=8.6,2.4Hz,1H),7.76(d,J=8.4Hz,1H),6.78(s,1H ),3.92(s,4H),2.71-2.64(m,2H),2.49-2.43(m,2H),1.83(t,J=6.5Hz,2H).

[0497] Step 2: 2-(1,4-dioxaspiro[4.5]decan-8-yl)-5-(trifluoromethyl)pyridine [ka]

[0498] A solution of 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-(trifluoromethyl)pyridine (2850 mg, 10.0 mmol) and palladium hydroxide on carbon (750 mg, 5.34 mmol) in methanol (50.0 mL) was stirred under a hydrogen atmosphere at 50° C. for 18 hours. The mixture was diluted with dichloromethane (100 mL) and filtered through a celite pad. The solid was washed with dichloromethane (2×20 mL), and the filtrate was concentrated under reduced pressure to give the crude title compound (4170 mg, approximately 100% yield). LCMS (ESI) [M+H] + =288.1. 1 H NMR(400MHz,DMSO-d6)δ 8.87(s,1H),8.14-8.06(m,1H),7.52(d,J=8.2Hz,1H),3.89(s,4H),2.93-2.81(m,1H),1.85-1.75(m,6H),1.66-1.58(m,2H).

[0499] Step 3: 4-(5-(trifluoromethyl)pyridin-2-yl)cyclohexan-1-one [ka]

[0500] A solution of 2-(1,4-dioxaspiro[4.5]decan-8-yl)-5-(trifluoromethyl)pyridine (2870 mg, 10.0 mmol) in acetic acid (33.3 mL) and water (11.1 mL) was stirred at 50° C. for 18 hours. The mixture was diluted with saturated aqueous NaHCO (50 mL), water (50 mL), and dichloromethane (50 mL). The mixture was neutralized with solid NaHCO, and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic extracts were dried (NaSO) and concentrated under reduced pressure to give the crude title compound (3360 mg, approximately 100% yield). LCMS (ESI) [M+H] + =244.0. 1H NMR(400MHz,DMSO-d6)δ 8.90(d,J=2.4Hz,1H),8.16(dd,J=8.2,2.5Hz,1H),7.62(d,J=8.2Hz,1H),3.42-3.32(m,1H),2. 59(td,J=14.0,6.0Hz,2H),2.36-2.26(m,2H),2.24-2.12(m,2H),2.00(td,J=12.4,4.3Hz,2H).

[0501] Step 4: 7-((1r,4r)-4-(5-(trifluoromethyl)pyridin-2-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0502] To a solution of 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (138 mg, 0.65 mmol) and 4-(5-(trifluoromethyl)pyridin-2-yl)cyclohexan-1-one (122 mg, 0.50 mmol) in methanol (3.3 mL) was added N,N-diisopropylethylamine (0.261 mL, 1.50 mmol) and titanium(IV) isopropoxide (0.222 mL, 0.75 mmol). The mixture was stirred at 30 °C for 18 h. Sodium cyanoborohydride (94.3 mg, 1.50 mmol) was added, and the reaction mixture was stirred at 50 °C for 18 h. The mixture was diluted with 1N aqueous NH4Cl (1.0 mL) and DMSO, filtered, and purified by preparative reverse-phase HPLC (acetonitrile / water gradient + 0.1% TFA) to afford the first eluting peak as the title compound (Compound 50A) as a pure single stereoisomer (39.8 mg, 20% yield). LCMS (ESI) [M+H] + =403.1. 1H NMR(400MHz,DMSO-d6)δ 8.86(s,1H),8.11(d,J=8.4Hz,1H),7.52(d,J=8.3Hz,1H),3.92(s,4H),2.75(t,J=12.3Hz,1H),2.49-2.25(m,5 Relative trans stereochemistry 1 Assignment was based on 1 H NMR analysis.

[0503] 7-((1s,4s)-4-(5-(trifluoromethyl)pyridin-2-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0504] The crude reaction mixture from Step 4 of Example 50A was purified by preparative reverse-phase HPLC (acetonitrile / water gradient with 0.1% TFA) to afford the second eluting peak as the title compound (Compound 50B) as a pure single stereoisomer (71.5 mg, 36% yield). LCMS (ESI) [M+H] + =403.1. 1 H NMR(400MHz,DMSO-d6)δ 8.89(s,1H),8.10(dd,J=8.7,2.4Hz,1H),7.53(d,J=8.7Hz,1H),3.90(s,4H),3.02-2.92(m,1H),2.48 -2.29(m,4H),2.29-2.20(m,1H),2.11-1.95(m,2H),1.88-1.71(m,6H),1.69-1.45(m,4H).The relative cis stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0505] Example UU: 6-((1r,4r)-4-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 51A) and 6-((1s,4s)-4-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 51B) [ka] The title compound was synthesized following a similar procedure to compound 47A using 3-bromo-2-methyl-6-(trifluoromethyl)pyridine.

[0506] The mixture of diastereomers was purified by reverse-phase chromatography (water (0.05% NH3 in water + 10 mM NH4HCO3); ACN, 55-85%, 25 mL / min) to give compound 51A (second peak in SFC, 118 mg, 49% yield) and compound 51B (first peak in SFC, 47.1 mg, 20% yield). LCMS (ESI): [M+H] + =403.2.

[0507] Compound 51A: 1 H NMR(400MHz,CDCl3)δ 7.61(d,J=8.0Hz,1H),7.48(d,J=8.0Hz,1H),4.08(s,4H),2.93(s,2H),2.82-2.80(m,2H),2.77-2.70(m ,1H),2.64(s,3H),2.30-2.21(m,1H),2.19-2.09(m,4H),1.93-1.90(m,2H),1.49-1.41(m,4H).The relative stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0508] Compound 51B: 1H NMR(400MHz,CDCl3)δ 7.62(d,J=8.0Hz,1H),7.49(d,J=8.0Hz,1H),4.14-4.05(m,4H),2.85-2.78(m,2H),2.76-2.73(m,2H),2.65(s ,3H),2.47(brs,1H),2.18(t,J=7.2Hz,2H),2.02-1.99(m,2H),1.85-1.77(m,3H),1.66-1.55(m,4H).The relative stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0509] Example VV: 7-(1-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (Compound 52) [ka] The title compound was synthesized using 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine following the same procedure as for compound 45. The title compound was purified by preparative TLC (ethyl alcohol:ethyl acetate:petroleum ether=1:3:4) to give the title compound (36.6 mg, 0.084 mmol, 44% yield). LCMS (ESI) [M+H] + =422.2.1H NMR(400MHz,CDCl3)δ 8.22(s,1H),7.37(dd,J=2.0,13.6Hz,1H),4.38(d,J=12.4Hz,2H),3.85(s,4H ),2.94(t,J=12.4Hz,2H),2.55(s,5H),1.93-1.87(m,6H),1.64-1.61(m,2H).

[0510] Example WW: (Compounds 53A*, 53B*, 53C*, and 53D*): 6-((1S,3S)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 6-((1R,3S)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3 .4]octane 2,2-dioxide, 6-((1S,3R)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and 6-((1R,3R)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka] [ka] Step 1: (R)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentanone [ka]

[0511] To a solution of (R)-3-oxocyclopentanecarboxylic acid (1.0 g, 7.8 mmol) and 4-(trifluoromethyl)benzamidine hydrochloride (2.63 g, 11.71 mmol) in N,N-dimethylformamide (45 mL) was added HATU (3.26 g, 8.59 mmol) and N,N-diisopropylethylamine (3.98 mL, 23.41 mmol). The reaction mixture was stirred at 20 °C for 1 hour. Isopropylhydrazine hydrochloride (1.29 g, 11.7 mmol) and acetic acid (4.46 mL, 78.05 mmol) were added to the above mixture and stirred at 80 °C for an additional 1.5 hours. The mixture was diluted with ethyl acetate (200 mL), and the resulting mixture was washed with water (50 mL) and brine (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (700 mg, 26% yield). LCMS (ESI) [M+H] + =338.1.SFC showed 99% ee.

[0512] Step 2: (S)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentanone [ka]

[0513] The title compound was synthesized following a procedure similar to that for (R)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentanone, but using instead (S)-3-oxocyclopentanecarboxylic acid (compound 36A, procedure, step 1).

[0514] Step 3A: 6-((1S,3S)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and 6-((1R,3S)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0515] To a mixture of (S)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentanone (100 mg, 0.30 mmol) and 2-thia-6-azaspiro[3.4]octane 2,2-dioxide (57 mg, 0.36 mmol) in methanol (5 mL), sodium cyanoborohydride (56 mg, 0.89 mmol) and acetic acid (0.1 mL, 1.19 mmol) were added. The reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was quenched with water (10 mL), and the resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 120 mg of crude product, which was separated using chiral SFC (Daicel Chiralpak (250 mm x 30 mm, 10 μm); 0.1% NH in water; EtOH, 25%, 60 mL / min) to give title compound 53A* (first peak in SFC, 26.3 mg, 23% yield) and title compound 53B* (second peak in SFC, 84.8 mg, 69% yield). LCMS (ESI) [M+H] + =483.1.

[0516] Compound 53A*: 1H NMR(400MHz,CD3OD)δ 8.20(d,J=8.0Hz,2H),7.74(d,J=8.4Hz,2H),4.80-4.75(m,1H),4.20-4.08(m,4H),3.64-3.53(m,1H),3.08 -2.99(m,1H),2.94(s,2H),2.80(t,J=7.6Hz,2H),2.31-1.86(m,7H),1.78-1.64(m,1H),1.60-1.50(m,6H).

[0517] Compound 53B*: 1 H NMR(400MHz,CD3OD)δ 8.19(d,J=8.0Hz,2H),7.75(d,J=8.0Hz,2H),4.80-4.75(m,1H),4.31-4.16(m,4H),3.64-3 .18(m,1H),2.57-2.45(m,1H),2.40(t,J=6.8Hz,2H),2.31-1.85(m,6H),1.59-1.46(m,6H).

[0518] Step 3B: 6-((1S,3R)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and 6-((1R,3R)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0519] To a mixture of (R)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentanone (100 mg, 0.30 mmol) and 2-thia-6-azaspiro[3.4]octane 2,2-dioxide (57 mg, 0.36 mmol) in methanol (5 mL), sodium cyanoborohydride (56 mg, 0.89 mmol) and acetic acid (0.1 mL, 1.19 mmol) were added, and the mixture was stirred at 60 °C for 1 hour. The reaction mixture was quenched with water (10 mL), and the resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give 120 mg of crude product, which was separated using chiral SFC (Daicel Chiralpak OJ-H (250 mm x 30 mm, 5 μm); 0.1% NH in water; EtOH, 15%, 60 mL / min) to give the title compound 53C* (first peak in SFC, 23.6 mg, 15% yield) and the title compound 53D* (second peak in SFC, 65.7 mg, 44% yield). LCMS (ESI), [M+H] + =483.1.

[0520] Compound 53C*: 1 H NMR(400MHz,CD3OD)δ 8.20(d,J=8.4Hz,2H),7.74(d,J=8.0Hz,2H),4.78-4.70(m,1H),4.23-4.07(m,4H),3.69-3.53(m, 1H),3.10-3.00(m,1H),2.95(s,2H),2.81(t,J=7.2Hz,2H),2.33-1.64(m,8H),1.57-1.50(m,6H).

[0521] Compound 53D*: 1H NMR(400MHz,CD3OD)δ 8.21(d,J=8.0Hz,2H),7.73(d,J=8.0Hz,2H),4.77-4.70(m,1H),4.19-4.07(m,4H),3.56-3.41(m,1H),2.96(s,2H),2 .94-2.74(m,3H),2.39-2.29(m,1H),2.22(t,J=7.2Hz,2H),2.19-1.94(m,4H),1.94-1.79(m,1H),1.57-1.49(m,6H).

[0522] Example XX: (Compounds 54A*, 54B*, 54C*, and 54D*): 6-((1R,3S)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 6-((1R,3R)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3. 4]octane 2,2-dioxide, 6-((1S,3R)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, and 6-((1S,3S)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka] [ka] Step 1: 3-(6-(trifluoromethyl)pyridin-3-yl)cyclohex-2-enone [ka]

[0523] To a mixture of 5-bromo-2-(trifluoromethyl)pyridine (900 mg, 3.98 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one (1000 mg, 4.5 mmol), and K2CO3 (1800 mg, 13.02 mmol) in 1,4-dioxane (24 mL) and water (4 mL) was added Pd(dppf)Cl2 (280 mg, 0.38 mmol). The resulting mixture was then stirred at 90 °C under a nitrogen atmosphere for 5 hours. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-40% ethyl acetate in petroleum ether) to give the title compound (900 mg, 3.62 mmol, 91% yield). LCMS (ESI) [M+H] + =242.1.

[0524] Step 2: 3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexanol [ka]

[0525] To a solution of 3-(6-(trifluoromethyl)pyridin-3-yl)cyclohex-2-enone (900 mg, 3.73 mmol) in ethyl acetate (20 mL) was added platinum(IV) oxide (180 mg, 0.79 mmol). The suspension was then purged with H2 three times. The mixture was stirred under H2 (15 psi) at 20 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (810 mg, 3.30 mmol, 88.5% yield). LCMS (ESI), [M+H] + =246.1.

[0526] Step 3: 3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexanone [ka]

[0527] To a solution of 3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexanol (1100 mg, 4.49 mmol) in anhydrous dichloromethane (26 mL) was added Dess-Martin periodinane (4000 mg, 9.43 mmol) at 0 °C, and the resulting mixture was stirred at 25 °C for 16 h. The mixture was then quenched with NaSO solution (50 mL), followed by saturated NaHCO solution (50 mL). The resulting mixture was extracted with dichloromethane (300 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0-40% ethyl acetate in petroleum ether) to give the title compound (930 mg, 3.59 mmol, 80.1% yield). LCMS (ESI) [M+H] + =244.1.

[0528] Step 4: (R)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexanone and (S)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexanone [ka]

[0529] The mixture of enantiomers (930 mg, 3.82 mmol) was separated by chiral SFC (Daicel Chiralpak AD-H (250 mm × 30 mm, 5 μm); EtOH + NH₃·H₂O = 30 / 30, 60 mL / min) to give the title compound 54A (first peak in SFC, 340 mg, 1.40 mmol, 36.6% yield) and the title compound 54B (second peak in SFC, 350 mg, 1.44 mmol, 38% yield). LCMS (ESI) [M+H] + =244.1.

[0530] Step 5: 6-((1R,3S)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 6-((1R,3R)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0531] To a solution of (R)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexanone (100 mg, 0.41 mmol) and 2-thia-6-azaspiro[3.4]octane 2,2-dioxide (135 mg, 0.84 mmol) in methanol (4 mL) was added NaBHCN (130 mg, 2.06 mmol) and acetic acid (0.1 mL, 1.75 mmol) at 20 °C. The reaction mixture was then stirred at 70 °C for 4 h. The reaction mixture was quenched with saturated NaHCO solution (10 mL) and extracted with dichloromethane (30 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by preparative TLC (10% methanol in dichloromethane) to give the title compound 54A* (first peak, 30.37 mg, 0.077 mmol, 23.3% yield) and the title compound 54B* (second peak, 59.11 mg, 0.14 mmol, 43.5% yield). LCMS (ESI) [M+H] + =389.1.

[0532] Compound 54A*: 1H NMR(400MHz,CDCl3)δ 8.59(s,1H),7.68(d,J=8.0Hz,1H),7.62(d,J=8.0Hz,1H),4.14-4.06(m,4H),3.09(t,J=12.4Hz,1H),2.99(d,J=9.2Hz,1H),2.89-2.80(m, 1H),2.72(d,J=9.2Hz,1H),2.69-2.61(m,1H),2.58(brs,1H),2.23-2.14(m,2H),2.00-1.92(m,3H),1.83-1.78(m,1H),1.71-1.47(m,4H).

[0533] Compound 54B*: 1 H NMR(400MHz,CDCl3)δ 8.59(s,1H),7.70(d,J=8.4Hz,1H),7.64(d,J=8.4Hz,1H),4.07(s,4H),2.95-2.67(m,5H),2.36-1.87(m,6H),1.76-1.45(m,5H). [ka]

[0534] To a solution of (S)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexanone (100 mg, 0.41 mmol) and 2-thia-6-azaspiro[3.4]octane 2,2-dioxide (135 mg, 0.84 mmol) in anhydrous methanol (4 mL) was added NaBHCN (130 mg, 2.06 mmol) and acetic acid (0.1 mL, 1.75 mmol) at 20 °C. The resulting mixture was then stirred at 70 °C for 4 h. The reaction was quenched with saturated NaHCO solution (10 mL) and extracted with dichloromethane (50 mL × 2). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (10% methanol in dichloromethane) to give the title compound 54C* (first peak in SFC, 33.29 mg, 0.082 mmol, 20% yield) and the title compound 54D* (second peak in SFC, 65.05 mg, 0.16 mmol, 38.7% yield). LCMS (ESI) [M+H]+ =389.1.

[0535] Compound 54C*: 1 H NMR(400MHz,CDCl3)δ 8.59(s,1H),7.68(d,J=8.0Hz,1H),7.62(d,J=8.0Hz,1H),4.14-4.06(m,4H),3.09(t,J=12.4Hz,1H),2.99(d,J=9.2Hz,1H),2.89-2.80(m, 1H),2.73(d,J=9.2Hz,1H),2.67-2.61(m,1H),2.58(brs,1H),2.24-2.15(m,2H),2.00-1.92(m,3H),1.83-1.78(m,1H),1.71-1.47(m,4H).

[0536] Compound 54D*: 1 H NMR(400MHz,CDCl3)δ 8.59(brs,1H),7.69(brs,1H),7.67-7.60(m,1H),4.07(brs,4H),2.92(d,J=19.6Hz,2H),2.81(brs,2H), 2.72(d,J=11.6Hz,2H),2.15(brs,4H),1.99(d,J=7.2Hz,1H),1.89(d,J=10.4Hz,1H),1.54-1.36(m,4H).

[0537] Example YY: (Compounds 55A and 55B): (R)-7-(1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and (S)-7-(1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka] Step 1: tert-Butyl 3-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)piperidine-1-carboxylate [ka]

[0538] To a solution of tert-butyl 3-oxopiperidine-1-carboxylate (350 mg, 1.76 mmol) and 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (400 mg, 2.28 mmol) in dichloromethane (10 mL) was added N,N-diisopropylethylamine (0.93 mL, 5.27 mmol) and 4A molecular sieves. The reaction mixture was stirred at 65 °C for 12 hours. Sodium triacetoxyborohydride (1116 mg, 5.27 mmol) was then added. The mixture was stirred at 65 °C for 1 hour, quenched with brine (20 mL), and extracted with dichloromethane (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-10% methanol in dichloromethane) to give the title compound (300 mg, 47.6% yield). LCMS (ESI), [M+H] + =359.1.

[0539] Step 2: 7-(piperidin-3-yl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0540] tert-Butyl 3-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)piperidine-1-carboxylate (300.0 mg, 0.84 mmol) was dissolved in HCl / dioxane (8.0 mL, 32 mmol, 4 M). The reaction mixture was stirred at 25° C. for 1 hour and concentrated in vacuo to give the title compound (220 mg, 100% yield).

[0541] Step 3: 7-(1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0542] To a solution of 7-(piperidin-3-yl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (60 mg, 0.23 mmol) and 4-bromobenzotrifluoride (190 mg, 0.84 mmol) in toluene (5.0 mL) was added (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (70 mg, 0.08 mmol), 2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl (79 mg, 0.17 mmol), and cesium carbonate (825 mg, 2.53 mmol). The reaction mixture was stirred at 110 °C under N for 16 h. The mixture was filtered and concentrated in vacuo. The residue was purified by silica flash chromatography (0-2% methanol in dichloromethane). LCMS (ESI) [M+H] + =403.1.

[0543] Step 4: (R)-7-(1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and (S)-7-(1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0544] The mixture of enantiomers (110 mg, 0.27 mmol) was separated using chiral SFC (Daicel Chiralpak AD-H (250 mm*30 mm, 5 μm); 0.1% NH in HO; MeOH, 40%, 60 mL / min) to give compound 55A* (first peak in SFC, 31.45 mg, 27.2% yield) and compound 55B* (second peak in SFC, 36.1 mg, 31.2% yield).

[0545] Compound 55A*: 1H NMR(400MHz,CD3OD)δ 7.45(d,J=8.8Hz,2H),7.02(d,J=8.8Hz,2H),3.98(d,J=12.4Hz,1H),3.92(s,4H),3.81(d,J=13.2Hz,1H),2.83-2.73( m,2H),2.67(brs,4H),2.59-2.52(m,1H),2.08-2.02(m,1H),1.94-1.91(m,4H),1.87-1.82(m,1H),1.68-1.59(m,2H).

[0546] Compound 55B*: 1 H NMR(400MHz,CD3OD)δ 7.45(d,J=8.8Hz,2H),7.02(d,J=8.8Hz,2H),3.98(d,J=12.4Hz,1H),3.92(s,4H),3.81(d,J=12.8Hz,1H),2.83-2.72( m,2H),2.67(brs,4H),2.59-2.52(m,1H),2.08-2.02(m,1H),1.94-1.91(m,4H),1.87-1.83(m,1H),1.66-1.45(m,2H).

[0547] Example ZZ: (Compounds 56A*, 56B*, 56C*, and 56D*): 7-((1R,3S)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide, 7-((1S,3S)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-7-azaspiro[ 3.5]nonane 2,2-dioxide, 7-((1S,3R)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and 7-((1R,3R)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide 7-((1R,3S)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and 7-((1S,3S)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0548] The title compound was synthesized using 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide following a procedure similar to that for compound 54A. The mixture of diastereomers was purified by preparative TLC (10% methanol in dichloromethane) to give compound 56A* (first peak, 40.1 mg, 0.096 mmol, 23.2% yield) and compound 56B* (second peak, 20.6 mg, 0.049 mmol, 11.8% yield). LCMS (ESI) [M+H] + =403.1.

[0549] Compound 56A*: 1 H NMR(400MHz,CDCl3)δ 8.60(s,1H),7.71(d,J=7.8Hz,1H),7.65-7.57(m,1H),3.87(s,4H),3.20-3.12(m ,1H),2.65-2.40(m,4H),2.11-2.09(m,2H),1.98-1.85(m,6H),1.80-1.49(m,5H).

[0550] Compound 56B*: 1 H NMR(400MHz,CDCl3)δ 8.59(s,1H),7.68(dd,J=2.0,8.4Hz,1H),7.63(d,J=8.0Hz,1H),3.84(s,4H) ,2.73-2.70(m,1H),2.59-2.49(m,4H),2.04-1.92(m,8H),1.54-1.27(m,5H).

[0551] 7-((1S,3R)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and 7-((1R,3R)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0552] The title compound was synthesized using 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide following a procedure similar to that for compound 54A. The mixture of diastereomers was purified by reverse-phase chromatography (70-100% acetonitrile / (0.05% NH in HO + 10 mM NHHCO in water) to give compound 56A* (second peak, 39.69 mg, 0.095 mmol, 11.5% yield) and compound 56B* (first peak in SFC, 56.03 mg, 0.14 mmol, 16.4% yield). LCMS (ESI) [M+H] + =403.1.

[0553] Compound 56C*: 1 H NMR(400MHz,CDCl3)δ 8.59(s,1H),7.68(dd,J=2.0,8.0Hz,1H),7.63(d,J=8.0Hz,1H),3.84(s,4H) ,2.78-2.63(m,1H),2.58-2.45(m,5H),2.04-1.92(m,8H),1.49-1.31(m,4H).

[0554] Compound 56D*: 1 H NMR(400MHz,CDCl3)δ 8.60(s,1H),7.71(d,J=8.0Hz,1H),7.62(d,J=8.0Hz,1H),3.87(s,4H),3.20-3.12(m,1H),2.65-2.40( m,4H),2.11-2.09(m,2H),1.98-1.85(m,6H),1.80-1.69(m,2H),1.65-1.58(m,1H),1.55-1.43(m,2H).

[0555] Example AAA: (Compounds 57A*, 57B*, 57C* and 57D*): 7-((1R,3R)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide, 7-((1S,3R)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopentyl)-2-thia-7-azaspiro[3 .5]nonane 2,2-dioxide, 7-((1R,3S)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide, and 7-((1S,3S)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka] The title compound was synthesized following a procedure similar to that for compound 54A, using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one in the first step and 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide in step 5. The mixture of diastereomers was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to give compound 57A* (first peak, 31.61 mg, 0.07 mmol, 17.9% yield) and compound 57B* (second peak, 34.06 mg, 0.08 mmol, 19.3% yield). LCMS (ESI): [M+H] + =389.2.

[0556] Compound 57A*: 1 H NMR(400MHz,CD3OD)δ 8.62(s,1H),7.97(d,J=6.4Hz,1H),7.76(d,J=8.0Hz,1H),3.94(s,4H),3.28-3.23(m,1H),2. 92-2.37(m,5H),2.35-2.03(m,3H),1.98-1.95(m,4H),1.85-1.76(m,2H),1.65-1.62(m,1H).

[0557] Compound 57B*: 1 H NMR(400MHz,CD3OD)δ 8.61(s,1H),7.95(d,J=6.4Hz,1H),7.75(d,J=8.4Hz,1H),3.95(s,4H),3.43-3.35( m,1H),3.20-2.39(m,5H),2.32-2.05(m,4H),2.05-1.95(m,4H),1.78-1.68(m,2H).

[0558] The mixture of diastereomers was purified by preparative TLC (dichloromethane:methanol = 10:1) to give compound 57C* (first peak in SFC, 41.82 mg, 0.10 mmol, 24.4% yield) and compound 57D* (second peak in SFC, 30.05 mg, 0.07 mmol, 17.6% yield). LCMS (ESI) [M+H] + =389.1.

[0559] Compound 57C*: 1 H NMR(400MHz,CD3OD)δ 8.64(s,1H),7.99(d,J=6.8Hz,1H),7.78(d,J=8.4Hz,1H),4.01(s,4H),3.30-3.24( m,1H),2.95-2.51(s,5H),2.37-2.15(m,3H),2.12-2.08(m,4H),1.97-1.74(m,3H).

[0560] Compound 57D*: 1 H NMR(400MHz,CD3OD)δ 8.60(d,J=1.6Hz,1H),7.94(d,J=8.0Hz,1H),7.75(d,J=8.0Hz,1H),3.94(s,4H),3.39-3 .35(m,1H),3.16-2.31(m,5H),2.20-2.15(m,4H),2.02-1.95(m,4H),1.76-1.66(m,2H).

[0561] Example BBB: 7-((1R,3S)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (Compound 58A) and 7-((1S,3S)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (Compound 58B) [ka] Step 1: (S)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentanone [ka]

[0562] To a solution of (S)-3-oxocyclopentanecarboxylic acid (1 g, 7.8 mmol) and 4-(trifluoromethyl)benzamidine hydrochloride (2.63 g, 11.71 mmol) in DMF (45 mL) was added HATU (3.26 g, 8.59 mmol) and N,N-diisopropylethylamine (3.98 mL, 23.41 mmol). The mixture was stirred at 20 °C for 1 hour. To the above mixture was added isopropylhydrazine hydrochloride (1.29 g, 11.71 mmol) and acetic acid (4.46 mL, 78.05 mmol). The reaction mixture was stirred at 80 °C for an additional 1.5 hours. The mixture was diluted with ethyl acetate (200 mL), and the resulting mixture was washed with water (50 mL) and brine (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (700 mg, 26% yield). LCMS (ESI) [M+H] + = 338.1. SFC showed 99% ee.

[0563] Step 2: 7-((1R,3S)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and 7-((1S,3S)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide

[0564] To a solution of (3S)-3-[2-isopropyl-5-[4-(trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]cyclopentanone (100 mg, 0.2964 mmol) in methanol (4 mL) was added acetic acid (89 mg, 1.48 mmol), 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (82 mg, 0.386 mmol), and sodium cyanoborohydride (93 mg, 1.48 mmol). The reaction mixture was stirred at 70° C. for 4 hours and then diluted with ethyl acetate (50 mL). The resulting mixture was washed with water (25 mL) and brine (50 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (20-80% ethyl acetate in petroleum ether) to give the title compound (140 mg, 95% yield). LCMS (ESI): [M+H] + = 497.1. The mixture of diastereomers (140 mg, 0.28 mmol) was separated using chiral SFC (Daicel Chiralcel OJ (250 mm x 30 mm, 10 μm); 0.1% NH in HO; EtOH) to give title compound 58A (second peak in SFC, 67.82 mg, 0.1352 mmol, 48% yield) and title compound 58B (first peak in SFC, 23.05 mg, 0.0446 mmol, 15.8% yield). LCMS (ESI): [M+H] + =497.1. The relative stereochemistry was assigned based on NOE NMR analysis.

[0565] Compound 58A: 1H NMR(400MHz,CDCl3)δ 8.19(d,J=8.0Hz,2H),7.66(d,J=8.0Hz,2H),4.55-4.49(m,1H),3.88(s,4H),3.45-3.35(m,1H),2 .98-2.92(m,1H),2.53-2.33(m,3H),2.30-2.10(m,3H),2.07-1.98(m,6H),1.54(d,J=6.4Hz,8H).

[0566] Compound 58B: 1 H NMR(400MHz,CDCl3)δ 8.19(d,J=8.0Hz,2H),7.66(d,J=8.0Hz,2H),4.55-4.49(m,1H),3.88(s,4H),3.28-3.22 (m,1H),2.88-2.82(m,1H),2.56-2.33(m,2H),2.30-1.72(m,10H),1.54(d,J=6.4Hz,8H).

[0567] Example CCC: 6-((1r,4r)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 59) [ka] The title compound was synthesized in the same manner as Compound 80A and Compound 80B using 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine.

[0568] Example DDD: 6-((1r,4r)-4-(2-(trifluoromethyl)pyridin-4-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 60A) and 6-((1s,4s)-4-(2-(trifluoromethyl)pyridin-4-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 60B) [ka]

[0569] The title compound was synthesized using 4-bromo-2-(trifluoromethyl)pyridine following a procedure similar to that for compound 47A. The mixture of diastereomers was purified by preparative HPLC (water (0.05% NH + 10 nM NHHCO)-ACN) to give compound 60 (first peak in HPLC, 48.4 mg, 0.12 mmol, 41.5% yield) and compound 96 (second peak in HPLC, 31.8 mg, 0.081 mmol, 28.2% yield). LCMS (ESI) [M+H] + =389.2. Relative stereochemistry, 1 Assignment was based on 1 H NMR analysis.

[0570] Compound 60A: 1 H NMR(400MHz,CDCl3)δ 8.63(d,J=4.8Hz,1H),7.53(s,1H),7.32(d,J=3.6Hz,1H),4.08(s,4H),2.93(s,2H),2.82-2.81(m, 2H),2.63-2.57(m,1H),2.26-2.18(m,5H),2.01-1.96(m,2H),1.54-1.48(m,2H),1.44-1.35(m,2H).

[0571] Compound 60B: 1 H NMR(400MHz,CDCl3)δ 8.63(d,J=4.8Hz,1H),7.52(s,1H),7.33(d,J=4.8Hz,1H),4.13-4.05(m,4H),2.85(s,2H),2.76-2. 67(m,3H),2.44(s,1H),2.20-2.16(m,2H),2.02-1.95(m,2H),1.90-1.80(m,2H),1.68-1.64(m,4H).

[0572] Example EEE: (Compounds 61A*, 61B*, 61C*, and 61D*): 6-((1R,3R)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 6-((1R,3S)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3 .4]octane 2,2-dioxide, 6-((1S,3R)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, and 6-((1S,3S)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka] [ka] Step 1: 1-Isopropyl-3-(trifluoromethyl)-1H-pyrazole [ka]

[0573] To a suspension of 3-(trifluoromethyl)pyrazole (4 g, 29.39 mmol) in acetonitrile (50 mL) was added 2-iodopropane (15 g, 88.18 mmol) and cesium carbonate (48 g, 146.97 mmol) at 25° C. The reaction mixture was stirred for 16 hours. The reaction mixture was then filtered, and the organic layer was diluted with MTBE (200 mL). The organic layer was washed with brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude title compound (4.2 g, 80% yield). 1H NMR(400MHz,CDCl3)δ 7.46(d,J=1.6Hz,1H),6.50(d,J=2.0Hz,1H),4.61-4.51(m,1H),1.53(d,J=6.8Hz,6H).

[0574] Step 2: 5-Bromo-1-isopropyl-3-(trifluoromethyl)-1H-pyrazole [ka]

[0575] To a solution of 1-isopropyl-3-(trifluoromethyl)pyrazole (3.2 g, 17.96 mmol) in tetrahydrofuran (50 mL) stirred at -78°C was added n-butyllithium (15 mL, 37.5 mmol, 2.3 M in THF) dropwise. The reaction mixture was stirred at -78°C for 1 hour. Bromine (3.0 mL, 58.55 mmol) was then added dropwise. The rate of addition was slow enough to allow complete decolorization of the bromine before the next addition. The temperature was raised to -30°C over 1 hour. o After warming to 25°C, the reaction mixture was quenched with a saturated solution of NaHCO3 (40 mL) and the reaction o The mixture was warmed to C. The two phases were separated, and the aqueous layer was extracted with tert-butyl methyl ether (100 mL × 3). The combined organic layers were washed with a saturated solution of Na2SO3 (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (3.8 g, 82% yield). LCMS (ESI): [M+H]+ = 258.9. 1 H NMR(400MHz,CDCl3)δ 6.54(s,1H),4.78-4.71(m,1H),1.50(d,J=6.8Hz,6H).

[0576] Step 3: 3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohex-2-enone [ka]

[0577] To a solution of 5-bromo-1-isopropyl-3-(trifluoromethyl)pyrazole (2 g, 7.78 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one (1728 mg, 7.78 mmol), and potassium carbonate (3226 mg, 23.34 mmol) in water (2 mL) and 1,4-dioxane (8 mL) was added Pd(dppf)Cl (569 mg, 0.78 mmol). The reaction mixture was stirred at 80 °C under N for 4 h and concentrated in vacuo. The residue was purified by silica column chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound (1.5 g, 71% yield).

[0578] Step 4: 3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexanone [ka]

[0579] To a solution of 3-[2-isopropyl-5-(trifluoromethyl)pyrazol-3-yl]cyclohex-2-en-1-one (1.5 g, 5.51 mmol) in methyl alcohol (3 mL) was added 10% palladium on carbon (500 mg). The reaction mixture was stirred under H2 (15 psi) at 25 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound (830 mg, 55% yield). LCMS (ESI): [M+H]+ = 275.1.

[0580] Step 5: (R)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexanone and (S)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexanone [ka]

[0581] Both enantiomers of 3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexanone (960 mg, 3.5 mmol) were separated using chiral SFC (WHELK-O1, 250 mm x 30 mm, 5 μm), 0.1% NH in HO; EtOH, 10%, 60 mL / min) to give (R)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexanone (first peak in SFC, 200 mg, 21% yield) and (S)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexanone (second peak in SFC, 270 mg, 28% yield). LCMS (ESI): [M+H] 275.1. Absolute stereochemistry was arbitrarily assigned.

[0582] Step 6A: To a solution of (R)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexanone (120 mg, 0.44 mmol), 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (85 mg, 0.53 mmol), and acetic acid (26 mg, 0.44 mmol) in methyl alcohol (3 mL) was added sodium cyanoborohydride (137 mg, 2.19 mmol). The reaction mixture was stirred at 60 °C for 16 hours. The pH of the resulting solution was adjusted to about 9 with aqueous NaHCO3. The resulting mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse-phase chromatography (DB, Boston Prime C18 150 x 30 mm x 5 μm, water (0.05% NH3H2O ​​+ 10 mM NH4HCO3); ACN, 55-85%) to give a mixture of diastereomers (120 mg, 72% yield), which was further separated using chiral SFC (Daicel Chiralpak AD-H (250 mm x 30 mm, 5 μm), 0.1% NH3 in HO; EtOH, 10%, 60 mL / min) to give compound 61A* (first SFC peak, 58.8 mg) and compound 61B* (second SFC peak, 41.75 mg). LCMS (ESI): [M+H]+ 420.2.

change

[0583] Compound 61A*: 1 H NMR(400MHz,CD3OD)δ 6.37(s,1H),4.68-4.61(m,1H),4.16-4.06(m,4H),3.02-2.95(m,2H),2.90-2.82(m,3H),2.48-2.38(m,1H),2.21-2 .13(m,3H),2.10-2.01(m,1H),1.96-1.87(m,2H),1.59-1.49(m,1H),1.47(dd,J=2.0,6.4Hz,6H),1.41-1.21(m,3H).

[0584] Compound 61B*: 1 H NMR(400MHz,CD3OD)δ 6.36(s,1H),4.66-4.56(m,1H),4.22-4.00(m,4H),3.29-3.20(m,1H),2.98-2.94(m,1H),2.88-2.75(m,2H),2.71-2.62(m,1H),2.54( brs,1H),2.24-2.13(m,2H),2.07-1.99(m,1H),1.96-1.93(m,2H),1.89-1.78(m,1H),1.68-1.50(m,4H),1.48(dd,J=2.0,6.4Hz,6H).

change

[0585] Step 6B: To a solution of (S)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclohexanone (150 mg, 0.55 mmol), 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (106 mg, 0.66 mmol), and acetic acid (33 mg, 0.55 mmol) in methyl alcohol (3 mL) was added sodium cyanoborohydride (172 mg, 2.73 mmol). The reaction mixture was stirred at 60 °C for 16 hours. The pH of the resulting solution was adjusted to 9 with aqueous NaHCO3, and then the resulting mixture was extracted with ethyl acetate (50 mL × 2). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography (DG, Phenomenex Gemini-NX 150 x 30 mm x 5 um, water (0.05% NH3H2O)-ACN, 44% to 74%) to give the title compound (160 mg, 68% yield), as a mixture of diastereomers. LCMS (ESI): [M+H]+ 420.2. The mixture of diastereomers was further separated using chiral SFC (SFC-22, Daicel Chiralpak AD (250 mm x 30 mm, 10 um) 0.1% NH3H2O ​​ETOH, 10% to 10%, 60 mL / min) to give compound 61C* (first peak in SFC, 51.18 mg) and compound 61D* (second peak in SFC, 35.17 mg). LCMS (ESI) [M+H] + =420.2.

[0586] Compound 61C*: 1 H NMR(400MHz,CD3OD)δ 6.37(s,1H),4.70-4.58(m,1H),4.17-4.06(m,4H),2.98(d,J=0.8Hz,2H),2.90-2.81(m,3H),2.48-2.37(m,1H),2.22- 2.12(m,3H),2.11-2.03(m,1H),1.97-1.86(m,2H),1.60-1.49(m,1H),1.47(dd,J=2.0,6.8Hz,6H),1.41-1.21(m,3H).

[0587] Compound 61D*: 1H NMR(400MHz,CD3OD)δ 6.36(s,1H),4.63-4.59(m,1H),4.21-4.12(m,2H),4.11-4.02(m,2H),3.29-3.18(m,1H),2.96(d,J=8.8Hz,1H),2.88-2.75(m,2H),2.7 1-2.63(m,1H),2.55(brs,1H),2.24-2.12(m,2H),2.07-1.99(m,1H),1.95-1.79(m,3H),1.68-1.50(m,4H),1.48(dd,J=2.0,6.8Hz,6H).

[0588] Example FFF: 6-((1s,4s)-4-(6-(trifluoromethyl)pyridin-2-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 62A) and 6-((1r,4r)-4-(6-(trifluoromethyl)pyridin-2-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 62B) [ka] The title compound was synthesized using 2-bromo-6-(trifluoromethyl)pyridine following a procedure similar to that for compound 47A. The mixture of diastereoisomers (70.0 mg, 0.18 mmol) was purified by chiral SFC (Cellulose 2; (150 mm × 4.6 mm, 5 μm); 0.1% NH in water; EtOH, 45%, 25 mL / min) to give compound 62A (first peak in SFC, 23.1 mg, 33% yield) and compound 62B (second peak in SFC, 33.2 mg, 47.4% yield). LCMS (ESI) [M+H] + =389.1. Relative stereochemistry, 1 Assignment was based on 1 H NMR analysis.

[0589] Compound 62A: 1H NMR(400MHz,CD3OD)7.92(t,J=7.6Hz,1H),7.57(t,J=8.0Hz,2H),4.17-4.08(m,4H),3.02-2.89(m,3H),2.81( t,J=7.2Hz,2H),2.47(s,1H),2.20(t,J=7.2Hz,2H),2.17-2.05(m,2H),1.96-1.84(m,2H),1.76-1.65(m,4H).

[0590] Compound 62B: 1 H NMR(400MHz,CD3OD)7.92(t,J=8.0Hz,1H),7.59(d,J=7.2Hz,1H),7.51(d,J=8.0Hz,1H),4.21-4.09(m,4H),3.11(s,2H),2.96(t,J=7.2Hz,2 H),2.86-2.74(m,1H),2.44-2.38(m,1H),2.25(t,J=7.2Hz,2H),2.18- 2.16(m,2H),2.06-2.02(m,2H),1.72-1.68(m,2H),1.53-1.40(m,2H).

[0591] Example GGG: 6-((1r,4r)-4-(5-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 63A) and 6-((1s,4s)-4-(5-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 63B) [ka] The title compound was synthesized using 3-bromo-5-(trifluoromethyl)pyridine following a procedure similar to that for compound 47A. The mixture of diastereomers was purified by preparative TLC (10% methanol in dichloromethane) to give compound 63A (first peak, 53.3 mg, 0.13 mmol, 55% yield) and compound 63B (second peak, 32.06 mg, 0.08 mmol, 33% yield). LCMS (ESI): [M+H] + =389.1. Relative stereochemistry,1 Assignment was based on 1 H NMR analysis.

[0592] Compound 63A: 1 H NMR(400MHz,CDCl3)δ 8.73(s,1H),8.67(d,J=1.6Hz,1H),7.74(s,1H),4.09(s,4H),2.93(s,2H),2.80(t,J=7.2Hz,2H) ,2.67-2.59(m,1H),2.28-2.10(m,5H),2.10-1.97(m,2H),1.57-1.52(m,2H),1.43-1.36(m,2H).

[0593] Compound 63B: 1 H NMR(400MHz,CDCl3)δ 8.73(s,1H),8.67(d,J=1.6Hz,1H),7.72(s,1H),4.15-4.03(m,4H),2.85(s,2H),2.76-2.72(m,3H) ),2.47-2.42(m,1H),2.23-2.18(m,2H),2.08-2.01(m,2H),1.97-1.89(m,2H),1.71-1.59(m,4H).

[0594] Example HHH: 6-((1r,4r)-4-(2-ethyl-6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 64A) and 6-((1s,4s)-4-(2-ethyl-6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 64B) [ka] The title compound was synthesized using 3-bromo-2-ethyl-6-(trifluoromethyl)pyridine following a procedure similar to that for compound 47A. The mixture of diastereomers was purified by reverse-phase chromatography (water (0.05% NH in H2O + 10 mM NH4HCO3); ACN, 60-90%) to give compound 64A (first peak by HPLC, 46.8 mg, 25.1% yield) and compound 64B (second peak by HPLC, 19.2 mg, 10.3% yield). LCMS (ESI): [M+H] + =417.2. Relative stereochemistry, 1 Assignment was based on 1 H NMR analysis.

[0595] Compound 64A: 1 H NMR(400MHz,CDCl3)δ 7.61(d,J=8.0Hz,1H),7.46(d,J=8.0Hz,1H),4.08(s,4H),2.95-2.91(m,4H),2.83-2.76(m,3H),2 .29-2.24(m,1H),2.19-2.12(m,4H),1.90-1.80(m,2H),1.55-1.45(m,4H),1.31(t,J=7.6Hz,3H).

[0596] Compound 64B: 1 H NMR(400MHz,CDCl3)δ 7.61(d,J=8.0Hz,1H),7.47(d,J=8.0Hz,1H),4.14-4.06(m,4H),2.96-2.90(m,3H),2.85(s,2H),2.75(t,J=7.2Hz,2H),2. 47(t,J=2.4Hz,1H),2.19(t,J=7.2Hz,2H),2.08-1.98(m,2H),1.85-1.75(m,2H),1.55-1.40(m,4H),1.30(t,J=7.6Hz,3H).

[0597] Example III: 6-((1r,4r)-4-(2-isopropyl-6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 65A) and 6-((1s,4s)-4-(2-isopropyl-6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (Compound 65B) [ka] The title compound was synthesized using 3-bromo-2-isopropyl-6-(trifluoromethyl)pyridine following a procedure similar to that for compound 47A. The mixture of diastereomers was purified by reverse-phase chromatography (water (0.05% NH in H2O + 10 mM NH4HCO3); ACN) to give compound 65A (first peak by HPLC, 60.18 mg, 0.13 mmol, 37.1% yield) and compound 65B (second peak by HPLC, 16.1 mg, 0.037 mmol, 10.6% yield). LCMS (ESI) [M+H] + =431.2.Relative stereochemistry, 1 Assignment was based on 1 H NMR analysis.

[0598] Compound 65A: 1 H NMR(400MHz,CDCl3)δ 7.59(d,J=8.4Hz,1H),7.42(d,J=8.0Hz,1H),4.08(s,4H),3.36-3.33(m,1H),2.93(s,2H),2.81(t,J=7.2Hz,3H),2.2 9-2.23(m,1H),2.17(t,J=7.2Hz,2H),2.11-2.08(m,2H),1.91-1.82(m,2H),1.52-1.46(m,4H),1.29(d,J=6.4Hz,6H).

[0599] Compound 65B: 1H NMR(400MHz,CDCl3)δ 7.59(d,J=8.4Hz,1H),7.43(d,J=8.0Hz,1H),4.14-4.06(m,4H),3.38-3.33(m,1H),2.93-2.87(m,1H),2.85(s,2H),2.75(t,J=7.2Hz,2H ),2.47(s,1H),2.19(t,J=7.2Hz,2H),2.09-1.99(m,2H),1.86-1.76(m,2H),1.65-1.62(m,2H),1.55-1.52(m,2H),1.29(d,J=6.4Hz,6H).

[0600] Example JJJ: (Compounds 66A* and 66B*) (R)-6-(1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (S)-6-(1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka] The title compound was synthesized following a similar procedure to compound 55A, using 2-thia-6-azaspiro[3.4]octane 2,2-dioxide in the first step and 5-bromo-2-(trifluoromethyl)pyridine in the third step. The mixture (130 mg, 0.33 mmol) was separated using chiral SFC (Daicel Chiralpak AD (250 mm*30 mm, 10 μm); 0.1% NH in HO; EtOH, 30%, 70 mL / min) to give compound 66A* (first peak in SFC, 46.7 mg, 36% yield) and compound 66B* (second peak in SFC, 50 mg, 38% yield). LCMS (ESI) [M+H] + =390.2.

[0601] Compound 66A*: 1H NMR(400MHz,CD3OD)δ 8.31(d,J=2.8Hz,1H),...

Claims

1. Formula I 【Chemistry 321】 or a pharmaceutically acceptable salt thereof, wherein j １、 j ２ , and m １ are each independently 1, 2, or 3; m ２ is 0, 1, 2 or 3, j １ and ２ The sum of and m １ and m ２ The sum of each is 5 or less, and j １ and ２ and m １ and m ２ The sum of the above is 9 or less, Ring A is 【Chemistry 322】 and 【Chemical 323】 indicates the attachment of the ring to the rest of the molecule, * indicates the attachment of ring A to ring B, X is N or CH and Y is O or CH ２ and when X is N, Y is CH ２ and R ｚ is, if present, in each occurrence, halogen, hydroxy, C １ ~C ６ Alkyl, halo-C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halo-C １ ~C ６ independently selected from the group consisting of alkoxy, —CN, and —NRR′; Two R's ｚ may form a bridge together with the atoms on ring A to which they are attached, p is 0, 1, 2, or 3; Ring B is phenyl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, N, and S; R ｙ is, if present, in each occurrence, halogen, C １ ~C ６ Alkyl, halo-C １ ~C ６ Alkyl, hydroxy, C １ ~C ６ Alkoxy, halo-C １ ~C ６ Alkoxy, C ３ ~C ７ Cycloalkyl, C ３ ~C ７ Halocycloalkyl, —SO ２ (C １ ~C ６ independently selected from the group consisting of —alkyl), —CN, and —NRR′; n is 0, 1, 2, 3, or 4; R ｘ is halogen, hydroxy, C １ ~C １０ Alkyl, halo-C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halo-C １ ~C ６ Alkoxy, 5- to 7-membered heterocyclyl, C ３ ~C ７ Cycloalkyl, C ６ ~C １０ Aryl, 5- to 6-membered heteroaryl, —SO ２ (C １ ~C ６ alkyl), —CN, and —NRR′; The heterocyclyl, cycloalkyl, aryl, or heteroaryl is (R ｘＡ ) ｑ is replaced by q is 0, 1, 2, 3, 4, or 5; R ｘＡ is, if present, in each occurrence, halogen, C １ ~C ６ Alkyl, hydroxy, C １ ~C ６ Alkoxy, halo-C １ ~C ６ Alkoxy, halo-C １ ~C ６ Alkyl, —SO ２ (C １ ~C ６ independently selected from the group consisting of -NR"R"", -CN, and -NR"R""; R, R', R'', and R''' are each independently H, C １ ~C ６ Alkyl, or halo-C １ ~C ６ A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

2. The compound is of formula Ia 【Chemical 324】 (In the formula, Y １ , Y ２ , Y ３ , Y ４ , and Y ５ are each independently selected from the group consisting of CH, C, and N, and C is R ｘ or R ｙ 10. The compound of claim 1, wherein the compound is:

3. Y １ , Y ２ , Y ３ , Y ４ , and Y ５ One of them is N and one is CR ｘ and the remainder are each independently CH or CR ｙ 3. The compound of claim 2, wherein:

4. Y １ , Y ２ , Y ３ , Y ４ , and Y ５ One of them is CR ｘ and the remainder are each independently CH or CR ｙ 3. The compound of claim 2, wherein:

5. The compound has the formula Ic 【Chemistry 326】 (In the formula, E １ is N or CH), or a pharmaceutically acceptable salt thereof.

6. R ｘ But, Halo-C １ ~C ６ Alkyl, C ３ ~C ５ cycloalkyl, phenyl, and 6-membered heteroaryl, wherein said cycloalkyl, phenyl, or heteroaryl is selected from the group consisting of (R ｘＡ ) ｑ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, substituted with:

7. R ｘ 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, and fluoroethyl.

8. R ｘ The compound of claim 7, wherein is trifluoromethyl.

9. R ｘ 7. The compound of claim 6, wherein is cyclopropyl and q is 0, or a pharmaceutically acceptable salt thereof.

10. The compound has the formula Id 【Chemistry 327】 (In the formula, D １ , D ２ , D ３ , D ４ , and D ５ are each independently N, R ｘＡ When bonded to D, it is C or CH. １ , D ２ , D ３ , D ４ , and D ５ and q is 1 or 2, or a pharmaceutically acceptable salt thereof.

11. D １ ~D ５ 11. The compound of claim 10, wherein one of: is N, or a pharmaceutically acceptable salt thereof.

12. D ３ or D ４ But, C-R ｘＡ 12. The compound of claim 10 or 11, wherein:

13. D １ is CH and D ２ is CH and D ３ is C-R ｘＡ and D ４ is N and D ５ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein is CH.

14. R ｘＡ But, Halo-C １ ~C ６ Alkyl or C １ ~C ６ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, which is haloalkoxy.

15. R ｘＡ But, Halo-C １ ~C ６ 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

16. R ｘＡ 16. The compound of claim 14 or 15, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, and fluoroethyl.

17. R ｘＡ 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein is trifluoromethyl.

18. R ｙ But halogen, C ３ ~C ７ cycloalkyl, and C １ ~C ６ 11. The compound of any one of claims 1, 2, 3, 4, or 10, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkyl.

19. R ｙ 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, methyl, ethyl, n-propyl, isopropyl, and butyl.

20. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 0.

21. Ring A is 【Chemical 328】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

22. j １ is 1, and j ２ is 1, and m １ is 2 and m ２ is 1 or j １ is 1, and j ２ is 1, and m １ is 1, and m ２ is 2 or j １ is 1, and j ２ is 2 and m １ is 1, and m ２ is 3 or j １ is 1, and j ２ is 2 and m １ is 1, and m ２ is 2 or j １ is 1, and j ２ is 2 and m １ is 2 and m ２ is 1 or j １ is 2 and j ２ is 2 and m １ is 2 and m ２ is 1 or j １ is 2 and j ２ is 1, and m １ is 3 and m ２ is 1 or j １ is 1, and j ２ is 1, and m １ is 3 and m ２ is 1 or or j １ is 1, and j ２ is 1, and m １ is 2 and m ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

23. Ring A is 【Chemical 333】 2. The compound of claim 1, wherein:

24. The compound is 【Chemistry 334】 【Chemistry 335】 【Chemistry 336】 【Chemistry 337】 【Chemical 338】 【Chemistry 339】 【Chemistry 340】 【Chemistry 341】 【Chemistry 342】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

26. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof for treating a disorder.

27. 26. A composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 25, for use in promoting myelination in a subject in need thereof.

28. 27. The pharmaceutical composition of claim 26, wherein the disorder is a myelin-related disorder.

29. The myelin-related disorder may be multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, childhood leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander disease, Pelizaeus-Merzbacher disease (PMD), vanishing white matter disease, Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, or Alzheimer's disease.

29. The pharmaceutical composition of claim 28, wherein the condition is selected from the group consisting of Marsh's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post-radiation injury, neurological complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Marchiafaver-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barré syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination.

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