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 myelin-related disorders. TIFF2024542296000301.tif32124

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 282,362, 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, Marchiafer-Va-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 current therapies do not prevent the progression of MS. 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] Quick 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.

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

[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 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.

[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 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 methods 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 myelin-promoting compounds of Formula I, methods for making the compounds, pharmaceutical compositions thereof, and their use in treating myelin-related disorders.

[0015] Enhancement and / or induction of 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 by inhibiting the accumulation of Δ8,9-unsaturated sterol intermediates and / or modulating and / or inhibiting enzymes in the cholesterol biosynthesis pathway in OPCs 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 OPC differentiation, survival, proliferation, and / or maturation, and can treat 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 of 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, a compound of Formula I can inhibit CYP51, sterol 14 reductase (TM7SF2 and / or LBR), SC4MOL, NSDHL, and / or EBP enzyme-mediated synthesis of sterol intermediates in the cholesterol biosynthetic pathway. In certain embodiments, a compound of Formula I can inhibit CYP51, sterol 14 reductase, and / or EBP. In certain embodiments, a compound of Formula I can inhibit EBP.

[0018] For example, in certain embodiments, the compounds of Formula I 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 compounds of Formula I 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 foregoing description. 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 having 2 to 20 carbon atoms (i.e., C2-C6). 20Alkenyl refers to an alkyl group having 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 ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0029] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C2-C6). 20 The term "alkynyl" refers to an alkyl group having 2 to 8 carbon atoms (i.e., C2-C8 alkynyl), 2 to 6 carbon atoms (i.e., C2-C6 alkynyl), or 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 taken 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 C10 aryl). 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 to a heteroaryl, the resulting ring system is a heteroaryl, regardless of the point of attachment. When one or more aryl groups are fused to 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, including 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 one to three 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 one to six 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. (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. 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 multiple rings may be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered heterocyclyl, regardless of attachment (i.e., it may be attached via a carbon atom or a heteroatom). Furthermore, the term heterocyclyl is intended to encompass moieties containing any non-aromatic ring containing at least one heteroatom, which may be fused to an aryl or heteroaryl ring, regardless of attachment 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 attachment 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, octahydroisoindolyl, 2-hydroxybenzo ... -oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl)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 (-NO).

[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 -SO2(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 term "optionally" or "optionally" means 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., 1-5, 1-4, or 1-3) 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 has been replaced by a bond to a non-hydrogen atom, e.g., alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbazole, carbazole-substituted ... Bamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, 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 by 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 taken together with the atom to which they are attached form a heterocyclyl ring optionally substituted with oxo, halo, or an 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 than one / one or more than one" as used herein refers to one to five. In certain embodiments, the phrase "one or more than one / one or more than one" as used herein refers to one to four. In certain embodiments, the phrase "one or more than one / one or more than one" as used herein refers to one to three.

[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 shown herein except that one or more atoms are replaced by atoms 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, such as 3 H, 13 C and 14A radioactive isotope such as C is 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.

[0075] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and organic acids. Furthermore, if 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., Examples of suitable amines include, but are not limited to, NH(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 tautomers, it is understood by those skilled in the art that the compound includes both amide and imidic acid tautomers. Therefore, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[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 clinical results. Beneficial or desired clinical results can include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by 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).

[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, refers to 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. Examples of binders include carbomer, povidone, xanthan gum, etc.; examples of coating materials include cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coatings, etc.; examples of compression / encapsulation materials include 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.; examples of disintegrants include croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; examples of creams or lotions include Examples of suitable excipients 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 may 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] (In the formula, j1, j2, m1, and m2 are each independently 1 or 2, 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 6 or less; R 1a , R 1b , R 2a , and R 2b are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and C1-C6 alkoxy; X is O or C(R 10 )(R 20 ) and R 10 and R 20 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and C1-C6 alkoxy; or R 1a and R 1b , R 2a and R 2b , or R 10 and R 20 together with the atoms to which they are attached form a C3-C5 cycloalkyl optionally substituted with halogen, hydroxy, halo-C1-C6 alkoxy, C1-C6 alkoxy, -SO2(C1-C6 alkyl), -CN or -NRR'; Ring A 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; Each R yare independently 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 or -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 aryl, 5- to 6-membered heteroaryl, -SO2(C1-C6 alkyl), -CN, or -NRR'; the heterocyclyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, halo-C1-C6 alkyl, -SO2(C1-C6 alkyl), -CN, and -NR'R'"; R, R', R'', and R''' are each independently hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0090] Useful compounds include all compounds having the variables described above.

[0091] In certain embodiments, the compounds include those in which one of m1 and m2 is 1 and the other is 2 (and the sum is 3). In certain embodiments, the compounds include those in which m1 and m2 are each 1 (and the sum is 2). In certain embodiments, the compounds include those in which m1 and m2 are each 2 (and the sum is 4).

[0092] In certain embodiments, the compounds include those in which one of j1 and j2 is 1 and the other is 2 (and the sum is 3). In certain embodiments, the compounds include those in which j1 and j2 are each 1 (and the sum is 2). In certain embodiments, the compounds include those in which j1 and j2 are each 2 (and the sum is 4).

[0093] In certain embodiments, the sum of j1, j2, m1, and m2 is 5. In certain embodiments, the sum of j1, j2, m1, and m2 is 6.

[0094] In certain embodiments, the compounds include those in which j1, j2, m1, and m2 are as shown in Table 1A.

[0095] [Table 1A]

[0096] In certain embodiments (embodiment A), the compound of formula I has formula Ia: [ka] (In the formula, E1, E2, E3, and E4 each independently represent CH, CR x , C.R. y , N.R. x , N.R. y , N, NH, O, and S, and one, two, or three of E1, E2, E3, and E4 are selected from the group consisting of N, NH, NR x , N.R. y , O, or S, and j1, j2, m1, m2, R 1a , R 2a , R 1b , R 2b , X, R y , R x and n is as defined for Formula I), or a pharmaceutically acceptable salt thereof.

[0097] In a particular embodiment (embodiment B), the compound of formula I has formula Ib: [ka] or a pharmaceutically acceptable salt thereof, wherein Y1, Y2, Y3, Y4, and Y5 each independently represent CH, CR y , C.R. x , N, or S, and one, two, or three of Y1, Y2, Y3, Y4, and Y5 are N or S; j1, j2, m1, m2, R 1a , R 2a , R 1b , R 2b , X, R y , R x and n is as defined for Formula I.

[0098] In certain embodiments of embodiment A above, the compound is x and E4 is CH. In certain embodiments, the compound is a compound of formula Ia, or a pharmaceutically acceptable salt thereof, wherein E1 is CH and E2 is CR x and E3 is N and E4 is NR y or a pharmaceutically acceptable salt thereof.

[0099] In certain embodiments of embodiment B above, the compound of formula Ib, or a pharmaceutically acceptable salt thereof, is a compound of formula Ib, wherein Y1, Y2, Y4, and Y5 are each CH; and Y3 is CR x or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula Ib, wherein Y, Y, and Y are each CH, Y is N, and Y is CR x In certain embodiments, the compound includes a compound of formula Ib, wherein Y, Y, and Y are each CH and Y is CR. y and Y3 is CR x In certain embodiments, the compound includes a compound of formula Ib, wherein Y, Y, and Y are each CH and Y is CR.x and Y3 is N. In certain embodiments, compounds include those of formula Ib where Y2 and Y4 are each N, Y1 and Y5 are each CH, and Y3 is CR x In certain embodiments, the compound includes compounds of formula Ib, wherein Y5 is N and Y3 is CR x and Y, Y, and Y are each CH. In certain embodiments, the compound is x and Y2 is N, and Y1, Y3, and Y5 are each CH. In certain embodiments, the compound is a compound of formula Ib where Y1, Y2, Y3, and Y4 are each CH, and Y5 is CR x In certain embodiments, the compound includes compounds of formula Ib, wherein Y and Y are CH and Y is CR y and Y3 is CR x and Y2 is N. In certain embodiments, the compound includes compounds of formula Ib where Y1 is CH and Y5 is CR y and Y4 is N and Y3 is CR x and Y2 is CH.

[0100] In certain embodiments of any of the above, the compounds of Formula I, Ia, and Ib, or pharmaceutically acceptable salts thereof, may be R y In certain embodiments, the compound includes compounds where R y is halogen, C1-C3 alkyl, or halo-C1-C6 alkyl. In certain embodiments, the compound is y In certain embodiments, compounds include those in which R yis selected from the group consisting of chloro, trifluoromethyl, methyl, and fluoro. In some embodiments, such compounds are compounds of Formula I, or a pharmaceutically acceptable salt thereof. In other embodiments, such compounds are compounds of Formula Ia, or a pharmaceutically acceptable salt thereof. In still further embodiments, such compounds are compounds of Formula Ib, or a pharmaceutically acceptable salt thereof.

[0101] In certain embodiments of any of the above, the compounds of Formula I, Ia, and Ib, or pharmaceutically acceptable salts thereof, may be R x In certain embodiments, the compound includes compounds where R x is selected from the group consisting of fluoro, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, and trifluoromethoxy. x is —CF3, —CH2CF3, —CHF2, or —CH2F. In certain embodiments, the compound is x is -CF3. In some embodiments, such compounds are compounds of formula I, or a pharmaceutically acceptable salt thereof. In other embodiments, such compounds are compounds of formula Ia, or a pharmaceutically acceptable salt thereof. In still further embodiments, such compounds are compounds of formula Ib, or a pharmaceutically acceptable salt thereof.

[0102] In certain embodiments of any of the above, the compounds of Formula I, Ia, and Ib, or pharmaceutically acceptable salts thereof, may be R x is C3-C7 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, and halo-C1-C6 alkyl. xis selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each optionally substituted with one or two substituents independently selected from the group consisting of fluoro, methyl, hydroxy, and trifluoromethyl. x is selected from the group consisting of cyclohexyl substituted with 1 or 2 substituents each independently selected from the group consisting of fluoro, methyl, hydroxy, and trifluoromethyl. x but, [ka] In certain embodiments, the compound is x is unsubstituted cyclohexyl, unsubstituted cyclopropyl, or unsubstituted cyclobutyl. x is cyclopropyl substituted once or twice with methyl. In certain embodiments, the compound is x but, [ka] In some embodiments, such compounds are compounds of formula I, or a pharmaceutically acceptable salt thereof. In other embodiments, such compounds are compounds of formula Ia, or a pharmaceutically acceptable salt thereof. In still further embodiments, such compounds are compounds of formula Ib, or a pharmaceutically acceptable salt thereof.

[0103] In certain embodiments of any of the above, the compounds of Formula I, Ia, and Ib, or pharmaceutically acceptable salts thereof, may be R x In certain embodiments, the compound includes compounds where R x In certain embodiments, the compound includes compounds where R x In certain embodiments, the compound includes compounds where Rx but, [ka] In some embodiments, such compounds are compounds of formula I, or a pharmaceutically acceptable salt thereof. In other embodiments, such compounds are compounds of formula Ia, or a pharmaceutically acceptable salt thereof. In still further embodiments, such compounds are compounds of formula Ib, or a pharmaceutically acceptable salt thereof.

[0104] In certain embodiments of any of the above, the compounds of Formula I, Ia, and Ib, or pharmaceutically acceptable salts thereof, may be R x However, C1~C 10 In certain embodiments, the compound is R x is selected from the group consisting of propyl, butyl, pentyl, hexyl, and heptyl. x is selected from the group consisting of n-pentyl, tert-pentyl, neopentyl, isopentyl, and sec-pentyl. x is tert-pentyl. In some embodiments, such compounds are compounds of formula I, or a pharmaceutically acceptable salt thereof. In other embodiments, such compounds are compounds of formula Ia, or a pharmaceutically acceptable salt thereof. In still further embodiments, such compounds are compounds of formula Ib, or a pharmaceutically acceptable salt thereof.

[0105] In certain embodiments of any of the above, the compounds of Formula I, Ia, and Ib, or pharmaceutically acceptable salts thereof, may be R x In certain embodiments, the compound includes compounds where R x but, [ka] In some embodiments, such compounds are compounds of formula I, or a pharmaceutically acceptable salt thereof. In other embodiments, such compounds are compounds of formula Ia, or a pharmaceutically acceptable salt thereof. In still further embodiments, such compounds are compounds of formula Ib, or a pharmaceutically acceptable salt thereof.

[0106] In certain embodiments of any of the above, compounds of Formula I, Ia, and Ib, or pharmaceutically acceptable salts thereof, include compounds where X is O.

[0107] In certain embodiments of any of the above, compounds of Formula I, Ia, and Ib, or pharmaceutically acceptable salts thereof, may be those in which X is C(R 10 )(R 20 ) and R 10 and R 20 are each independently hydrogen or fluoro. In certain embodiments, the compound includes compounds where R 10 and R 20 and each is hydrogen.

[0108] In certain embodiments of any of the above, the compounds of Formula I, Ia, and Ib, or pharmaceutically acceptable salts thereof, may be R 2a and R 2b are each independently selected from the group consisting of hydrogen, C1-C6 alkoxy, halogen, and C1-C6 alkyl. 2a and R 2b are each independently methoxy, fluoro, hydrogen, or methyl. 2a is hydrogen and R 2b In certain embodiments, the compound includes compounds where R 2a and R 2b and R are each methyl. In certain embodiments, the compound is 2a and R 2b and each is hydrogen.

[0109] In certain embodiments of any of the above, the compounds of Formula I, Ia, and Ib, or pharmaceutically acceptable salts thereof, may be R 1a and R 1b are each independently hydrogen or methyl. In certain embodiments, the compound includes compounds where R 1a and R 1b and each is hydrogen.

[0110] In a particular embodiment (Embodiment A1), the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein: E1, E2, E3, and E4 are each independently CH, CR x , C.R. y , N.R. x , N.R. y , N, and NH, and one, two, or three of E1, E2, E3, and E4 are selected from the group consisting of N, NH, NR x , or NR y and one of m1 and m2 is 1 and the other is 2, or m1 and m2 are each 2; j1 and j2 are each 1, n is 0 or 1, R x is halo-C1-C6 alkyl, R y is a C1-C6 alkyl, X is O or C(R 10 )(R 20 ) and R 10 and R 20 are hydrogen, R 1a , R 1b , R 2a , and R 2b are each independently hydrogen or C1-C3 alkyl.

[0111] In certain embodiments of the above embodiment A1, the compound of formula Ia, or a pharmaceutically acceptable salt thereof, is R 1a and R1b are hydrogen, and R 2a is hydrogen and R 2b is methyl and X is CH2, or R 1a , R 1b , R 2a , and R 2b are each hydrogen and X is O. In certain of the above embodiments, the compound is x and E4 is CH and R x In certain of the above embodiments, the compound includes compounds where E1 is CH and E2 is CR x and E3 is N and E4 is NR y and R x is trifluoromethyl and R y Includes compounds where is isopropyl.

[0112] In a particular embodiment (Embodiment B1), the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt thereof, wherein: j1, j2, m1, and m2 are each independently 1 or 2, 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 6 or less; Four of Y1, Y2, Y3, Y4, and Y5 are CH and one is CR x and R x is halo-C1-C6 alkyl, halogen, halo-C1-C6 alkoxy, C1-C 10 selected from the group consisting of alkyl, pyridinyl, and C3-C7 cycloalkyl, wherein the C3-C7 cycloalkyl or pyridinyl is optionally substituted one or more times with C1-C6 alkyl or halo-C1-C6 alkyl; n is 0, X is C(R 10 )(R 20 ) or O, and R 10 and R 20are each independently hydrogen, methyl or fluoro; R 1a and R 1b are each independently hydrogen or methyl; R 2a and R 2b are each independently hydrogen, fluoro, methoxy, or methyl, or R 2a and R 2b together with the carbon atom to which they are attached form a C3-C5 cycloalkyl.

[0113] In certain embodiments of the above embodiment B1, the compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, is one in which Y1, Y2, Y4, and Y5 are CH and Y3 is CR x In certain embodiments of the above embodiments, the compound is x is trifluoromethyl, difluoromethyl, pyridinyl, trifluoromethoxy, fluoro, pentyl, cyclopropyl, or cyclobutyl, wherein the cyclopropyl or cyclobutyl is optionally substituted once or twice with C1-C3 alkyl, and the pyridinyl is optionally substituted once with halo-C1-C6 alkyl. x -C(CH3)2CH2CH3, -CF3, -CHF2, -OCF3 fluoro, [ka] In certain embodiments of the above embodiments, the compound is 1a , R 1b , R 2a , and R 2b are hydrogen, or (2) R 1a and R 2a One of the groups is methyl and the other is hydrogen, and R 2a and R 2b are hydrogen, or (3) R 2a and R 2b is methyl and R 1a and R1b is hydrogen, or (4) R 1a and R 1b is hydrogen and R 2a and R 2b taken together with the carbon to which they are attached form a cyclobutyl or cyclopentyl ring. In certain of the above embodiments, the compound is 10 )(R 20 ), wherein R 10 is hydrogen and R 20 is fluoro or R 10 and R 20 are hydrogen, and R 1a and R 1b are hydrogen, and R 2a is hydrogen and R 2b is fluoro, hydrogen, methyl or methoxy, or R 2a and R 2b are methyl, respectively.

[0114] In a particular embodiment (embodiment B2), the compound is a compound of formula Ib, or a pharmaceutically acceptable salt thereof, wherein: j1, j2, m1, and m2 are each independently 1 or 2, 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 6 or less; Three of Y1, Y2, Y3, Y4, and Y5 are CH and one is CR x and the other is CR y and R y is halogen or halo-C1-C6 alkyl, R x is halogen, halo-C1-C6 alkyl, 5- to 7-membered heterocyclyl, or C3-C7 cycloalkyl, and the heterocyclyl or cycloalkyl is halogen, halo-C 1~ optionally substituted one or more times with C6 alkoxy, hydroxy, or C1-C6 alkyl; n is 1, X is C(R 10 )(R 20 ) or O, and R 10 and R 20 are hydrogen, R 1a , R 1b , R 2a、 and R 2b are each independently hydrogen or methyl.

[0115] In certain embodiments of embodiment B2 above, the compound of formula Ib, or a pharmaceutically acceptable salt thereof, includes compounds in which Y1, Y2, and Y5 are each CH and Y4 is CR y and Y3 is CR x In certain embodiments of the above embodiments, the compound is y is chloro, fluoro or trifluoromethyl, and R x is fluoro, chloro, tetrahydropyranyl, or cyclohexyl, wherein the cyclohexyl is substituted once with fluoro or hydroxy and once with trifluoromethyl, methyl, or fluoro. y is chloro or fluoro, and R x But fluoro, chloro, -CF3, [ka] In certain embodiments of the above embodiments, the compound is y In certain embodiments of the above embodiments, the compound includes compounds where X is CH or O and R 1a and R 1b are hydrogen, and R 2a and R 2b are each independently hydrogen or methyl.

[0116] In a particular embodiment (embodiment B3), the compound is a compound of formula Ib, or a pharmaceutically acceptable salt thereof, wherein: j1, j2, m1, and m2 are each independently 1 or 2, 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 6 or less; One or two of Y1, Y2, Y3, Y4, and Y5 are N, and one of Y1, Y2, Y3, Y4, and Y5 is CR. x and the remaining parts of Y1, Y2, Y3, Y4, and Y5 are CH or CR, respectively. y and n is 0 or 1, R y is halogen, halo-C1-C6 alkyl, or C1-C6 alkyl; R x is halo-C1-C6 alkyl, halogen, pyridinyl, or C3-C7 cycloalkyl, wherein the pyridinyl or cycloalkyl is optionally substituted one, two, or three times with halogen or halo-C1-C6 alkyl; X is C(R 10 )(R 20 ) or O, and R 10 and R 20 are each hydrogen or R 10 is hydrogen and R 20 is fluoro, R 1a and R 1b are hydrogen, R 2a and R 2b are each independently hydrogen or methyl, or R 2a and R 2b together with the carbons to which they are attached form a C3-C5 cycloalkyl.

[0117] In certain embodiments of embodiment B3 above, the compound of Formula Ib, or a pharmaceutically acceptable salt thereof, is a compound of Formula Ib, wherein Y1, Y2, and Y5 are each CH; Y4 is N; and Y3 is CR x Y1, Y2, and Y5 are each CH, and Y4 is CR xY3 is N, Y2 and Y4 are each N, Y1 and Y5 are each CH, and Y3 is CR x and Y5 is N and Y3 is CR x Y1, Y2, and Y4 are each CH, and Y4 is CR x Y2 is N, Y1, Y3, and Y5 are each CH, Y5 is CH, and Y4 is CR y and Y3 is CR x and Y2 is N, or Y1 is CH and Y5 is C- y and Y4 is N and Y3 is CR x and Y2 is CH. In certain embodiments of the above embodiments, the compound is x is trifluoromethyl, fluoro, or cyclohexyl optionally substituted with trifluoromethyl, and R y In certain embodiments of the above embodiments, the compound includes compounds where R x But -CF3, fluoro, [ka] The present invention includes compounds in which:

[0118] In a particular embodiment (embodiment B4), the compound is a compound of formula Ib, or a pharmaceutically acceptable salt thereof, wherein: Y1, Y2, Y4, and Y5 are each CH, and Y3 is CR x and R x is halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C1-C 10 alkyl, and C3-C7 cycloalkyl, wherein the C3-C7 cycloalkyl is optionally substituted one or more times with C1-C6 alkyl; n is 0, X is C(R 10 )(R 20 ) and R 10 and R 20are each independently hydrogen, methyl or fluoro; R 1a and R 1b are each independently hydrogen or methyl; R 2a and R 2b are each independently hydrogen, fluoro, methoxy, or methyl; one of m1 and m2 is 1 and the other is 2, or m1 and m2 are each 2, or m1 and m2 are each 1; j1 and j2 are each 1, or one of j1 and j2 is 1 and the other is 2, or j1 and j2 are each 2, with the proviso that the sum of j1, j2, m1, and m2 is 6 or less.

[0119] In certain embodiments of embodiment B4 above, the compound of formula Ib, or a pharmaceutically acceptable salt thereof, is R x is selected from the group consisting of trifluoromethyl, trifluoromethoxy, pentyl, cyclopropyl, and cyclobutyl, wherein the cyclopropyl or cyclobutyl is optionally substituted once or twice with methyl; R 10 and R 20 are hydrogen, respectively; R 1a and R 1b are hydrogen, R 2a and R 2b are each independently hydrogen or methyl; one of m1 and m2 is 1 and the other is 2; j1 and j2 are each 1; The compound includes the compound, or a pharmaceutically acceptable salt thereof.

[0120] In a particular embodiment (embodiment B5), the compound is a compound of formula Ib, or a pharmaceutically acceptable salt thereof, wherein: Y1, Y2, and Y5 are each CH, and Y4 is CRy and Y3 is CR x and R y is a halogen, n is 1, R x is a 5-7 membered heterocyclyl or C-C cycloalkyl optionally substituted one or more times with halogen, halo-C-C alkoxy, hydroxy, or C-C alkyl; X is C(R 10 )(R 20 ) and R 10 and R 20 are hydrogen, R 1a and R 1b are hydrogen, R 2a and R 2b are each independently hydrogen or methyl; one of m1 and m2 is 1 and the other is 2; j1 and j2 are each 1.

[0121] In certain embodiments of embodiment B5 above, the compound of formula Ib, or a pharmaceutically acceptable salt thereof, is R y is chloro and R x is cyclohexyl or 6-membered heterocyclyl optionally substituted with 1 or 2 substituents each independently selected from the group consisting of fluoro, trifluoromethyl, methyl, and hydroxy.

[0122] In a particular embodiment (embodiment B6), the compound is a compound of formula Ib, or a pharmaceutically acceptable salt thereof, wherein: One or two of Y1, Y2, Y3, Y4, and Y5 are N, and one of Y1, Y2, Y3, Y4, and Y5 is CR. x and the remainder of Y1, Y2, Y3, Y4, and Y5 are each CH; R x is halo-C1-C6 alkyl, n is 0, X is C(R 10 )(R 20 ) or O, and R 10 and R 20 are hydrogen, R 1a and R 1b are hydrogen, R 2a and R 2b are each independently hydrogen or methyl; one of m1 and m2 is 1 and the other is 2, or m1 and m2 are each 2; j1 and j2 are each 1, or one of j1 and j2 is 1 and the other is 2, or j1 and j2 are each 2, with the proviso that the sum of j1, j2, m1, and m2 is 6 or less.

[0123] In certain embodiments of the above embodiment B6, the compound of formula Ib, or a pharmaceutically acceptable salt thereof, is R x In certain embodiments of the above embodiments, the compound includes compounds where R 2a is hydrogen and R 2b In certain embodiments of the above embodiments, the compound includes compounds where R 2a and R 2b and Y are each hydrogen. In certain of the above embodiments, the compound is x wherein Y4 is N or CH and Y5 is CH. In certain embodiments of the above embodiments, the compounds include compounds where one of m1 and m2 is 1 and the other is 2, and j1 and j2 are each 1. In certain embodiments of the above embodiments, the compounds include compounds where m1 and m2 are each 2 and j1 and j2 are each 1. In certain embodiments of the above embodiments, the compounds include compounds where m1 and m2 are each 1 and j1 and j2 are each 2.

[0124] In a particular embodiment (embodiment B7), the compound is a compound of formula Ib, or a pharmaceutically acceptable salt thereof, wherein: X is O or C(R 10 R 20 ) and R 10 and R 20 are hydrogen, Four of Y1, Y2, Y3, Y4, and Y5 are CH and one is CR x Or or three of Y1, Y2, Y3, Y4, and Y5 are CH and one is CR x and the other is CR y and R x is selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkyl, and C3-C7 cycloalkyl; R y is halogen or halo-C1-C6 alkyl, n is 0 or 1, R 1a and R 1b are hydrogen, R 2a and R 2b are each independently hydrogen or methyl; Or, R 2a and R 2b together with the carbon atoms to which they are attached form a C3-C5 cycloalkyl; one of m1 and m2 is 1 and the other is 2, or m1 and m2 are each 1, or m1 and m2 are each 2; j1 and j2 are each 1, or one of j1 and j2 is 1 and the other is 2, or j1 and j2 are each 2, with the proviso that the sum of j1, j2, m1, and m2 is 6 or less.

[0125] In a particular aspect of embodiment B7 above, the compound of formula Ib, or a pharmaceutically acceptable salt thereof, is a compound in which Y1, Y2, Y4, and Y5 are CH and Y3 is CRx In certain aspects of the above embodiments, the compound is one in which Y1, Y4, and Y5 are CH and Y2 is CR y and Y3 is CR x In certain aspects of the above embodiments, the compound is x In certain aspects of the above embodiment, the compound includes compounds where R y is fluoro. In certain aspects of the above embodiments, the compounds include compounds where m1 and m2 are each 2 and j1 and j2 are each 1. In certain aspects of the above embodiments, the compounds include compounds where m1 and m2 are each 1 and j1 and j2 are each 2. In certain aspects of the above embodiments, the compounds include compounds where R x In certain aspects of the above embodiment, the compounds include compounds where X is O. In certain aspects of the above embodiment, the compounds include compounds where X is C(R 10 R 20 ) is included.

[0126] In a particular embodiment (embodiment B8), the compound is a compound of formula Ib, or a pharmaceutically acceptable salt thereof, wherein: X is O, Four of Y1, Y2, Y3, Y4, and Y5 are CH and one is CR x and R x is selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkyl, and C3-C7 cycloalkyl; n is 0, R 1a and R 1b are hydrogen, R 2a and R 2b are each independently hydrogen or methyl; one of m1 and m2 is 1 and the other is 2, or m1 and m2 are each 1, or m1 and m2 are each 2; j1 and j2 are each 1, or one of j1 and j2 is 1 and the other is 2, or j1 and j2 are each 2, with the proviso that the sum of j1, j2, m1, and m2 is 6 or less.

[0127] In a particular aspect of embodiment B8 above, the compound of formula Ib, or a pharmaceutically acceptable salt thereof, contains R 2a and R 2b are methyl, and R x is trifluoromethyl, fluoro, or trifluoromethoxy. In certain aspects of the above embodiments, compounds include compounds where m1 and m2 are each 2 and j1 and j2 are each 1. In certain aspects of the above embodiments, compounds include compounds where Y1, Y2, Y4, and Y5 are CH and Y3 is CR x In certain aspects of the above embodiments, the compound is x Includes compounds where is trifluoromethyl.

[0128] In certain embodiments (Embodiment A2), the compound is a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein E1 is CH, E2 is N, and E3 is NR x E4 is CH, one of m1 and m2 is 2 and the other is 1, j1 and j2 are each 1, and R 1a and R 1b are hydrogen, and R 2a is hydrogen and R 2b is methyl and X is C(R 10 R 20 ) and R 10 and R 20 are hydrogen, and R x is halo-C1-C6 alkyl. In certain embodiments, R x is trifluoroethyl.

[0129] In certain embodiments (embodiment A3), the compound comprises a compound of formula Ia, or a pharmaceutically acceptable salt thereof, wherein E1 is CH and E2 is CR y and E3 is N and E4 is NR x one of m1 and m2 is 2 and the other is 1, or m1 and m2 are each 2, j1 and j2 are each 1, and R 1a and R 1b are hydrogen, and R 2a is hydrogen and R 2b is methyl and X is C(R 10 R 20 ) and R 10 and R 20 are hydrogen, and R x is C1-C6 alkyl, and R y is halo-C1-C6 alkyl. In certain embodiments, R x is propyl, and R y is trifluoromethyl. In certain embodiments, R x is isopropyl.

[0130] The subject matter described herein includes the following compounds in Table 1, or pharmaceutically acceptable salts thereof. Individual enantiomers and diastereomers are included in the table below by compound name, and their corresponding structures can be readily determined therefrom. In Table 1, an asterisk (*) indicates an isolated isomer or group of isolated isomers, but no stereochemistry has been assigned. In some cases, 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), but the absolute configuration of one or more chiral centers has not been assigned.

[0131] [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

[0132] 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 excipients.Suitable pharmaceutically acceptable excipients can 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.).

[0133] 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.

[0134] 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.

[0135] Oral administration can be another route for administering the compounds described herein. Administration can be 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 excipient and / or enclosed in such a carrier, which can be in the form of a capsule, sachet, paper, or other container. When an excipient 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.

[0136] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, 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.

[0137] 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.

[0138] To prepare solid compositions such as tablets, the principal active ingredient can be mixed with a pharmaceutical excipient 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 thereof. 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.

[0139] 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.

[0140] 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 excipients 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.

[0141] 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.

[0142] 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.

[0143] In certain embodiments, in a method of 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] In certain embodiments, the presently disclosed subject matter 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. 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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, Pelizabeth-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, Heimer'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, Marchiafer-Va-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barré syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination.

[0155] 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. As used herein, myelin-related disorders can result from genetic disorders or various 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.

[0156] 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).

[0157] 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.

[0158] 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.

[0159] As used herein, "baseline level of myelin production rate" refers to the myelin production rate in a subject being treated before treatment begins.

[0160] V. Methods of Preparing Compounds of Formula I and Their Pharmaceutically Acceptable Salts The compounds can be synthesized by synthetic routes that include processes similar to those known in the chemical arts, particularly in light of the description contained herein, and processes for other heterocycles described in: 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 prepared by methods generally described in Beilstein's Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

[0161] 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 rd Ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

[0162] 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]

[0163] 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. Example 102: 6-((2S)-3-(4-(2,2-dimethylcyclopropyl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and 6-((2R)-3-(4-(2,2-dimethylcyclopropyl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0164] Step 1: Synthesis of 1-iodo-4-(2-methylprop-1-enyl)benzene [ka]

[0165] To a mixture of isopropyl(triphenyl)phosphonium iodide (11.2 g, 25.9 mmol) in THF (50 mL) was added tBuOK (2.90 g, 25.86 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min, then 4-iodobenzaldehyde (5 g, 21.55 mmol) was added at 0 °C, and the mixture was stirred at 25 °C for 16 h. The mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100 / 1 to 80 / 1). 1-iodo-4-(2-methylprop-1-enyl)benzene (4.5 g, 17.4 mmol, 80.9% yield) was obtained. 1 H NMR(400MHz,CDCl3):δppm;7.65-7.61(m,2H),6.97(d,J=8.3Hz,2H),6.18(s,1H),1.90(d,J=1.2Hz,3H),1.84(d,J=1.0Hz,3H).

[0166] Step 2: Synthesis of 1-(2,2-dimethylcyclopropyl)-4-iodo-benzene [ka]

[0167] To a mixture of ZnEt2 (1 M solution in hexane, 4.74 mL) in DCM (10 mL) was added diiodomethane (1.27 g, 4.74 mmol, 382.53 μL) under N2 at 0 °C. The mixture was stirred at 0 °C for 30 min, then 1-iodo-4-(2-methylprop-1-enyl)benzene (500 mg, 1.94 mmol) was added, and the mixture was stirred at 0 °C for 1 h. The residue was poured into water (20 mL). The mixture was filtered. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×40 mm, 15 μm; mobile phase: [water (0.1% TFA)-ACN] 75% to 100%, 10 min) to give the title compound (130 mg, 477 μmol, yield 24.6%). 1 H NMR (400MHz, CDCl3): δppm7.61-7.55(m,2H),6.91(d,J=8.2Hz,2H),1.81(dd,J=6.2,8.1Hz,1H),1.22(s,3H),0.83-0.74(m,5H).

[0168] Step 3: Synthesis of (2R)-3-(4-(2,2-dimethylcyclopropyl)phenyl)-2-methylpropanal and (2S)-3-(4-(2,2-dimethylcyclopropyl)phenyl)-2-methylpropanal [ka]

[0169] To a mixture of 1-(2,2-dimethylcyclopropyl)-4-iodo-benzene (160 mg, 588 μmol), triethylamine (89.2 mg, 881.9 μmol, 123 μL), and 2-methylprop-2-en-1-ol (50.9 mg, 706 mol, 60 L) in CH3CN (2 mL) was added Pd(OAc)2 (13.20 mg, 58.80 mol) under N2. The mixture was stirred at 80 °C under N2 for 16 h. The mixture was concentrated under reduced pressure. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (8 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge C18; 150 × 50 mm, 10 μm; [water (10 mM NH4HCO3)-ACN]; B%: 52%-82%, 10 min) to give the title compound (53 mg, 245 μmol, 41.6% yield). 1 H NMR (400MHz, CDCl3): δppm9.72(d,J=1.6Hz,1H),7.12-7.04(m,4H),3.05(dd,J=5.6,13.4Hz,1H),2.7 1-2.55(m,2H),1.87-1.81(m,1H),1.22(s,3H),1.08(d,J=6.8Hz,3H),0.79(s,3H),0.78-0.74(m,2H).

[0170] Step 4: Synthesis of the title compound. A mixture of 2-thia-7-azaspiro[3.4]octane 2,2-dioxide (40 mg, 202 μmol, HCl) and triethylamine (20.5 mg, 202 μmol, 28.2 μL) in DCM (2 mL) was stirred at 25° C. for 30 minutes. 3-[4-(2,2-dimethylcyclopropyl)phenyl]-2-methyl-propanal (52.52 mg, 242.8 μmol) and HOAc (24.30 mg, 404.7 μmol, 23.15 μL) were added. The mixture was stirred at 25° C. for 1 hour, and then NaBH(OAc) (85.77 mg, 404.69 μmol) was added, and the mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by HPLC (Phenomenex luna C18, 150 × 25 mm, 10 μm; [water (0.1% TFA)-ACN]; 27% to 57%, 10 min) to give a racemic mixture of the title compounds (44.5 mg, 93.5 μmol, 46% yield).

[0171] Compound 102 (mixture): 1 H NMR(400MHz,CD3OD):δppm7.43(t,J=7.7Hz,1H),7.27(d,J=7.9Hz,1H),7.18(dd,J=1.6,10.4Hz,1H),4.21(br s,1H),4.01(br d,J=8.8Hz,1H),3.86-3.66(m,3H),3.42(br d,J=6.8Hz,2H),3.06(s,3H),2.65-2.50(m,1H),2.47-2.30(m,4H),2.29-2.02(m,6H),1.97-1.59(m,5H).LCMS(ESI)[M+H] + =362.2. Example 104: (S)-6-(2-methyl-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(2-methyl-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0172] Step 1: Synthesis of (R)-2-methyl-3-(4-(trifluoromethyl)phenyl)propanal and (S)-2-methyl-3-(4-(trifluoromethyl)phenyl)propanal [ka]

[0173] To a mixture of 1-iodo-4-(trifluoromethyl)benzene (1 g, 3.68 mmol, 541 μL), 2-methylprop-2-en-1-ol (331 mg, 5 μmmol, 389 μL), and Pd(OAc) (25 mg, 110 μmol) in ACN (10 mL) was added triethylamine (465 mg, 5 mmol, 640 μL). The mixture was purged with N for 10 seconds and stirred at 80 °C for 16 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in petroleum ether (20 mL) and washed with water (20 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether / ethyl acetate = 10:1) to give the title compound (170 mg, 786 μmol, 21% yield). 1 H NMR (400MHz, CDCl3): δppm9.73(d,J=1.2Hz,1H),7.56(d,J=8.1Hz,2H),7.30( d,J=7.9Hz,2H),3.22-3.11(m,1H),2.76-2.62(m,2H),1.12(d,J=7.0Hz,3H).

[0174] Step 2: Synthesis of the title compound. To a mixture of 2-thia-7-azaspiro[3.4]octane-2,2-dioxide hydrochloride (20 mg, 101 μmol) in DCM (1 mL), triethylamine (9 mg, 91 μmol, 13 μL) was added, and the mixture was stirred at 25° C. for 15 minutes. Then, (+ / -)2-methyl-3-[4-(trifluoromethyl)phenyl]propanal (25 mg, 114 μmol) was added, and the mixture was stirred at 25° C. for 1 hour. NaBH(OAc) (43 mg, 202 μmol) was added to the mixture at 0° C., and the mixture was stirred at 25° C. for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by HPLC (Nano-micro Kromasil C18, 80 × 25 mm, 3 μm; 25-45% acetonitrile in 0.1% trifluoroacetic acid solution in water, 7 min gradient) to give the title compound as a racemic mixture (17 mg, 34% yield).

[0175] Compound 104 (mixture): 1 H NMR (400MHz, CD3OD): δppm7.63(d,J=8.19Hz,2H),7.44(d,J=8.19Hz,2H),4.36-4.17(m,4H),4.10-3.40(m,2H),3.29-3. 11(m,4H),2.88(dd,J=13.39,5.69Hz,1H),2.66-2.38(m,3H),2.36-2.20(m,1H),1.02(d,J=6.60Hz,3H).LCMS(ESI)[M+H] + =362.1 Example 105: (S)-6-(4-(4-(tert-pentyl)phenyl)butan-2-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(4-(4-(tert-pentyl)phenyl)butan-2-yl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0176] Step 1: Synthesis of 4-[4-(1,1-dimethylpropyl)phenyl]butan-2-one [ka]

[0177] To a stirred solution of 1-(1,1-dimethylpropyl)-4-iodo-benzene (1 g, 3.65 mmol) in ACN (5 mL) was added but-3-en-2-ol (329 mg, 4.56 mmol, 395 μL), Pd(OAc) (25 mg, 109 μmol, 0.03 equiv.), and triethylamine (461 mg, 4.56 mmol, 635 μL). The mixture was purged with N for 1 min, and the mixture was stirred at 80 °C under N for 16 h. The reaction mixture was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica flash column chromatography (10–12% ethyl acetate in petroleum ether) to give the title compound (300 mg, 1.37 mmol, 38% yield). 1 H-NMR (400MHz, CDCl3): δppm7.24(d,J=8.4Hz,m,2H),7.11(d,J=8.4Hz,2H),2.94-2.83(m,2H) ),2.80-2.72(m,2H),2.15(bs,3H),1.68-1.60(m,2H),1.28-1.26(bs,6H),0.71-0.65(m,3H).

[0178] Step 2: Synthesis of the title compound. To a stirred mixture of 2-thia-7-azaspiro[3.4]octane 2,2-dioxide hydrochloride (20 mg, 101 μmol) in DCM (1 mL) was added triethylamine (9 mg, 91 μmol, 12 μL), and the resulting mixture was stirred at 25° C. for 15 minutes. 4-[4-(1,1-dimethylpropyl)phenyl]butan-2-one (24 mg, 111 μmol) was added, and the mixture was stirred at 25° C. for 2 hours. NaBH(OAc) (43 mg, 202 μmol) was added, and the mixture was stirred at 25° C. for 16 hours. The reaction mixture was concentrated in vacuo. The crude residue was purified by HPLC (Nano-micro Kromasil C18 80 × 25 mm, 3 μm column; 30–48% acetonitrile in 0.1% trifluoroacetic acid solution in water, 7 min gradient) to give the title compound as a racemic mixture (28 mg, 57% yield).

[0179] Compound 105 (mixture): 1 H NMR(400MHz,CD3OD):δppm7.29(d,J=8.4Hz,2H),7.18(d,J=8.4Hz,2H),4.45-4.06(m,5H),3.95- 3.83(m,1H),3.73-3.63(m,1H),3.59-3.49(m,1H),3.39-3.35(m,1H),2.80(ddd,J=14.13,9.44,5 .07Hz,1H),2.67-2.57(m,1H),2.54-2.36(m,2H),2.21-2.09(m,1H),1.92-1.80(m,1H),1.65(q,J =7.42Hz,2H),1.44(d,J=6.50Hz,3H),1.32-1.15(m,6H),0.65(t,J=7.44Hz,3H).LCMS(ESI)[M+H] + =364.2. Example 106: (R)-7-((S)-2-methyl-3-(4-(tert-pentyl)phenyl)propyl)-2-thia-7-azaspiro[4.4]nonane 2,2-dioxide, (S)-7-((R)-2-methyl-3-(4-(tert-pentyl)phenyl)propyl)-2-thia-7-azaspiro[4.4]nonane 2,2-dioxide, (S)-7-((S)-2-methyl-3-(4-(tert-pentyl)phenyl)propyl)-2-thia-7-azaspiro[4.4]nonane 2,2-dioxide, and (R)-7-((R)-2-methyl-3-(4-(tert-pentyl)phenyl)propyl)-2-thia-7-azaspiro[4.4]nonane 2,2-dioxide [ka]

[0180] The title compound was synthesized using the synthetic route of Example 103, utilizing (+ / -)2-thia-7-azaspiro[4.4]nonane 2,2-dioxide hydrochloride, to give a mixture of diastereomers.

[0181] Compound 106 (mixture): 1 H NMR(400MHz,CD3OD)δppm7.30(d,J=8.31Hz,2H),7.15(d,J=8.19Hz,2H),3.9 9-3.70(m,2H),3.45-3.32(m,1H),3.30-3.09(m,7H),2.79-2.68(m,1H),2.49 (dd,J=13.69,8.31Hz,1H),2.44-2.08(m,5H),1.65(q,J=7.38Hz,2H),1.27(s ,6H),1.03(dd,J=6.66,1.53Hz,3H),0.66(t,J=7.46Hz,3H).LCMS(ESI)[M+H] + =378.2.

[0182] Example 107: (R)-6-(2-methyl-3-(4-(tert-pentyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (S)-6-(2-methyl-3-(4-(tert-pentyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka] The title compound was synthesized using the synthetic route of Example 103 utilizing 2-thia-7-azaspiro[3.4]octane 2,2-dioxide hydrochloride to give a racemic mixture.

[0183] Compound 107 (mixture): 1 H NMR(400MHz,CD3OD):δppm7.30(d,J=8.25Hz,2H),7.15(d,J=8.25Hz,2H),4.40-4.14(m,5H),4.07-3.94( m,1H),3.84-3.73(m,1H),3.62-3.42(m,1H),3.22-3.15(m,2H),2.73(dd,J=13.63,6.13Hz,1H),2.49(br dd,J=13.51,8.38Hz,3H),2.27-2.16(m,1H)1.66(q,J=7.38Hz,2H),1.32-1 .24(m,6H),1.03(d,J=6.63Hz,3H),0.66(t,J=7.44Hz,3H).LCMS(ESI)[M+H] + =364.2. Example 108: (R)-6-(3-(4-cyclopropylphenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (S)-6-(3-(4-cyclopropylphenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0184] Step 1: Synthesis of 1-cyclopropyl-4-iodo-benzene [ka]

[0185] To a solution of 4-cyclopropylaniline (0.5 g, 3.75 mmol) in HO (5 mL) was slowly added HSO (5.06 g, 51.6 mmol, 2.75 mL) at 0 °C. Then, NaNO (259.01 mg, 3.75 mmol) dissolved in HO (2 mL) was slowly added at 0 °C. The resulting mixture was added to a solution of potassium iodide (1.25 g, 7.51 mmol) in HO (2 mL), and the mixture was stirred at 60 °C for 2 h. The mixture was diluted with water (10 mL), and the resulting mixture was extracted with DCM (10 mL × 3). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 20:1) to give the title compound (650 mg, 2.66 mmol, 71% yield). 1 H-NMR (400MHz, CDCl3): δppm7.59-7.53(m,2H),6.87-6.79(m,2H),1.89-1.80(m,1H),1.00-0.94(m,2H),0.69-0.64(m,2H).

[0186] Step 2: Synthesis of (R)-3-(4-cyclopropylphenyl)-2-methylpropanal and (S)-3-(4-cyclopropylphenyl)-2-methylpropanal [ka]

[0187] To a mixture of 1-cyclopropyl-4-iodobenzene (0.4 g, 1.64 mmol) and (+ / -) 2-methylprop-2-en-1-ol (177.26 mg, 2.46 mmol, 208.05 μL) in acetonitrile (2 mL), triethylamine (249 mg, 2.46 mmol, 342 μL) and Pd(OAc) (11.04 mg, 49.17 μmol) were added under N. The mixture was stirred at 80 °C for 16 h. The mixture was diluted with EtOAc (30 mL), and the resulting mixture was washed with brine (10 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (Column: Waters Xbridge 150 × 25 mm, 5 μm; Mobile phase: [water (10 mM NHHCO)-ACN]; 38%-68%, 10 min). The fractions were extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (30 mL x 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound (150 mg, 797 μmol, 48.62% yield). 1 H NMR (400MHz, CDCl3): δppm9.72(d,J=1.6Hz,1H),7.09-7.04(m,2H),7.03-6.98(m,2H),3.04(dd,J=5.8,13.4Hz, 1H),2.70-2.53(m,2H),1.87(tt,J=5.1,8.4Hz,1H),1.09(d,J=6.9Hz,3H),0.99-0.89(m,2H),0.72-0.64(m,2H).

[0188] Step 3: Synthesis of the title compound. To a mixture of hydrochloride 2-thia-7-azaspiro[3.4]octane 2,2-dioxide hydrochloride (30 mg, 152 μmol) in DCM (3 mL) was added triethylamine (23.03 mg, 227.6 μmol, 31.68 μL). The mixture was stirred at 30° C. for 30 minutes, and then (+ / -)3-(4-cyclopropylphenyl)-2-methyl-propanal (34.28 mg, 182.1 μmol) and NaBH(OAc) (96.49 mg, 455.3 μmol) were added, and the mixture was stirred at 30° C. for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by HPLC (Phenomenex luna C18; 150×40 mm, 15 μm; [water (0.1% TFA)-ACN] 20% to 50%, 10 min) to give the title compound as a racemic mixture (28.3 mg, 41.67% yield).

[0189] Compound 108 (mixture): 1 H NMR(400MHz,CD3OD):δppm7.08(d,J=8.4,2H),7.02(d,J=8.4,2H),4.38-4.17(m,4H),4.10- 3.69(m,2H),3.55-3.33(m,2H),3.16(d,J=7.2Hz,2H),2.69(dd,J=6.3,13.5Hz,1H),2.48(br dd,J=8.2,13.6Hz,3H),2.19(qd,J=6.9,13.9Hz,1H),1.92-1.83(m,1H),1. 02(d,J=6.6Hz,3H),0.97-0.91(m,2H),0.66-0.61(m,2H).LCMS(ESI)[M+H] + =333.9. Examples 109A, 109B*, and 109C*: (R)-6-(3-(4-cyclobutylphenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (S)-6-(3-(4-cyclobutylphenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0190] Step 1. Synthesis of (R)-3-(4-cyclobutylphenyl)-2-methylpropanal and (S)-3-(4-cyclobutylphenyl)-2-methylpropanal [ka]

[0191] To a mixture of 1-cyclobutyl-4-iodo-benzene (200 mg, 775 μmol), triethylamine (98 mg, 969 μmol, 135 μL), and 2-methylprop-2-en-1-ol (67 mg, 930 μmol, 79 μL) in acetonitrile (2 mL) was added Pd(OAc) (17.40 mg, 77.49 μmol) under N. The mixture was stirred at 80 °C under N for 16 h. The mixture was filtered and concentrated in vacuo. The residue was purified by HPLC (Waters Xbridge C, 150 × 50 mm, 10 μm; [water (10 mM NHHCO)-ACN]; 48% to 78%, 10 min gradient) to give the title compound (65.0 mg, 41.5% yield).

[0192] Step 2: Synthesis of the title compound. A mixture of 2-thia-7-azaspiro[3.4]octane-2,2-dioxide hydrochloride (40 mg, 202 μmol) and triethylamine (20.48 mg, 202.3 μmol, 28.16 μL) in DCM (2 mL) was stirred at 25° C. for 30 minutes. 3-(4-Cyclobutylphenyl)-2-methyl-propanal (49.12 mg, 242.8 μmol) and HOAc (12.15 mg, 202.3 μmol, 11.57 μL) were added. The mixture was stirred at 25° C. for 30 minutes, and then NaBH(OAc) (85.77 mg, 404.7 μmol) was added and stirred for 1 hour. The mixture was filtered and concentrated under vacuum. The residue was purified by HPLC (Phenomenex luna C18, 150×25 mm, 10 μm; [water (0.1% TFA)-ACN]; 24% to 54%, 10 min) to give the title compound as a racemic mixture (59 mg, 63% yield).

[0193] Compound 109A (mixture): 1 H NMR(400MHz,CD3OD)δppm7.18(d,J=8.1Hz,2H),7.14(d,J=8.1Hz,2H),4.38-4.29(m,1H),4.22(br s,1H),4.01(br s,1H),3.81(br s,1H),3.53(quin,J=8.6Hz,1H),3.45-3.32(m,1H),3.30-3.12(m,3H),2.71(dd,J=6.2,13.6Hz,1H),2.50(br dd,J=8.1,13.5Hz,3H),2.38-2.28(m,2H),2.26-2.16(m,1H),2.16-1.97(m,3H),1.90-1.81(m,1H),1.03(d,J=6.6Hz,3H).LCMS(ESI)[M+H] + =348.1.

[0194] The racemic mixture from Example 109A was separated by chiral SFC (Daicel Chiralcel OJ-H (250 mm × 30 mm, 5 μm) 0.1% NH₃H₂O-EtOH, 40%) to give the first eluting peak, Compound 109B, as a pure single undefined / unassigned enantiomer of the title compound, and the second eluting peak, Compound 109C, as a pure single undefined / unassigned enantiomer of the title compound.

[0195] Compound 109B*: 1H NMR(400MHz,CD3OD)δppm7.18(d,J=8.1Hz,2H),7.14(d,J=8.1Hz,2H),4.38-4.29(m,1H),4.22(br s,1H),4.01(br s,1H),3.81(br s,1H),3.53(quin,J=8.6Hz,1H),3.45-3.32(m,1H),3.30-3.12(m,3H),2.71(dd,J=6.2,13.6Hz,1H),2.50(br dd,J=8.1,13.5Hz,3H),2.38-2.28(m,2H),2.26-2.16(m,1H),2.16-1.97(m,3H),1.90-1.81(m,1H),1.03(d,J=6.6Hz,3H).LCMS(ESI)[M+H] + =348.1.

[0196] Compound 109C*: 1 H NMR(400MHz,CD3OD)δppm7.18(d,J=8.1Hz,2H),7.14(d,J=8.1Hz,2H),4.38-4.29(m,1H),4.22(br s,1H),4.01(br s,1H),3.81(br s,1H),3.53(quin,J=8.6Hz,1H),3.45-3.32(m,1H),3.30-3.12(m,3H),2.71(dd,J=6.2,13.6Hz,1H),2.50(br dd,J=8.1,13.5Hz,3H),2.38-2.28(m,2H),2.26-2.16(m,1H),2.16-1.97(m,3H),1.90-1.81(m,1H),1.03(d,J=6.6Hz,3H).LCMS(ESI)[M+H] + =348.1. Example 110: (R)-7-(2-methyl-3-(4-(tert-pentyl)phenyl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and (S)-7-(2-methyl-3-(4-(tert-pentyl)phenyl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0197] The title compound was synthesized using the synthetic route of Example 103 utilizing 2-thia-7-azaspiro[3.5]nonane-2,2-dioxide hydrochloride to give a racemic mixture.

[0198] Compound 110 (mixture): 1 H NMR(400MHz,CD3OD):δppm7.30(d,J=8.31Hz,2H),7.15(d,J=8.31Hz,2H),4.04 (bs,4H),3.66-3.51(m,2H),3.17-2.99(m,3H),2.96-2.84(m,1H),2.75-2.65(m ,1H),2.57-2.47(m,1H),2.35-2.21(m,3H),2.16-2.04(m,2H),1.69-1.62(m,3H ),1.27(s,6H),1.03(d,J=6.60Hz,3H),0.66(t,J=7.46Hz,3H).LCMS(ESI)[M+H] + =378.2. Examples 111A, 111B*, and 111C*: (R)-6-(2-methyl-3-(4-(1-methylcyclopropyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (S)-6-(2-methyl-3-(4-(1-methylcyclopropyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0199] Step 1: Synthesis of 1-iodo-4-(1-methylcyclopropyl)benzene [ka]

[0200] To a mixture of ZnEt (3.04 g, 24.6 mmol) in DCM (20 mL) was added CHCl (8.78 g, 32.8 mmol, 2.64 mL) under N at 0 °C. The mixture was stirred at 0 °C for 30 min, and then 1-iodo-4-isopropenyl-benzene (2.0 g, 8.2 mmol) was added at 0 °C and stirred at 0 °C for 1 h. The residue was poured into water (50 mL). The mixture was filtered. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by reverse-phase HPLC (0.1% TFA condition) to give the title compound (1.1 g, 4.3 mmol, 52% yield). 1 H NMR (400MHz, CDCl3): δppm7.59(br d,J=7.8Hz,2H),7.00(br d,J=7.7Hz,2H),1.38(s,3H),0.83(br s,2H),0.74(br s,2H).

[0201] Step 2: Synthesis of (R)-2-methyl-3-(4-(1-methylcyclopropyl)phenyl)propanal and ()-2-methyl-3-(4-(1-methylcyclopropyl)phenyl)propanal [ka]

[0202] To a mixture of 1-iodo-4-(1-methylcyclopropyl)benzene (200 mg, 775 μmol), 2-methylprop-2-en-1-ol (69.84 mg, 968.6 μmol, 81.98 μL), and triethylamine (135 μL, 969 μmol) in acetonitrile (1 mL) was added Pd(OAc) (17.40 mg, 77.49 μmol) under N. The mixture was stirred at 80 °C under N for 16 h. The mixture was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (8 mL × 3). The combined organic phase was washed with brine (8 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (Waters Xbridge C18 150 x 50 mm, 10 μm; [water (10 mM NH4HCO3)-ACN]; 45% to 75%, 10 min gradient) to give the title compound (80 mg, 51% yield).

[0203] Step 3: Synthesis of the title compound. A mixture of 2-thia-7-azaspiro[3.4]octane-2,2-dioxide hydrochloride (30.0 mg, 152 μmol) and TEA (15.36 mg, 151.8 μmol, 21.12 μL) in DCM (2 mL) was stirred at 25° C. for 30 minutes, and then 2-methyl-3-[4-(1-methylcyclopropyl)phenyl]propanal (30.70 mg, 151.8 μmol) and HOAc (18.23 mg, 303.5 μmol, 17.36 μL) were added and stirred at 25° C. for 1 hour. NaBH(OAc) (64.33 mg, 303.5 μmol) was added. The mixture was stirred at 25° C. for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by HPLC (Phenomenex luna C18 150×40 mm, 15 μm; [water (0.1% TFA)-ACN]; 22% to 52%, 10 min gradient) to give the title compound as a racemic mixture (8.4 mg, 69% yield).

[0204] Compound 111A (mixture): 1H NMR(400MHz,CD3OD)δppm7.21(d,J=8.0Hz,2H),7.12(d,J=8.0Hz,2H),4.40-4.14(m,4H),3.98(br s,1H),3.79(br s,1H),3.52(br s,1H),3.16(d,J=7.2Hz,2H),2.70(dd,J=6.4,13.6Hz,1H),2.49(br dd,J=8.1,13.6Hz,3H),2.27-2.13(m,1H),1.38(s,3H),1.02(d,J=6.6Hz,3H),0.85-0.79(m,2H),0.74-0.70(m,2H).LCMS(ESI)[M+H] + =348.1.

[0205] The racemic mixture from Example 111A was separated by chiral SFC (Daicel Chiralcel OJ-H (250 mm × 30 mm, 5 μm) 0.1% NH₃HO-EtOH, 40%) to give the first eluting peak, compound 111B, as a pure single undefined / unassigned enantiomer of the title compound, and the second eluting peak, compound 111C, as a pure single undefined / unassigned enantiomer of the title compound.

[0206] Compound 111B*: 1 H NMR(400MHz,CD3OD)δppm7.21(d,J=8.0Hz,2H),7.12(d,J=8.0Hz,2H),4.40-4.14(m,4H),3.98(br s,1H),3.79(br s,1H),3.52(br s,1H),3.16(d,J=7.2Hz,2H),2.70(dd,J=6.4,13.6Hz,1H),2.49(br dd,J=8.1,13.6Hz,3H),2.27-2.13(m,1H),1.38(s,3H),1.02(d,J=6.6Hz,3H),0.85-0.79(m,2H),0.74-0.70(m,2H).Spec.M+H:348.1.

[0207] Compound 111C*: 1H NMR(400MHz,CD3OD)δppm7.21(d,J=8.0Hz,2H),7.12(d,J=8.0Hz,2H),4.40-4.14(m,4H),3.98(br s,1H),3.79(br s,1H),3.52(br s,1H),3.16(d,J=7.2Hz,2H),2.70(dd,J=6.4,13.6Hz,1H),2.49(br dd,J=8.1,13.6Hz,3H),2.27-2.13(m,1H),1.38(s,3H),1.02(d,J=6.6Hz,3H),0.85-0.79(m,2H),0.74-0.70(m,2H).LCMS(ESI)[M+H] + =348.1. Example 112: 6-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2-thia-6-azaspiro[3.4]octane-2,2-dioxide [ka]

[0208] Step 1: Synthesis of 1-(2-bromoethoxy)-4-(trifluoromethyl)benzene [ka]

[0209] To a solution of 4-(trifluoromethyl)phenol (1.0 g, 6.17 mmol) in N,N-dimethylformamide (10 mL) was added 1,2-dibromoethane (4.8 g, 25.6 mmol), K2CO3 (2.2 g, 15.9 mmol), and KI (100 mg, 0.60 mmol) at 20-30 °C. The mixture was then heated to 80 °C and stirred for 15 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic phases were washed with brine (25 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue that was purified by silica column chromatography (100% petroleum ether) to give the title compound (690 mg, 2.56 mmol, 42% yield). 1H NMR (400MHz, CDCl3): δppm7.57(d,J=8.8Hz,2H),6.99(d,J=8.8Hz,2H),4.37-4.32(m,2H),3.69-3.63(m,2H).

[0210] Step 2: Synthesis of the title compound. 1-(2-Bromoethoxy)-4-(trifluoromethyl)benzene (48 mg, 0.18 mmol) and 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (30 mg, 0.15 mmol) were dissolved in acetonitrile (1.5 mL), and N,N-diisopropylethylamine (0.12 mL, 0.73 mmol) was added at 20-30 °C. The reaction mixture was stirred at 80 °C for 5 hours. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with brine (25 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by reverse-phase chromatography and lyophilized to give the title compound (25.4 mg, 0.072 mmol, 40% yield).

[0211] Compound 112: 1 H NMR (400MHz, CDCl3): δppm7.56(d,J=8.4Hz,2H),6.96(d,J=8.4Hz,2H),4.21(t,J=5.6Hz,2H), 4.08(s,4H),3.00-2.92(m,4H),2.84(t,J=7.6Hz,2H),2.19(t,J=7.6Hz,2H).LCMS(ESI)[M+H] + =350.0. Example 113: 6-(3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane-2,2-dioxide [ka]

[0212] Step 1: Synthesis of (E)-methyl 3-(4-(trifluoromethyl)phenyl)acrylate [ka]

[0213] To a solution of methyl diethylphosphonoacetate (2.1 mL, 11.5 mmol) in tetrahydrofuran (20 mL) under nitrogen at 0°C, sodium hydride (0.46 g, 11.49 mmol, 60% in mineral oil) was added portionwise and stirred for 0.5 h. 4-(Trifluoromethyl)benzaldehyde (1.0 g, 5.74 mmol) was added at 0°C. The reaction mixture was then stirred at 20°C for 1 h. The reaction was quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue that was purified by silica column chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound (760 mg, 3.30 mmol, 57.5% yield). LCMS(ESI)[M+H] + =231.0.

[0214] Step 2: Synthesis of (E)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-ol [ka]

[0215] To a solution of methyl (E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoate (0.76 g, 3.3 mmol) in tetrahydrofuran (15 mL) was added LiBH (180 mg, 8.25 mmol) at 0 °C. The reaction was then warmed to 20 °C and stirred under nitrogen for 16 hours. The reaction was quenched with saturated sodium bicarbonate (10 mL). The mixture was extracted with dichloromethane (50 ml × 3). The combined organic layers were washed with brine (25 ml × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude title compound (650 mg, 3.22 mmol, 97% yield).

[0216] Step 3: Synthesis of (E)-3-(4-(trifluoromethyl)phenyl)allyl methanesulfonate [ka]

[0217] (E)-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-ol (60.0 mg, 0.30 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.89 mmol) were dissolved in dichloromethane (3 mL). Methanesulfonyl chloride (0.03 mL, 0.33 mmol) was added at 0° C. The mixture was stirred at 20° C. for 16 hours. The reaction was quenched with water (10 mL) and extracted with dichloromethane (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (70 mg, 0.25 mmol, 84.2% yield), which was used directly in the next step without further purification.

[0218] Step 4: Synthesis of (E)-6-(3-(4-(trifluoromethyl)phenyl)allyl)-2-thia-6-azaspiro[3.4]octane-2,2-dioxide: [ka]

[0219] N,N-Diisopropylethylamine (0.11 mL, 0.64 mmol) and (E)-3-(4-(trifluoromethyl)phenyl)allyl methanesulfonate (60.0 mg, 0.21 mmol) were dissolved in acetonitrile (5 mL), and 2-thia-6-azaspiro[3.4]octane-2,2-dioxide hydrochloride (50.0 mg, 0.25 mmol) was added at 25 °C. The reaction mixture was stirred at 80 °C for 16 h. After concentration in vacuo, the residue was purified by silica column chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (40 mg, 0.12 mmol, 54% yield). LCMS (ESI) [M+H] + =346.1.

[0220] Step 5: Synthesis of the title compound. To a solution of (E)-6-(3-(4-(trifluoromethyl)phenyl)allyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (30.0 mg, 0.09 mmol) in ethanol (10 mL) was added platinum(IV) oxide on carbon (2 mg, 0.01 mmol). The mixture was stirred under H (15 psi) at 25° C. for 2 hours. The mixture was filtered and concentrated to give a crude residue, which was purified by reverse-phase chromatography and lyophilized to give the title compound as the formate salt (4.4 mg, 0.012 mmol, 14.3% yield).

[0221] Compound 113: 1 H NMR(400MHz,CD3OD):δppm8.47(s,1H),7.58(d,J=8.0Hz,2H),7.41(d,J=7.6Hz,2H),4.19-4.11(m,4H),3.09 (s,2H),2.93(t,J=7.2Hz,2H),2.79-2.71(m,4H),2.27(t,J=7.2Hz,2H),1.96-1.88(m,2H).LCMS(ESI)[M+H] + =347.1. Examples 114A* and 114B*: (S)-6-(2-methyl-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(2-methyl-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0222] The title compound was synthesized using the synthetic route of Example 104, utilizing 2-thia-6-azaspiro[3.4]octane-2,2-dioxide hydrochloride. The racemic mixture was purified by SFC (Daicel Chiralcel OJ-H (250 mm × 30 mm, 5 μm) 0.1% NH HO; EtOH; 40%) to afford the first eluting peak, compound 114A, as a pure single undefined / unassigned enantiomer (48 mg, 28.2% yield), and the second eluting peak, compound 114B, as a pure single undefined / unassigned enantiomer (30.4 mg, 17.9% yield).

[0223] Compound 114A*: 1 H NMR(400MHz,CD3OD):δppm7.56(d,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H),4.08(s,4H),2.92-2.85(m,1H),2.80(s,2H),2 .72-2.62(m,2H),2.51-2.29(m,3H),2.16(t,J=7.2Hz,2H),1.97-1.87(m,1H),0.88(d,J=6.8Hz,3H).LCMS(ESI)[M+H] + =362.2.

[0224] Compound 114B*: 1 H NMR(400MHz,CD3OD):δppm7.56(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),4.08(s,4H),2.92-2.85(m,1H),2.80(s,2H),2 .72-2.62(m,2H),2.49-2.31(m,3H),2.16(t,J=7.2Hz,2H),1.97-1.87(m,1H),0.87(d,J=6.4Hz,3H).LCMS(ESI)[M+H] + =362.2. Examples 115A* and 115B*: (R)-6-(2-(4-(trifluoromethyl)phenoxy)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (S)-6-(2-(4-(trifluoromethyl)phenoxy)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0225] Step 1: Synthesis of methyl (R)-2-(4-(trifluoromethyl)phenoxy)propanoate and methyl (S)-2-(4-(trifluoromethyl)phenoxy)propanoate [ka]

[0226] To a solution of 4-(trifluoromethyl)phenol (500 mg, 3.08 mmol) in N,N-dimethylformamide (5 mL) was added methyl 2-bromopropionate (620 mg, 3.71 mmol) and K2CO3 (1.3 g, 9.41 mmol) at 25 °C. The reaction mixture was then heated to 80 °C and stirred for 15 h. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica column chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound (620 mg, 81% yield). 1 H NMR (400MHz, CDCl3): δppm7.55(d,J=8.8Hz,2H),6.94(d,J=8.8Hz,2H),4.82(q,J=6.4Hz,1H),3.78(s,3H),1.66(d,J=6.4Hz,3H).

[0227] Step 2: Synthesis of (R)-2-(4-(trifluoromethyl)phenoxy)propanal and (S)-2-(4-(trifluoromethyl)phenoxy)propanal [ka]

[0228] (+ / -) Methyl 2-[4-(trifluoromethyl)phenoxy]propanoate (200 mg, 0.81 mmol) was dissolved in dichloromethane (4 mL) under a nitrogen atmosphere and stirred at −78° C. Diisobutylaluminum hydride (1.0 mL, 1 mmol, 1 M in toluene) was added dropwise via syringe. The resulting mixture was stirred at −78° C. for 1 hour. The reaction was quenched with saturated aqueous NH4Cl (5 mL) and diluted with water (10 mL). The mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (160 mg, 91% yield) as a mixture of enantiomers, which was used directly in the next step without further purification. 1 H NMR (400MHz, CDCl3): δppm9.71(d,J=1.6Hz,1H),7.57(d,J=8.8Hz,2H),6.96(d,J=8.4Hz,2H),4.74-4.68(m,1H),1.53(d,J=7.2Hz,3H).

[0229] Step 3: Synthesis of the Title Compound. To a suspension of 2-thia-6-azaspiro[3.4]octane-2,2-dioxide hydrochloride (65 mg, 0.33 mmol) in anhydrous dichloromethane (3 mL), triethylamine (0.08 mL, 0.57 mmol) was added and stirred at 25° C. for 30 minutes. Then, a solution of (+ / -)2-[4-(trifluoromethyl)phenoxy]propanal (110 mg, 0.50 mmol) in dichloromethane (3 mL) and acetic acid (0.08 mL, 1.4 mmol) was added. The reaction mixture was stirred for 30 minutes, and then NaBH(OAc) (160 mg, 0.75 mmol) was added in portions. The reaction mixture was stirred at 30° C. for an additional 1 hour. The reaction was quenched with saturated NaHCO solution (15 mL) and extracted with dichloromethane (30 mL × 2). The combined organic phase was washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography (55-85% acetonitrile in water / (0.05% NHH0 + 10 mM NHHCO)) to give the title compound (67 mg, 52.4% yield) as a mixture of enantiomers. The racemic mixture was purified by chiral SFC (Daicel Chiralcel OJ-H (250 mm × 30 mm, 5 μm); supercritical CO 2; EtOH + NH3·H2O = 85 / 15; 60 mL / min) to give the first eluting peak, compound 115A (16.8 mg, 23.7% yield), as a single enantiomer of unassigned stereochemistry, and the second eluting peak, compound 115B (19.7 mg, 27.3% yield), as a pure single undefined / unassigned enantiomer.

[0230] Compound 115A*: 1 H NMR(400MHz,CD3OD):δppm7.57(d,J=8.8Hz,2H),7.08(d,J=8.8Hz,2H),4.74-4.66(m,1H),4.08-4.03(m, 4H),2.97-2.89(m,2H),2.86-2.71(m,4H),2.15(d,J=7.2Hz,2H),1.31(d,J=6.4Hz,3H).LCMS(ESI)[M+H] + =364.0.

[0231] Compound 115B*: 1 H NMR(400MHz,CD3OD):δppm7.57(d,J=8.8Hz,2H),7.08(d,J=8.8Hz,2H),4.76-4.63(m,1H),4.10-4.06(m, 4H),2.97-2.89(m,2H),2.86-2.71(m,4H),2.15(d,J=7.2Hz,2H),1.31(d,J=6.0Hz,3H).LCMS(ESI)[M+H] + =364.0. Examples 116A* and 116B*: 6-((S)-3-(3-chloro-4-((1s,4R)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 6-((R)-3-(3-chloro-4-((1s,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide 2-dioxide, 6-((S)-3-(3-chloro-4-((1s,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, and 6-((R)-3-(3-chloro-4-((1r,4R)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0232] Step 1: Synthesis of (E)-ethyl 3-(4-bromo-3-chlorophenyl)-2-methylacrylate [ka]

[0233] To a solution of triethyl 2-phosphonopropionate (21.71 g, 91.13 mmol) in tetrahydrofuran (200 mL) under nitrogen at 0°C, sodium hydride (3.65 g, 91.13 mmol, 60% in mineral oil) was added portionwise and stirred for 0.5 h. 4-Bromo-3-chlorobenzaldehyde (10.0 g, 45.57 mmol) was added at 0°C, and the reaction mixture was then stirred at 30°C for 2 h. The reaction mixture was quenched with a saturated solution of NH4Cl (100 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-5% ethyl acetate in petroleum ether) to give the title compound (13 g, 93% yield). LCMS(ESI)[M+H] + =303.0.

[0234] Step 2: Synthesis of (E)-ethyl 3-(3-chloro-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl)-2-methylacrylate [ka]

[0235] A solution of K2CO3 (6.83 g, 49.41 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (1.21 g, 1.65 mmol), ethyl (E)-3-(4-bromo-3-chloro-phenyl)-2-methyl-prop-2-enoate (5.0 g, 16.47 mmol), and 1,4-dioxa-spiro[4,5]dec-7-ene-8-boronic acid pinacol ester (4.38 g, 16.47 mmol) in water (10 mL) and 1,4-dioxane (60 mL) was stirred at 90 °C under a nitrogen atmosphere for 16 h. The solvent was removed under vacuum. The residue was purified by silica column chromatography (0-5% ethyl acetate in petroleum ether) to give the title compound (5.0 g, 83.7% yield). LCMS (ESI) [M+H] + =363.1.

[0236] Step 3: Synthesis of ethyl (R)-3-(3-chloro-4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl)-2-methylpropanoate and ethyl (S)-3-(3-chloro-4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl)-2-methylpropanoate [ka]

[0237] To a solution of ethyl (E)-3-[3-chloro-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl]-2-methyl-prop-2-enoate (500 mg, 1.38 mmol) in ethyl acetate (10 mL) was added platinum(iv)-oxide (31 mg, 0.14 mmol). The mixture was stirred under H2 (15 psi) at 25 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (500 mg, 98.9% yield). LCMS (ESI) [M+H] + =367.1.

[0238] Step 4: Synthesis of (R)-3-(3-chloro-4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl)-2-methylpropan-1-ol and (S)-3-(3-chloro-4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl)-2-methylpropan-1-ol [ka]

[0239] To a solution of ethyl 3-[3-chloro-4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl]-2-methyl-propanoate (0.5 g, 1.36 mmol) in tetrahydrofuran (15 mL) was added lithium borohydride (0.09 g, 4.09 mmol) at 0° C. The reaction was stirred under nitrogen at 20° C. for 16 hours. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (400 mg, 90.4% yield). LCMS (ESI) [M+H] + =325.1.

[0240] Step 5: Synthesis of (R)-3-(3-chloro-4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl)-2-methylpropanal and (S)-3-(3-chloro-4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl)-2-methylpropanal [ka]

[0241] To a cold (−75° C.) solution of dimethyl sulfoxide (0.48 g, 6.16 mmol) in dichloromethane (20 mL) was added dropwise a solution of oxalyl chloride (0.63 g, 4.93 mmol) in dichloromethane (5 mL) over 10 minutes at −75° C. and stirring was continued for 30 minutes at −75° C. Then, 3-[3-chloro-4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl]-2-methyl-propan-1-ol (400.0 mg, 1.23 mmol) in dichloromethane (5 mL) was added dropwise over 10 minutes and the mixture was stirred at −75° C. for an additional 1 hour. Triethylamine (0.85 mL, 6.16 mmol) in dichloromethane (5 mL) was added over 15 minutes while maintaining the temperature below -65°C and stirred at that temperature for 30 minutes, then the reaction mixture was warmed to 0°C. After an additional hour, the reaction was quenched with saturated NH4Cl solution (20 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated sodium bicarbonate (10 mL x 3) and brine (10 mL x 3), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (300 mg, 75.5% yield).

[0242] Step 6: Synthesis of (S)-6-(3-(3-chloro-4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(3-(3-chloro-4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0243] A solution of 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (300.0 mg, 1.52 mmol) and triethylamine (0.21 mL, 1.52 mmol) in dichloromethane (24 mL) was stirred at 25 °C for 30 minutes. Then, 3-[3-chloro-4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl]-2-methyl-propanal (520.0 mg, 1.61 mmol) and acetic acid (0.17 mL, 3.04 mmol) were added to adjust the pH to 6. The mixture was stirred at 25 °C for an additional hour. Then, NaBH(OAc) (643 mg, 3.04 mmol) was added and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL x 2), saturated sodium bicarbonate (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica column chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (320 mg, 45.1% yield). LCMS (ESI) [M+H] + =468.2.

[0244] Step 7: Synthesis of (S)-4-(2-chloro-4-(3-(2,2-dioxide-2-thia-6-azaspiro[3.4]octan-6-yl)-2-methylpropyl)phenyl)cyclohexan-1-one and (R)-4-(2-chloro-4-(3-(2,2-dioxide-2-thia-6-azaspiro[3.4]octan-6-yl)-2-methylpropyl)phenyl)cyclohexan-1-one [ka]

[0245] To a solution of 6-(3-(3-chloro-4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (320.0 mg, 0.68 mmol) in water (8 mL), HCl (4 mL, 48 mmol, 12 N) was added and stirred at 25 °C for 5 h. Saturated sodium bicarbonate was added to adjust the pH to 8 and extracted with dichloromethane (50 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, 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 (240 mg, 82.8% yield). LCMS (ESI) [M+H] + =424.2.

[0246] Step 8: Synthesis of the title compound. To a solution of 4-(2-chloro-4-(3-(2,2-dioxide-2-thia-6-azaspiro[3.4]octan-6-yl)-2-methylpropyl)phenyl)cyclohexanone (150.0 mg, 0.35 mmol) in tetrahydrofuran (5 mL) was added (trifluoromethyl)trimethylsilane (251 mg, 1.77 mmol). The mixture was stirred at 0° C. for 5 minutes, and then tetrabutylammonium fluoride (0.04 mL, 0.04 mmol, 1 M in tetrahydrofuran) was added, and the mixture was stirred at 25° C. under nitrogen for 1 hour. The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated ammonium chloride solution (20 mL×3). The dichloromethane phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0–50% ethyl acetate in petroleum ether) to give the title compound as a mixture of diastereomers (100 mg, 53.8% yield). The cis / trans diastereomers of the mixture were then separated by SFC (Daicel Chiralpak AD (250 mm × 30 mm, 10 μm); CO₂, 0.1% NH₃H₂O in 65 / 35 EtOH; 70 mL / min). The first eluting peak, compound 116A, was a racemic mixture of one cyclohexane diastereomer of undefined / unassigned relative stereochemistry (37.5 mg, 35.6% yield). The second eluting peak, compound 116B, was a racemic mixture of one cyclohexane diastereomer of undefined / unassigned relative stereochemistry (41.5 mg, 40.7% yield).

[0247] Compound 116A* (mixture of diastereomers): 1H NMR (400MHz, CDCl3): δppm7.16-7.14(m,2H),7.01-6.99(m,1H),4.08-4.01(m,4H),3.05-3.12(m,1H),2.82-2.76(m,2H),2.73-2.63(m, 3H),2.39-2.26(m,5H),2.14(t,J=7.2Hz,2H),2.09(s,1H),1.91-1.86(m,3H),1.76-1.74(m,4H),0.86(d,J=6.4Hz,3H).LCMS(ESI)[M+H] + =494.1.

[0248] Compound 116B* (mixture of diastereomers): 1 H NMR (400MHz, CDCl3): δppm7.16-7.14(m,2H),7.01-6.99(m,1H),4.08-4.01(m,4H),3.05-3.12(m,1H),2.82-2.63(m,5H),2.38 -2.26(m,5H),2.14(t,J=7.2Hz,2H),2.08(s,1H),1.91-1.86(m,3H),1.76-1.74(m,4H),0.86(d,J=6.8Hz,3H).LCMS(ESI)[M+H] + =494.1. Examples 117A* and 117B*: (S)-6-(3-(3-chloro-4-(4,4-difluorocyclohexyl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(3-(3-chloro-4-(4,4-difluorocyclohexyl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0249] To a solution of 4-(2-chloro-4-(3-(2,2-dioxido-2-thia-6-azaspiro[3.4]octan-6-yl)-2-methylpropyl)phenyl)cyclohexanone (from Example 38; 80.0 mg, 0.19 mmol) in dichloromethane (5 mL) stirred at 0 °C was added diethylaminosulfur trifluoride (0.25 mL, 1.89 mmol). The reaction mixture was stirred at 20 °C for 1 h. The reaction was quenched with saturated sodium bicarbonate solution (15 mL) and extracted with ethyl acetate (25 ml × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica column chromatography (0-50% ethyl acetate in petroleum ether) to give a racemic mixture of the title compounds (70 mg, 74% yield). LCMS (ESI) [M+H] + = 446.1. The mixture was separated by chiral SFC (Daicel Chiralpak AD (250 mm × 50 mm, 10 μm); CO, 0.1% NH₃H₂O in EtOH, 75 / 25; 60 mL / min). The first eluting peak, compound 117A, was obtained as a single enantiomer of undefined / unassigned absolute stereochemistry (17.7 mg, 23.5% yield). The second eluting peak, compound 117B, was obtained as a single enantiomer of undefined / unassigned absolute stereochemistry (17.6 mg, 24.6% yield).

[0250] Compound 117A*: 1 H NMR (400MHz, CDCl3): δppm7.17-7.15(m,2H),7.02-7.00(m,1H),4.08-4.05(m,4H),3.11-3.04(m,1H),2.85-2.60(m,5H) ,2.39-2.23(m,5H),2.14(t,J=7.2Hz,2H),1.96-1.83(m,5H),1.79-1.69(m,2H),0.86(d,J=6.4Hz,3H).LCMS(ESI)[M+H] + =446.1.

[0251] Compound 117B*: 1H NMR (400MHz, CDCl3): δppm7.17-7.15(m,2H),7.02-7.00(m,1H),4.08-4.05(m,4H),3.11-3.04(m,1H),2.82-2.61(m,5H) ,2.39-2.23(m,5H),2.14(t,J=7.2Hz,2H),1.96-1.83(m,5H),1.79-1.69(m,2H),0.86(d,J=6.4Hz,3H).LCMS(ESI)[M+H] + =446.1. Examples 118A* and 118B*: (S)-6-(2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0252] The title compound was synthesized using the synthetic procedure described for Example 113, utilizing methyl 2-(diethylphosphono)propionate and 2-trifluoromethyl-5-pyridinealdehyde in Step 1. The racemic mixture of the title compound was separated by SFC (Daicel Chiralpak AD (250 mm × 30 mm, 10 μm); CO₂, 0.1% DEA in EtOH, 5-40%; 25 mL / min). The first eluting peak, compound 118A, was obtained as a single enantiomer of undefined / unassigned absolute stereochemistry (32 mg, 52% yield). The second eluting peak, compound 118B, was obtained as a single enantiomer of undefined / unassigned absolute stereochemistry (24.8 mg, 37.8% yield).

[0253] Compound 118A*: 1H NMR(400MHz,CD3OD):δppm8.55(d,J=1.6Hz,1H),7.89(dd,J=8.0,1.2Hz,1H),7.75(d,J=8.0Hz,1H),4.07(d,J=4.4Hz,4H),3.06-2.88(m,2H),2. 80(s,2H),2.73-2.63(m,2H),2.61-2.55(m,1H),2.44-2.32(m,2H),2.17 -2.15(m,2H),2.05-1.96(m,1H),0.89(d,J=6.8Hz,3H).LCMS(ESI)[M+H] + =363.1.

[0254] Compound 118B*: 1 H NMR(400MHz,CD3OD):δppm8.55(d,J=1.6Hz,1H),7.89(dd,J=8.0,1.2Hz,1H),7.75(d,J=8.0Hz,1H),4.07(d,J=4.4Hz,4H),3.06-2.88(m,2H),2. 80(s,2H),2.73-2.63(m,2H),2.61-2.55(m,1H),2.44-2.32(m,2H),2.17 -2.15(m,2H),2.05-1.96(m,1H),0.89(d,J=6.8Hz,3H).LCMS(ESI)[M+H] + =363.1. Examples 119A* and 119B*: (S)-6-(2-methyl-3-(4-(trifluoromethoxy)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(2-methyl-3-(4-(trifluoromethoxy)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0255] The title compound was synthesized using the synthetic procedure described for Example 113, utilizing methyl 2-(diethylphosphono)propionate and 4-trifluoromethoxybenzaldehyde in Step 1. The racemic mixture of the title compound was separated by SFC (Daicel Chiralpak OJ (250 mm × 30 mm, 10 μm); CO₂, 0.1% DEA in EtOH, 5–40%; 28 mL / min). The first eluting peak, compound 119A, was obtained as a single enantiomer of undefined / unassigned absolute stereochemistry (33.7 mg, 60% yield). The second eluting peak, compound 119B, was obtained as a single enantiomer of undefined / unassigned absolute stereochemistry (12 mg, 21% yield).

[0256] Compound 119A*: 1 H NMR(400MHz,CD3OD):δppm7.26(d,J=8.0Hz,2H),7.17(d,J=8.0Hz,2H),4.08(s,4H),2.87-2.81(m,1H),2.80(s,2H),2.73-2.63 (m,2H),2.44-2.36(m,2H),2.35-2.29(m,1H),2.16(t,J=7.2Hz,2H),2.00-1.86(m,1H),0.87(d,J=6.4Hz,3H).LCMS(ESI)[M+H] + =378.1.

[0257] Compound 119B*:1H NMR(400MHz,CD3OD):δppm7.25(d,J=8.0Hz,2H),7.16(d,J=8.0Hz,2H),4.08(s,4H),2.86-2.81(m,1H),2.80(s,2H),2.71-2.63 (m,2H),2.43-2.36(m,2H),2.35-2.29(m,1H),2.16(t,J=7.2Hz,2H),2.00-1.86(m,1H),0.87(d,J=6.8Hz,3H).LCMS(ESI)[M+H] + =378.1. Example 120: 6-(2-methyl-2-(4-(trifluoromethyl)phenoxy)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0258] Step 1: Synthesis of methyl 2-methyl-2-[4-(trifluoromethyl)phenoxy]propanoate [ka]

[0259] To a solution of 4-(trifluoromethyl)phenol (1.2 g, 7.4 mmol) in N,N-dimethylformamide (20 mL) was added K2CO3 (3 g, 22.21 mmol) and methyl 2-bromo-2-methylpropanoate (1.1 g, 5.91 mmol). The mixture was stirred at 80 °C for 15 h. The reaction was quenched with saturated NH4Cl solution (40 mL) and extracted with ethyl acetate (40 mL × 3). The combined organics were washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under high vacuum. The residue was purified by silica chromatography (0–30% ethyl acetate in petroleum ether) to give the title compound (1.5 g, 77% yield). 1 H NMR (400MHz, CDCl3): δppm7.51(d,J=8.4Hz,2H),6.87(d,J=8.4Hz,2H),3.77(s,3H),1.65(s,6H).

[0260] Step 2: Synthesis of 2-methyl-2-[4-(trifluoromethyl)phenoxy]propanal [ka]

[0261] To a solution of methyl 2-methyl-2-[4-(trifluoromethyl)phenoxy]propanoate (200 mg, 0.76 mmol) in dichloromethane (2 mL) at −78° C. under nitrogen, diisobutylaluminum hydride (1 mL, 1 mmol, 1N in toluene) was added, followed by stirring at −78° C. for 2 hours. The reaction was quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL×3), dried over anhydrous Na2SO4, filtered, and removed under vacuum to give the title compound (160 mg, 90.3% yield). 1 H NMR (400MHz, CDCl3): δppm9.82(s,1H),7.54-7.48(m,2H),6.91-6.87(m,2H),1.49(s,6H).

[0262] Step 3: Synthesis of the title compound. To a solution of 2-methyl-2-[4-(trifluoromethyl)phenoxy]propanal (160 mg, 0.688 mmol) in methanol (4 mL), 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (40 mg, 0.2 mmol) and NaBHCN (64 mg, 1.0 mmol) were added. The mixture was stirred at 80 °C for 4 hours. The reaction mixture was purified by reverse-phase chromatography (1-28% acetonitrile / 0.2% formic acid in water) to give the title compound (20 mg, 30% yield).

[0263] Compound 120: 1 H NMR (400MHz, CDCl3): δppm7.53(d,J=8.4Hz,2H),7.05(d,J=8.4Hz,2H),4.09(s,4H) ,3.13-2.92(m,4H),2.80(brs,2H),2.20-2.18(m,2H),1.36(s,6H).LCMS(ESI)[M+H] + =378.0. Examples 121A* and 121B*: (S)-6-(2-methyl-3-(5-(trifluoromethyl)pyridin-2-yl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(2-methyl-3-(5-(trifluoromethyl)pyridin-2-yl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0264] The title compound was synthesized using the synthetic procedure described for Example 113, utilizing methyl-2-(diethylphosphono)propionate and 5-(trifluoromethyl)-2-pyridinecarboxaldehyde in Step 1. The racemic mixture of the title compound was separated by SFC (Daicel Chiralpak OD (250 mm × 30 mm, 10 μm); CO , 0.1% NH OH in EtOH, 45%; 60 mL / min). The first eluting peak, compound 121A, was obtained as a single enantiomer of undefined / unassigned absolute stereochemistry (5.1 mg, 10% yield). The second eluting peak, compound 121B, was obtained as a single enantiomer of undefined / unassigned absolute stereochemistry (5.8 mg, 11% yield).

[0265] Compound 121A*: 1 H NMR(400MHz,CD3OD):δppm8.77(s,1H),8.03(dd,J=8.0,2.0Hz,1H),7.50(d,J=8.0Hz,1H),4.05(s,4H),3.30-3.29(m,1H),3.07-3.03(m,1H) ),2.83-2.77(m,2H),2.70-2.61(m,3H),2.44-2.38(m,2H),2.25-2.17(m,1H),2.13(t,J=6.8Hz,2H),0.89(d,J=6.8Hz,3H).LCMS(ESI)[M+H] + =363.1.

[0266] Compound 121B*:1 H NMR(400MHz,CD3OD):δppm8.77(s,1H),8.03(dd,J=8.0,2.0Hz,1H),7.50(d,J=8.0Hz,1H),4.05(s,4H),3.30-3.29(m,1H),3.07-3.03(m,1H) ),2.83-2.77(m,2H),2.70-2.61(m,3H),2.44-2.38(m,2H),2.25-2.17(m,1H),2.13(t,J=6.8Hz,2H),0.89(d,J=6.8Hz,3H).LCMS(ESI)[M+H] + =363.1. Examples 122A* and 122B*: (R)-6-(3-fluoro-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (S)-6-(3-fluoro-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0267] Step 1: Synthesis of (S)-1-(4-(trifluoromethyl)phenyl)but-3-en-1-ol and (R)-1-(4-(trifluoromethyl)phenyl)but-3-en-1-ol [ka]

[0268] A solution of 4-(trifluoromethyl)benzaldehyde (2.00 g, 11.5 mmol) in tetrahydrofuran (20 mL) was stirred at 0 °C, to which a 1 M solution of allylmagnesium bromide (15 mL, 15 mmol, 1 M in hexanes) was added dropwise. The reaction mixture was then stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated NH4Cl solution (40 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica chromatography (0–70% ethyl acetate in petroleum ether) to give the title compound (2.24 g, 10.4 mmol, 90.2% yield) as a mixture of enantiomers. 1 H NMR (400MHz, DMSO-d6): δppm7.67(d,J=8.4Hz,2H),7.54(d,J=8.4Hz,2H),5.79-5.73(m,1H),5.01-4.93(m,2H),4.71-4.68(m,1H),2.43-2.38(m,2H).

[0269] Step 2: Synthesis of (S)-1-(1-fluorobut-3-en-1-yl)-4-(trifluoromethyl)benzene and (R)-1-(1-fluorobut-3-en-1-yl)-4-(trifluoromethyl)benzene [ka]

[0270] To a stirred solution of 1-[4-(trifluoromethyl)phenyl]but-3-en-1-ol (2.0 g, 9.25 mmol) in dichloromethane (10 mL) was added diethylaminosulfur trifluoride (4.0 mL, 27.7 mmol) at -78 °C, and the mixture was stirred at 20 °C for 3 h. The reaction was quenched with saturated NaHCO solution (15 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0–30% ethyl acetate in petroleum ether) to afford the title compound (1.86 g, 8.53 mmol, 92.2% yield) as a mixture of enantiomers. 1 H NMR (400MHz, DMSO-d6): δppm7.76(d,J=8.4Hz,2H),7.60(d,J=8.4Hz,2H),5.81-5.69(m,2H),5.15-5.08(m,2H),2.72-2.63(m,2H).

[0271] Step 3: Synthesis of (S)-3-fluoro-3-(4-(trifluoromethyl)phenyl)propanal and (R)-3-fluoro-3-(4-(trifluoromethyl)phenyl)propanal [ka]

[0272] A stream of ozone (15 psi) was bubbled through a mixture of 1-(1-fluorobut-3-enyl)-4-(trifluoromethyl)benzene (600.0 mg, 2.75 mmol) in dichloromethane (20 mL) at −78° C. for 30 minutes. The mixture was quenched with dimethyl sulfide (854.4 mg, 13.75 mmol) and stirred at 25° C. for 60 minutes. The reaction mixture was washed with water (20 mL × 3). The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title compound (400 mg, 66.1% yield) as a mixture of enantiomers. 1H NMR (400MHz, CDCl3): δppm9.86(s,1H),7.70(d,J=8.0Hz,2H),7.50(d,J=8.0Hz,2H),6.18-6.02(m,1H),3.25-3.19(m,1H),2.99-2.91(m,1H).

[0273] Step 4: Synthesis of the title compound. To a solution of 3-fluoro-3-[4-(trifluoromethyl)phenyl]propanal (217 mg, 0.99 mmol) in methanol (2 mL), 2-thia-6-azaspiro[3.4]octane-2,2-dioxide hydrochloride (65 mg, 0.33 mmol) and NaBHCN (103 mg, 1.64 mmol) were added. The mixture was stirred at 70 °C for 3 h. TLC indicated the reaction was complete. The reaction mixture was purified by reverse-phase chromatography (C18; 30-60% acetonitrile in water / 0.1% NHOH) to give the title compound (40 mg, 33% yield) as a mixture of enantiomers. The racemic mixture (40 mg, 0.109 mmol) was purified by chiral SFC (Daicel Chiralcel OJ-H (150 mm × 4.6 mm, 5 μm) CO, ethanol, 40%). The first eluting peak, Example 122A, was obtained as a single enantiomer of unassigned stereochemistry (19.6 mg, 49% yield). The second eluting peak, Example 122B, was obtained as a single enantiomer of unassigned stereochemistry (16.6 mg, 42% yield).

[0274] Compound 122A*: 1 H NMR(400MHz,CD3OD):δppm7.70(d,J=8.0Hz,2H),7.56(d,J=8.0Hz,2H),5.74-5.59(m, 1H),4.09(s,4H),2.85(s,2H),2.74-2.65(m,4H),2.21-2.04(m,4H).LCMS(ESI)[M+H] + =366.0.

[0275] Compound 122B*: 1H NMR(400MHz,CD3OD):δppm7.70(d,J=8.4Hz,2H),7.56(d,J=8.4Hz,2H),5.74-5.59(m, 1H),4.09(s,4H),2.85(s,2H),2.73-2.61(m,4H),2.21-2.11(m,4H).LCMS(ESI)[M+H] + =366.0. Examples 123A* and 123B*: 6-((R)-3-(3-chloro-4-((1r,4R)-4-hydroxy-4-methylcyclohexyl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 6-((S)-3-(3-chloro-4-((1r,4S)-4-hydroxy-4-methylcyclohexyl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide 2-dioxide, 6-((S)-3-(3-chloro-4-((1r,4S)-4-hydroxy-4-methylcyclohexyl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, and 6-((R)-3-(3-chloro-4-((1r,4R)-4-hydroxy-4-methylcyclohexyl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka] [ka]

[0276] Methylmagnesium bromide (0.39 mL, 1.18 mmol, 3 M in toluene) was added to a solution of 4-(2-chloro-4-(3-(2,2-dioxido-2-thia-6-azaspiro[3.4]octan-6-yl)-2-methylpropyl)phenyl)cyclohexanone (from Example 38; 100 mg, 0.24 mmol) in tetrahydrofuran (5 mL) at 0° C. The mixture was stirred at 0° C. for 3 h. The reaction was quenched with saturated ammonium chloride solution (5 mL) and extracted with dichloromethane (25 mL × 3). The combined dichloromethane fractions were dried over anhydrous NaSO, filtered, and concentrated under high vacuum. The residue was purified by reverse-phase chromatography (C18; water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, 65%-95%) to give compound 123A as the first eluting peak, which is a mixture of diastereomers of undefined / unassigned relative stereochemistry (8.6 mg, 8.2% yield), and compound 123B as the second eluting peak, which is a mixture of diastereomers of undefined / unassigned relative stereochemistry (10.5 mg, 10% yield).

[0277] Compound 123A*: 1 H NMR (400MHz, CDCl3): δppm7.17-7.14(m,2H),6.99(dd,J=8.0,2.0Hz,1H),4.08-4.04(m,4H),3.02-2.95(m,1H),2.82-2.61(m,5H),2.39-2.28(m,3H) ),2.14(t,J=7.2Hz,2H),1.86-1.83(m,5H),1.70-1.64(m,2H),1.54-1.50 (m,2H),1.40(s,1H),1.35(s,3H),0.86(d,J=6.4Hz,3H).LCMS(ESI)[M+H] + =440.1.

[0278] Compound 123B*: 1H NMR (400MHz, CDCl3): δppm7.23(d,J=8.0Hz,1H),7.13(d,J=1.6Hz,1H),7.0 0(dd,J=8.0,1.6Hz,1H),4.08-4.01(m,4H),2.95-2.89(m,1H),2.82-2.60(m ,5H),2.39-2.25(m,3H),2.13(t,J=7.2Hz,2H),1.86-1.60(m,7H),1.54-1. 50(m,2H),1.30(s,3H),1.17(s,1H),0.86(d,J=6.4Hz,3H).LCMS(ESI)[M+H] + =440.1. Examples 124A* and 124B*: 6-((R)-3-(3-chloro-4-((R)-tetrahydro-2H-pyran-2-yl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 6-((S)-3-(3-chloro-4-((R)-tetrahydro-2H-pyran-2-yl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide 2-dioxide, 6-((R)-3-(3-chloro-4-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide, and 6-((S)-3-(3-chloro-4-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0279] The title compound was synthesized using the synthetic procedure described for Example 116, utilizing 3,4-dihydro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyran in step 2 and omitting steps 7 and 8. The diastereomeric mixture was purified by reverse-phase chromatography (C18; water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, 30%) to give compound 124A* as the first eluting peak, which was obtained as a mixture of diastereomers of undefined / unassigned relative stereochemistry (9.8 mg, 23% yield), and compound 124B* as the second eluting peak. The title compound was obtained as a mixture of diastereomers of undefined / unassigned relative stereochemistry (13.7 mg, 31.6% yield).

[0280] Compound 124A*: 1 H NMR(400MHz,CD3OD):δppm7.51-7.49(m,1H),7.24-7.12(m,2H),4.71-4.6 7(m,1H),4.12(s,4H),3.65-3,55(m,1H),3.22(s,1H),2.89-2.82(m,2H),2 .77-2.69(m,2H),2.23-2.19(m,2H),2.05-1.94(m,2H),1.94-1.84(m,4H) ,1.74-1.59(m,3H),1.48-1.34(m,2H),1.31-1.25(m,3H).LCMS(ESI)[M+H] + =410.1.

[0281] Compound 124B*: 1 H NMR(400MHz,CD3OD):δppm7.50(d,J=8.0Hz,1H),7.25-7.22(m,2H),4.71-4.67(m,1H),4.12(s,4H),3.65-3,55(m,1H),3.21(s,2H),2.86(s,2) H),2.74(t,J=7.2Hz,2H),2.21(t,J=7.2Hz,2H),1.95-1.91(m,3H),1.82-1.61(m,3H),1.54-1.35(m,2H),1.31-1.25(m,3H).LCMS(ESI)[M+H]+ =410.1. Example 125: 6-(2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane-2,2-dioxide [ka]

[0282] Step 1: Synthesis of 2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)propanal [ka]

[0283] To a mixture of tribromoindium (297 mg, 0.84 mmol) and 4-(trifluoromethyl)benzyl bromide (2.0 g, 8.37 mmol) dissolved in dichloromethane (20 mL), 2-methyl-1-(trimethylsiloxy)-1-propene (3.62 g, 25.1 mmol) was added and stirred at 20 °C for 16 h. The reaction was quenched with saturated sodium bicarbonate (50 mL) and extracted with dichloromethane (50 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound (500 mg, 26% yield). LCMS (ESI) [M+H] + =231.0.

[0284] Step 2: Synthesis of the title compound: 2-Thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (30 mg, 0.15 mmol) and triethylamine (15 mg, 0.15 mmol) were added to dichloromethane (4 mL) and stirred at 25 °C for 30 minutes. 2,2-Dimethyl-3-[4-(trifluoromethyl)phenyl]propanal (35 mg, 0.15 mmol) and acetic acid (18 mg, 0.3 mmol) were added to the above mixture and stirred at 25 °C for another hour. NaBH(OAc) (64 mg, 0.3 mmol) was then added and the reaction mixture was stirred for 1 hour. The reaction was quenched with saturated sodium bicarbonate (10 mL) and extracted with dichloromethane (15 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by reverse-phase chromatography (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, 70% to 100%) to give the title compound (9.5 mg, 16.5% yield).

[0285] Compound 125: 1 H NMR(400MHz,CD3OD):δppm7.55(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),4.09(s,4H),2.96(s,2H),2 .85(t,J=7.2Hz,2H),2.67(s,2H),2.39(s,2H),2.15(t,J=7.2Hz,2H),0.88(s,6H).LCMS(ESI)[M+H] + =375.1. Examples 126A* and 126B*: (S)-6-(2-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(2-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0286] Step 1: Synthesis of methyl (E)-2-methyl-3-[2-(trifluoromethyl)-4-pyridyl]propenoate [ka]

[0287] To a solution of 4-iodo-2-(trifluoromethyl)pyridine (1.1 g, 4 mmol) in anhydrous DMF (11 mL) was added methyl methacrylate (1.21 g, 12 mmol), NaHCO3 (813 mg, 9.7 mmol), and Pd(Cy*Phine)2Cl2 (103 mg, 0.08 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction was quenched with saturated NH4Cl (20 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0–10% ethyl acetate in petroleum ether) to give the title compound (210 mg, 21% yield).

[0288] Step 2: Synthesis of methyl (R)-2-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)propanoate and methyl (S)-2-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)propanoate [ka]

[0289] To a solution of methyl (E)-2-methyl-3-[2-(trifluoromethyl)-4-pyridyl]prop-2-enoate (210 mg, 0.86 mmol) in ethyl acetate (7 mL) was added PtO2 / C (20 mg, 0.09 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 1 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was further purified by silica column chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (180 mg, 85% yield) as a mixture of enantiomers. LCMS (EIS): [M+H] + =248.1.

[0290] Step 3: Synthesis of (S)-2-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)propanal and (R)-2-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)propanal [ka]

[0291] To a solution of methyl 2-methyl-3-[2-(trifluoromethyl)-4-pyridyl]propanoate (180 mg, 0.728 mmol) in dry dichloromethane (4 mL) was added diisobutylaluminum hydride (1 mL, 1 mmol, 1 M in DCM) dropwise at -78 °C and stirred at that temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution (3 mL) and extracted with ethyl acetate (25 mL × 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (110 mg, 70% yield) as a mixture of enantiomers.

[0292] Step 4: Synthesis of the title compound. A mixture of 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (80 mg, 0.4 mmol) and triethylamine (82 mg, 0.81 mmol) in dichloromethane (10 mL) was stirred at 25 °C for 30 minutes, and then 2-methyl-3-[2-(trifluoromethyl)-4-pyridyl]propanal (88 mg, 0.4 mmol) and acetic acid (24 mg, 0.4 mmol) were added. The mixture was stirred at 25 °C for 1 hour, NaBH(OAc) (172 mg, 0.81 mmol) was added, and the mixture was stirred at 25 °C for another 1 hour. The reaction was quenched with a saturated solution of NaHCO and extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reverse phase chromatography (water (0.05% NH3H2O)-ACN, 40%-70%) to give the title compound (70 mg, 48% yield) as a mixture of enantiomers. LCMS (ESI) [M+H] + = 363.2. The racemic mixture (70 mg, 0.19 mmol) was purified by chiral SFC (Daicel Chiralpak AD-H (250 mm × 30 mm, 5 μm); CO, 0.1% NHHO in EtOH; 15%, 60 mL / min) to give compound 126A as the first eluting peak (16.2 mg, 23% yield) as a pure enantiomer of undetermined absolute stereochemistry, and compound 126B as the second eluting peak (16.5 mg, 24% yield) as a pure enantiomer of undetermined absolute stereochemistry.

[0293] Compound 126A*: 1 H NMR (400MHz, CDCl3): δppm8.62(d,J=4.8Hz,1H),7.49(s,1H),7.28(d,J=4.8Hz,1H),4.11-3.99(m,4H),2.95-2.62(m,5) LCMS(ESI)[M+H] + =363.2.

[0294] Compound 126B*: 1 H NMR (400MHz, CDCl3): δppm8.62(d,J=4.8Hz,1H),7.49(s,1H),7.29(d,J=4.8Hz,1H),4.10-4.00(m,4H),2.93-2.59(m,5 LCMS(ESI)[M+H] + =363.2. Example 127: 6-(2-(3-fluorophenoxy)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane-2,2-dioxide [ka]

[0295] Using the synthetic procedure described for Example 120, utilizing 3-fluorophenol in Step 1, the title compound was synthesized (28.9 mg, 44% yield).

[0296] Compound 127: 1 H NMR(400MHz,CD3OD):δppm8.33(brs,1H),7.35-7.21(m,1H),6.89-6.73(m,3H),4.13(s,4H),3.1 6(s,2H),3.01(t,J=7.2Hz,2H),2.88(s,2H),2.21(t,J=7.2Hz,2H),1.33(s,6H).LCMS(ESI)[M+H] + =328.1. Examples 128A* and 128B*: (S)-6-(3-(4-(difluoromethyl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(3-(4-(difluoromethyl)phenyl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0297] The title compound was synthesized using the synthetic procedure described for Example 103, utilizing 4-difluoromethyl-iodobenzene and 2-thia-6-azaspiro[3.4]octane-2,2-dioxide hydrochloride. The crude diastereomeric mixture of the title compounds was separated by chiral SFC (OJ-3, 150 × 4.6 mm, 3 μm; CO₂-EtOH, 5% to 40%). Compound 128A was obtained as the first eluting peak (10.5 mg, 26% yield) as a single enantiomer of undefined / unassigned absolute stereochemistry, and compound 128B was obtained as the second eluting peak (9.9 mg, 25% yield) as a single enantiomer of undefined / unassigned absolute stereochemistry.

[0298] Compound 128A*: 1 H NMR (400MHz, CD3OD): δppm7.44(d,J=8.0Hz,2H),7.29(d,J=8.0Hz,2H),6.90-6.54(m,1H),4.09(d,J=1.6Hz,4H),2.89-2.82( m,3H),2.77-2.67(m,2H),2.47-2.32(m,3H),2.17(t,J=7.2Hz,2H),2.02-1.92(m,1H),0.88(d,J=6.4Hz,3H).LCMS(ESI)[M+H] + =343.9.

[0299] Compound 128B*: 1 H NMR (400MHz, CD3OD): δppm7.44(d,J=8.0Hz,2H),7.29(d,J=8.0Hz,2H),6.89-6.54(m,1H),4.09(d,J=1.6Hz,4H),2.88-2.81( m,3H),2.76-2.66(m,2H),2.46-2.32(m,3H),2.17(t,J=7.2Hz,2H),2.02-1.93(m,1H),0.88(d,J=6.4Hz,3H).LCMS(ESI)[M+H] + =343.9. Example 129: 6-(2-(4-cyclobutylphenoxy)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane-2,2-dioxide [ka]

[0300] Step 1: Synthesis of 4-cyclobutylphenol [ka]

[0301] To a mixture of 4-bromophenol (1.0 g, 5.78 mmol) and bromocyclobutane (780 mg, 5.78 mmol) in N,N-dimethylacetamide (10 mL) was added 4,4'-di-tert-butyl-2,2'-dipyridyl (155 mg, 0.58 mmol), 4-ethylpyridine (309 mg, 2.89 mmol), manganese (635 mg, 11.56 mmol), KI (959 mg, 5.78 mmol), and NiCl dimethoxyethane adduct (127 mg, 0.58 mmol) in a glove box under argon. The mixture was stirred at 80 °C for 16 h. The mixture was diluted with ethyl acetate (200 mL), washed with brine (30 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-25% ethyl acetate in petroleum ether) to give the title compound (500 mg, 58.4% yield).

[0302] Step 2: Synthesis of methyl 2-(4-cyclobutylphenoxy)-2-methylpropanoate [ka]

[0303] A suspension of 4-cyclobutylphenol (400 mg, 2.7 mmol), methyl 2-bromo-2-methylpropanoate (733 mg, 4.05 mmol), and K2CO3 (1119 mg, 8.10 mmol) in N,N-dimethylformamide (8 mL) was stirred at 80 °C for 16 h. Ethyl acetate (500 mL) was added, and the resulting mixture was washed with brine (100 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0-5% ethyl acetate in petroleum ether) to give the title compound (180 mg, 26.9% yield). LCMS (ESI) [M+H] + =249.1.

[0304] Step 3: Synthesis of 2-(4-cyclobutylphenoxy)-2-methylpropanal [ka]

[0305] To a solution of methyl 2-(4-cyclobutylphenoxy)-2-methyl-propanoate (100 mg, 0.4 mmol) in dichloromethane (4 mL) was added diisobutylaluminum hydride (0.6 mL, 0.6 mmol, 1 M in DCM) at −78° C. The reaction was stirred at −78° C. for 1 hour. The reaction was quenched with aqueous potassium tartrate (5 mL). The resulting solution was extracted with ethyl acetate (50 mL×2), and the combined organic phases were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title compound (100 mg, 90% yield).

[0306] Step 4: Synthesis of the title compound. A solution of 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (30 mg, 0.15 mmol) and triethylamine (0.02 mL, 0.15 mmol) in anhydrous dichloromethane (4 mL) was stirred at 25 °C for 30 minutes. Then, 2-(4-cyclobutylphenoxy)-2-methyl-propanal (40 mg, 0.18 mmol) and acetic acid (0.02 mL, 0.3 mmol) were added and stirred at 25 °C for 1 hour. NaBH(OAc) (64 mg, 0.3 mmol) was added and stirred at 25 °C for 1 hour. The reaction mixture was diluted with ethyl acetate (60 mL), and the resulting mixture was washed with water (30 mL × 2). The organic layer was washed with saturated sodium bicarbonate (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by silica column chromatography (0-50% ethyl acetate in petroleum ether) to give the pure title compound (32.3 mg, 57.4% yield).

[0307] Compound 129: 1 H NMR (400MHz, CDCl3): δppm7.11(d,J=8.4Hz,2H),6.89(d,J=8.4Hz,2H),4.10-4.03(m,4H),3.55-3.46(m,1H),3.02(s,2H),2.90(t,J =7.2Hz,2H),2.71(s,2H),2.36-2.29(m,2H),2.17-2.07(m,4H),2.03-1.96(m,1H),1.88-1.81(m,1H),1.26(s,6H).LCMS(ESI)[M+H] + =364.3. Example 130: 6-(2-methyl-2-(3-(trifluoromethyl)phenoxy)propyl)-2-thia-6-azaspiro[3.4]octane-2,2-dioxide [ka]

[0308] Using the synthetic procedure described for Example 120, utilizing 3-trifluoromethylphenol in Step 1, the title compound was synthesized (22.5 mg, 38.9% yield).

[0309] Compound 130: 1 H NMR(400MHz,CD3OD):δppm7.50-7.46(m,1H),7.39-7.37(m,1H),7.29-7.27(m,2H),4.13-4.10(m,4H) ,3.17(s,2H),3.03(t,J=7.2Hz,2H),2.92(s,2H),2.22(t,J=7.2Hz,2H),1.34(s,6H).LCMS(ESI)[M+H] + =378.1. Example 131: 6-(2-methyl-2-(3-(trifluoromethoxy)phenoxy)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0310] Using the synthetic procedure described in Example 120, utilizing 3-trifluoromethoxyphenol in Step 1, the title compound was synthesized (12.5 mg, 21% yield).

[0311] Compound 131: 1 H NMR (400MHz, CDCl3): δppm7.30-7.29(m,1H),7.01-6.90(m,2H),6.85(s,1H),4.07(s, 4H),3.02-2.91(m,4H),2.74(s,2H),2.16-2.11(m,2H),1.31(s,6H).LCMS(ESI)[M+H] + =394.0. Example 132: 6-(2-(4-fluorophenoxy)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0312] Using the synthetic procedure described in Example 120, utilizing 4-fluorophenol in Step 1, the title compound was synthesized (11 mg, 16% yield).

[0313] Compound 132: 1 H NMR(400MHz,CD3OD):δppm7.20-7.00(m,4H),4.09(s,4H),3.04(s,2H),2.90(t, J=7.2Hz,2H),2.77(s,2H),2.16(t,J=7.2Hz,2H),1.28(s,6H).LCMS(ESI)[M+H] + =328.1. Example 133: 6-(2-(2-fluorophenoxy)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0314] Using the synthetic procedure described for Example 120, utilizing 2-fluorophenol in Step 1, the title compound was synthesized (15 mg, 23% yield).

[0315] Compound 133: 1 H NMR(400MHz,CD3OD):δppm7.15-7.06(m,4H),4.09(s,4H),3.04(s,2H),2.90(t, J=7.2Hz,2H),2.77(s,2H),2.16(t,J=7.2Hz,2H),1.28(s,6H).LCMS(ESI)[M+H] + =328.1. Example 135: 6-(2-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)propyl)-2-thia-6-azaspiro[3.4]octane-2,2-dioxide [ka]

[0316] Using the synthetic procedure described in Example 120, utilizing 2-trifluoromethyl-5-hydroxypyridine in Step 1, the title compound was synthesized (30.2 mg, 51.5% yield).

[0317] Compound 135: 1 H NMR (400MHz, CDCl3): δppm8.39(s,1H),7.61(d,J=8.4Hz,1H),7.41(dd,J=8.4,2.4Hz,1H),4.10-4.02(m,4H),3. 02(s,2H),2.90(t,J=7.2Hz,2H),2.79(s,2H),2.15(t,J=7.2Hz,2H),1.59(s,2H),1.37(s,6H).LCMS(ESI)[M+H] + =379.1. Example 136: 6-(2-methyl-2-(4-(trifluoromethoxy)phenoxy)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0318] Using the synthetic procedure described in Example 120, utilizing 4-trifluoromethoxyphenol in Step 1, the title compound was synthesized (26.3 mg, 30.4% yield).

[0319] Compound 136: 1 H NMR (400MHz, CDCl3): δppm7.12(d,J=8.4Hz,2H),6.98-6.94(m,2H),4.07(s,4H),3.02(s,2) H),2.90(t,J=7.2Hz,2H),2.72(s,2H),2.14(t,J=7.2Hz,2H),1.28(s,6H).LCMS(ESI)[M+H] + =394.2. Example 138: 7-(2-methyl-2-(4-(trifluoromethyl)phenoxy)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0320] Using the synthetic procedure described in Example 120, utilizing 4-trifluoromethylphenol in step 1 and 2-thia-7-azaspiro[3.5]nonane-2,2-dioxide hydrochloride in step 3, the title compound was synthesized (21.4 mg, 30.5% yield).

[0321] Compound 138: 1 H NMR(400MHz, CDCl3): δppm7.52(d,J=8.4Hz,2H),7.05(d,J=8.4Hz,2H),3.86(s,4H ),2.60(brs,4H),2.53(s,2H),1.92(t,J=5.2Hz,4H),1.32(s,6H).LCMS(ESI)[M+H] + =392.1. Example 139: 6-(3-(3-chloro-4-(4,4-difluorocyclohexyl)phenyl)-2,2-dimethylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0322] Step 1: Synthesis of 4-(bromomethyl)-2-chloro-1-(4,4-difluorocyclohexyl)benzene [ka]

[0323] To a mixture of 3-chloro-4-(4,4-difluorocyclohexyl)phenyl]methanol (1000 mg, 3.84 mmol) in dichloromethane (10 mL) was added phosphorus tribromide (0.15 mL, 1.53 mmol) at 0 °C, and the reaction mixture was stirred at 25 °C for 2 h. The reaction was quenched with NaHCO solution (50 mL) and extracted with dichloromethane (60 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography (0–10% ethyl acetate in petroleum ether) to give the title compound (600 mg, 48.3% yield).

[0324] Step 2: Synthesis of methyl 3-(3-chloro-4-(4,4-difluorocyclohexyl)phenyl)-2,2-dimethylpropanoate [ka]

[0325] To a solution of methyl isobutyrate (26 mL, 3.29 mmol) in tetrahydrofuran (8 mL) was added lithium diisopropylamide (1.55 mL, 3.09 mmol) at −78°C under N2 at −75°C and stirred at that temperature for 1 h. Then, 4-(bromomethyl)-2-chloro-1-(4,4-difluorocyclohexyl)benzene (500 mg, 1.55 mmol) in tetrahydrofuran (2 mL) was added slowly at −75°C and stirred at −75°C for 1 h. The reaction mixture was quenched with saturated NH4Cl (20 mL) solution and extracted with ethyl acetate (50 mL × 3). The combined organics were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica flash chromatography (0–5% ethyl acetate in petroleum ether) to give the title compound (250 mg, 46.9% yield).

[0326] Step 3: Synthesis of 3-(3-chloro-4-(4,4-difluorocyclohexyl)phenyl)-2,2-dimethylpropanal [ka]

[0327] To a solution of methyl 3-[3-chloro-4-(4,4-difluorocyclohexyl)phenyl]-2,2-dimethylpropanoate (240 mg, 0.70 mmol) in dichloromethane (7 mL) was added diisobutylaluminum hydride (1.04 mL, 1.04 mmol, 1 M in toluene) at −75° C. and stirred at −75° C. for 2 h. The reaction mixture was quenched with sodium potassium tartrate solution (10 mL) / water (10 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica flash chromatography (0–5% ethyl acetate in petroleum ether) to give the title compound (35 mg, 16% yield).

[0328] Step 4: Synthesis of the title compound. A solution of 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (30 mg, 0.15 mmol) and triethylamine (15 mg, 0.15 mmol) in dichloromethane (3 mL) was stirred at 25° C. for 30 minutes. Then, 3-[3-chloro-4-(4,4-difluorocyclohexyl)phenyl]-2,2-dimethyl-propanal (35 mg, 0.12 mmol) and acetic acid (18 mg, 0.30 mmol) were added. The mixture was stirred at 25° C. for 1 hour. Then, NaBH(OAc) (64 mg, 0.30 mmol) was added and stirred at 25° C. for another 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate (10 mL) and extracted with dichloromethane (15 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica flash chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (21.3 mg, 29.3% yield). LCMS (ESI) [M+H] + =460.2.

[0329] Compound 139: 1 H NMR(400MHz,CD3OD):δppm7.24-7.19(m,2H),7.07(d,J=7.6Hz,1H),4.09(s,4H),3.16-3.10(m,2H),2.93(s,2H),2.84(t,J= 7.2Hz,2H),2.54(s,2H),2.35(s,2H),2.17-2.13(m,4H),2.06-1.87(m,4H),1.79-1.73(m,2H),0.86(s,6H).LCMS(ESI)[M+H] + =460.2. Example 140: 6-(2,2-dimethyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-thia-6-azaspiro[3.4]octane-2,2-dioxide [ka]

[0330] Step 1: Synthesis of methyl 2,2-dimethyl-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate [ka]

[0331] To a solution of methyl isobutyrate (271 mg, 2.66 mmol) in tetrahydrofuran (5 mL) was added lithium diisopropylamide (1.25 mL, 2.5 mmol, 2 M) at -78 °C and stirred at -78 °C for 1 h. 5-(bromomethyl)-2-(trifluoromethyl)pyridine (300 mg, 1.25 mmol) was then slowly added at -78 °C and stirred for 2 h. The reaction was quenched with aqueous NH4Cl (15 mL) and extracted with ethyl acetate (25 mL x 3). The combined organics were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica column chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (300 mg, 81.2% yield). LCMS (ESI) [M+H] + =262.2.

[0332] Step 2: Synthesis of 2,2-dimethyl-3-(6-(trifluoromethyl)pyridin-3-yl)propanal [ka]

[0333] To a solution of methyl 2,2-dimethyl-3-[6-(trifluoromethyl)-3-pyridyl]propanoate (300 mg, 1.15 mmol) in dichloromethane (10 mL) was added diisobutylaluminum hydride (1.72 mL, 1.72 mmol, 1 M in DCM) at -78 °C and stirred at that temperature for 2 hours. The reaction was quenched with aqueous potassium sodium tartrate solution (5 mL). The resulting solution was extracted with ethyl acetate (25 mL × 3). The combined organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (80 mg, 30.1% yield). LCMS (ESI) [M+H] + =232.1.

[0334] Step 3: Synthesis of the title compound. A solution of 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (30 mg, 0.15 mmol) and triethylamine (0.02 mL, 0.15 mmol) in anhydrous dichloromethane (6 mL) was stirred at 25° C. for 30 minutes. 2,2-Dimethyl-3-[6-(trifluoromethyl)-3-pyridyl]propanal (35 mg, 0.15 mmol) and acetic acid (0.02 mL, 0.30 mmol) were then added and stirred at 25° C. for 1 hour. NaBH(OAc) (64 mg, 0.30 mmol) was then added and stirred at 25° C. for an additional 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water. The organic layer was washed with saturated sodium bicarbonate 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 (30 mg, 49.9% yield).

[0335] Compound 140: 1 H NMR (400MHz, CDCl3): δppm8.51(s,1H),7.64-7.60(m,2H),4.10-4.03(m,4H),2.97(s,2H),2.86 (t,J=7.2Hz,2H),2.64(s,2H),2.38(s,2H),2.15(t,J=7.2Hz,2H),0.87(s,6H).LCMS(ESI)[M+H] + =377.2. Examples 141A* and 141B*: (R)-7-(2-methyl-2-(4-(trifluoromethyl)phenoxy)propyl)-2-thia-7-azaspiro[4.4]nonane 2,2-dioxide and (S)-7-(2-methyl-2-(4-(trifluoromethyl)phenoxy)propyl)-2-thia-7-azaspiro[4.4]nonane 2,2-dioxide [ka]

[0336] The title compound was synthesized using the synthetic procedure described for Example 120, utilizing 4-trifluoromethylphenol in Step 1 and 2-thia-7-azaspiro[4.4]nonane-2,2-dioxide hydrochloride in Step 3. The title compound was isolated as a racemic mixture (35 mg), and the enantiomers were separated by chiral SFC (Daicel Chiralpak AD-H (250 mm × 30 mm, 5 μm) CO, 0.1% NH 3 HO / EtOH=25:75; 60 mL / min) to give compound 141A as the first eluting peak (8.8 mg, 22.9% yield) as a single enantiomer of undefined / unassigned absolute stereochemistry, and compound 141B as the second eluting peak (8.8 mg, 22.9% yield) as a single enantiomer of undefined / unassigned absolute stereochemistry.

[0337] Compound 141A*: 1H NMR (400MHz, CDCl3): δppm7.54(d,J=6.8Hz,2H),7.06(d,J=6.8Hz,2H),3.25-3.18(m,2H),3.17-2 .96(m,4H),2.85-2.65(m,4H),2.27-2.24(m,2H),2.09-1.78(m,2H),1.35(s,6H).LCMS(ESI)[M+H] + =392.1.

[0338] Compound 141B*: 1 H NMR (400MHz, CDCl3): δ7.54(d,J=6.8Hz,2H),7.06(d,J=6.8Hz,2H),3.25-3.18(m,2H),3.17-2.9 6(m,4H),2.85-2.65(m,4H),2.27-2.24(m,2H),2.09-1.78(m,2H),1.35(s,6H).LCMS(ESI)[M+H] + =392.1. Example 142: (S)-6-(2-fluoro-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(2-fluoro-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0339] Step 1: Synthesis of 2-(4-(trifluoromethyl)benzyl)oxirane [ka]

[0340] To a solution of 1-allyl-4-(trifluoromethyl)benzene (200 mg, 1.07 mmol) in dichloromethane (10 mL) was added 3-chloroperoxybenzoic acid (436 mg, 2.15 mmol, 85% purity) and stirred at 25 °C for 16 h. The reaction was quenched with saturated aqueous NaHCO (15 mL) and the organic layer was separated. The aqueous layer was further extracted with dichloromethane, and the combined organic phases were dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (0–5% ethyl acetate in petroleum ether) to give the title compound (180 mg, 82.9% yield). 1 H NMR (400MHz, CDCl3): δppm7.59(d,J=8.0Hz,2H),7.39(d,J=8.0Hz,2H),3.20-3. 16(m,1H),3.00-2.88(m,2H),2.83(t,J=4.4Hz,1H),2.55(dd,J=4.8,2.8Hz,1H).

[0341] Step 2: Synthesis of (R)-6-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (S)-6-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0342] To a solution of 2-[[4-(trifluoromethyl)phenyl]methyl]oxirane (150 mg, 0.74 mmol) in ethanol (5 mL), triethylamine (0.31 mL, 2.23 mmol) and 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (166 mg, 0.84 mmol) were added and stirred at 80 °C for 16 h. After concentration under reduced pressure, the residue was purified by silica column chromatography (0-65% ethyl acetate in petroleum ether) to give the title compound (130 mg, 46.8% yield). LCMS (ESI) [M+H] + =364.1.

[0343] Step 3: Synthesis of the title compound. To a solution of 6-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane-2,2-dioxide (50 mg, 0.14 mmol) in tetrahydrofuran (2 mL), perfluorobutanesulfonyl fluoride (83 mg, 0.28 mmol) and 2-tert-butyl-1,1,3,3-tetramethylguanidine (71 mg, 0.41 mmol) were added and stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure and purified by silica column chromatography (0 to 70% ethyl acetate in petroleum ether) to give the title compound (11.5 mg, 22.6% yield) as a racemic mixture.

[0344] Compound 142 (mixture): 1 H NMR (400MHz, CDCl3): δ7.58(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),4.89-4.74(m,1H),4.07(s,4H),3.05(d,J= 5.2Hz,1H),3.00(t,J=6.4Hz,1H),2.95-2.88(m,2H),2.81-2.69(m,4H),2.17(t,J=7.2Hz,2H).LCMS(ESI)[M+H] + =366.2. Example 143: (S)-6-(2-methoxy-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(2-methoxy-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0345] To a solution of 6-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide (from Example 142, 80 mg, 0.22 mmol) in dichloromethane (4 mL) was added diethylaminosulfur trifluoride (0.15 mL, 1.1 mmol) at −78° C. and stirred at the same temperature for 1 h. Methanol (5 mL) was added and stirred at 25° C. for another 1 h. The reaction mixture was diluted with saturated sodium bicarbonate (10 mL) and extracted with dichloromethane (25 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0–100% ethyl acetate in petroleum ether) to give the title compound (19.8 mg, 22.9% yield) as a racemic mixture of enantiomers.

[0346] Compound 143 (mixture): 1 H NMR (400MHz, CDCl3): δ7.55(d,J=8.0Hz,2H),7.32(d,J=8.0Hz,2H),4.06(s,4H),3.54-3.47(m,1H),3.36(s,3H),2.94 -2.87(m,3H),2.84-2.80(m,1H),2.73(t,J=7.2Hz,2H),2.53(d,J=5.6Hz,2H),2.14(t,J=7.2Hz,2H).LCMS(ESI)[M+H] + =378.2. Example 144: 6-(2-methyl-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)propyl)-2-thia-6-azaspiro[3.4]octane-2,2-dioxide [ka]

[0347] Using the synthetic procedure described in Example 120, utilizing 2-trifluoromethyl-5-hydroxypyrimidine in Step 1, the title compound was synthesized (27 mg, 22.5% yield).

[0348] Compound 144: 1H NMR (400MHz, CDCl3): δppm8.56(s,2H),4.10-4.03(m,4H),3.02(s,2H),2.90(t, J=7.2Hz,2H),2.82(s,2H),2.16(t,J=7.2Hz,2H),1.42(s,6H).LCMS(ESI)[M+H] + =380.1. Examples 145A* and 145B*: (S)-6-(2-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(2-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0349] The title compound was prepared using the synthetic procedure described for Example 126, utilizing 2-trifluoromethyl-4-iodopyrimidine in Step 1. The crude racemic mixture was separated by chiral SFC (Chiral Pak AD-3, 150 mm × 4.6 mm, 3 μm, CO₂-0.1% NH₃H₂O in EtOH, 5-40%). Compound 145A* was obtained as the first eluting peak (4 mg, 12% yield) as a single enantiomer of undefined / unassigned absolute stereochemistry. Compound 145B* was obtained as the second eluting peak (7 mg, 22% yield) as a single enantiomer of undefined / unassigned absolute stereochemistry.

[0350] Compound 145A*: 1 H NMR(400MHz,CD3OD):δppm8.84(s,2H),4.09(s,4H),2.94-2.87(m,2H),2.78-2.68(m,2H),2.66-2.61( m,1H),2.58-2.40(m,2H),2.17-2.07(m,2H),1.37-1.31(m,2H),0.94(d,J=6.4Hz,3H).LCMS(ESI)[M+H] +=364.1.

[0351] Compound 145B*: 1 H NMR(400MHz,CD3OD):δppm8.84(s,2H),4,05(s,4H),2.93-2.89(m,1H),2.78(s,2H),2.66-2.61(m,3H), 2.41(d,J=8.8Hz,1H),2.35(d,J=6.0Hz,1H),2.17-2.11(m,3H),0.92(d,J=6.8Hz,3H).LCMS(ESI)[M+H] + =364.1. Examples 148A* and 148B*: (S)-7-(2,2-dimethyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-thia-7-azaspiro[4.4]nonane 2,2-dioxide and (R)-7-(2,2-dimethyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-thia-7-azaspiro[4.4]nonane 2,2-dioxide [ka]

[0352] The title compound was synthesized using the synthetic procedure described for Example 140, utilizing 2-thia-7-azaspiro[4.4]nonane-2,2-dioxide in Step 3. The crude racemic mixture was separated by chiral SFC (Daicel Chiralpak IG-H (250 mm × 30 mm, 5 μm); CO -0.1% NH H O in EtOH, 55%; 80 mL / min) to give compound 148A* as the first eluting peak (63 mg, 40% yield) as a single enantiomer of undefined / unassigned absolute stereochemistry, and compound 148B* as the second eluting peak (64 mg, 40% yield) as a single enantiomer of undefined / unassigned absolute stereochemistry.

[0353] Compound 148A*: 1H NMR (400MHz, CDCl3): δppm8.53(s,1H),7.63-7.61(m,2H),3.31-3.07(m,4H),2.92-2.89(m,2H),2.78-2.72(m,1H),2 .66-2.57(m,3H),2.33(s,2H),2.27-2.18(m,2H),2.03-2.01(m,1H),1.92-1.87(m,1H),0.88(s,6H).LCMS(ESI)[M+H] + =391.0.

[0354] Compound 148B*: 1 H NMR (400MHz, CDCl3): δppm8.53(s,1H),7.63-7.61(m,2H),3.31-3.07(m,4H),2.92-2.89(m,2H),2.78-2.72(m,1H),2 .66-2.57(m,3H),2.33(s,2H),2.27-2.18(m,2H),2.03-2.01(m,1H),1.92-1.87(m,1H),0.88(s,6H).LCMS(ESI)[M+H] + =391.0. Example 149: 6-(2,2-dimethyl-3-(5-(trifluoromethyl)pyridin-3-yl)propyl)-2-thia-6-azaspiro[3.4]octane-2,2-dioxide [ka]

[0355] Step 1: Synthesis of [5-(trifluoromethyl)-3-pyridyl]methanol [ka]

[0356] 5-(Trifluoromethyl)nicotinic acid (2200 mg, 11.51 mmol) was dissolved in borane-THF (58 mL, 58 mmol, 1 M in THF) and the mixture was stirred at 25° C. for 16 hours. The reaction was quenched with methanol (60 mL). The reaction mixture was heated at 70° C. for 4 hours. The resulting mixture was concentrated under reduced pressure to give the crude title compound (1900 mg, 10.7 mmol, 93.2% yield). LCMS (ESI) [M+H] + =178.1. 1 H NMR(400MHz,CDCl3)δ8.82(s,1H),8.79(s,1H),8.00(s,1H),4.85(s,2H).

[0357] Step 2: Synthesis of 3-(bromomethyl)-5-(trifluoromethyl)pyridine [ka]

[0358] To a solution of [5-(trifluoromethyl)-3-pyridyl]methanol (900 mg, 5.08 mmol) in dichloromethane (18 mL) was added phosphorus tribromide (0.97 mL, 10.16 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction was quenched with NaHCO3 solution (50 mL). The mixture was extracted with dichloromethane (60 mL × 3). The combined organic layers were washed with water (50 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (500 mg, 2.08 mmol, 41% yield). LCMS (ESI) [M+H] + =240.1.

[0359] Step 3: Synthesis of m-ethyl 2,2-dimethyl-3-[5-(trifluoromethyl)-3-pyridyl]propanoate [ka]

[0360] To a cooled (-75°C) solution of methyl isobutyrate (26.04 mL, 3.33 mmol) in tetrahydrofuran (15 mL) under nitrogen, lithium diisopropylamide (2 mL, 4.0 mmol, 2 M in THF) was added, and the reaction mixture was stirred at -75°C for 5 hours. 3-(Bromomethyl)-5-(trifluoromethyl)pyridine (500 mg, 2.08 mmol) was then added slowly at -75°C and stirred at that temperature for 2 hours. The reaction was quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (10 mL) and brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (400 mg, 1.53 mmol, 74%) 0-20% to give the title compound. LCMS (ESI) [M+H] + =262.1.

[0361] Step 4: Synthesis of 2,2-dimethyl-3-[5-(trifluoromethyl)-3-pyridyl]propan-1-ol [ka]

[0362] To a solution of methyl 2,2-dimethyl-3-[5-(trifluoromethyl)-3-pyridyl]propanoate (120 mg, 0.46 mmol) in dichloromethane (5 mL) was added diisobutylaluminum hydride (0.69 mL, 0.69 mmol, 1 M in toluene) at -75 °C, and the mixture was stirred at -75 °C for 2 h. The reaction was quenched with sodium potassium tartrate solution (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous 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 (38 mg, 0.163 mmol, 35.5% yield). LCMS (ESI) [M+H] + =234.1.

[0363] Step 5: Synthesis of [2,2-dimethyl-3-[5-(trifluoromethyl)-3-pyridyl]propyl]methanesulfonate [ka]

[0364] To a solution of 2,2-dimethyl-3-[5-(trifluoromethyl)-3-pyridyl]propan-1-ol (38 mg, 0.16 mmol) and N,N-diisopropylethylamine (0.06 mL, 0.36 mmol) in dichloromethane (4 mL), methanesulfonyl chloride (0.02 mL, 0.21 mmol) was added at 0° C. and stirred at 25° C. for 1 hour. The mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (50 mg, 0.161 mmol, 98.6% yield). LCMS (ESI) [M+H] + =312.1.

[0365] Step 6: Synthesis of the title compound. To a solution of 2-thia-6-azaspiro[3.4]octane 2,2-dioxide (39 mg, 0.24 mmol) and K2CO3 (110 mg, 0.80 mmol) in N,N-dimethylacetamide (5 mL), [2,2-dimethyl-3-[5-(trifluoromethyl)-3-pyridyl]propyl]methanesulfonate (50 mg, 0.161 mmol) and KI (53 mg, 0.32 mmol) were added. The mixture was stirred in a microwave at 140 °C for 1 hour. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue 0% was purified by silica column chromatography (12.4 mg, 0.032 mmol, yield 19.9%) 10% to give the title compound.

[0366] Compound 149: 1H NMR(400MHz,CD3OD):δppm8.73(d,J=1.2Hz,1H),8.64(d,J=1.6Hz,1H),7.96(s,1H),4.10(s,4H),2.96(s, 2H),2.85(t,J=7.2Hz,2H),2.75(s,2H),2.39(s,2H),2.16(t,J=7.2Hz,2H),0.89(s,6H).LCMS(ESI)[M+H] + =377.2. Example 150: 6-(2,2-dimethyl-3-(5-(trifluoromethyl)pyridin-2-yl)propyl)-2-thia-6-azaspiro[3.4]octane-2,2-dioxide [ka]

[0367] Using the synthetic procedure described for Example 149, utilizing 2-hydroxymethyl-5-trifluoromethylpyridine in step 1 and 2-thia-6-azaspiro[3.4]octane-2,2-dioxide in step 5, the title compound was synthesized (61.3 mg, 36.1% yield).

[0368] Compound 150: 1 H NMR(400MHz,CDCl3)δppm8.81(s,1H),7.82(d,J=8.4Hz,1H),7.24(d,J=8.4Hz,1H),4.06(s,4H),2.98(s, 2H),2.88(t,J=7.2Hz,2H),2.82(s,2H),2.44(s,2H),2.13(t,J=7.2Hz,2H),0.90(s,6H).LCMS(ESI)[M+H] + =377.1. Example 152: 7-(2,2-dimethyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-thia-7-azaspiro[3.5]nonane-2,2-dioxide [ka]

[0369] The synthetic procedure described for Example 147 was used to synthesize the title compound (30.6 mg, 31% yield), utilizing 2-thia-7-azaspiro[3.5]nonane in Step 2.

[0370] Compound 152: 1 H NMR (400MHz, CDCl3): δppm8.50(s,1H),7.61(s,2H),3.86(s,4H),2.61(s,2H),2.51( brs,4H),2.18(s,2H),1.95-1.90(m,4H),1.56(s,4H),0.83(s,6H).LCMS(ESI)[M+H] + =391.2. Example 153: 7-(2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-7-azaspiro[3.5]nonane-2,2-dioxide [ka]

[0371] Using a synthetic procedure similar to that described for Example 147, utilizing 2-thia-7-azaspiro[3.5]nonane in step 2 and 2,2-dimethyl-3-[4-(trifluoromethyl)phenyl]propanoate in step 1, the title compound was synthesized (30.6 mg, 31% yield).

[0372] Compound 153: 1 H NMR(400MHz,CD3OD):δ7.55(d,J=8.0Hz,2H),7.33(d,J=8.0Hz,2H),3.88(s,4H),2.64(s, 2H),2.55-2.45(m,4H),2.19(s,2H),1.89(t,J=5.2Hz,4H),0.84(s,6H).LCMS(ESI)[M+H] + =390.1. Examples 154A* and 154B*: (S)-6-(2-methyl-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(2-methyl-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)propyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0373] Step 1: 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carbaldehyde [ka]

[0374] To a solution of 1H-pyrazole-4-carbaldehyde (2000 mg, 20.81 mmol) in N,N-dimethylformamide (20 mL) was added CsCO (2.03 g, 62.44 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (7.25 g, 31.22 mmol) and stirred at 40 °C for 2 h. The reaction was quenched with water (40 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (0–75% ethyl acetate in petroleum ether) to give the title compound (3.4 g, 91.7% yield). 1 H NMR(400MHz, CDCl3)δ9.93(s,1H),8.07(d,J=6.4Hz,2H),4.81-4.66(m,2H).

[0375] Step 2: Synthesis of (E)-ethyl 2-methyl-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)acrylate [ka]

[0376] To an ice-cold solution of triethyl 2-phosphonopropionate (5002 mg, 21 mmol) in tetrahydrofuran (60 mL), NaH (916 mg, 22.91 mmol, 60% in mineral oil) was added portionwise and stirred for 30 minutes. Then, 1-(2,2,2 trifluoroethyl)pyrazole-4-carbaldehyde (3.4 g, 19.09 mmol) was added and stirred at 25 °C for 2 hours. The reaction was quenched with water (25 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (25 mL × 3), dried over anhydrous sodium sulfate, 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 (3940 mg, 78.7% yield). LCMS (ESI) [M+H] + =263.2.

[0377] Step 3: Synthesis of ethyl (S)-2-methyl-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)propanoate and ethyl (R)-2-methyl-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)propanoate [ka]

[0378] To a solution of ethyl (E)-2-methyl-3-[1-(2,2,2 trifluoroethyl)pyrazol-4-yl]prop-2-enoate (1000 mg, 3.81 mmol) in ethanol (20 mL), 10% palladium on carbon (490 mg, 0.46 mmol) was added and stirred under H2 (15 psi) at 25 °C for 2 h. The reaction mixture was filtered and the organic layer was concentrated to give the title compound (1000 mg, 99.2% yield). LCMS (ESI) [M+H] + =265.1.

[0379] Step 4: Synthesis of (R)-2-methyl-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)propan-1-ol and (S)-2-methyl-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)propan-1-ol [ka]

[0380] To a stirred suspension of lithium aluminum hydride (430 mg, 11.35 mmol) in tetrahydrofuran (15 mL) was added a solution of ethyl 2-methyl-3-[1-(2,2,2 trifluoroethyl)pyrazol-4-yl]propanoate (1000 mg, 3.78 mmol) in tetrahydrofuran (8 mL) at 0° C. The mixture was then stirred at 20° C. for 1 hour. The mixture was cooled to 0° C. and quenched with water (1 mL), 15% aqueous NaOH (1 mL), and water (3 mL), then filtered. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (520 mg, 61.8% yield). LCMS (ESI) [M+H] + =223.1

[0381] Step 5: Synthesis of (S)-2-methyl-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)propyl methanesulfonate and (R)-2-methyl-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)propyl methanesulfonate [ka]

[0382] To an ice-cold solution of 2-methyl-3-[1-(2,2,2 trifluoroethyl)pyrazol-4-yl]propan-1-ol (520 mg, 2.36 mmol) and N,N diisopropylethylamine (0.96 mL, 5.2 mmol) in dichloromethane (15 mL), methanesulfonyl chloride (297 mg, 2.6 mmol) was added and stirred at 20 °C for 4 hours. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (50 mL × 3). The combined organic layer was washed with saturated sodium bicarbonate (20 mL × 3) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (700 mg, 98.7% yield), which was used directly for the next step.

[0383] Step 6: Synthesis of the title compound. To a solution of 2-methyl-3-[1-(2,2,2 trifluoroethyl)pyrazol-4-yl]propyl methanesulfonate (200 mg, 0.68 mmol), 2-thia-6-azaspiro[3.4]octane 2,2-dioxide (116 mg, 0.72 mmol), and N,N-diisopropylethylamine (128 mg, 1 mmol) in acetonitrile (8 mL), K2CO3 (220 mg, 1.32 mmol) was added and then stirred at 100 °C for 1 hour under microwave irradiation. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layer was washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-75% ethyl acetate in petroleum ether) to give the title compound (150 mg, 61% yield). LCMS (ESI) [M+H] += 366.1. The mixture of enantiomers (120 mg, 0.33 mmol) was separated by chiral SFC (SFC-17; Daicel Chiralcel OJ-H (250 mm x 30 mm, 5 μm) with 0.1% NH₃H₂O / EtOH = 10:90; 60 mL / min). Compound 154A* was obtained as the first peak by SFC (41.8 mg, 33% yield) as a single enantiomer of undefined / unassigned absolute stereochemistry. Compound 154B* was obtained as the second peak by SFC (21.7 mg, 17% yield) as a single enantiomer of undefined / unassigned absolute stereochemistry.

[0384] Compound 154A*: 1 H NMR(400MHz,CD3OD)δ7.55(s,1H),7.42(s,1H),4.87-4.83(m,2H),4.12(s,4H),2.91(brs,2H),2.78(brs,2H),2.62(dd,J=14.2,5 .2Hz,1H),2.52-2.42(m,1H),2.40-2.30(m,2H),2.21(t,J=7.2Hz,2H),1.88-1.87(m,1H),0.91(d,J=6.8Hz,3H).LCMS(ESI)[M+H] + =366.2.

[0385] Compound 154B*: 1 H NMR(400MHz,CD3OD)δ7.55(s,1H),7.42(s,1H),4.87-4.83(m,2H),4.12(s,4H),2.91(brs,2H),2.78(brs,2H),2.62(dd,J=14.2,5 .2Hz,1H),2.52-2.42(m,1H),2.40-2.30(m,2H),2.21(t,J=7.2Hz,2H),1.88-1.87(m,1H),0.91(d,J=6.8Hz,3H).LCMS(ESI)[M+H] + =366.2. Example 155: (S)-6-(3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (R)-6-(3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0386] Step 1: Synthesis of 1-isopropyl-3-(trifluoromethyl)-1H-pyrazole [ka]

[0387] To a stirred suspension of 3-(trifluoromethyl)pyrazole (4 g, 29.39 mmol) in acetonitrile (50 mL) was added 2-iodopropane (15 g, 88.18 mmol) and CsCO (48 g, 146.97 mmol) at 25 °C for 16 h. The reaction mixture was filtered, and the organic layer was diluted with water (50 mL). The mixture was then extracted with MTBE (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (4.2 g, 80% yield). 1 H NMR(400MHz, CDCl3) δ7.46(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).

[0388] Step 2: Synthesis of 1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-5-carbaldehyde [ka]

[0389] To a stirred solution of 1-isopropyl-3-(trifluoromethyl)pyrazole (1 g, 5.61 mmol) in tetrahydrofuran (20 mL) was added n-butyllithium (3 mL, 7.5 mmol, 2.5 M in hexane) dropwise at −78° C. The reaction mixture was stirred at the same temperature for 1 hour. Then, N,N-dimethylformamide (1.5 mL, 19.47 mmol) was added dropwise, and the reaction was stirred at −78° C. for another 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with MTBE (50 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.5 g). 1 H NMR(400MHz, CDCl3) δ9.87(s,1H),7.13(s,1H),5.49-5.39(m,1H),1.53(d,J=6.8Hz,6H).

[0390] Step 3: Synthesis of (E)-ethyl 3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methylacrylate [ka]

[0391] To an ice-cold solution of triethyl 2-phosphonopropionate (1907 mg, 8.01 mmol) in tetrahydrofuran (10 mL) was slowly added NaH (349 mg, 8.73 mmol, 60% in mineral oil), and the reaction mixture was stirred for 30 min. 2-Isopropyl-5-(trifluoromethyl)pyrazole-3-carbaldehyde (1.5 g, 7.28 mmol) was then added and stirred at 25 °C for an additional 1 h. The reaction mixture was quenched with NHCl (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-3% ethyl acetate in petroleum ether) to give the title compound (900 mg, 43% yield). LCMS (ESI [M+H] + =291.1

[0392] Step 4: Ethyl (S)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methylpropanoate and Ethyl (R)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methylpropanoate [ka]

[0393] To a solution of ethyl (E)-3-[2-isopropyl-5-(trifluoromethyl)pyrazol-3-yl]-2-methyl-prop-2-enoate (900 mg, 3.1 mmol) in methanol (5 mL) was added 10% palladium on carbon (330 mg, 0.31 mmol) and stirred under H2 (15 psi) at 25 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (520 mg, 57% yield). LCMS (ESI): [M+H] + =293.1.

[0394] Step 5: Synthesis of (S)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methylpropan-1-ol and (R)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methylpropan-1-ol [ka]

[0395] To a stirred solution of ethyl 3-[2-isopropyl-5-(trifluoromethyl)pyrazol-3-yl]-2-methyl-propanoate (720 mg, 2.46 mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (280 mg, 7.39 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 1 hour. The mixture was cooled to 0° C., and then water (0.3 mL), 15% NaOH solution (1.2 mL), and water (1.2 mL) were slowly added to quench the reaction. The suspension mixture was filtered, and the filtrate was concentrated. The residue was purified by silica column chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (500 mg, 81% yield). LCMS (ESI): [M+H] + =251.1.

[0396] Step 6: Synthesis of (R)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methylpropyl methanesulfonate and (S)-3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methylpropyl methanesulfonate [ka]

[0397] To an ice-cold solution of 3-[2-isopropyl-5-(trifluoromethyl)pyrazol-3-yl]-2-methyl-propan-1-ol (500 mg, 2 mmol) and triethylamine (607 mg, 5.99 mmol) in dichloromethane (5 mL) was added methanesulfonyl chloride (252 mg, 2.2 mmol). The reaction mixture was stirred at 0° C. for 0.5 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (15 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (650 mg, 99% yield). LCMS (ESI) [M+H] + =329.1.

[0398] Step 7: Synthesis of the title compound. To a mixture of [3-[2-isopropyl-5-(trifluoromethyl)pyrazol-3-yl]-2-methyl-propyl]methanesulfonate (150 mg, 0.46 mmol) in acetonitrile (3 mL), 2-thia-6-azaspiro[3.4]octane 2,2-dioxide (89 mg, 0.55 mmol), N,N-diisopropylethylamine (89 mg, 0.69 mmol), and potassium iodide (152 mg, 0.91 mmol) were added. The mixture was stirred at 80 °C for 16 hours. The resulting solution was concentrated in vacuo. The residue was purified by reverse-phase chromatography (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, 50% to 80%) to give the title compound (81.8 mg, 45% yield) as a mixture of enantiomers. LCMS(ESI)[M+H] + =394.2.

[0399] Compound 155 (mixture): 1 H NMR(400MHz,CDCl3)δ6.23(s,1H),4.50-4.45(m,1H),4.09-4.02(m,4H),2.86-2.78(m,3H),2.74-2.62(m,2H),2.46-2. 31(m,3H),2.16(t,J=6.8Hz,2H),1.95-1.85(m,1H),1.49(dd,J=6.8,2.4Hz,6H),0.95(d,J=6.4Hz,3H).LCMS(ESI)[M+H] + =394.2. Example 156: 7-(2-(3,4-difluorophenoxy)-2-methylpropyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0400] Step 1: Synthesis of (3S)-1-[1-[5-(trifluoromethyl)-2-pyridyl]-4-piperidyl]piperidin-3-ol [ka]

[0401] To a solution of 3,4-difluorophenol (2 g, 15.3 mmol) in N,N-dimethylformamide (15 mL) was added K2CO3 (5 g, 34.97 mmol) and methyl 2-bromo-2-methylpropanoate (3 g, 17 mmol). The mixture was stirred at 80 °C for 15 h. Ethyl acetate (90 mL) was added, and the resulting mixture was washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica column chromatography (eluted with 0-10% ethyl acetate in petroleum ether) to give the title compound (2 g, 56.5% yield). LCMS (ESI) [M+H] + =231.0

[0402] Step 2: Synthesis of 2-(3,4-difluorophenoxy)-2-methyl-propanoic acid [ka]

[0403] To a solution of methyl 2-(3,4-difluorophenoxy)-2-methyl-propanoate (500 mg, 2.17 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium hydroxide hydrate (456 mg, 10.86 mmol) in water (6 mL). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was adjusted to pH 2 with HCl (1 M), then diluted with water (10 ml) and extracted with ethyl acetate (30 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (340 mg, 72.4% yield). 1 H NMR(400MHz,CD3OD)δ7.23-7.08(m,1H),6.90-6.80(m,1H),6.73-6.67(m,1H),1.55(s,6H)

[0404] Step 3: Synthesis of 2-(3,4-difluorophenoxy)-1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)-2-methylpropan-1-one [ka]

[0405] To a mixture of 2-(3,4-difluorophenoxy)-2-methyl-propanoic acid (50 mg, 0.23 mmol), N,N-diisopropylethylamine (0.1 mL, 0.58 mmol), and 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (25 mg, 0.12 mmol) in dichloromethane (2 mL), HATU (132 mg, 0.35 mmol) was added. The resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated, and the residue was purified by silica column chromatography (0-60% ethyl acetate in petroleum ether) to give the title compound (80 mg, 92.6% yield). LCMS (ESI) [M+H] + =374.1.

[0406] Step 4: Synthesis of the title compound: To a cold (0° C.) solution of 2-(3,4-difluorophenoxy)-1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)-2-methylpropan-1-one (55 mg, 0.15 mmol) in tetrahydrofuran (3 mL) was added borane-THF (7 mL, 7 mmol, 1 M). After stirring for 10 minutes, the mixture was heated to 70° C. and stirred for 4 hours. The reaction mixture was diluted with brine (10 mL) and extracted with ethyl acetate (40 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (water (0.2% FA)-ACN 60%-80%) to give the title compound (33.1 mg, 57.9% yield). LCMS (ESI) [M+H] + =360.1.

[0407] Compound 156: 1H NMR(400MHz,CD3OD)δ7.20-7.16(m,1H),6.99-6.96(m,1H),6.84-6.82(m,1H),3. 95(s,4H),2.93-2.89(m,6H),2.03(t,J=5.2Hz,4H),1.31(s,6H).LCMS(ESI)[M+H] + =360.1. Example 157: 6-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)cyclopropyl)methyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0408] Step 1: Synthesis of tert-butyl 1-((6-(trifluoromethyl)pyridin-3-yl)methyl)cyclopropanecarboxylate [ka]

[0409] To a cooled (-75°C) solution of tert-butyl cyclopropanecarboxylate (533 mg, 3.75 mmol) in tetrahydrofuran (12 mL) was added dropwise lithium diisopropylamide (2.5 mL, 5 mmol, 2 M in THF) under N2 and stirred at -75°C for 6 hours. 5-(Bromomethyl)-2-(trifluoromethyl)pyridine (600 mg, 2.5 mmol) was then added slowly at -75°C under N2 and stirred at that temperature for 4 hours, then at 20°C for 10 hours. The reaction mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), 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 (0.26 g, 34.5% yield). LCMS (ESI) [M+H] + =302.2.

[0410] Step 2: Synthesis of 1-((6-(trifluoromethyl)pyridin-3-yl)methyl)cyclopropanecarbaldehyde [ka]

[0411] To a cooled (-75°C) solution of tert-butyl 1-[[6-(trifluoromethyl)-3-pyridyl]methyl]cyclopropanecarboxylate (260 mg, 0.86 mmol) in dichloromethane (10 mL) was added diisobutylaluminum hydride (1.2 mL, 1.2 mmol, 1 M in toluene) dropwise, and the mixture was stirred at -75°C for 2 h. The reaction mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (120 mg, 52.8% yield). LCMS (ESI) [M+H] + =230.1.

[0412] Step 3: Synthesis of the title compound. A mixture of 2-thia-6-azaspiro[3.4]octane 2,2-dioxide hydrochloride (40 mg, 0.2 mmol) and triethylamine (20 mg, 0.2 mmol) in dichloromethane (2 mL) was stirred at 25° C. for 30 minutes, and then 1-[[6-(trifluoromethyl)-3-pyridyl]methyl]cyclopropanecarbaldehyde (69 mg, 0.3 mmol) and acetic acid (12 mg, 0.2 mmol) were added. The reaction mixture was stirred at 25° C. for 1 hour. NaBHCN (128 mg, 0.61 mmol) was added, and the reaction mixture was stirred at 25° C. for 8 hours. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by reverse phase chromatography (water (0.225% FA)-ACN) to give the title compound (44.5 mg, 57.6% yield).

[0413] Compound 157: 1 H NMR(400MHz,CD3OD)δ8.61(s,1H),7.95(d,J=8.0Hz,1H),7.75(d,J=8.0Hz,1H),4.12(s,4H),2.77(d,J=8.0Hz ,4H),2.65(t,J=7.2Hz,2H),2.22-2.13(m,4H),0.63(t,J=5.2Hz,2H),0.41(t,J=5.2Hz,2H).LCMS(ESI)[M+H] + =375.2. Example 158: 7-(2-(3,4-difluorophenoxy)ethyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0414] Step 1: Synthesis of 4-(2-bromoethoxy)-1,2-difluoro-benzene [ka]

[0415] To a solution of 3,4-difluorophenol (1.6 g, 12.34 mmol) in acetone (20 mL) was added 1,2-dibromoethane (7 g, 37.01 mmol), K2CO3 (4.4 g, 31.84 mmol), and KI (200 mg, 1.2 mmol) at 20 °C. The reaction mixture was heated to 60 °C and stirred for 15 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (100% petroleum ether) to give the title compound (1.3 g, 44.5% yield). 1 H NMR(400MHz,CD3OD)δ7.22-7.18(m,1H),6.93-6.90(m,1H),6.76-6.74(m,1H),4.30(t,J=5.6Hz,2H),3.72(t,J=6.0Hz,2H).

[0416] Step 2: Synthesis of the Title Compound. To a solution of 4-(2-bromoethoxy)-1,2-difluorobenzene (89 mg, 0.38 mmol) and 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (40 mg, 0.19 mmol) in acetonitrile (4 mL), N,N-diisopropylethylamine (0.16 mL, 0.97 mmol) and potassium iodide (3 mg, 0.02 mmol) were added at 20° C. and stirred at 20° C. for 5 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by reverse-phase chromatography (water (0.2% FA)-acetonitrile, 50% to 80%) to give the title compound (58 mg, 91.7% yield). LCMS(ESI)[M+H] + =332.1.

[0417] Compound 158: 1 H NMR(400MHz,CD3OD)δ7.22-7.13(m,1H),6.95-6.92(m,1H),6.77-6.75(m,1H),4.20(t,J=5.2Hz ,2H),3.97(s,4H),3.12(t,J=5.2Hz,2H),2.91(brs,3H),2.05(t,J=5.6Hz,4H).LCMS(ESI)[M+H] + =332.1. Example 201: 2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-7-thia-2-azaspiro[3.5]nonane 7,7-dioxide [ka]

[0418] Step 1: 1-(2-bromoethoxy)-4-(trifluoromethyl)benzene [ka]

[0419] To a solution of 4-(trifluoromethyl)phenol (1.0 g, 6.17 mmol) in N,N-dimethylformamide (10 mL) was added 1,2-dibromoethane (4.8 g, 25.55 mmol), K2CO3 (2.2 g, 15.92 mmol), and potassium iodide (100 mg, 0.60 mmol) at 20-30 °C. The mixture was then heated to 80 °C and stirred for 15 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic phases were washed with brine (25 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica column chromatography (solvent gradient: 100% petroleum ether) to give the title compound (690 mg, 2.56 mmol, 42% yield). 1 H NMR (400MHz, CDCl3) δ7.57(d,J=8.8Hz,2H),6.99(d,J=8.8Hz,2H),4.37-4.32(m,2H),3.69-3.63(m,2H).

[0420] Step 2: Synthesis of the title compound. To a mixture of 1-(2-bromoethoxy)-4-(trifluoromethyl)benzene (100 mg, 0.37 mmol) and N,N-diisopropylethylamine (0.29 mL, 1.86 mmol) in acetonitrile (2 mL), 7-thia-2-azaspiro[3.5]nonane 7,7-dioxide hemioxalate (98 mg, 0.22 mmol) and KI (62 mg, 0.37 mmol) were added. The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with brine (25 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (10% methanol in dichloromethane) to give the title compound (61 mg, 0.161 mmol, 43% yield). LCMS (ESI) [M+H] + =364.1.

[0421] Compound 201: 1H NMR(400MHz,CDCl3)δppm7.55(d,J=8.8Hz,2H),6.95(d,J=8.8Hz,2H),4.03(t,J=5. 6Hz,2H),3.20(s,4H),2.99-2.96(m,4H),2.90(t,J=5.6Hz,2H),2.34-2.31(m,4H). Example 202: 7-((1-(4-(trifluoromethyl)phenoxy)cyclopentyl)methyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0422] Step 1: Methyl 1-chlorocyclobutanecarboxylate [ka]

[0423] To a solution of cyclopentanecarboxylic acid (2.2 g, 19.27 mmol) in 1,2-dichloroethane (22 mL) was added bromine (0.99 mL, 19.27 mmol) and chlorosulfonic acid (2.23 mL, 22.4 mmol). The reaction mixture was stirred at 85° C. for 2 hours. The reaction mixture was concentrated, and the residue was dissolved in methanol (618 mg, 19.27 mmol). The mixture was then stirred at 70° C. for an additional 12 hours. The mixture was concentrated, and the crude residue was diluted with methyl tert-butyl ether (100 mL) and washed with water (80 mL×3) and brine (80 mL). The organic layer was concentrated to give the product, methyl 1-bromocyclopentanecarboxylate (3 g, 75% yield). The crude material was used directly without further purification. 1 H NMR(400MHz,CD3OD)δ3.80(s,3H),2.34-2.26(m,4H),2.04-1.90(m,2H),1.87-1.73(m,2H).

[0424] Step 2: Methyl 1-(4-(trifluoromethyl)phenoxy)cyclopentanecarboxylate [ka]

[0425] To a solution of 4-(trifluoromethyl)phenol (1.3 g, 8.02 mmol) in acetonitrile (20 mL) was added methyl 1-bromocyclopentanecarboxylate (2.0 g, 9.66 mmol) and cesium carbonate (7.87 g, 24.15 mmol) at 20 °C. The reaction mixture was stirred at 70 °C for 3 h. The mixture was then diluted with ethyl acetate (80 mL), washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound (2 g, 72% yield). 1 H NMR(400MHz,CD3OD)δ7.54(d,J=8.4Hz,2H),6.86(d,J=8.4Hz,2H),3.72(s,3H),2.38-2.32(m,2H),2.21-2.12(m,2H),1.85-1.81(m,4H).

[0426] Step 3: 1-[4-(trifluoromethyl)phenoxy]cyclopentanecarboxylic acid [ka]

[0427] To a solution of methyl 1-[4-(trifluoromethyl)phenoxy]cyclopentanecarboxylate (500.0 mg, 1.73 mmol) in tetrahydrofuran (2.5 mL) was added hydroxylithium hydrate (255 mg, 6.07 mmol) in water (1.5 mL). The reaction mixture was stirred at 20° C. for 2 hours and then adjusted to pH=2 with HCl (1 mol / L). The mixture was then diluted with water (20 mL), and the resulting mixture was extracted with ethyl acetate (30×3 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated under vacuum to give the title compound (470 mg, 99% yield).

[0428] Step 4: (2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)(1-(4-(trifluoromethyl)phenoxy)cyclopentyl)methanone [ka]

[0429] To a mixture of 1-[4-(trifluoromethyl)phenoxy]cyclopentanecarboxylic acid (50.0 mg, 0.18 mmol), N,N-diisopropylethylamine (0.08 mL, 0.46 mmol), and 2-thia-7-azaspiro[3.5]nonane 2-oxide hydrochloride (38.6 mg, 0.18 mmol) in dichloromethane (1 mL) was added HATU (104 mg, 0.27 mmol). The resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was then diluted with brine (20 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic layers were concentrated under reduced pressure. The resulting residue was directly purified by silica column chromatography (solvent gradient: 0-50% ethyl acetate in petroleum ether) to give the title compound (70 mg, 63% yield). LCMS (ESI) [M+H] + =432.1.

[0430] Step 5: Synthesis of the Title Compound. To a cold (0° C.) solution of (2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)(1-(4-(trifluoromethyl)phenoxy)cyclopentyl)methanone (100 mg, 0.23 mmol) in tetrahydrofuran (2 mL), borane-THF (3 mL, 3 mmol) was added, and the mixture was stirred at 70° C. for 4 hours. The reaction was quenched with MeOH (1 mL), and the mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with water (2×10 mL). The organics were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC (water (0.05% FA)-ACN, 40% to 70%) to give the title compound as the formate salt (88.2 mg, 88.4% yield).

[0431] Compound 202: 1H NMR(400MHz,CD3OD)δ8.23(s,1H),7.58(d,J=8.4Hz,2H),7.15(d,J=8.4Hz,2H),3.93(s,4H),3.18(s,2H),2 .88(s,4H),2.20-2.12(m,2H),2.00(t,J=5.2Hz,4H),1.96-1.93(m,2H),1.76-1.66(m,4H).LCMS(ESI)[M+H] + =418.1. Examples 203* and 217*: (S)-7-(2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and (R)-7-(2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide

[0432] Step 1: (E)-Ethyl 2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)acrylate [ka]

[0433] To a solution of triethyl 2-phosphonopropionate (10.2 g, 42.83 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (1.71 g, 42.83 mmol) (60%) portionwise at 0 °C. The reaction mixture was stirred for 0.5 h. Then, 6-(trifluoromethyl)nicotinaldehyde (5.0 g, 28.55 mmol) was added at 0 °C. The reaction mixture was then stirred at 20 °C for 2 h. The reaction was quenched with saturated ammonium chloride solution (100 mL), diluted with water (20 mL), and extracted with ethyl acetate (500 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by column silica chromatography (0-6% ethyl acetate in petroleum ether) to give the title compound (7.0 g, 95% yield). LCMS (ESI) [M+H] + =260.0.

[0434] Step 2: Ethyl 2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate [ka]

[0435] A solution of ethyl (E)-2-methyl-3-[6-(trifluoromethyl)-3-pyridyl]prop-2-enoate (7.0 g, 27 mmol) and 10% palladium on carbon (5747 mg, 5.4 mmol) in ethanol (100 mL) was stirred under H (40 psi) at 25° C. for 2 h. The resulting mixture was filtered, and the filtrate was concentrated to give the title compound (7000 mg, 99.2% yield). LCMS [M+H]=262.1.

[0436] Step 3: 2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol [ka]

[0437] To a solution of ethyl 2-methyl-3-[6-(trifluoromethyl)-3-pyridyl]propanoate (7.0 g, 26.8 mmol) in tetrahydrofuran (100 mL) was added borane and lithium hydride (1.17 g, 53.59 mmol) at 0 °C. The reaction was stirred under N at 20 °C for 48 h. The reaction was quenched with ammonium chloride solution (100 mL). The mixture was extracted with ethyl acetate (500 mL x 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica flash chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (5000 mg, 83.4% yield). LCMS (ESI) [M+H] + =220.1.

[0438] Step 4: (R)-2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol and (S)-2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol [ka]

[0439] 2-Methyl-3-[6-(trifluoromethyl)-3-pyridyl]propan-1-ol (13.0 g, 59.31 mmol) was separated using chiral SFC (SFC-9; 0.1% NH3HOEtOH 15 / 15; 200 mL / min) to give (R)-2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (4500 mg, 34.3% yield) (first peak in SFC). LCMS (ESI) [M+H]+ = 220.0. (S)-2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (4000 mg, 30.2% yield) (second peak in SFC). LCMS (ESI) [M+H]+ = 220.0. The absolute stereochemistry was unambiguously assigned.

[0440] Step 5: (S)-2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl methanesulfonate and (R)-2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl methanesulfonate [ka]

[0441] (S)-2-Methyl-3-[6-(trifluoromethyl)-3-pyridyl]propan-1-ol (200 mg, 0.91 mmol) and N,N-diisopropylethylamine (0.37 mL, 2.01 mmol) were dissolved in dichloromethane (8 mL), and methanesulfonyl chloride (0.8 mL, 1 mmol) was added at 0° C. The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was quenched with water (25 mL), and the resulting mixture was extracted with dichloromethane (25 mL x 3). The combined organic layer was washed with saturated sodium bicarbonate (20 mL x 3) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give (S)-2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl methanesulfonate (arbitrarily assigned stereochemistry) (270 mg, 99.5% yield). [M+H] + =298.0. The other isomer, (R)-2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl methanesulfonate (arbitrarily assigned stereochemistry), was prepared analogously to the synthetic procedure described above.

[0442] Step 6A: Synthesis of the title compound (S)-7-(2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (Compound 203*). [ka]

[0443] To (S)-2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl methanesulfonate (50.0 mg, 0.17 mmol) and N,N-diisopropylethylamine (32 mg, 0.25 mmol) in acetonitrile (5 mL) were added 2-thia-7-azaspiro[3.5]nonane 2-oxide hydrochloride (40 mg, 0.19 mmol) and potassium iodide (55 mg, 0.34 mmol). The mixture was stirred at 80° C. for 16 hours. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether) to give the title compound (39.05 mg, 62% yield). Compound 203*: 1 H NMR(400MHz,CD3OD)δ8.55(s,1H),7.88(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),3.87(s,4H),2.93-2.83(m,1H),2.58(dd,J=13. 6,7.6Hz,1H),2.41(brs,4H),2.20(brs,2H),2.14-2.03(m,1H),1.86(d,J=5.2Hz,4H),0.88(d,J=6.4Hz,3H).LCMS(ESI):[M+H] + =377.2. Absolute stereochemistry was unambiguously assigned.

[0444] Step 6B: Synthesis of the title compound (R)-7-(2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (Compound 217*). [ka]

[0445] The title compound was synthesized in a similar manner to Step 6A using (R)-2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl methanesulfonate to give the title compound (54.06 mg, 80.3% yield). LCMS (ESI): [M+H] + =377.1.Compound 217*: 1H NMR (400 MHz, CD3OD) δ 8.55 (d, J = 1.6 Hz, 1H), 7.88 (dd, J = 8.0, 1.6 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 3.87 (s, 4H), 2.91-2.84 (m, 1H), 2.58-2.55 (m, 1H), 2.46-2.25 (m, 4H), 2.19-2.17 (m, 2H), 2.13-2.06 (m, 1H), 1.89-1.80 (m, 4H), 0.88 (d, J = 6.4 Hz, 3H). The absolute stereochemistry was unambiguously assigned. Example 204: 7-(2-(2,4-difluorophenoxy)ethyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0446] The title compound (66.23 mg, 84.6% yield) was synthesized in the same manner as in Example 201 using 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and 2,4-difluorophenol. LCMS (ESI) [M+H] + =332.1.

[0447] Compound 204: 1 H NMR(400MHz,CD3OD)δ8.38(s,1H),7.20-7.18(m,1H),7.07-7.02(m,1H),6.97-6.88(m,1H),4.3 7(t,J=4.8Hz,2H),4.05(s,4H),3.38(t,J=4.8Hz,2H),3.33-3.07(m,4H),2.17(t,J=5.6Hz,4H). Example 205: 7-(2-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0448] Step 1: Ethyl 2-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)propanoate [ka]

[0449] To a solution of ethyl 2-bromo-2-methylpropanoate (2622 mg, 14.49 mmol) in acetonitrile (40 mL) was added 6-(trifluoromethyl)pyridin-3-ol (2.0 g, 9.66 mmol) and CsCO (7867 mg, 24.15 mmol) at 20 °C. The reaction mixture was then stirred at 70 °C for 6 hours and diluted with ethyl acetate (70 mL). The mixture was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0-35% ethyl acetate in petroleum ether) to give the title compound (2.38 g, 8.77 mmol, 91% yield). LCMS (ESI) [M+H] + =264.1.

[0450] Step 2: 2-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)propanoic acid [ka]

[0451] To a solution of 2-methyl-2-[[6-(trifluoromethyl)-3-pyridyl]oxy]propanoate (500 mg, 1.9 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added hydroxyllithium hydrate (318 mg, 7.6 mmol). The reaction mixture was stirred at 25° C. for 2 hours and then concentrated in vacuo. The residue was adjusted to pH 5 with HCl (1 mol / L). The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title compound (455 mg, 1.79 mmol, 94% yield). LCMS (ESI) [M+H]=250.1.

[0452] Step 3: 1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)-2-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)propan-1-one [ka]

[0453] To a solution of 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (50 mg, 0.24 mmol) in dichloromethane (2 mL) was added 2-methyl-2-[[6-(trifluoromethyl)-3-pyridyl]oxy]propanoic acid (50 mg, 0.20 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) at 20 °C. After stirring for 5 minutes, HATU (229 mg, 0.6 mmol) was added. The reaction mixture was stirred at 20 °C for 4 hours. The reaction mixture was extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica flash column chromatography (0-2% methanol in dichloromethane) to give the title compound (70 mg, 0.124 mmol, 62% yield). LCMS (ESI) [M+H]+ = 407.1.

[0454] Step 4: Synthesis of the title compound. To a solution of 1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)-2-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)propan-1-one (70 mg, 0.20 mmol) in tetrahydrofuran (2 mL), borane-THF (5 mL, 5.0 mmol, 1 M) was added within 5 minutes at 0° C., and the mixture was then stirred at 70° C. for 2 hours. The reaction was quenched with methanol (5 mL), and then ethyl acetate (20 mL) was added. The resulting mixture was washed with brine (30 mL×3), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (75% ethyl acetate in petroleum ether) to give the title compound (54.93 mg, 0.1372 mmol, 70% yield). LCMS(ESI)[M+H] + =393.1.

[0455] Compound 205: 1 H NMR(400MHz,CD3OD)δ8.38(d,J=2.4Hz,1H),7.89-7.51(m,2H),3.89(s,4H),2.61(s,6H),1.90(t,J=5.2Hz,4H),1.39(s,6H). Example 206: 7-(2-(4-chloro-3-fluorophenoxy)ethyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0456] The title compound (40 mg, 47% yield) was synthesized in the same manner as in Example 201 using 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and 4-chloro-3-fluorophenol. LCMS (ESI) [M+H] + =348.1.

[0457] Compound 206: 1H NMR(400MHz,CD3OD)δ7.41(t,J=8.8Hz,1H),6.97(dd,J=3.2,11.2Hz,1H),6.88-6.86(m, 1H),4.31(t,J=5.2Hz,2H),4.04(s,4H),3.31(s,2H),3.12(s,4H),2.14(t,J=5.6Hz,4H). Examples 207A* and 207B*: (S)-7-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and (R)-7-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0458] Step 1: 2-((6-(trifluoromethyl)pyridin-3-yl)oxy)propan-1-ol [ka]

[0459] To a solution of ethyl 2-[[6-(trifluoromethyl)-3-pyridyl]oxy]propanoate (500 mg, 1.9 mmol) in dichloromethane (5 mL) was slowly added diisobutylaluminum hydride (3.0 mL, 3 mmol) at -78 °C, and the mixture was then warmed to 25 °C and stirred for 16 h. The reaction mixture was quenched with 2 N aqueous HCl (2 mL), and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0-50% ethyl acetate in petroleum ether) to afford the title compound (350 mg, 73% yield) as a mixture of enantiomers. LCMS (ESI): [M+H] + =222.1

[0460] Step 2: 2-((6-(trifluoromethyl)pyridin-3-yl)oxy)propyl methanesulfonate [ka]

[0461] To a mixture of 2-[[6-(trifluoromethyl)-3-pyridyl]oxy]propan-1-ol (350 mg, 1.58 mmol) and triethylamine (480 mg, 4.75 mmol) in dichloromethane (5 mL) was added methanesulfonyl chloride (199 mg, 1.74 mmol) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The reaction was quenched with water (2 mL), and the resulting mixture was extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with NaHCO3 (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (330 mg, 70% yield) as a mixture of enantiomers. LCMS (ESI): [M+H] + =300.0.

[0462] Step 3: 7-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0463] To a mixture of 2-[[6-(trifluoromethyl)-3-pyridyl]oxy]propyl methanesulfonate (150 mg, 0.50 mmol) and N,N-diisopropylethylamine (97 mg, 0.75 mmol) in acetonitrile (3 mL), 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (127 mg, 0.60 mmol) and potassium iodide (166 mg, 1 mmol) were added, and the mixture was then stirred at 80° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC to give the title compound (140 mg, 74% yield) as a mixture of enantiomers. LCMS (ESI): [M+H]+ = 379.1

[0464] Step 4: Synthesis of the title compound. 7-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (140 mg, 0.37 mmol) was separated using chiral SFC (DAICEL CHIRALPAK AD-H (250 mm × 30 mm, 10 μm), 0.1% NH₃H₂O EtOH; 15% to 15%, 50 mL / min) to give title compound 207A* (first peak in SFC, 36.16 mg, 26% yield) and title compound 207B* (second peak in SFC, 46.78 mg, 33% yield), each with undefined / unassigned absolute stereochemistry. LCMS (ESI): [M+H]+ = 379.1

[0465] Example 207A: 1 H NMR(400MHz,CDCl3)δ8.38(d,J=2.4Hz,1H),7.61(d,J=8.8Hz,1H),7.31(d,J=7.6Hz,1H),4.63( brs,1H),3.84(s,4H),2.73-2.68(m,1H),2.49(brs,5H),1.87(brs,4H),1.35(d,J=6.4Hz,3H).

[0466] Example 207B: 1H NMR(400MHz,CDCl3)δ8.38(d,J=2.4Hz,1H),7.61(d,J=8.8Hz,1H),7.31(d,J=7.6Hz,1H),4.63( brs,1H),3.84(s,4H),2.73-2.68(m,1H),2.49(brs,5H),1.87(brs,4H),1.35(d,J=6.4Hz,3H). Example 208: 7-(2-(3-fluoro-4-(trifluoromethyl)phenoxy)-2-methylpropyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0467] The title compound (68.68 mg, 0.1661 mmol, 59% yield) was synthesized in the same manner as in Example 205 using 3-fluoro-4-(trifluoromethyl)phenol. LCMS (ESI) [M+H] + =410.2.

[0468] Compound 208: 1 H NMR(400MHz,CDCl3)δppm7.49-7.44(m,1H),6.85-6.80(m,2H),3.86(s,4H),2.59-2.53(m,6H),1.92(t,J=5.2Hz,4H),1.36(s,6H). Example 209: 2-(2-methyl-2-(4-(trifluoromethyl)phenoxy)propyl)-7-thia-2-azaspiro[3.5]nonane 7,7-dioxide [ka]

[0469] The title compound (48.48 mg, 0.1152 mmol, 52% yield) was synthesized in the same manner as in Example 205 using 7-thia-2-azaspiro[3.5]nonane 7,7-dioxide. LCMS (ESI) [M+H] + =392.1.

[0470] Compound 209:1 H NMR(400MHz,CDCl3)δ7.53(d,J=8.0Hz,2H),7.05(d,J=8.0Hz,2H),3.25(s,4H),2.99-2.98(m,4H),2.71(brs,2H),2.35(brs,4H),1.31(s,6H). Example 210: 7-(2-((5-fluoropyridin-3-yl)oxy)ethyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0471] The title compound (47.29 mg, 0.15 mmol, 64% yield) was synthesized in the same manner as in Example 201 using 5-fluoropyridin-3-ol and 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide. LCMS (ESI) [M+H] + =315.2.

[0472] Compound 210: 1 H NMR(400MHz,CDCl3)δ8.18-8.12(m,2H),6.96(d,J=10.0Hz,1H),4.16-4.12(m,2H),3.87(s,4H),2.83-2.80(m,2H),2.53(s,4H),1.95(s,4H). Examples 212A* and 212B*: (S)-7-(3-(3,4-difluorophenyl)-2-methylpropyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and (R)-7-(3-(3,4-difluorophenyl)-2-methylpropyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0473] Step 1: (E)-ethyl 3-(3,4-difluorophenyl)-2-methylacrylate [ka]

[0474] To a solution of ethyl 2-(diethoxyphosphoryl)propanoate (3688 mg, 15.48 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (676 mg, 16.89 mmol) at 0 °C. The reaction mixture was stirred for 1 h, then 3,4-difluorobenzaldehyde (2 g, 14.07 mmol) was added, and the reaction mixture was stirred at 25 °C for an additional 1 h. The reaction mixture was quenched with NH4Cl (10 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0-3% ethyl acetate in petroleum ether) to give the title compound (2.17 g, 66% yield). LCMS (ESI): [M+H] + =227.1

[0475] Step 2: Ethyl 3-(3,4-difluorophenyl)-2-methylpropanoate [ka]

[0476] To a solution of (E)-ethyl 3-(3,4-difluorophenyl)-2-methylacrylate (1 g, 4.42 mmol) in ethanol (10 mL) was added 10% palladium on carbon (470 mg, 0.44 mmol), and the mixture was stirred under H2 (15 Psi) at 25 °C for 16 h. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (1 g, 99% yield) as a mixture of enantiomers. LCMS (ESI): [M+H] + =229.2.

[0477] Step 3: 3-(3,4-difluorophenyl)-2-methylpropanoic acid [ka]

[0478] To a solution of ethyl 3-(3,4-difluorophenyl)-2-methylpropanoate (1 g, 4.38 mmol) in tetrahydrofuran (8 mL) and methanol (2 mL) was added a solution of lithium hydroxide monohydrate (552 mg, 13.14 mmol) in water (2 mL), and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was adjusted to pH 2 with HCl (1 mol / L). The resulting mixture was then 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 in vacuo to give the title compound (800 mg, 91% yield) as a mixture of enantiomers. 1 H NMR (400MHz, CDCl3) δ7.12-6.97(m,2H),6.92-6.89(m,1H),3.04-3.00(m,1H),2.75-2.64(m,2H),1.20(d,J=7.2Hz,3H).

[0479] Step 4: 3-(3,4-difluorophenyl)-1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)-2-methylpropan-1-one [ka]

[0480] To a mixture of 3-(3,4-difluorophenyl)-2-methylpropanoic acid (130 mg, 0.65 mmol) and 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (154 mg, 0.73 mmol) in dichloromethane (7 mL) was added N,N-diisopropylethylamine (252 mg, 1.95 mmol) and HATU (741 mg, 1.95 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The resulting solution was diluted with water (5 mL) and extracted with dichloromethane (50 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica column chromatography (0 → 80% ethyl acetate in petroleum ether) to give the title compound (200 mg, 86% yield) as a mixture of enantiomers. LCMS (ESI): [M+H] + =358.0.

[0481] Step 5: 7-(3-(3,4-difluorophenyl)-2-methylpropyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0482] To a solution of 3-(3,4-difluorophenyl)-1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)-2-methylpropan-1-one (150 mg, 0.42 mmol) in tetrahydrofuran (3 mL) was added borane-THF (5 mL, 5 mmol) at 0° C. and stirred at 70° C. for 2 hours. The reaction was quenched with methanol (5 mL) and stirred at 70° C. for 1 hour. The resulting solution was concentrated in vacuo, and the residue was purified by silica column chromatography (0→100% ethyl acetate in petroleum ether) to give the title compound (110 mg, 76% yield) as a mixture of enantiomers. LCMS (ESI): [M+H] + =344.1

[0483] Step 6: Synthesis of the title compound. 7-(3-(3,4-Difluorophenyl)-2-methylpropyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (110 mg, 0.32 mmol) was separated using chiral SFC (Daicel Chiralpak AY-H (250 mm × 30 mm, 10 μm) 0.1% NH 3 H 2 O EtOH; 15%, 60 mL / min) to give title compound 212A* (first peak in SFC, 31.75 mg, 28% yield), with undefined / unassigned absolute stereochemistry, respectively. LCMS (ESI): [M+H] + = 344.2, and the title compound 212B* (second peak in SFC, 34.48 mg, 30% yield). LCMS (ESI): [M+H] + =344.2.

[0484] Compound 212*: 1 H NMR(400MHz,CD3OD)δ7.17-7.07(m,2H),6.97-6.94(m,1H),3.88(s,4H),2.78-2.71(m ,1H),2.48-2.33(m,4H),2.21-2.10(m,2H),2.04-1.86(m,6H),0.85(d,J=6.4Hz,3H).

[0485] Compound 212B*: 1 H NMR(400MHz,CD3OD)δ7.17-7.05(m,2H),6.97-6.93(m,1H),3.88(s,4H),2.78-2.71(m ,1H),2.48-2.32(m,4H),2.21-2.11(m,2H),2.04-1.83(m,6H),0.84(d,J=6.8Hz,3H). Example 213: 7-(3-(4-(trifluoromethoxy)phenyl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0486] Step 1: Ethyl (E)-3-[4-(trifluoromethoxy)phenyl]prop-2-enoate [ka]

[0487] To a mixture of 4-(trifluoromethoxy)benzaldehyde (2.0 g, 10.52 mmol) in dichloromethane (20 mL) was added (carbethoxymethylene)triphenylphosphorane (4.03 g, 11.6 mmol) at 20 °C. The reaction mixture was stirred at that temperature for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL). The resulting mixture was washed with water (20 mL) and brine (20 mL). The organic layer was concentrated in vacuo, and the residue was purified by silica column chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound (2500 mg, 91% yield). 1 H NMR(400MHz,CD3OD)δ7.76-7.68(m,3H),7.31(d,J=8.0Hz,2H),6.56(d,J=16.0Hz,1H),4.26(q,J=7.2Hz,2H),1.33(t,J=7.2Hz,3H).

[0488] Step 2: Ethyl 3-[4-(trifluoromethoxy)phenyl]propanoate [ka]

[0489] To a solution of ethyl (E)-3-[4-(trifluoromethoxy)phenyl]prop-2-enoate (2.5 g, 9.61 mmol) in ethanol (30 mL) was added 10% palladium on carbon (2.044 g, 1.92 mmol). The reaction mixture was stirred under H (15 psi) at 25° C. for 2 hours. The mixture was filtered and concentrated in vacuo to give the title compound (2500 mg, 93% yield).

[0490] Step 3: 3-[4-(trifluoromethoxy)phenyl]propanoic acid [ka]

[0491] To a solution of ethyl 3-[4-(trifluoromethoxy)phenyl]propanoate (2500 mg, 9.53 mmol) in tetrahydrofuran (20 mL) and ethanol (2 mL) was added a solution of hydroxyllithium hydrate (1400 mg, 33.37 mmol) in water (4 mL). The reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was adjusted to pH=2 with HCl (1 mol / L). The mixture was then extracted with ethyl acetate (30×3 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (2200 mg, 99% yield).

[0492] Step 4: 1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-(4-(trifluoromethoxy)phenyl)propan-1-one [ka]

[0493] To a solution of 4-(trifluoromethoxy)hydrocinnamic acid (66.37 mg, 0.28 mmol), 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (50 mg, 0.24 mmol), and N,N-diisopropylethylamine (0.1 mL, 0.59 mmol) in dichloromethane (1.0 mL) was added HATU (134.7 mg, 0.35 mmol). The resulting mixture was stirred at 20 °C for 2 hours, then diluted with brine (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were concentrated under reduced pressure, and the resulting residue was purified by silica column chromatography (0 → 50% ethyl acetate in petroleum ether) to give the title compound (80 mg, 87% yield).

[0494] Step 5: Synthesis of the title compound. To a cold (0° C.) solution of 1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-(4-(trifluoromethoxy)phenyl)propan-1-one (80 mg, 0.20 mmol) in tetrahydrofuran (1 mL) was added borane-THF (2.0 mL, 2 mmol). The reaction mixture was stirred at 70° C. for 4 hours. The reaction was quenched with MeOH (1 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC (water (0.05% FA)-ACN, 40%-70%) to give the title compound (55 mg, 69% yield). LCMS (ESI) [M+H] + =378.1.

[0495] Compound 213: 1 H NMR(400MHz,CD3OD)δ7.33(d,J=8.0Hz,2H),7.20(d,J=8.0Hz,2H),4.00(s,4H), 3.05(s,4H),2.94-2.81(m,2H),2.73(t,J=7.6Hz,2H),2.10(s,4H),1.93(m,2H). Example 214: 2-(2-(3,4-difluorophenoxy)ethyl)-7-thia-2-azaspiro[3.5]nonane 7,7-dioxide [ka]

[0496] The title compound (53.4 mg, 73% yield) was synthesized in the same manner as in Example 201 using 2,4-difluorophenol. LCMS (ESI) [M+H] + =332.1.

[0497] Compound 214: 1H NMR(400MHz,CD3OD)δ7.17-7.14(m,1H),6.90-6.84(m,1H),6.74-6.68(m,1H),3.98(t,J= 5.2Hz,2H),3.27(s,4H),3.05(t,J=6.0Hz,4H),2.92(t,J=5.6Hz,2H),2.30-2.26(m,4H). Examples 215A* and 215B*: (S)-7-(2-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and (R)-7-(2-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0498] Step 1: (S)-2-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-ol and (R)-2-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-ol [ka]

[0499] To a solution of ethyl 2-methyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]propanoate (200 mg, 0.76 mmol) in dichloromethane (10 mL) under a nitrogen atmosphere was added diisobutylaluminum hydride (1.53 mL, 1.53 mmol, 1 M in toluene) dropwise at −78° C. The mixture was then stirred at 0° C. for 2 hours. TLC showed that the starting material was completely consumed and a new spot had formed. The reaction was stirred at 0° C. oThe mixture was quenched with aqueous potassium sodium tartrate (5 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed three times with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (150 mg, 85.7% yield). LCMS (ESI) [M+H] + =221.1.

[0500] Step 2: 2-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propyl methanesulfonate [ka]

[0501] To a solution of (S)-2-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-ol and (R)-2-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-ol) and N,N-diisopropylethylamine (0.3 mL, 1.6 mmol) dissolved in dichloromethane (5 mL) was added methanesulfonyl chloride (91 mg, 0.79 mmol) at 0° C. The mixture was stirred at 25° C. for 0.5 hours. The reaction was quenched with water (10 mL) and extracted with dichloromethane (20 mL×3). The combined organic layers were washed with saturated sodium bicarbonate (20 mL×3) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (200 mg, 92.3% yield). LCMS (ESI) [M+H] + =299.0.

[0502] Step 3: 7-(2-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0503] To a solution of [2-methyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]methanesulfonate (120.0 mg, 0.40 mmol) and N,N-diisopropylethylamine (260 mg, 2.01 mmol) in acetonitrile (5 mL) was added 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (94 mg, 0.44 mmol) and potassium iodide (133 mg, 0.80 mmol). The mixture was then stirred at 80 °C for 48 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica flash chromatography on silica (0-80% ethyl acetate in petroleum ether) to afford the title compound (110 mg, 71% yield) as a mixture of enantiomers. LCMS (ESI) [M+H] + =378.2.

[0504] Step 4: Synthesis of the title compound. A mixture of enantiomers of 7-(2-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (110 mg, 0.29 mmol) was purified by chiral SFC (SFC-12; Daicel Chiralpak AD-H (250 mm × 30 mm, 5 μm); CO / 0.1% NH HO + MeOH 30 / 30; 60 mL / min) to give compound 215A (first peak in SFC, 34.5 g, 30.1% yield) and compound 215B (second peak in SFC, 30.46 mg, 26% yield), each with undefined / unassigned absolute stereochemistry. LCMS (ESI) [M+H] + =378.2.

[0505] Compound 215A*: 1 H NMR(400MHz,CD3OD)δ8.82(s,2H),3.85(s,4H),2.83-2.81(m,1H),2.68-2.66(m,1 H),2.45-2.25(m,4H),2.20-2.14(m,3H),1.81-1.77(m,4H),0.91(d,J=6.0Hz,3H).

[0506] Compound 215B*:1 H NMR(400MHz,CD3OD)δ8.82(s,2H),3.86(s,4H),2.86-2.81(m,1H),2.68-2.66(m,1 H),2.46-2.21(m,4H),2.19-2.11(m,3H),1.81-1.77(m,4H),0.91(d,J=6.0Hz,3H). Examples 216A* and 216B*: (S)-7-(2-methyl-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and (R)-7-(2-methyl-3-(4-(trifluoromethyl)phenyl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0507] The title compound was synthesized analogously to Examples 215A and 215B using ethyl 2-methyl-3-(4-(trifluoromethyl)phenyl)propanoate.

[0508] The mixture of enantiomers (130 mg, 0.35 mmol) was purified by chiral SFC (SFC-17, Daicel Chiralpak IG (250 mm x 30 mm, 10 μm), supercritical CO₂ / 0.1% NH₃H₂O, MeOH, 40 / 40, 70 mL / min) to give compound 216A* (first peak in SFC, 41.0 mg, 31% yield) and compound 216B* (second peak in SFC, 35.8 mg, 27% yield), each with undefined / unassigned absolute stereochemistry. LCMS (ESI): [M+H] + =376.3.

[0509] Compound 216A*: 1H NMR(400MHz,CD3OD)δ7.56(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),3.88(s,4H),2.88-2.84(m,1H), 2.45-2.25(m,4H),2.20-2.17(m,3H),2.09-2.00(m,1H),1.91-1.88(m,4H),0.86(d,J=6.8Hz,3H).

[0510] Compound 216B*: 1 H NMR(400MHz,CD3OD)δ7.56(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),3.88(s,4H),2.90-2.82(m,1H), 2.45-2.25(m,4H),2.20-2.17(m,3H),2.09-2.00(m,1H),1.91-1.89(m,4H),0.86(d,J=6.8Hz,3H). Example 218: 7-(2-(4-(trifluoromethoxy)phenoxy)ethyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0511] Step 1: 1-(2-bromoethoxy)-4-(trifluoromethoxy)benzene [ka]

[0512] A mixture of 4-(trifluoromethoxy)phenol (2.0 g, 11.23 mmol), 1,2-dibromoethane (6.35 g, 33.8 mmol), potassium carbonate (3.81 g, 27.56 mmol), and potassium iodide (184 mg, 1.11 mmol) was dissolved in acetonitrile (20 mL) at 20° C., and the mixture was then stirred at 60° C. for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL×2). The combined organic layers were concentrated under reduced pressure, and the resulting residue was purified by silica flash chromatography (100% petroleum ether) to give the title compound (3 g, 10.52 mmol, 93.7% yield). 1 H NMR(400MHz,CD3OD)δ7.20(d,J=8.4Hz,2H),7.01(d,J=8.4Hz,2H),4.32(t,J=5.6Hz,2H),3.70(t,J=5.6Hz,2H).

[0513] Step 2: Synthesis of the title compound. 1-(2-Bromoethoxy)-4-(trifluoromethoxy)benzene (220.0 mg, 0.77 mmol), 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (80.0 mg, 0.38 mmol), N,N-diisopropylethylamine (0.32 mL, 1.94 mmol), and potassium iodide (80.0 mg, 0.5 mmol) were dissolved in acetonitrile (5 mL), and the reaction mixture was stirred at 80° C. for 5 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were concentrated under reduced pressure, and the resulting residue was purified by reverse-phase chromatography (column: Welch Xtimate C18 150 x 25 mm x 5 μm; water (0.2% formic acid)-CAN) to give the title compound as the formate salt (68.76 mg, 0.17 mmol, 47% yield). LCMS (ESI): [M+H] + =380.1.

[0514] Compound 218: 1H NMR(400MHz,CD3OD)δ8.32(s,1H),7.23(d,J=9.2Hz,2H),7.06(d,J=9.2Hz,2H), 4.35(s,2H),4.04(s,4H),3.42(s,2H),3.31-3.04(m,4H),2.17(t,J=5.2Hz,4H). Example 219: 2-(2-(3-chloro-4-fluorophenoxy)ethyl)-7-thia-2-azaspiro[3.5]nonane 7,7-dioxide [ka]

[0515] Step 1: 4-(2-bromoethoxy)-2-chloro-1-fluorobenzene [ka]

[0516] To a solution of 3-chloro-4-fluorophenol (1 g, 6.82 mmol) in acetonitrile (10 mL) were added 1,2-dibromoethane (3846 mg, 20.47 mmol), potassium carbonate (2358 mg, 17.06 mmol), and potassium iodide (113 mg, 0.68 mmol) at 25° C., and the reaction mixture was then stirred at 60° C. for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL×2). The combined organic layers were concentrated under reduced pressure, and the resulting residue was purified by silica flash chromatography (100% petroleum ether) to give the title compound (400 mg, 23.1% yield). 1 H NMR(400MHz,CDCl3)δ7.07(t,J=8.4Hz,1H),6.96(dd,J=6.0,3.2Hz,1H),6.81-6.77(m,1H),4.25(t,J=6.0Hz,2H),3.63(t,J=6.0Hz,2H).

[0517] Step 2: Synthesis of the title compound. To a mixture of 4-(2-bromoethoxy)-2-chloro-1-fluorobenzene (70 mg, 0.28 mmol) in acetonitrile (3 mL), 7-thia-2-azaspiro[3.5]nonane 7,7-dioxide hemioxalate (61 mg, 0.14 mmol), N,N-diisopropylethylamine (54 mg, 0.41 mmol), and potassium iodide (92 mg, 0.55 mmol) were added, and the mixture was then stirred at 80° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude residue. The residue was purified by reverse-phase chromatography (water (0.05% NH 3 H 2 O + 10 mM NH 4 HCO 3 )-ACN, 40% to 70%) to obtain the title compound (39.79 mg, 41% yield). LCMS (ESI): [M+H] + =348.1.

[0518] Compound 219: 1 H NMR(400MHz,CD3OD)δ7.14(t,J=9.2Hz,1H),7.05(dd,J=6.0,2.8Hz,1H),6.90-6.86(m,1H),3. 99(t,J=5.2Hz,2H),3.27(s,4H),3.07-3.03(m,4H),2.92(t,J=5.2Hz,2H),2.30-2.26(m,4H). Example 220: 7-(2-(4-fluoro-3-(trifluoromethyl)phenoxy)-2-methylpropyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0519] Step 1: Methyl 2-[4-fluoro-3-(trifluoromethyl)phenoxy]-2-methyl-propanoate [ka]

[0520] To a stirred solution of 4-fluoro-3-(trifluoromethyl)phenol (3.0 g, 16.66 mmol) and methyl 2-bromo-2-methylpropanoate (3.92 g, 21.65 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (6.91 g, 49.97 mmol), and the mixture was stirred at 80 °C for 12 hours. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (60 mL × 3), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica flash chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound (3.5 g, 12.5 mmol, 75% yield). 1 H NMR(400MHz,CD3OD)δ7.26-7.21(m,1H),7.15-7.12(m,2H),3.76(m,3H),1.57(s,6H).

[0521] Step 2: 2-[4-fluoro-3-(trifluoromethyl)phenoxy]-2-methyl-propanoic acid [ka]

[0522] To a solution of methyl 2-[4-fluoro-3-(trifluoromethyl)phenoxy]-2-methyl-propanoate (1.5 g, 5.35 mmol) in water (3 mL), tetrahydrofuran (5 mL), and methyl alcohol (1 mL), hydroxylithium hydrate (2246 mg, 53.53 mmol) was added, and the mixture was then stirred at 20° C. for 2 hours. The reaction mixture was adjusted to pH=5 with HCl and extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title compound (1.4 g, 5.25 mmol, 98.3% yield).

[0523] Step 3: 1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)-2-(4-fluoro-3-(trifluoromethyl)phenoxy)-2-methylpropan-1-one [ka]

[0524] To a mixture of 2-[4-fluoro-3-(trifluoromethyl)phenoxy]-2-methyl-propanoic acid (50.0 mg, 0.19 mmol), N,N-diisopropylethylamine (13 mg, 0.38 mmol), and 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (40 mg, 0.19 mmol) in dichloromethane (3 mL) was added HATU (107 mg, 0.28 mmol). The resulting mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with brine (20 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic layers were concentrated in vacuo, and the resulting residue was purified by silica flash chromatography (0 → 50% ethyl acetate in petroleum ether) to give the title compound (70 mg, 0.165 mmol, 88% yield). LCMS (ESI): [M+H] + =424.1.

[0525] Step 4: Synthesis of the title compound. To a cold (0° C.) solution of 1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)-2-(4-fluoro-3-(trifluoromethyl)phenoxy)-2-methylpropan-1-one (70 mg, 0.165 mmol) in tetrahydrofuran (1 mL), borane-THF complex (1.0 mL, 1 mmol) was added, and the mixture was stirred at 70° C. for 4 hours. The reaction was quenched with methanol (1 mL) in an ice bath, and the resulting solution was concentrated in vacuo. The crude product was purified by silica flash chromatography on silica (0→50% ethyl acetate in petroleum ether) to give the title compound (48.01 mg, 0.117 mmol, 71% yield). LCMS (ESI): [M+H] + =410.0.

[0526] Compound 220: 1 H NMR(400MHz,CD3OD)δ7.35-7.29(m,2H),7.27-7.22(m,1H),3.95(s,4H),2.86-2.82(s,4H),2.80(s,2H),2.01(t,J=5.2Hz,4H),1.31(s,6H). Examples 221A* and 221B*: (S)-7-(2-(3,4-difluorophenoxy)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and (R)-7-(2-(3,4-difluorophenoxy)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0527] Step 1: Ethyl (R)-2-(3,4-difluorophenoxy)propanoate and Ethyl (S)-2-(3,4-difluorophenoxy)propanoate [ka]

[0528] To a solution of 3,4-difluorophenol (2.0 g, 15.37 mmol) in N,N-dimethylformamide (15 mL) was added cesium carbonate (11 g, 34.97 mmol) and ethyl 2-bromopropanoate (3 g, 17.7 mmol), and the mixture was stirred at 80 °C for 15 h. Ethyl acetate (90 mL) was added, and the resulting mixture was washed with brine (30 mL × 3). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue. The residue was purified by silica flash chromatography (0–10% ethyl acetate in petroleum ether) to give the title compound (1.9 g, 53.7% yield). 1H NMR(400MHz,CD3OD)δ7.17-7.12(m,1H),6.85-6.82(m,1H),6.68-6.66(m,1H),4.8 4-4.81(m,1H),4.20(q,J=7.2Hz,2H),1.56(d,J=6.8Hz,3H),1.24(t,J=7.2Hz,3H).

[0529] Step 2: (R)-2-(3,4-difluorophenoxy)propanoic acid and (S)-2-(3,4-difluorophenoxy)propanoic acid [ka]

[0530] To a solution of ethyl 2-(3,4-difluorophenoxy)propanoate (500 mg, 2.17 mmol) in tetrahydrofuran (10 mL) and water (6 mL), hydroxylithium hydrate (455 mg, 10.86 mmol) was added, and the mixture was then stirred at 20° C. for 2 hours. The reaction mixture was adjusted to pH 2 with HCl (1N). The resulting mixture was extracted with ethyl acetate (30×3 mL), and the combined organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (200 mg, 45.6% yield). The product was used directly without further purification.

[0531] Step 3: (S)-2-(3,4-difluorophenoxy)-1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)propan-1-one and (R)-2-(3,4-difluorophenoxy)-1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)propan-1-one [ka]

[0532] To a mixture of 2-(3,4-difluorophenoxy)propanoic acid (100 mg, 0.49 mmol), N,N-diisopropylethylamine (0.22 mL, 1.24 mmol), and 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (52 mg, 0.25 mmol) in dichloromethane (4 mL), HATU (282 mg, 0.74 mmol) was added, and the resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with brine (20 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic layers were concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica (0-60% ethyl acetate in petroleum ether) to give the title compound (150 mg, 84.4% yield). LCMS (ESI) [M+H] + =360.1.

[0533] Step 4: Synthesis of the title compound. To a cold (0° C.) solution of 2-(3,4-difluorophenoxy)-1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)propan-1-one (130 mg, 0.36 mmol) in tetrahydrofuran (2 mL), borane-THF complex (3 mL, 3 mmol, 1 M) was added, and the mixture was then stirred at 70° C. for 4 hours. The reaction mixture was quenched with methanol (3 mL) at 0° C. and concentrated under reduced pressure to give a crude residue. The resulting residue was purified by silica column chromatography (0→100% ethyl acetate in petroleum ether) to give the title compound (100 mg, 80% yield) as a mixture of enantiomers. LCMS (ESI) [M+H] += 346. A mixture of enantiomers of 1,7-(2-(3,4-difluorophenoxy)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (100 mg, 0.29 mmol) was purified by SFC (Daicel Chiralcel OJ-H (250 mm x 30 mm, 5 μm), supercritical CO₂ / 0.1% NH₃H₂O + MeOH, 40 / 40, 60 mL / min) to give compound 221A* (first peak in SFC, 27 mg, 26.5% yield) and compound 221B* (second peak in SFC, 31 mg, 29.4% yield), each with undefined / unassigned absolute stereochemistry. LCMS (ESI) [M+H] + =346.1.

[0534] Compound 221A*: 1 H NMR(400MHz,CD3OD)δ7.18-7.14(m,1H),6.92-6.88(m,1H),6.74-6.69(m,1H),4.61-4.54(m,1H ),3.89(s,4H),2.72-2.66(m,2H),2.55-2.45(m,4H),1.91-1.88(m,4H),1.25(d,J=6.0Hz,3H).

[0535] Compound 221B*: 1 H NMR(400MHz,CD3OD)δ7.17-7.13(m,1H),6.92-6.89(m,1H),6.74-6.70(m,1H),4.62-4.55(m,1H) ),3.89(s,4H),2.72-2.67(m,2H),2.55-2.42(m,4H),1.89-1.88(m,4H),1.25(d,J=6.0Hz,3H). Example 222: 7-((1-(4-(trifluoromethyl)phenoxy)cyclobutyl)methyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0536] The title compound (53.26 mg, 92% yield) was synthesized using cyclobutanecarboxylic acid in the same manner as in Example 202. LCMS (ESI) [M+H] + =404.1.

[0537] Compound 222: 1 H NMR(400MHz,CD3OD)δ7.55(d,J=9.2Hz,2H),6.98(d,J=8.8Hz,2H),3.88(s,4H),3.0 6(s,2H),2.65(s,4H),2.45-2.34(m,4H),1.91(t,J=5.6Hz,4H),1.89-1.69(m,2H). Example 223: 2-(3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-7-thia-2-azaspiro[3.5]nonane 7,7-dioxide [ka]

[0538] Step 1: Ethyl 3-(6-(trifluoromethyl)pyridin-3-yl)propanoate [ka]

[0539] To a solution of ethyl (E)-3-[6-(trifluoromethyl)-3-pyridyl]prop-2-enoate (500 mg, 2.04 mmol) in ethanol (15 mL) was added 10% palladium on carbon (217 mg), and the mixture was stirred under H2 (15 Psi) at 25 °C for 1 h. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (400 mg, 79% yield). LCMS (ESI): [M+H] + =248.1

[0540] Step 2: 3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol [ka]

[0541] To a stirred solution of ethyl 3-(6-(trifluoromethyl)pyridin-3-yl)propanoate (400 mg, 1.62 mmol) in tetrahydrofuran (4 mL) was added lithium aluminum hydride (184 mg, 4.85 mmol) at 0° C., and the mixture was stirred at 25° C. for 1 h. The mixture was quenched with 0.3 mL of HO, 0.3 mL of 15% aqueous NaOH, and 0.9 mL of HO at 0° C. The resulting mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (250 mg, 75% yield).

[0542] Step 3: 3-(6-(trifluoromethyl)pyridin-3-yl)propyl methanesulfonate [ka]

[0543] To a cooled (0° C.) solution of 3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (250 mg, 1.22 mmol) and triethylamine (370 mg, 3.66 mmol) in dichloromethane (3 mL), methanesulfonyl chloride (154 mg, 1.34 mmol) was added and stirred for 0.5 h. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (200 mg, 58% yield). LCMS (ESI): [M+H] + =284.0

[0544] Step 4: Synthesis of the title compound. To a mixture of 3-(6-(trifluoromethyl)pyridin-3-yl)propyl methanesulfonate (100 mg, 0.35 mmol) and N,N-diisopropylethylamine (68 mg, 0.53 mmol) in acetonitrile (3 mL), 7-thia-2-azaspiro[3.5]nonane 7,7-dioxide oxalate (93 mg, 0.21 mmol) and potassium iodide (117 mg, 0.71 mmol) were added. The reaction mixture was stirred at 80° C. for 16 hours. The mixture was concentrated in vacuo, and the residue was purified by reverse-phase chromatography (water (0.05% NH 3 H 2 O + 10 mM NH 4 HCO 3 )-ACN, 35%-65%) and lyophilized to give the title compound (35.1 mg, 26% yield). LCMS (ESI): [M+H] + =363.2

[0545] Compound 223: 1 H NMR(400MHz,CD3OD)δ8.57(s,1H),7.90(J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),3.19(s,4H),3.06-3 .02(m,4H),2.78(t,J=8.0Hz,2H),2.60(t,J=8.0Hz,2H),2.25(t,J=6.0Hz,4H),1.78-1.70(m,2H). Example 225: 7-(3-(3,4-difluorophenyl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0546] The title compound (36.45 mg, 52% yield) was synthesized in the same manner as in Example 213 using 3,4-difluorobenzaldehyde. LCMS (ESI) [M+H] + =330.1.

[0547] Compound 225: 1H NMR(400MHz,CD3OD)δ7.19-7.12(m,2H),7.05-7.02(m,1H),3.96(d,J=14.0Hz,4H),2.98-2.89(m, 2H),2.85-2.66(m,4H),2.61(t,J=8.0Hz,2H),2.28(s,2H),2.15-2.08(m,2H),1.98-1.92(s,2H). Example 226: 7-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0548] The title compound (40 mg, 47% yield) was synthesized in the same manner as in Example 201 using 4-(trifluoromethyl)phenol and 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide. LCMS (ESI) [M+H] + =364.2.

[0549] Compound 226: 1 H NMR(400MHz,CD3OD)δ7.61(d,J=8.8Hz,2H),7.12(d,J=8.8Hz,2H),4.29(t,J=5.2Hz ,2H),3.98(s,4H),3.13(t,J=5.2Hz,2H),3.00-2.90(m,4H),2.05(t,J=5.2Hz,4H). Examples 227A* and 227B*: (S)-7-(2-(4-(trifluoromethyl)phenoxy)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and (R)-7-(2-(4-(trifluoromethyl)phenoxy)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0550] Step 1: Ethyl 2-(4-(trifluoromethyl)phenoxy)propanoate [ka]

[0551] To a solution of 4-(trifluoromethyl)phenol (3.0 g, 18.51 mmol) in N,N-dimethylformamide (18 mL) was added cesium carbonate (13.71 g, 42.09 mmol) and ethyl 2-bromopropionate (3.86 g, 21.31 mmol), and the mixture was stirred at 80 °C for 15 h. The reaction mixture was diluted with ethyl acetate (90 mL), and the resulting mixture was washed with brine (30 mL × 3) and dried over anhydrous NaSO. The mixture was filtered, and the filtrate 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 (2.55 g, 9.72 mmol, 53% yield).

[0552] Step 2: 2-(4-(trifluoromethyl)phenoxy)propanoic acid [ka]

[0553] To a solution of ethyl 2-[4-(trifluoromethyl)phenoxy]propanoate (1.0 g, 3.81 mmol) in THF (12 mL) was added a solution of hydroxyllithium hydrate (800 mg, 19.1 mmol) in water (4 mL), and the mixture was stirred at 20° C. for 2 hours. The reaction mixture was adjusted to pH 2 with HCl (1 mol / L), and then the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give the title compound (820 mg, 3.50 mmol, 92% yield).

[0554] Step 3: 1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)-2-(4-(trifluoromethyl)phenoxy)propan-1-one [ka]

[0555] HATU (325 mg, 0.85 mmol) was added to 2-[4-(trifluoromethyl)phenoxy]propanoic acid (100.0 mg, 0.43 mmol), 2λ^{6}-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (99.0 mg, 0.4700 mmol), and N,N-diisopropylethylamine (0.3 mL, 1.71 mmol) dissolved in dichloromethane (2 mL). The resulting mixture was stirred at 20 °C for 2 h.

[0556] The mixture was concentrated in vacuo and the residue was purified by silica column chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (165 mg, 0.422 mmol, 99% yield). LCMS (ESI) [M+H] + =392.2.

[0557] Step 4: 7-(2-(4-(trifluoromethyl)phenoxy)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0558] To a solution of 1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)-2-(4-(trifluoromethyl)phenoxy)propan-1-one (165 mg, 0.42 mmol) in THF (2.0 mL) was added borane-THF (11.6 mL, 11.6 mmol) at 0 °C, and the mixture was stirred at 80 °C for 4 h. The reaction mixture was quenched with methanol (10 mL), and the mixture was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% ethyl acetate in petroleum ether) to afford the title compound (150 mg, 0.397 mmol, 94% yield) as a mixture of enantiomers. LCMS (ESI): [M+H] + =378.1.

[0559] Step 5: Synthesis of the title compound. 7-(2-(4-(trifluoromethyl)phenoxy)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (180.0 mg, 0.48 mmol) was separated using chiral SFC (DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); 0.1% NH 3 H 2 O EtOH) to give compound 227A* (62 mg, 0.163 mmol, 34% yield, first peak in SFC) and compound 227B* (58.81 mg, 0.154 mmol, 32% yield, second peak in SFC), each with undefined / unassigned absolute stereochemistry. LCMS (ESI): [M+H] + =378.1.

[0560] Compound 227A*: 1 H NMR(400MHz,CDCl3)δ7.54(d,J=8.4Hz,2H),6.96(d,J=8.4Hz,2H),4.58(s,1H),3.84 (s,4H),2.73-2.64(m,2H),2.53-2.50(m,4H),1.89(brs,4H),1.32(d,J=6.0Hz,4H).

[0561] Compound 227B*: 1 H NMR(400MHz,CDCl3)δ7.54(d,J=8.4Hz,2H),6.96(d,J=8.4Hz,2H),4.58(s,1H),3.84 (s,4H),2.73-2.64(m,2H),2.53-2.50(m,4H),1.89(brs,4H),1.32(d,J=6.0Hz,4H). Example 228: 7-(2-(3-fluoro-4-(trifluoromethyl)phenoxy)ethyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0562] The title compound (69.1 mg, 76% yield) was synthesized in the same manner as in Example 201 using 3-fluoro-4-(trifluoromethyl)phenol and 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide. LCMS (ESI) [M+H] + =382.2.

[0563] Compound 228: 1 H NMR(400MHz, CDCl3)δ7.53-7.48(m,1H),6.78-6.68(m,2H),4.11(t,J=5.2Hz ,2H),3.87(s,4H),2.81(t,J=5.2Hz,2H),2.53(s,4H),1.94(t,J=5.2Hz,4H). Example 229: 7-(2-((5-fluoropyridin-2-yl)oxy)ethyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0564] The title compound (71.52 mg, 90% yield) was synthesized in the same manner as in Example 205 using 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and 5-fluoropyridin-2-ol. LCMS (ESI) [M+H] + =315.2.

[0565] Compound 229: 1 H NMR(400MHz,CDCl3)δ7.97(d,J=3.2Hz,1H),7.37-7.32(m,1H),6.74-6.71(m,1H),4.40( t,J=5.6Hz,2H),3.86(s,4H),2.78(t,J=5.6Hz,2H),2.54(s,4H),1.94(t,J=5.2Hz,4H). Example 230: 7-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)ethyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0566] Step 1: 5-(2-bromoethoxy)-2-(trifluoromethyl)pyridine [ka]

[0567] To a solution of 6-(trifluoromethyl)pyridin-3-ol (4.0 g, 24.52 mmol) in acetone (20 mL) was added 1,2-dibromoethane (13.82 g, 73.57 mmol), potassium carbonate (8.47 g, 61.3 mmol), and potassium iodide (407 mg, 2.45 mmol) at 20 °C, and the reaction mixture was then stirred at 60 °C for 1 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with brine (100 mL). The organics were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (5.0 g, 76% yield). 1 H NMR(400MHz,CDCl3)δ8.35(d,J=2.4Hz,1H),7.59(d,J=8.4Hz,1H),7.32-7.22(m,1H),4.36(t,J=5.6Hz,2H),3.64(t,J=5.6Hz,2H).

[0568] Step 2: Synthesis of the title compound. To a solution of 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (400 mg, 1.89 mmol) and 5-(2-bromoethoxy)-2-(trifluoromethyl)pyridine (1530 mg, 5.67 mmol) in acetonitrile (10 mL) was added potassium iodide (31 mg, 0.19 mmol) and N,N-diisopropylethylamine (1.67 mL, 9.45 mmol). The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica column chromatography (0-5% methanol in ethyl acetate) to give the title compound (520 mg, 75% yield). LCMS (ESI) [M+H] + =365.1.

[0569] Compound 230: 1 H NMR(400MHz,CDCl3)δ8.38(d,J=2.8Hz,1H),7.62(d,J=8.4Hz,1H),7.29(dd,J=2.4,8.8Hz,1H), 4.18(t,J=5.6Hz,2H),3.86(s,4H),2.83(t,J=5.2Hz,2H),2.53(brs,4H),1.94(t,J=5.2Hz,4H). Example 231: 7-(2-(4-chloro-3-fluorophenoxy)-2-methylpropyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0570] The title compound (114.71 mg, 87% yield) was synthesized in the same manner as in Example 205 using 4-chloro-3-fluorophenol. LCMS (ESI) [M+H] + =376.0.

[0571] Compound 231: 1 H NMR(400MHz,CD3OD)δ7.38-7.33(m,1H),6.99-6.92(m,1H),6.89-6.82(m,1H ),3.94(s,4H),2.83(brs,4H),2.77(s,2H),2.08-1.94(m,4H),1.34(s,6H). Examples 232A* and 232B*: (R)-2-(2-methyl-3-(4-(trifluoromethyl)phenyl)propyl)-7-thia-2-azaspiro[3.5]nonane 7,7-dioxide and (S)-2-(2-methyl-3-(4-(trifluoromethyl)phenyl)propyl)-7-thia-2-azaspiro[3.5]nonane 7,7-dioxide [ka]

[0572] The title compound was synthesized in the same manner as in Example 113 using ethyl 2-methyl-3-(4-(trifluoromethyl)phenyl)propanoate and 7-thia-2-azaspiro[3.5]nonane 7,7-dioxide.

[0573] 2-(2-Methyl-3-(4-(trifluoromethyl)phenyl)propyl)-7-thia-2-azaspiro[3.5]nonane 7,7-dioxide (150 mg, 0.40 mmol) was separated using chiral SFC (Daicel Chiralpak AD-H (250 mm x 30 mm, 10 μm), 0.1% NH₃HO EtOH 15%, 50 mL / min) to give compound 232A* (first peak in SFC, 52.9 mg, 34% yield) and compound 232B* (second peak in SFC, 51.9 mg, 33% yield), each with undefined / unassigned absolute stereochemistry.

[0574] Compound 232A*: 1 H NMR(400MHz,CDCl3)δ7.54(d,J=8.0Hz,2H),7.24(d,J=8.0Hz,2H),3.15-2.92(m,8H),2.85-2.73( m,1H),2.47-2.41(m,2H),2.32(s,4H),1.81-1.59(m,2H),0.88(d,J=5.6Hz,3H).LCMS(ESI)[M+H] + =376.2

[0575] Compound 232B*: 1 H NMR(400MHz,CDCl3)δ7.53(d,J=8.0Hz,2H),7.25(d,J=8.0Hz,2H),3.11-2.92(m,8H),2.84-2.73( m,1H),2.47-2.39(m,2H),2.31(s,4H),1.79-1.63(m,2H),0.86(d,J=6.4Hz,3H).LCMS(ESI)[M+H] + =376.2 Example 233: 7-(2-methyl-2-(3-(trifluoromethyl)phenoxy)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0576] The title compound (40 mg, 48% yield) was synthesized in the same manner as in Example 205 using 3-(trifluoromethyl)phenol. LCMS (ESI) [M+H] + =392.1.

[0577] Compound 233: 1 HNMR(400MHz,CD3OD)δ7.58-7.51(m,1H),7.50-7.48(m,1H),7.41-7.39(m,2H),4.06(s,4H),3.36(brs,2H),2.68(s,4H),2.23(br s,4H),1.43(s,6H). Examples 234A* and 234B*: (R)-2-(2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-7-thia-2-azaspiro[3.5]nonane 7,7-dioxide and (S)-2-(2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-7-thia-2-azaspiro[3.5]nonane 7,7-dioxide [ka]

[0578] The title compound was synthesized in the same manner as in Example 203 using ethyl 2-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate and 7-thia-2-azaspiro[3.5]nonane 7,7-dioxide. Compound 234A*: 51.73 mg, yield 78%, LCMS (ESI) [M + H] + =377.2; Compound 234B*: 34.93 mg, yield 55%, LCMS (ESI) [M+H] + =377.2, undefined / unassigned absolute stereochemistry, respectively.

[0579] Compound 234A*: 1H NMR(400MHz,CD3OD)δ8.54(s,1H),7.87(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),3.13(s,4H),3.06-3.00( m,4H),2.92-2.82(m,1H),2.56-2.39(m,3H),2.27-2.21(m,4H),1.92-1.84(m,1H),0.88(d,J=6.4Hz,3H).

[0580] Compound 234B*: 1 H NMR(400MHz,CD3OD)δ8.55(s,1H),7.88(d,J=7.6Hz,1H),7.75(d,J=7.6Hz,1H),3.19(m,4H),3.08-3.02( m,4H),2.92-2.80(m,1H),2.56-2.51(m,3H),2.31-2.24(m,4H),2.00-1.86(m,1H),0.89(d,J=6.8Hz,3H). Examples 235A* and 235B*: (R)-6-(3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide and (S)-6-(3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methylpropyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide [ka]

[0581] Step 1: 1-Isopropyl-3-(trifluoromethyl)-1H-pyrazole [ka]

[0582] To a stirred suspension of 3-(trifluoromethyl)pyrazole (4 g, 29.39 mmol) in acetonitrile (50 mL) was added 2-iodopropane (15 g, 88.18 mmol) and CsCO (48 g, 146.97 mmol). The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was then filtered, and the organic layer was diluted with water (50 mL). The mixture was then extracted with MTBE (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (4.2 g, 80% yield). 1 H NMR(400MHz, CDCl3) δ7.46(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).

[0583] Step 2: 1-Isopropyl-3-(trifluoromethyl)-1H-pyrazole-5-carbaldehyde [ka]

[0584] To a stirred solution of 1-isopropyl-3-(trifluoromethyl)pyrazole (1 g, 5.61 mmol) in THF (20 mL) was added n-butyllithium (3 mL, 7.5 mmol, 2.5 M in hexane) dropwise at −78° C. The mixture was stirred at the same temperature for 1 h. N,N-Dimethylformamide (1.5 mL, 19.47 mmol) was added dropwise, and the reaction mixture was stirred at −78° C. for another 1 h. The reaction mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with MTBE (50 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.5 g). 1 H NMR(400MHz, CDCl3) δ9.87(s,1H),7.13(s,1H),5.49-5.39(m,1H),1.53(d,J=6.8Hz,6H).

[0585] Step 3: (E)-Ethyl 3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methylacrylate [ka]

[0586] To an ice-cold solution of triethyl 2-phosphonopropionate (1907 mg, 8.01 mmol) in tetrahydrofuran (10 mL) was slowly added NaH (349 mg, 8.73 mmol, 60% in mineral oil) and stirred for 30 min. 2-Isopropyl-5-(trifluoromethyl)pyrazole-3-carbaldehyde (1.5 g, 7.28 mmol) was then added, and the reaction mixture was stirred at 25 °C for an additional 1 h. The reaction mixture was quenched with NHCl (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0-3% ethyl acetate in petroleum ether) to give the title compound (900 mg, 43% yield). LCMS (ESI) [M+H] + =291.1.

[0587] Step 4: Ethyl 3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methylpropanoate [ka]

[0588] To a solution of ethyl (E)-3-[2-isopropyl-5-(trifluoromethyl)pyrazol-3-yl]-2-methyl-prop-2-enoate (900 mg, 3.1 mmol) in methanol (5 mL) was added 10% palladium on carbon (330 mg, 0.31 mmol). The reaction mixture was stirred under H2 (15 psi) at 25 °C for 2 h, filtered, and the filtrate was concentrated in vacuo to give the title compound (520 mg, 57% yield). LCMS (ESI): [M+H] + =293.1.

[0589] Step 5: 3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methylpropan-1-ol [ka]

[0590] To a stirred solution of ethyl 3-[2-isopropyl-5-(trifluoromethyl)pyrazol-3-yl]-2-methyl-propanoate (720 mg, 2.46 mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (280 mg, 7.39 mmol) at 0° C., and the mixture was then stirred at 25° C. for 1 hour. The reaction mixture was cooled to 0° C. The reaction was quenched by slow addition of 15% NaOH solution (1.2 mL) and water (1.2 mL). The suspension 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 (500 mg, 81% yield). LCMS (ESI): [M+H] + =251.1.

[0591] Step 6: 3-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methylpropyl methanesulfonate [ka]

[0592] To an ice-cold solution of 3-[2-isopropyl-5-(trifluoromethyl)pyrazol-3-yl]-2-methyl-propan-1-ol (500 mg, 2 mmol) and triethylamine (607 mg, 5.99 mmol) in dichloromethane (5 mL) was added methanesulfonyl chloride (252 mg, 2.2 mmol). The reaction mixture was stirred at 0° C. for 0.5 hours. The reaction mixture was quenched with water (5 mL) and extracted with dichloromethane (15 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (650 mg, 99% yield). LCMS (ESI) [M+H] + = 329.1. The mixture of enantiomers was separated using chiral SFC (Phenomenex-Cellulose-2 (250 mm x 30 mm, 5 μm), 0.1% NH3HO; IPA; 25%, 60 mL / min) to give compound 235A* (first peak in SFC, 36.1 mg, 30% yield) and compound 235B* (second peak in SFC, 43.8 mg, 35% yield), each with unassigned stereochemistry. LCMS (ESI): [M+H] + =408.3.

[0593] Compound 235A*: 1 H NMR(400MHz,CD3OD)δ6.34(s,1H),4.69-4.62(m,1H),3.89(s,4H),2.95-2.88(m,1H),2.49-2.29 (m,4H),2.23-2.19(m,2H),2.04-1.84(m,6H),1.45(dd,J=6.4,2.0Hz,6H),0.93(d,J=6.4Hz,3H).

[0594] Compound 235B*: 1 H NMR(400MHz,CD3OD)δ6.34(s,1H),4.69-4.62(m,1H),3.89(s,4H),2.95-2.88(m,1H),2.49-2.29 (m,4H),2.23-2.19(m,2H),2.04-1.84(m,6H),1.45(dd,J=6.4,2.0Hz,6H),0.93(d,J=6.4Hz,3H). Example 236: 7-(2-((2-(trifluoromethyl)pyridin-4-yl)oxy)ethyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0595] Step 1: tert-butyl 2-((2-(trifluoromethyl)pyridin-4-yl)oxy)acetate [ka]

[0596] To a stirred suspension of tert-butyl bromoacetate (1.0 mL, 6.14 mmol), 2-(trifluoromethyl)pyridin-4-ol (200.0 mg, 1.23 mmol), and silver(I) oxide (569 mg, 2.45 mmol) in dry N,N-dimethylformamide (4 mL) at 0 °C, potassium iodide (41.6 mg, 0.25 mmol) was added. The mixture was then warmed to 25 °C and stirred for an additional 15 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica column chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (0.32 g, 1.15 mmol, 94% yield). LCMS (ESI) [M+H] + =278.1.

[0597] Step 2: 2-((2-(trifluoromethyl)pyridin-4-yl)oxy)acetic acid [ka]

[0598] A solution of tert-butyl 2-[[2-(trifluoromethyl)-4-pyridyl]oxy]acetate (100.0 mg, 0.36 mmol) in hydrochloric acid (0.9 mL, 3.6 mmol, 4 M in 1,4-dioxane). The mixture was stirred at 25° C. for 1 h. The mixture was concentrated in vacuo to give the title compound (78 mg, 0.353 mmol, 98% yield). LCMS (ESI) [M+H] + =222.0.

[0599] Step 3: 1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)ethanone [ka]

[0600] To a mixture of 2-[[2-(trifluoromethyl)-4-pyridyl]oxy]acetic acid (78 mg, 0.353 mmol), 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (82.4 mg, 0.388 mmol), and HATU (201 mg, 0.529 mmol) in dichloromethane (3 mL) was added N,N-diisopropylethylamine (182 mg, 1.41 mmol). The resulting mixture was stirred at 20° C. for 2 hours. The mixture was concentrated, and the residue was purified by silica flash chromatography (100% ethyl acetate) to give the title compound (110 mg, 0.291 mmol, 82% yield). LCMS (ESI) [M+H] + =379.1.

[0601] Step 4: Synthesis of the title compound. oTo a stirred solution of 1-(2,2-dioxide-2-thia-7-azaspiro[3.5]nonan-7-yl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)ethanone (110 mg, 0.291 mmol) in tetrahydrofuran (2 mL) of C was added dropwise borane in tetrahydrofuran (1 M, 8.0 mL, 8.0 mmol). The reaction mixture was stirred at 70° C. for 4 hours. The reaction mixture was quenched with methyl alcohol (10 mL) at 0° C., and then the mixture was stirred at 70° C. for 2 hours. The mixture was concentrated in vacuo, and the residue was purified by reverse-phase chromatography (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN) to give the title compound (29.9 mg, 0.0812 mmol, 27.9% yield). LCMS (ESI) [M+H] + =365.1.

[0602] Compound 236: 1 H NMR(400MHz,CDCl3)δppm8.55(d,J=5.6Hz,1H),7.21(d,J=2.4Hz,1H),6.97(dd,J=2.4,5.6Hz,1H) ,4.19(t,J=5.6Hz,2H),3.87(s,4H),2.83(t,J=5.6Hz,2H),2.54(brs,4H),1.95(t,J=5.6Hz,4H). Example 237* and 237B*: (S)-7-(3-fluoro-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and (R)-7-(3-fluoro-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0603] Step 1: 1-(6-(trifluoromethyl)pyridin-3-yl)but-3-en-1-ol [ka]

[0604] To a stirred solution of 6-(trifluoromethyl)nicotinaldehyde (3000 mg, 17.13 mmol) in tetrahydrofuran (30 mL) was added allylmagnesium bromide (20.56 mL, 20.56 mmol, 1 M) at −78°C. The reaction mixture was stirred at −78°C for 2 h. The reaction mixture was then quenched with a saturated aqueous solution of NH4Cl (25 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica (petroleum ether 0 to 50% ethyl acetate) to afford the title compound (2000 mg, 53.8% yield) as a mixture of enantiomers. 1 H NMR(400MHz, CDCl3)8.69(d,J=1.2Hz,1H),7.94-7.88(m,1H),7.68(d,J=8.0Hz ,1H),5.87-5.72(m,1H),5.26-5.15(m,2H),4.89(brs,1H),2.65-2.45(m,3H).

[0605] Step 2: 5-(1-fluorobut-3-en-1-yl)-2-(trifluoromethyl)pyridine [ka]

[0606] To a stirred solution of 1-[6-(trifluoromethyl)-3-pyridyl]but-3-en-1-ol (2100 mg, 9.67 mmol) in dichloromethane (30 mL) was added diethylaminosulfur trifluoride (1.66 mL, 12.57 mmol) at -78 °C, and the mixture was stirred at -78 °C for 2 h. The reaction was quenched with saturated aqueous NaHCO (15 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The resulting residue was purified by silica flash chromatography (0-30% ethyl acetate in petroleum ether) to afford the title compound (1000 mg, 45.1% yield) as a mixture of enantiomers. LCMS (ESI) [M+H] = 220.1.

[0607] Step 3: 3-fluoro-3-(6-(trifluoromethyl)pyridin-3-yl)propanal [ka]

[0608] To a solution of 5-(1-fluorobut-3-enyl)-2-(trifluoromethyl)pyridine (300 mg, 1.37 mmol) in water (6 mL) and tetrahydrofuran (12 mL) was added osmium tetroxide (70 mg, 0.28 mmol) at 0 °C. The reaction mixture was stirred for 20 minutes, then sodium periodate (1171 mg, 5.47 mmol) was added, and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with saturated NaSO quench solution and extracted with ethyl acetate (25 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title compound (0.2 g, 66.1% yield) as a mixture of enantiomers. 1 H NMR(400MHz,CDCl3)9.85(s,1H),8.76(s,1H),7.92(d,J=8.4Hz,1H),7.75(d,J=8.4Hz,1H),6.26-6.08(m,1H),3.38-2.93(m,2H).

[0609] Step 4: 7-(3-fluoro-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0610] To a solution of 3-fluoro-3-[6-(trifluoromethyl)-3-pyridyl]propanal (90.0 mg, 0.41 mmol) in methanol (5 mL) was added 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (80.0 mg, 0.38 mmol), acetic acid (0.11 mL, 1.89 mmol), and sodium cyanoborohydride (71 mg, 1.13 mmol), and the mixture was stirred at 70 °C for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate (30 mL × 2). The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0–5% methanol in ethyl acetate) to give the title compound (100 mg, 68.9% yield) as a mixture of enantiomers. LCMS (ESI) [M+H] = 381.1.

[0611] Step 5: Synthesis of the title compound. 7-(3-Fluoro-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (112 mg, 0.29 mmol) was separated using chiral SFC (Daicel Chiralpak AD (250 mm × 30 mm, 10 μm); Neu-EtOH 20 / 20; 70 mL / min) to give title compound 237A* (35.72 mg, 30.9% yield, first peak in SFC) and title compound 237B* (32.57 mg, 28.5% yield, second peak in SFC), each with unassigned stereochemistry. LCMS (ESI) [M+H]+ = 381.1.

[0612] Compound 237A*: 1H NMR(400MHz,CDCl3)δ8.69(s,1H),7.87(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),5.78- 5.63(m,1H),3.85(s,4H),2.58-2.41(m,6H),2.24-1.97(m,2H),1.90(t,J=5.2Hz,4H).

[0613] Compound 237B*: 1 H NMR(400MHz,CDCl3)δ8.69(s,1H),7.87(d,J=6.8Hz,1H),7.73(d,J=8.0Hz,1H),5.78-5.53(m,1 H),3.85(s,4H),2.58-2.41(m,6H),2.24-2.13(m,1H),2.09-1.95(m,1H),1.90(t,J=5.2Hz,4H). Example 238: 7-(2-(4-(6-(trifluoromethyl)pyridin-3-yl)phenoxy)ethyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0614] The title compound was synthesized in the same manner as in Example 241, except that 4-bromophenol was used instead of 6-bromopyridin-3-ol (42.65 mg, 31.2% yield). LCMS (ESI) [M+H] = 441.1.

[0615] Compound 238: 1 H NMR(400MHz,CD3OD)δ8.96(d,J=1.6Hz,1H),8.25(d,J=3.2Hz,1H),7.88(d,J=8.4Hz,1H),7.74(d,J=8.8Hz,2H),7.17(d,J=8 .8Hz,2H),4.35(t,J=5.2Hz,2H),4.02(s,4H),3.25(t,J=5.2Hz,2H),3.03(s,4H),2.11(t,J=5.6Hz,4H),2.21-2.05(m,4H). Example 239: 7-[2-[4-[6-(trifluoromethyl)-3-pyridyl]phenoxy]ethyl]-26-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0616] Step 1: 2-Isopropyl-5-(trifluoromethyl)pyrazol-3-ol [ka]

[0617] To a stirred solution of ethyl 4,4,4-trifluoroacetoacetate (1.0 g, 5.43 mmol) in ethanol (10 mL) was added isopropylhydrazine hydrochloride (0.6 g, 5.43 mmol) and HCl (1 mL, 1 mmol), and the reaction mixture was stirred at 60° C. for 2.5 hours. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (25 mL). The resulting residue was extracted with ethyl acetate:MeOH (10:1, 200 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica column chromatography (50% ethyl acetate in petroleum ether) to give the title compound (0.50 g, 47.4% yield).

[0618] Step 2: 5-(2-bromoethoxy)-1-isopropyl-3-(trifluoromethyl)pyrazole [ka]

[0619] To a solution of 2-isopropyl-5-(trifluoromethyl)pyrazol-3-ol (400 mg, 2.06 mmol) and potassium carbonate (711.87 mg, 5.15 mmol) in acetone (2 mL) was added 1,2-dibromoethane (0.54 mL, 6.18 mmol) at 20 °C. The reaction mixture was then stirred at 60 °C for 15 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were concentrated under reduced pressure, and the resulting residue was purified by silica column chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (0.50 g, 81% yield).

[0620] Step 3: Synthesis of the title compound. To a solution of 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (77.34 mg, 0.37 mmol) and 5-(2-bromoethoxy)-1-isopropyl-3-(trifluoromethyl)pyrazole (100.0 mg, 0.33 mmol) in acetonitrile (2.0 mL), N,N-diisopropylethylamine (0.14 mL, 0.83 mmol) and potassium iodide (5.51 mg, 0.03 mmol) were added at 80 °C and stirred for 15 hours. The reaction mixture was concentrated, and the resulting residue was purified by preparative HPLC (water (0.05% FA)-ACN, 40-70%) to give the title compound (66.12 mg, 50% yield). LCMS (ESI) [M+H] = 396.1

[0621] Compound 239: 1 H NMR(400MHz,CD3OD)δ6.03(s,1H),4.66-4.60(m,1H),4.31(t,J=5.2Hz,2H),3.93(s, 4H),2.94(t,J=5.2Hz,2H),2.68(s,4H),1.97(t,J=5.6Hz,4H),1.42(d,J=6.4Hz,6H). Example 240: 7-[2-[(5-chloro-6-cyclohexyl-3-pyridyl)oxy]ethyl]-26-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0622] Step 1: 2-Bromo-5-(2-bromoethoxy)-3-chloro-pyridine [ka]

[0623] To a solution of 1,2-dibromoethane (1351 mg, 7.2 mmol) in acetonitrile (10 mL) was added K2CO3 (828 mg, 6 mmol) and 6-bromo-5-chloropyridin-3-ol (500 mg, 2.4 mmol) at 20 °C. The reaction mixture was then heated to 60 °C and stirred for 15 h. The reaction solution 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 (629 mg, 1.95 mmol, 81.5% yield). LCMS (ESI) [M+H] + =315.9.

[0624] Step 2: 7-[2-[(6-bromo-5-chloro-3-pyridyl)oxy]ethyl]-26-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0625] To a solution of 2-bromo-5-(2-bromoethoxy)-3-chloro-pyridine (150 mg, 0.48 mmol) and 2-thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (151 mg, 0.71 mmol) in acetonitrile (6 mL) was added N,N-diisopropylethylamine (0.39 mL, 2.38 mmol) and potassium iodide (7 mg, 0.05 mmol) at 20 °C. The reaction mixture was stirred at 80 °C for 15 hours. The reaction mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were concentrated in vacuo, and the resulting residue was purified by preparative TLC (10% methanol in dichloromethane) to give the title compound (161 mg, 0.39 mmol, 82.6% yield). LCMS (ESI) [M+H]+ =411.0.

[0626] Step 3: 7-[2-[[5-chloro-6-(cyclohexan-1-yl)-3-pyridyl]oxy]ethyl]-26-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0627] To a solution of 7-[2-[(6-bromo-5-chloro-3-pyridyl)oxy]ethyl]-26-thia-7-azaspiro[3.5]nonane 2,2-dioxide (60 mg, 0.15 mmol) in degassed 1,4-dioxane (8 mL) and water (1.6 mL) was added 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (22 mg, 0.11 mmol), K2CO3 (60 mg, 0.44 mmol), and Pd(dppf)Cl2 (10 mg, 0.01 mmol). The reaction mixture was then stirred at 100 °C under N2 for 1 h. The reaction mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC (10% methanol in dichloromethane) to give the title compound (40 mg, 0.09 mmol, 61.1% yield). LCMS (ESI) [M+H] + =411.1.

[0628] Step 4: Synthesis of the title compound. To a solution of 7-[2-[[5-chloro-6-(cyclohexen-1-yl)-3-pyridyl]oxy]ethyl]-26-thia-7-azaspiro[3.5]nonane 2,2-dioxide (50 mg, 0.12 mmol) in tetrahydrofuran (4 mL) was added rhodium on carbon (33 mg, 0.02 mmol) under H2. The mixture was stirred at 20°C under H2 (15 psi) for 5 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (10% methanol in dichloromethane) to give the title compound 43.37 mg, 0.11 mmol, 92% yield. LCMS (ESI) [M+H] + =413.1.

[0629] Compound 240: 1 H NMR(400MHz,CDCl3)δ8.18(d,J=2.4Hz,1H),7.21(d,J=2.4Hz,1H),4.11(s,2H),3.87(s,4H),3.15-3.07 (m,1H),2.79(s,2H),2.59-2.42(m,3H),1.95(s,3H),1.89-1.72(m,6H),1.54(s,2H),1.48-1.26(m,4H). Example 241: 7-[2-[[6-[6-(trifluoromethyl)-3-pyridyl]-3-pyridyl]oxy]ethyl]-26-thia-7-azaspiro[3.5]nonane 2,2-dioxide [ka]

[0630] Step 1: 6-[6-(trifluoromethyl)-3-pyridyl]pyridin-3-ol [ka]

[0631] To a mixture of 6-bromopyridin-3-ol (200 mg, 1.15 mmol), 2-trifluoromethyl-5-pyridineboronic acid (329 mg, 1.72 mmol), and potassium carbonate (477 mg, 3.45 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (84 mg, 0.11 mmol), and the reaction mixture was stirred at 90 °C under a nitrogen atmosphere for 16 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica flash column chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (130 mg, 0.5064 mmol, 44.1% yield). LCMS (ESI) [M+H] + =241.0.

[0632] Step 2: 5-(2-bromoethoxy)-6'-(trifluoromethyl)-2,3'-bipyridine [ka]

[0633] A mixture of 6-[6-(trifluoromethyl)-3-pyridyl]pyridin-3-ol (130 mg, 0.54 mmol), 1,2-dibromoethane (1.53 g, 8.12 mmol), and potassium carbonate (224 mg, 1.62 mmol) in acetonitrile (5 mL) was stirred at ...

Claims

1. Formula I: 【Chemistry 261】 (In the formula, j １ , j ２ , m １ , and m ２ are each independently 1 or 2, １ and ２ The sum of and m １ and m ２ The sum of each is 4 or less, and j １ and ２ and m １ and m ２ The sum of is 6 or less, R １ａ , R １ｂ , R ２ａ , and R ２ｂ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl, halo-C １ ~C ６ Alkyl, halo-C １ ~C ６ Alkoxy, and C １ ~C ６ alkoxy; X is O or C(R １０ ) (R ２０ ) and R １０ and R ２０ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl, halo-C １ ~C ６ Alkyl, halo-C １ ~C ６ Alkoxy, and C １ ~C ６ alkoxy; or R １ａ and R １ｂ , R ２ａ and R ２ｂ , or R １０ and R ２０ together with the atom to which they are attached, represent halogen, hydroxy, halo-C １ ~C ６ Alkoxy, C １ ~C ６ Alkoxy, —SO ２ (C １ -C ６ alkyl), C optionally substituted with —CN or —NRR′ ３ ~C ５ forming a cycloalkyl, Ring A 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; Each R ｙ are independently 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 alkyl), —CN or —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, or —NRR′, wherein said heterocyclyl, cycloalkyl, aryl, or heteroaryl is selected from the group consisting of 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 optionally substituted with one or more substituents independently selected from the group consisting of -NR"R"", -CN, and -NR"R""; R, R', R'', and R''' are each independently hydrogen, C １ ~C ６ Alkyl, or halo-C １ ~C ６ alkyl) or a pharmaceutically acceptable salt thereof.

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

3. The compound has the formula Ia: 【Chemistry 262】 (In the formula, E １ , E ２ , E ３ , and E ４ are each independently CH, C—R ｘ , C-R ｙ , N-R ｘ , N-R ｙ , N, NH, O and S; １ , E ２ , E ３ and E ４ One, two or three of the following are N, NH, N-R ｘ , N-R ｙ 3. The compound of claim 1 or 2, wherein R is O or S, or a pharmaceutically acceptable salt thereof.

4. E １ is CH, and E ２ is N and E ３ N-R ｘ and E ４ is CH, or 4. The compound of claim 3, wherein E 1 is CH, E 2 is C—R x , E 3 is N, and E 4 is N—R y , or a pharmaceutically acceptable salt thereof.

5. The compound has the formula Ib: 【Chemical 263】 (In the formula, Y １ , Y ２ , Y ３ , Y ４ , and Y ５ is CH, C-R ｙ , C-R ｘ and N, １ , Y ２ , Y ３ , Y ４ , and Y ５ wherein no more than three of are N, or a pharmaceutically acceptable salt thereof.

6. a. Y １ , Y ２ , Y ４ , and Y ５ are CH, and Y ３ But, C-R ｘ That is, b. Y 1 , Y 2 and Y 5 are each CH, Y 4 is N and Y 3 is C—R x ; c. Y 1 , Y 2 and Y 5 are each CH, Y 4 is C—R y and Y 3 is C—R x ; d. Y 1 , Y 2 and Y 5 are each CH, Y 4 is C—R x and Y 3 is N; e. Y 2 and Y 4 are each N, Y 1 and Y 5 are each CH, and Y 3 is C—R x ; f. Y 5 is N, Y 3 is C—R x , and Y 1 , Y 2 , and Y 4 are each CH; g. Y 4 is C—R x , Y 2 is N, and Y 1 , Y 3 , and Y 5 are each CH; h. Y 1 , Y 2 , Y 3 , and Y 4 are each CH, and Y 5 is C—R x ; i. Y 1 and Y 5 are CH, Y 4 is C—R y , Y 3 is C—R x , and Y 2 is N, or j. The compound of claim 5, wherein Y 1 is CH, Y 5 is C—R y , Y 4 is N, Y 3 is C—R x , and Y 2 is CH, or a pharmaceutically acceptable salt thereof.

7. R ｙ But halogen, C １ ~C ３ Alkyl, or halo-C １ ~C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

8. R ｙ 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein is chloro, trifluoromethyl, fluoro, methyl, or isopropyl.

9. R ｘ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is fluoro, trifluoromethyl, trifluoroethyl, difluoromethyl, fluoromethyl, or trifluoromethoxy.

10. R ｘ But, -CF ３ , -CH ２ CF ３ , -CHF ２ , or -CH ２ 10. The compound of claim 9, wherein R is H, or a pharmaceutically acceptable salt thereof.

11. R ｘ But, -CF ３ 11. The compound of claim 10, wherein:

12. R ｘ But halogen, C １ ~C ６ Alkyl, hydroxy, C １ ~C ６ Alkoxy, halo-C １ ~C ６ Alkoxy and halo-C １ ~C ６ C optionally substituted with one or more substituents independently selected from the group consisting of alkyl ３ ~C ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

13. R ｘ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each optionally substituted with one or two substituents independently selected from the group consisting of fluoro, methyl, hydroxy, and trifluoromethyl, or a pharmaceutically acceptable salt thereof.

14. R ｘ is unsubstituted cyclohexyl, unsubstituted cyclopropyl, or unsubstituted cyclobutyl, 【Chemical 265】 【Chemistry 264】 14. The compound of claim 13, wherein:

15. 2. The compound of claim 1, wherein X is O, or a pharmaceutically acceptable salt thereof.

16. X is C(R １０ ) (R ２０ ) and R １０ and R ２０ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

17. R ２ａ and R ２ｂ are each independently hydrogen, C １ ~C ６ Alkoxy, halogen, and C １ ~C ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkyl.

18. R ２ａ and R ２ｂ 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein each is independently methoxy, fluoro, hydrogen, or methyl.

19. R ２ａ is hydrogen, and R ２ｂ 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein is methyl.

20. R ２ａ and R ２ｂ 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein each is methyl.

21. R １ａ and R １ｂ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

22. the compound is of formula Ib, Y １ , Y ２ , Y ３ , Y ４ , and Y ５ Four of them are CH and one is C-R ｘ and R ｘ But, Halo-C １ ~C ６ Alkyl, halogen, halo-C １ ~C ６ Alkoxy, C １ ~C １０ Alkyl, pyridinyl, and C ３ ~C ７ cycloalkyl; Said C ３ ~C ７ Cycloalkyl or pyridinyl is C １ ~C ６ Alkyl or halo-C １ ~C ６ optionally substituted one or more times with alkyl; n is 0, X is C(R １０ ) (R ２０ ) or O, and R １０ and R ２０ are each independently hydrogen, methyl or fluoro; R １ａ and R １ｂ are each independently hydrogen or methyl; R ２ａ and R ２ｂ are each independently hydrogen, fluoro, methoxy or methyl, or R ２ａ and R ２ｂ together with the carbon atoms to which they are attached, C ３ ~C ５ forming a cycloalkyl, 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof.

23. The compound is 【Chemistry 271】 【Chemistry 272】 【Chemistry 273】 【Chemistry 274】 【Chemistry 275】 【Chemistry 276】 【Chemistry 277】 【Chemistry 278】 【Chemistry 279】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

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

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

26. 25. A composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 24, for use in promoting myelination in a subject in need thereof.

27. 26. The pharmaceutical composition of claim 25, wherein the disorder is a myelin-related disorder.

28. 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.

28. The pharmaceutical composition of claim 27, wherein the condition is selected from the group consisting of: Marger'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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