Azole modulators of cholesterol biosynthesis and their use to promote remyelination

Abstract

The subject matter described herein relates to myelin-promoting compounds of Formula I and pharmaceutical salts thereof, methods for preparing the compounds, pharmaceutical compositions comprising the compounds, and methods of administering the compounds to treat disorders, such as myelin-related disorders. 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, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. JPEG2025533043000337.jpg9399

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 377,821, filed September 30, 2022, the entire contents of which are incorporated herein by reference.

[0002] 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] Myelin-related disorders are disorders that result in abnormalities of the myelin sheath (e.g., dysmyelination, demyelination, and hypomyelination) in the target nerve cells, 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 (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, and Alzheimer's disease. These include, but are not limited to, Marr's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post-radiation injury, neurological complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barré syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination.

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

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

[0006] In certain embodiments, the subject matter described herein relates to a compound of formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, 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, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0008] In certain embodiments, the subject matter described herein relates to a method of treating a disorder in a subject in need of treatment, wherein the disorder is a myelin-related disorder, comprising administering to the subject an effective amount of a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] In certain embodiments, the subject matter described herein relates to a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2 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, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] In certain embodiments, the subject matter described herein relates to the use of a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a myelin-related disorder.

[0012] In certain embodiments, the subject matter described herein relates to a method of preparing a compound of formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof.

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

[0014] Described herein are compounds of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, and Ib2, as well as pharmaceutically acceptable salts thereof, methods for preparing the compounds, pharmaceutical compositions thereof, and their use in treating myelin-related disorders. In some embodiments, the compounds provided herein are promyelinating.

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

[0016] Thus, in some embodiments, an agent capable of enhancing and / or inducing the accumulation of Δ8,9-unsaturated sterol intermediates of the cholesterol biosynthetic pathway in OPCs, such as a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, 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, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof, is a compound that inhibits enzyme-mediated synthesis of one or more sterol intermediates in the cholesterol biosynthetic pathway in OPCs and / or promotes the accumulation of Δ8,9-unsaturated sterol intermediates.

[0017] In certain embodiments, a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof, can modulate 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 modulating and / or inhibiting these one or more steps in OPCs can promote and / or induce the generation of oligodendrocytes. For example, in some embodiments, a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof, can inhibit CYP51, sterol 14 reductase (TM7SF2 and / or LBR), SC4MOL, NSDHL, and / or emopamil-binding protein (EBP) enzyme-mediated synthesis of sterol intermediates in the cholesterol biosynthetic pathway. In certain embodiments, a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof, can inhibit CYP51, sterol 14-reductase, and / or EBP. In certain embodiments, a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof, can inhibit EBP.

[0018] For example, in certain embodiments, a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof, used in the methods described herein can inhibit the enzyme-mediated conversion of zymostenol to lathosterol through inhibition of emopamil-binding protein (EBP) isomerase enzyme activity. Alternatively, in certain embodiments, a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof, used in the methods described herein can inhibit sterol C14 reductase enzyme activity or CYP51 enzyme activity in the cholesterol biosynthetic pathway.

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

[0020] Without being bound by any particular theory, it is believed that a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof, can inhibit 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 subject matter disclosed herein is described in more detail below. However, many modifications and other embodiments of the subject matter disclosed herein will occur to those skilled in the art to which the subject matter relates having the benefit of the teachings presented in the description herein. Therefore, the subject matter disclosed herein should not be limited to the specific embodiments disclosed, and modifications and other embodiments should be considered as intended to be included within the scope of the appended claims. In other words, the subject matter described herein encompasses all variations, 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. If one or more of the incorporated documents, patents, and similar materials differ from or conflict with this application, including, but not limited to, defined terms, term usage, described techniques, etc., this 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 the 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 an alkyl group having 1 to 20 carbon atoms (i.e., C1 to C6). 20 alkyl), 1 to 12 carbon atoms (i.e., C1 to C 12alkyl), 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); "propyl" includes n-propyl (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 contains the atom by which that moiety is attached to the remainder of the molecule.

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

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

[0030] "Alkoxy" refers to the group "alkyl-O-" (e.g., C1-C3 alkoxy or C1-C6 alkoxy). Examples of 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] "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.

[0032] An "amide" is the group -C(O)NR y R z refers to the "C-amido" group, and the group -NR y C(O)Rz "N-amido" refers to both a hydroxyl group and a hydroxyl group, y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein, or R y and R z together form a heterocyclyl, which may be optionally substituted as defined herein.

[0033] "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.

[0034] "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 an aromatic carbocyclic group having 6 to 20 ring carbon atoms (i.e., C6-C6). 20 aryl), 6 to 12 carbon ring atoms (i.e., C6-C 12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-C 10 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 with a heteroaryl, the resulting ring system is a heteroaryl, regardless of the point of attachment. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl, regardless of the point of attachment.

[0035] "Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-", e.g., (C-C 10 A non-limiting example of arylalkyl is benzyl.

[0036] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having single or multiple rings, which may include fused, bridged, and spiro ring systems. The term "cycloalkyl" refers to cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and at least one sp 3 As used herein, cycloalkyl includes carbocyclic fused ring systems (i.e., at least one non-aromatic ring) having 3 to 20 ring carbon atoms (i.e., C3 to C6). 20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3 to C 12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3 to C 10 Cycloalkyl groups include cycloalkyls having 3 to 8 ring carbon atoms (i.e., C-C cycloalkyls), 3 to 7 ring carbon atoms (i.e., C-C cycloalkyls), or 3 to 6 ring carbon atoms (i.e., C-C cycloalkyls). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Furthermore, the term cycloalkyl is intended to encompass any moiety containing a non-aromatic alkyl ring that may be fused to an aryl ring, regardless of attachment to the rest of the molecule. Additionally, cycloalkyl also includes "spirocycloalkyl" when there are two positions for substitution on the same carbon atom (eg, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl).

[0037] As used herein, "halocycloalkyl," eg, C3-C7 halocycloalkyl, refers to a C3-C7 cycloalkyl group substituted with one or more halogens.

[0038] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-", e.g., (C3-C6 cycloalkyl)-C1-C3 alkyl.

[0039] "Halogen" or "halo" refers to atoms occupying Group VIIA of the periodic table, such as fluoro (fluorine), chloro (chlorine), bromo (bromine) or iodo (iodine).

[0040] "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") halogen groups, which may, but need not, be 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.

[0041] "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.

[0042] "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 a hydroxy group (e.g., hydroxy-C1-C3-alkyl, hydroxy-C1-C6-alkyl). The term "hydroxy-C1-C3 alkyl" refers to a 1 to 3 carbon alkyl chain in which one or more hydrogens on any carbon have been replaced with a hydroxy group, particularly one hydrogen on one carbon of the chain has been replaced with a hydroxy group. The term "hydroxy-C1-C6 alkyl" refers to a 1 to 6 carbon alkyl chain in which one or more hydrogens on any carbon have been replaced with a hydroxy group, 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.

[0043] "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 y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CHOCH, -CH(CH)OCH, -CHCHOCH, -CHCHOCH, -CHCHOCHCHOCH, etc.), thioethers (e.g., -CHSCH, -CH(CH)SCH, -CHCHSCH, -CHCHSCHCHSCH, etc.), sulfones (e.g., -CHS(O)CH, -CH(CH)S(O)CH, -CHCHS(O)CH, -CHCHS(O)CHCHOCH, etc.), and amines (e.g., -CHNR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2CH2NR y CH3, etc.), wherein R yis 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.

[0044] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings containing 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-C6). 20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-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 containing 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 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, 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 Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. 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 may 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.

[0045] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-", e.g., (5- to 10-membered monocyclic heteroaryl)-C1-C3 alkyl.

[0046] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or may have multiple fused, bridged, or spiro rings. Any non-aromatic ring containing at least one heteroatom is considered heterocyclyl (i.e., it can be bonded via a carbon atom or a heteroatom), regardless of the bond. Furthermore, the term heterocyclyl is intended to encompass moieties containing any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the bond to the rest of the molecule. The term heterocyclyl is also intended to encompass moieties containing a cycloalkyl ring fused to a heteroaryl ring, regardless of the bond to the rest of the molecule. Additionally, the term heterocyclyl is intended to encompass moieties containing a cycloalkyl ring fused to a heterocyclyl ring, regardless of attachment to the rest of the molecule. As used herein, heterocyclyl refers to a group of 2 to 20 ring carbon atoms (i.e., C2 to C6). 20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2 to C 12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-C10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2 to C8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3 to C 12Heterocyclyls have 3 to 8 ring carbon atoms (i.e., C-C heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C-C heterocyclyl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. When a heterocyclyl ring contains 4 to 6 ring atoms, it is also referred to herein as a 4- to 6-membered heterocyclyl. Five- or 6-membered heterocyclyls, having 5 or 6 ring atoms, respectively, and 5- to 10-membered heterocyclyls, having 5 to 10 ring atoms, are also disclosed herein. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, and octahydroisoquinolyl. Examples of heterocyclyl include 2-oxoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In certain embodiments, the term "heterocyclyl" can include "spiroheterocyclyl" when two positions for substitution exist on the same carbon atom and at least one ring of the spiro system contains at least one heteroatom.Examples of spiro-heterocyclyl rings include bicyclic and tricyclic systems such as, for example, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be attached via either ring of the fused system.

[0047] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0048] "Oxo" refers to the group (=O).

[0049] "Cyano" refers to the group (-CN).

[0050] "Sulfonyl" refers to 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. A non-limiting example of a sulfonyl group is -SO(C-C alkyl), referred to herein as alkylsulfonyl. Examples of sulfonyl include methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0051] "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.

[0052] "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.

[0053] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. Also, the term "optionally substituted" refers to any one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms on a specified atom or group that may or may not be replaced with a non-hydrogen moiety.

[0054] As used herein, the term "substituted" means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl) in which at least one (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen moiety. Unless otherwise specified, such non-hydrogen moieties may be alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH, =NNH, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)OH, sulfonamide, thiol, thioxo, N-oxide, or -Si(R y )3(in the formula, each R y are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl).

[0055] In certain embodiments, "substituted" means that one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NRg S(=O) 1-2 R h , -C(=O)R g , -C(=O)OR g , -OC(=O)OR g , -OC(=O)R g , -C(=O)NR g R h , -OC(=O)NR g R h , -OR g , -SR g , -S(=O)R g , -S(=O)2R g , -OS(=O) 1-2 R g , -S(=O) 1-2 OR g , -NR g S(=O) 1-2 NR g R h , =NSO2R g , =NOR g , -S(=O) 1-2 NR g R h , -SF5, -SCF3, or -OCF3. In certain embodiments, "substituted" also means that one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced with -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , or -CH2SO2NR g R h In the above, R g and R hare the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, "substituted" also refers to one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms being replaced by a bond to amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or R g and R h and R i means any of the above groups, wherein two of these, together with the atom to which they are attached, form a heterocyclyl ring optionally substituted with oxo, halo, or alkyl optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy.

[0056] Polymers or similar indefinite structures arrived at by defining substituents 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, etc.) 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.

[0057] In certain embodiments, the phrase "one or more / one or more" as used herein refers to 1 to 5. In certain embodiments, the phrase "one or more / one or more" as used herein refers to 1 to 4. In certain embodiments, the phrase "one or more / one or more" as used herein refers to 1 to 3.

[0058] Any compound or structure provided herein is intended to represent unlabeled forms of the compound as well as isotopically labeled forms (isotopologues). These forms of compounds are also referred to as "isotopically enriched analogs," including "isotopically enriched analogs." Isotopically labeled compounds have the structures depicted herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. Various isotopically labeled compounds of the present disclosure include, for example, 3 H, 13 C and 14These include those into which a radioactive isotope such as C has been incorporated. Such isotopically labeled compounds may be useful in metabolism studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or radioactive treatment of patients.

[0059] 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, 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.

[0060] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use. Generally, such materials are not biologically or otherwise undesirable; e.g., the substance can be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious way with any of the other components of the composition in which it is contained.

[0065] The term "pharmaceutically acceptable salts" of a given compound generally includes salts that are safe and not biologically or otherwise undesirable, including those that are acceptable for veterinary and human pharmaceutical use. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and organic acids. Furthermore, when a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.Salts derived from organic bases include salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e. , HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3, mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3) or mixed amines, and the like. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0066] The term "hydrate" refers to a complex formed by combining a compound described herein with water. A "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. Any compound or structure shown herein is intended to encompass hydrates and / or solvates of the compound.

[0067] 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), for example, using chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other center of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. In some embodiments, the planar structures depicted herein include all possible stereochemistries. In certain embodiments of a compound of Formula I or a pharmaceutically acceptable salt thereof, e.g., a compound of Formula Ia, Ia', Ia1, or Ia2, or a pharmaceutically acceptable salt of any of the foregoing, ring A is [ka] and ring C is [ka] and the combination of ring A and ring C may include any one of the following stereoisomers: [ka] In certain embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, e.g., compounds of Formula Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt of any of the foregoing, ring A is [ka] and ring C is [ka] and the combination of ring A and ring C may include any one of the following stereoisomers: [ka]

[0068] The compounds described herein can contain any combination of stereocenters and any combination of stereochemistry at each stereocenter.

[0069] "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.

[0070] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0071] 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).

[0072] "Treatment" or "treating" is an approach to obtaining beneficial or desired results, including, but not limited to, clinical results. Beneficial or desired results can include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition and / or reducing the severity of the disease or condition), b) delaying or halting the onset of one or more clinical symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, preventing or slowing the worsening or progression of a disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of a disease or condition), and / or c) alleviating a disease or condition, i.e., causing a regression of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of a disease or condition, enhancing the effect of another drug, slowing disease progression, improving quality of life, and / or prolonging survival). Reduction of the pathological consequences of demyelination is also encompassed by "treatment" or "treating."

[0073] "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.

[0074] "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.

[0075] The term "therapeutically effective amount" or "effective amount" of a compound or a pharmaceutically acceptable salt thereof described herein means an amount sufficient to treat a subject when administered to the subject to provide a therapeutic benefit, such as amelioration of symptoms or delay of disease progression. The therapeutically effective amount may vary depending on the subject and the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the method of administration, and can be easily determined by one skilled in the art. An effective amount of a compound of the present disclosure in such a treatment method is, for example, about 0.01 mg / kg / day to about 1000 mg / kg / day.

[0076] As used herein, the term "excipient" refers to an inert or inactive substance that may be used in the production of a drug or pharmaceutical composition, such as a tablet, containing a compound described herein (or a pharmaceutically acceptable salt) as an active ingredient. A variety of substances may be encompassed by the term excipient, including, but not limited to, a diluent, filler or bulking agent, binder, disintegrant, wetting agent, coating, emulsifier or dispersing agent, compression / encapsulation aid, cream or lotion, lubricant, solution for parenteral administration, material for chewable tablets, sweetener or flavoring agent, suspending / gelling agent, or any substance used as a wet granulator. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coating materials include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coating, etc.; compression / encapsulation materials include, for example, calcium carbonate, glucose, fructose dc (dc - "directly compressible"), honey dc, lactose (anhydrous or monohydrate, optionally combined with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, Examples of suitable additives include maltodextrin, carrageenan, etc.; lubricants include magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable tablet materials include dextrose, fructose dc, lactose (monohydrate, optionally combined with aspartame or cellulose), etc.; suspending / gelling agents include carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include dextrose, fructose dc, sorbitol, sucrose dc, etc.; and moistening agents include calcium carbonate, maltodextrin, microcrystalline cellulose, etc. In some cases, the term "excipient" encompasses a pharmaceutically acceptable carrier.

[0077] Additional definitions may also be provided below as needed.

[0078] II. Compounds In certain embodiments, the subject matter described herein is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, n is 0 or 1; p is 1 or 2; Ring A is a saturated 5- or 6-membered monocyclic or bicyclic carbocyclyl; Ring B is phenyl, a 6-membered heteroaryl, or a 6-membered saturated or partially saturated cycloalkyl, wherein the heteroaryl contains 1 or 2 heteroatoms; R 3 is independently selected at each occurrence from the group consisting of C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, halo-C-C alkoxy, halo, and cyano; G is N or CR G and R G is selected from the group consisting of hydrogen, C1-C6 alkyl, and halo-C1-C6 alkyl; R N1 is selected from the group consisting of hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, and C3-C5 cycloalkyl; R 2 is selected from the group consisting of C1-C6 alkyl, halo, and halo-C1-C6 alkyl; y is 1 or 2; m is 0, 1, 2, or 3; X is O or NR H and; R H is selected from the group consisting of hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C5 cycloalkyl, hydroxy-C1-C6 alkyl, and C1-C6 alkoxy-C1-C6 alkyl; and, R 1 is, in each occurrence, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, hydroxy, NR E R F , halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, and C1-C6 alkoxy-C1-C6 alkyl; or two R 1 The groups together form a -CH2- or -CH2CH2- bridge R E and R F are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C5 cycloalkyl, hydroxy-C1-C6 alkyl, and C1-C6 alkoxy-C1-C6 alkyl.

[0079] Ring systems shown in Formula I, and various subgenera as described herein, having the following structures: [ka] is also referred to herein as "Ring C."

[0080] Ring systems shown in Formula I, and various subgenera as described herein, having the following structures: [ka] is also referred to herein as "Ring D."

[0081] In certain embodiments, the compound comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of cyclopentyl, cyclohexyl, and bicyclo[3.1.0]hexanyl.

[0082] In certain embodiments, the compound comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of cyclohexyl, phenyl, pyridinyl, pyrimidinyl, and pyrazinyl.

[0083] In certain embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound of Formula Ia or Formula 1a′, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently N, C, or CH, with the proviso that Y 1 , Y 2 , Y 3 , Y 4 and Y 5 and only one or two of the following may be N; or [ka] Includes.

[0084] In certain embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound of Formula Ib, or a pharmaceutically acceptable salt thereof: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently N, C, or CH, with the proviso that Y 1 , Y 2 , Y 3 , Y 4 and Y 5 can be N; and u is 1 or 2.

[0085] In certain embodiments, the compound comprises a compound of formula Ib, where u is 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound comprises a compound of formula Ib, where u is 2, or a pharmaceutically acceptable salt thereof.

[0086] In certain embodiments, the compound is Y 1 is CH and Y 2 is CR 3 and Y 3 is CH and Y 4 is N and Y 5 In certain embodiments, the compound includes compounds of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y is CH. 1 is CH and Y 2 is N and Y 3 is CR 3 and Y 4 is CH and Y 5 In certain embodiments, the compound includes compounds of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y is CH. 1 is N and Y 2 is CR 3 and Y 3 is CH and Y 4 is CH and Y 5 In certain embodiments, the compound includes compounds of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y is CH. 1 is CH and Y 2 is CR 3 and Y 3 is CH and Y 4 is CH and Y 5 In certain embodiments, the compound includes compounds of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y is CH. 1 is CH and Y 2 is CR 3 and Y 3 is CH and Y 4 is CH and Y 5 is N. In certain embodiments, the compound includes compounds of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 is CH and Y2 is N and Y 3 is CR 3 and Y 4 is N and Y 5 In certain embodiments, the compound includes compounds of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y is CH. 1 is N and Y 2 is CR 3 and Y 3 is N and Y 4 is CH and Y 5 In certain embodiments, the compound includes compounds of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y is CH. 1 is CH and Y 2 is CR 3 and Y 3 is N and Y 4 is CH and Y 5 is N. In certain embodiments, the compound includes compounds of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 is N and Y 2 is CR 3 and Y 3 is CH and Y 4 is N and Y 5 In certain embodiments, the compound includes compounds of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y is CH. 1 is CH and Y 2 is CR 3 and Y 3 is CR 3 and Y 4 is CH and Y 5 In certain embodiments, the compound includes compounds of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y is CH. 1 is CH and Y 2 is N and Y 3 is CR 3 and Y 4 is CR 3 and Y 5 In certain embodiments, the compound includes compounds of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y is CH. 1is CH and Y 2 is CR 3 and Y 3 is N and Y 4 is CH and Y 5 In certain embodiments, the compound includes compounds of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y is CH. 1 is CH and Y 2 is CR 3 and Y 3 is N and Y 4 is CH and Y 5 In certain embodiments, the compound includes compounds of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y is CH. 1 is CH and Y 2 is CH and Y 3 is CR 3 and Y 4 is CH and Y 5 In certain embodiments, the compound includes compounds of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y is CH. 1 is N and Y 2 is CH and Y 3 is CR 3 and Y 4 is CH and Y 5 In certain embodiments, the compound includes compounds of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y is CH. 1 is CR 3 and Y 2 is CH and Y 3 is CH and Y 4 is CH and Y 5 is CH, or a pharmaceutically acceptable salt thereof.

[0087] In certain embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is a compound of formula Ib': [ka] or a pharmaceutically acceptable salt thereof.

[0088] In certain embodiments, the compound comprises a compound of formula Ib', where u is 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound comprises a compound of formula Ib, where u is 2, or a pharmaceutically acceptable salt thereof.

[0089] In certain embodiments, the compound is R 3 is selected from the group consisting of halo-C1-C6 alkyl, halo, cyano, C1-C6 alkyl, and halo-C1-C6 alkoxy, or a pharmaceutically acceptable salt thereof. 3 is selected from the group consisting of -CF3, -CHF2, methyl, fluoro, chloro, cyano, -OCF3, and -OCHF2, or a pharmaceutically acceptable salt thereof. 3 is —CF 3 , or a pharmaceutically acceptable salt thereof.

[0090] In certain embodiments, the compound comprises at least one R 3 In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, wherein R is halo. 3 or a pharmaceutically acceptable salt thereof, wherein at least one of is fluoro.

[0091] In certain embodiments, the compound comprises a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, wherein G is N. In certain embodiments, the compound comprises a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, wherein G is CH.

[0092] In certain embodiments, the compound is R N1is selected from the group consisting of C1-C6 alkyl and C3-C5 cycloalkyl, or a pharmaceutically acceptable salt thereof. N1 is selected from the group consisting of methyl, ethyl, propyl, butyl, and cyclopropyl. N1 In certain embodiments, the compound includes a compound of Formula I, Ia, or Ib, or a pharmaceutically acceptable salt thereof, wherein R is propyl. N1 is isopropyl.

[0093] In certain embodiments, the compound comprises a compound of Formula I, Ia, 1a', Ib, or 1b', wherein n is 0, or a pharmaceutically acceptable salt thereof.

[0094] In certain embodiments, the compound comprises a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, wherein X is O. In certain embodiments, the compound comprises a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, wherein y is 1. In certain embodiments, the compound comprises a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, wherein y is 2. In certain embodiments, the compound comprises a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of C1-C6 alkyl and halo-C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. 1 is selected from the group consisting of methyl, ethyl, and —CHF. In certain embodiments, the compound includes compounds of Formula I, Ia, 1a′, Ib, or 1b′, or a pharmaceutically acceptable salt thereof, wherein R 1In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, wherein each occurrence of R is methyl. 1 and the groups taken together form a -CH2- or -CH2CH2- bridge. In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, where m is 0. In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, where m is 1. In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, where m is 2. In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, where ring C is any one of the following: [ka]

[0095] In certain embodiments, the compound is H or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is H is selected from the group consisting of C-C cycloalkyl, hydroxy-C-C alkyl, and C-C alkoxy-C-C alkyl, or a pharmaceutically acceptable salt thereof. His selected from the group consisting of -CH2CHOCH3, cyclobutyl, and -CH2CH2OH, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, where m is 0. In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, where ring C is any one of the following: [ka]

[0096] In certain embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound of Formula Ia1 or Formula Ib1, or a pharmaceutically acceptable salt thereof: [ka] [ka] During the ceremony, u is 1 or 2; m is 0, 1 or 2; Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently CH, CR 3 , or N, where Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 Only one or two of can be N; G is N or CH; and R 1 is, when present, independently selected at each occurrence from the group consisting of C-C alkyl and halo-C-C alkyl; or two R 1The groups taken together form a -CH2- or -CH2CH2- bridge, or a pharmaceutically acceptable salt thereof.

[0097] In certain embodiments, the compound comprises a compound of Formula Ib, 1b', or Ib1, or a pharmaceutically acceptable salt thereof, wherein u is 1. In certain embodiments, the compound comprises a compound of Formula Ib, 1b', or Ib1, or a pharmaceutically acceptable salt thereof, wherein u is 2.

[0098] In certain embodiments, the compound is R N1 is selected from the group consisting of 1-C6 alkyl and C3-C5 cycloalkyl. N1 is selected from the group consisting of methyl, ethyl, propyl, butyl, and cyclopropyl. N1 In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ib, 1b', Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein R is propyl. N1 is isopropyl.

[0099] In certain embodiments, the compound comprises a compound of Formula I, Ia, 1a', Ib, 1b', Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein y is 1. In certain embodiments, the compound comprises a compound of Formula I, Ia, 1a', Ib, 1b', Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein y is 2.

[0100] In certain embodiments, the compound is R 1is selected from the group consisting of methyl, ethyl, and —CH 2 F, at each occurrence, or a pharmaceutically acceptable salt thereof.

[0101] In certain embodiments, the compound comprises a compound of Formula I, Ia, 1a', Ib, 1b', Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein m is 0. In certain embodiments, the compound comprises a compound of Formula I, Ia, 1a', Ib, 1b', Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0102] In certain embodiments, the compound is Y 1 is CH and Y 2 is CR 3 and Y 3 is CH and Y 4 is N and Y 5 is CH;Y 1 is CH and Y 2 is N and Y 3 is CR 3 and Y 4 is CH and Y 5 is CH;Y 1 is N and Y 2 is CR 3 and Y 3 is CH and Y 4 is CH and Y 5 is CH;Y 1 is CH and Y 2 is CR 3 and Y 3 is CH and Y 4 is CH and Y 5 is CH;Y 1 is CH and Y 2 is CR 3 and Y 3 is CH and Y 4 is CH and Y 5 is N;Y 1 is CH and Y 2 is N and Y 3 is CR 3 and Y 4is N and Y 5 is CH;Y 1 is N and Y 2 is CR 3 and Y 3 is N and Y 4 is CH and Y 5 is CH;Y 1 is CH and Y 2 is CR 3 and Y 3 is N and Y 4 is CH and Y 5 is N;Y 1 is N and Y 2 is CR 3 and Y 3 is CH and Y 4 is N and Y 5 is CH;Y 1 is CH and Y 2 is CR 3 and Y 3 is CR 3 and Y 4 is CH and Y 5 is CH;Y 1 is CH and Y 2 is N and Y 3 is CR 3 and Y 4 is CR 3 and Y 5 is CH;Y 1 is CH and Y 2 is CR 3 and Y 3 is N and Y 4 is CH and Y 5 is CH;Y 1 is CH and Y 2 is CH and Y 3 is CR 3 and Y 4 is CH and Y 5 is CH;Y 1 is N and Y 2 is CH and Y 3 is CR 3 and Y 4 is CH and Y 5 is CH; or Y1 is CR 3 and Y 2 is CH and Y 3 is CH and Y 4 is CH and Y 5 is CH, or a pharmaceutically acceptable salt thereof.

[0103] In certain embodiments, the compound is R 3 is selected from the group consisting of halo-C1-C6 alkyl, halo, cyano, C1-C6 alkyl, and halo-C1-C6 alkoxy, or a pharmaceutically acceptable salt thereof. 3 is selected from the group consisting of -CF3, -CHF2, methyl, fluoro, chloro, cyano, -OCF3, and -OCHF2, or a pharmaceutically acceptable salt thereof. 3 or a pharmaceutically acceptable salt thereof.

[0104] In certain embodiments, the compound has at least one R 3 In certain embodiments, the compound includes compounds of Formula I, Ia, 1a', Ib, 1b', Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein R 3 or a pharmaceutically acceptable salt thereof, wherein at least one of is fluoro.

[0105] In certain embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound of Formula Ia2 or Formula Ib2, or a pharmaceutically acceptable salt thereof: [ka] [ka] During the ceremony, u is 1 or 2; Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently CH, CR 3 , or N, where Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 can be N; and G is N or CH, or a pharmaceutically acceptable salt thereof.

[0106] In certain embodiments, the compound comprises a compound of Formula Ib, 1b', Ib1, or Ib2, where u is 1, or a pharmaceutically acceptable salt thereof.

[0107] In certain embodiments, the compound comprises a compound of Formula I, Ia, 1a', Ia1, Ia2, Ib, 1b', Ib1, or Ib2, wherein y is 1, or a pharmaceutically acceptable salt thereof.

[0108] In certain embodiments, the compound is R H is selected from the group consisting of C-C cycloalkyl, hydroxy-C-C alkyl, and C-C alkoxy-C-C alkyl, or a pharmaceutically acceptable salt thereof. H is selected from the group consisting of —CH 2 CH 2 OCH 3 , cyclobutyl, and —CH 2 CH 2 OH, or a pharmaceutically acceptable salt thereof.

[0109] In certain embodiments, the compound is R N1In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ia1, Ia2, Ib, 1b', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein R N1 is selected from the group consisting of methyl, ethyl, propyl, and butyl, or a pharmaceutically acceptable salt thereof. N1 In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ia1, Ia2, Ib, 1b', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein R N1 is isopropyl.

[0110] In certain embodiments, the compound is Y 1 is CH and Y 2 is N and Y 3 is CR 3 and Y 4 is CH and Y 5 is CH; or Y 1 is N and Y 2 is CR 3 and Y 3 is CH and Y 4 is CH and Y 5 In certain embodiments, the compound includes a compound of Formula I, Ia, Ia1, Ia2, Ib, Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein R 3 In certain embodiments, the compound includes a compound of Formula I, Ia, Ia1, Ia2, Ib, Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein R 3 or a pharmaceutically acceptable salt thereof.

[0111] In certain embodiments, the compound comprises a compound of Formula I, Ia, Ia', Ia1, or Ia2, or a pharmaceutically acceptable salt thereof, wherein Ring A is bicyclo[3.1.0]hexanyl having the structure: [ka] wherein # is the point of attachment to C on ring D and * is the point of attachment to N on ring C.

[0112] In certain embodiments, the compound comprises a compound of Formula I, Ia, Ia', Ia1, or Ia2, or a pharmaceutically acceptable salt thereof, wherein Ring A is bicyclo[3.1.0]hexanyl having the structure: [ka] wherein # is the point of attachment to C on ring D and * is the point of attachment to N on ring C.

[0113] In certain embodiments, the compound comprises a compound of Formula I, Ia, Ia', Ia1, or Ia2, or a pharmaceutically acceptable salt thereof, wherein Ring A is bicyclo[3.1.0]hexanyl having the structure: [ka] wherein # is the point of attachment to C on ring D and * is the point of attachment to N on ring C.

[0114] In certain embodiments, the compound comprises a compound of Formula I, Ia, Ia', Ia1, or Ia2, or a pharmaceutically acceptable salt thereof, wherein Ring A is bicyclo[3.1.0]hexanyl having the structure: [ka] wherein # is the point of attachment to C on ring D and * is the point of attachment to N on ring C.

[0115] In certain embodiments, the compound comprises a compound of Formula I, Ia, Ia', Ia1, or Ia2, or a pharmaceutically acceptable salt thereof, wherein Ring A is bicyclo[3.1.0]hexanyl having the structure: [ka] wherein # is the point of attachment to C on ring D and * is the point of attachment to N on ring C.

[0116] In certain embodiments, the compound comprises a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclohexyl having the structure: [ka] wherein # is the point of attachment to C on ring D and * is the point of attachment to N on ring C.

[0117] In certain embodiments, the compound comprises a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclohexyl having the structure: [ka] wherein # is the point of attachment to C on ring D and * is the point of attachment to N on ring C.

[0118] In certain embodiments, the compound comprises a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclohexyl having the structure: [ka] wherein # is the point of attachment to C on ring D and * is the point of attachment to N on ring C.

[0119] In certain embodiments, the compound comprises a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclohexyl having the structure: [ka] wherein # is the point of attachment to C on ring D and * is the point of attachment to N on ring C.

[0120] In certain embodiments, the compound comprises a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclohexyl having the structure: [ka] wherein # is the point of attachment to C on ring D and * is the point of attachment to N on ring C.

[0121] In certain embodiments, the compound comprises a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclopentyl having the structure: [ka] wherein # is the point of attachment to C on ring D and * is the point of attachment to N on ring C.

[0122] In certain embodiments, the compound comprises a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclopentyl having the structure: [ka] wherein # is the point of attachment to C on ring D and * is the point of attachment to N on ring C.

[0123] In certain embodiments, the compound comprises a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclopentyl having the structure: [ka] wherein # is the point of attachment to C on ring D and * is the point of attachment to N on ring C.

[0124] In certain embodiments, the compound comprises a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclopentyl having the structure: [ka] wherein # is the point of attachment to C on ring D and * is the point of attachment to N on ring C.

[0125] In certain embodiments, the compound comprises a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclopentyl having the structure: [ka] wherein # is the point of attachment to C on ring D and * is the point of attachment to N on ring C.

[0126] In certain embodiments, the compound comprises a compound of the following formula: [ka] where the variables are as described herein.

[0127] The subject matter described herein includes the following compounds in Table 1, or pharmaceutically acceptable salts thereof. In Table 1, an asterisk (*) indicates an isolated isomer or group of isolated isomers, but the stereochemistry has been arbitrarily assigned. Individual enantiomers and diastereomers are included in the table below by compound name, and their corresponding structures can be readily determined therefrom. In some cases, the enantiomers or diastereomers of the present disclosure can be identified by their respective properties, such as retention time by chiral HPLC, NMR peaks, and / or biological activity (e.g., as further described in the Examples), with the absolute configuration of one or more chiral centers being arbitrarily assigned (e.g., the stereochemistry of all chiral centers is arbitrarily assigned, or the stereochemistry of one chiral center is known and the remaining chiral centers are arbitrarily assigned, etc.). [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

[0128] III. Pharmaceutical Compositions and Modes of Administration The compounds provided herein are usually administered in the form of pharmaceutical compositions.Therefore, also provided herein are pharmaceutical compositions comprising one or more compounds described herein, or their pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers, and one or more pharmaceutically acceptable additives.Suitable pharmaceutically acceptable additives may include, for example, inert solid diluents and fillers, liquid diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.Such compositions are prepared by methods well known in the pharmaceutical field.See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & C.T. Rhodes, Eds.).

[0129] In some embodiments, the pharmaceutical composition comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula Ib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the compound of Formula I is a compound of Formula Ib', or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula Ia1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula Ib1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula Ia2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula Ib2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Table 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0130] 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.

[0131] 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.

[0132] Oral administration can be another route for administering the compounds described herein. Administration can be, for example, via capsules or tablets, such as enteric-coated tablets. When preparing pharmaceutical compositions containing at least one compound described herein or its pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers, the active ingredient is usually diluted with an additive and / or enclosed in such a carrier, which can be in the form of a capsule, sachet, paper, or other container. When an additive serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injection solution, and sterile packaged powder.

[0133] Some examples of suitable additives include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterilized water, syrup, and methylcellulose.The preparation can further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate, sweeteners, and flavoring agents.

[0134] 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.

[0135] To prepare solid compositions such as tablets, the principal active ingredient can be mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers. When these preformulation compositions are referred to as homogeneous, the active ingredient can be dispersed evenly throughout the composition such that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0136] 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 long-acting action or to protect against the acidic conditions of the stomach.For example, the tablet or pill can comprise an inner dosage 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.

[0137] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable additives as described herein. In some embodiments, compositions are administered by oral or nasal respiratory routes for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by the use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0138] 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.

[0139] IV. Treatment Methods

[0001] 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, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutical composition comprising the same. In certain embodiments, the subject matter disclosed herein relates to a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, 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, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, 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.

[0140] 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, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2 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.

[0141] 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, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2 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.

[0142] 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, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2 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.

[0143] 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, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, induces, promotes, and / or regulates 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.

[0144] 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, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, 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 some embodiments, the compound of Formula I is a compound of Formula Ia', or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ib', or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ia1, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib1, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ia2 or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib2 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0145] In certain embodiments, the subject matter disclosed herein relates to a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, 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 some embodiments, the compound of Formula I is a compound of Formula Ia', or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib', or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ia1, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib1, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ia2, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib2 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0146] In certain embodiments, the subject matter disclosed herein relates to the use of a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, 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 some embodiments, the compound of Formula I is a compound of Formula Ia', or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib', or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ia1, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib1, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ia2, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib2 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0147] 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, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, 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. In other embodiments, the compound of Formula I is a compound of Formula Ia1, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib1, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ia2, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0148] In certain embodiments, the subject matter disclosed herein relates to a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, for use in promoting myelination in a subject in need thereof. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ia1, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib1, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ia2, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0149] In certain embodiments, the subject matter disclosed herein relates to the use of a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound, in the manufacture of a medicament for promoting myelination in a subject in need thereof. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ia1, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib1, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ia2, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0150] 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, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, 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.

[0151] 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, Pelizaeus-Merzbacher disease (PMD), vanishing white matter disease, Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, and Alzheimer's disease. These include, but are not limited to, Zheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post-radiation injury, neurological complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barré syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination.

[0152] A compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof, can be administered alone or in combination with another agent to a subject suffering from a myelin-related disorder to promote myelination of neurons (e.g., neuronal axons). Myelin-related disorders can include any disease, condition (e.g., those resulting from traumatic spinal cord injury and cerebral infarction), or disorder that results in abnormalities in the myelin sheath. Abnormalities can be caused by loss of myelin, referred to as demyelination, myelin dysfunction, referred to as dysmyelination, or failure to form sufficient myelin, referred to as hypomyelination. The myelin-related disorders described herein can result from genetic disorders or one or more of a variety of neurotoxic insults. In some embodiments, the compound of Formula I is a compound of Formula Ia or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ia1 or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib1 or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ia2 or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib2 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0153] 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).

[0154] Oligodendrocytes are required for myelination of neurons. As used herein, the term "myelination" refers to the production of myelin sheaths for nerves by replacing or restoring the function of myelin-producing cells. Neurons undergoing remyelination can be in the brain, spinal cord, or both the brain and spinal cord. Restoring the function of myelin-producing cells can include, for example, increasing the myelin production rate in a cell or cells that have a lower-than-average production level. Such an increase can include increasing the myelin production rate to or above the average production level, but can also include increasing the myelin production rate to a level that is still lower than average but higher than the previous level.

[0155] 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.

[0156] As used herein, "baseline level of myelin production rate" refers to the myelin production rate in a subject being treated before treatment begins.

[0157] V. Methods of Preparing Compounds of Formula I and Their Pharmaceutically Acceptable Salts Compounds can be synthesized by synthetic routes, including processes similar to those known in the chemical arts, and the processes for other heterocycles described below, particularly in light of the description contained herein. Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, for example, 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, WI), or are readily prepared using methods well known to those of skill in the art (e.g., Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, NY (1967-2006 ed.), or Beilstein's Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database).

[0158] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds, as well as the necessary reagents and intermediates, are known in the art and can be found, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 3 rdEd., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and successor editions thereof.

[0159] 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]

[0160] 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.

[0161] Example A: 4-((1s,4s)-4-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclohexyl)morpholine and 4-((1r,4r)-4-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclohexyl)morpholine (Compounds 1* and 2*) [ka] Step 1: 3-Bromo-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1-isopropyl-pyrazole [ka]

[0162] A mixture of 3,5-dibromo-1-isopropyl-pyrazole (500 mg, 1.87 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (575 mg, 2.05 mmol), bis(triphenylphosphine)palladium(II) dichloride (65 mg, 0.09 mmol), and cesium carbonate (1.28 g, 3.73 mmol) in 1,4-dioxane (7.5 mL) and water (7.5 mL) was stirred at 75° C. for 18 hours under N. The reaction mixture was cooled to room temperature, diluted with DCM, washed with brine, dried over anhydrous MgSO, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (heptane / isopropyl acetate) to give the title compound (380 mg, 62% yield). LCMS (ESI) [M+2H] + =328.1.

[0163] Step 2: 3-[5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1-isopropyl-pyrazol-3-yl]-5-(trifluoromethyl)pyridine [ka]

[0164] A mixture of 3-bromo-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1-isopropyl-pyrazole (380 mg, 1.16 mmol), 5-trifluoromethyl-pyridine-3-boronic acid (280 mg, 1.39 mmol), bis(triphenylphosphine)palladium(II) dichloride (41 mg, 0.06 mmol), and cesium carbonate (757 mg, 2.32 mmol) in 1,4-dioxane (4.6 mL) and water (4.6 mL) was stirred at 75 °C for 18 hours under N. The reaction mixture was cooled to room temperature, diluted with DCM, washed with brine, dried over anhydrous MgSO, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (heptane / isopropyl acetate) to give the title compound (80 mg, 18% yield). LCMS(ESI)[M+H] + =394.2.

[0165] Step 3: 3-[5-(1,4-dioxaspiro[4.5]decan-8-yl)-1-isopropyl-pyrazol-3-yl]-5-(trifluoromethyl)pyridine [ka]

[0166] A solution of 3-[5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1-isopropyl-pyrazol-3-yl]-5-(trifluoromethyl)pyridine (80 mg, 0.20 mmol) in ethanol (2 mL) was purged with nitrogen to remove oxygen and charged with 10% palladium on carbon (43 mg, 0.04 mmol), followed by a hydrogen balloon. The reaction mixture was stirred overnight at room temperature, filtered through a Celite cake, rinsed three times with ethanol, and dried to give the title compound as a crude intermediate, which was taken on to the next step without further purification. LCMS (ESI) [M+H] + =396.2.

[0167] Step 4: 4-[2-isopropyl-5-[5-(trifluoromethyl)-3-pyridyl]pyrazol-3-yl]cyclohexanone [ka]

[0168] To a solution of 3-[5-(1,4-dioxaspiro[4.5]decan-8-yl)-1-isopropyl-pyrazol-3-yl]-5-(trifluoromethyl)pyridine (70 mg, 0.18 mmol) in acetone (0.4 mL) and water (0.2 mL) was added TFA (0.16 mL, 2.12 mmol) at 0 °C, and the resulting mixture was stirred at room temperature for 18 hours. The reaction solution was neutralized with 1N NaOH solution. The resulting solution was extracted with saturated sodium bicarbonate solution and DCM. The organic layer was dried over anhydrous MgSO and concentrated under reduced pressure to give the title compound (62 mg, quantitative yield) as a crude intermediate, which was taken on to the next step without purification. LCMS (ESI) [M+H] + =352.2.

[0169] Step 5: 4-((1s,4s)-4-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclohexyl)morpholine and 4-((1r,4r)-4-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclohexyl)morpholine (Compounds 1* and 2*) [ka]

[0170] To a mixture of 4-[2-isopropyl-5-[5-(trifluoromethyl)-3-pyridyl]pyrazol-3-yl]cyclohexanone (62 mg, 0.18 mmol) and morpholine (0.19 mL, 0.22 mmol) in MeOH (2 mL) was added acetic acid (1 μL, 0.02 mmol) and sodium cyanoborohydride (25 mg, 0.40 mmol). The reaction was stirred at room temperature for 2 minutes, diluted with DCM, washed with saturated sodium bicarbonate solution, dried over anhydrous MgSO, filtered, and concentrated in vacuo. The mixture was purified by reverse-phase HPLC, and the cis / trans isomers were then separated by chiral SFC [Chiralpak ID (150 × 21.2 mm, 5 μm); 15% isocratic 0.1% NH4OH in MeOH (40 °C); 70 mL / min] to give the title compounds 1* (peak 1, 8.4 mg, 20% yield) and 2* (peak 2, 29.9 mg, 23% yield). LCMS (ESI) [M+H] + =423.20. Relative stereochemistry arbitrarily assigned.

[0171] Compound 1*: 1 H NMR:(400MHz,DMSO-d6)δ 9.31(d,J=1.9Hz,1H),8.87-8.82(m,1H),8.50-8.44(m,1H),6.82(s,1H),4.62(hept,J=6.5Hz,1H),3.65-3.59(m,4H),2.95-2. 85(m,1H),2.43-2.39(m,3H),2.21-2.15(m,1H),2.02-1.93(m,2H),1.86-1.74(m,2H),1.65-1.51(m,4H),1.44(d,J=6.5Hz,6H).

[0172] Compound 2*: 1H NMR:(400MHz,DMSO-d6)δ 9.27(d,J=2.1Hz,1H),8.89-8.83(m,1H),8.44-8.38(m,1H),6.80(s,1H),4.62(hept,J=6.5Hz,1H),3.61-3.54(m,4H) ),2.78-2.67(m,1H),2.60-2.52(m,1H),2.49-2.38(m,1H),2.34-2.24(m,1H),2.02-1.87(m,4H),1.52-1.34(m,10H).

[0173] Example B: 4-((1R,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane and 4-((1S,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane (Compounds 3 and 4) [ka] Step 1: (R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentanone [ka]

[0174] To a solution of (1R)-3-oxocyclopentanecarboxylic acid (500.0 mg, 3.9 mmol) and 6-(trifluoromethyl)pyridin-3-amidine HCl (1300.0 mg, 5.76 mmol) in N,N-dimethylformamide (4 mL), N,N-diisopropylethylamine (2.65 mL, 15.61 mmol) and HATU (1632 mg, 4.29 mmol) were added and stirred at 20 °C for 1 h. Acetic acid (2.20 mL, 39 mmol) and isopropylhydrazine HCl (647.0 mg, 5.85 mmol) were then added, and the mixture was heated to 80 °C and monitored by LCMS for consumption of the acylamidine intermediate. After 2 h, the reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate (20 mL), adjusted to pH = 8 with NaHCO (aq), and extracted with ethyl acetate (100 mL × 3). The combined organics were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in dioxane (10 mL) and HCl (12 M, 5 mL) and stirred at 20 °C for 2 h. The mixture was adjusted to pH = 8 with NaHCO3 (aq) and extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica flash column chromatography (eluting with 0-50% ethyl acetate in petroleum ether) to give the title compound (600 mg, 45% yield). LCMS (ESI), [M+H] + =339.1.

[0175] Step 2: 4-((3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane [ka]

[0176] To a solution of homomorpholine HCl (366.0 mg, 2.66 mmol), (3R)-3-[2-isopropyl-5-[6-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]cyclopentanone (600.0 mg, 1.77 mmol), and 4 Å molecular sieves in anhydrous 1,2-dichloroethane (3 mL) was added acetic acid (213.0 mg, 3.55 mmol). The reaction mixture was stirred at 25 °C for 1 hour. Sodium triacetoxyborohydride (1127 mg, 5.32 mmol) was then added and stirred at 25 °C for 16 hours. The reaction was quenched with saturated sodium bicarbonate (10 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-10% MeOH in DCM) to give the title compound (550 mg, 1.2858 mmol, 72.5% yield). LCMS (ESI), [M+H] + =424.2.

[0177] Step 3: 4-((1R,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane and 4-((1S,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane (compounds 3 and 4) [ka]

[0178] 4-[Rac-(3R)-3-[2-isopropyl-5-[6-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]cyclopentyl]-1,4-oxazepane (550.0 mg, 1.3 mmol) was separated using chiral SFC [Phenomenex-Cellulose-2 (250 mm x 30 mm, 10 μm); 0.1% NH in HO; MeOH 30 / 30; 70 mL / min] to give the title compounds 3 (first peak in SFC, 26.8 mg, 4.7% yield) and 4 (second peak in SFC, 454.2 mg, 81.8% yield). The relative stereochemistry was determined based on 2D-NMR analysis.

[0179] Compound 3: 1 H NMR(400MHz,DMSO-d6)δ 9.27(s,1H),8.53(dd,J=1.6,8.0Hz,1H),7.99(d,J=8.4Hz,1H),4.79-4.73(m,1H),3.70-3.56(m,6H) ,2.75(brs,4H),2.13-2.03(m,4H),1.91-1.78(m,3H),1.70-1.54(m,1H),1.45(dd,J=4.0,6.4Hz,6H).

[0180] Compound 4: 1 H NMR (400 MHz, DMSO-d6) δ 9.27(d,J=1.6Hz,1H),8.54(dd,J=1.6,8.0Hz,1H),7.98(d,J=8.0Hz,1H),4.79 -4.71(m,1H),3.67(t,J=6.0Hz,2H),3.63-3.61(m,2H),3.46-3.42(m,1H),3.1 6-3.07(m,1H),2.78-2.62(m,4H),2.30-2.25(m,1H),2.09-2.02(m,1H),1.97- 1.87(m,2H),1.84-1.75(m,3H),1.68-1.58(m,1H),1.45(dd,J=3.2,6.4Hz,6H).

[0181] Example C: 4-((1S,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane and 4-((1R,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane (Compounds 5 and 6) [ka] Step 1: (S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentanone [ka]

[0182] To a solution of (1S)-3-oxocyclopentanecarboxylic acid (500.0 mg, 3.9 mmol) and 6-(trifluoromethyl)pyridin-3-amidine HCl (1300.0 mg, 5.76 mmol) in N,N-dimethylformamide (4 mL), N,N-diisopropylethylamine (2.65 mL, 15.61 mmol) and HATU (1632 mg, 4.29 mmol) were added and stirred at 20 °C for 1 h. Then, acetic acid (2.20 mL, 39 mmol) and isopropylhydrazine HCl (647.0 mg, 5.85 mmol) were added. The reaction mixture was heated to 80 °C and monitored by LCMS for consumption of the acylamidine intermediate. After 2 h, the reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate (20 mL), adjusted to pH = 8 with NaHCO3 (aq), and extracted with ethyl acetate (100 mL × 3). The combined organics were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in dioxane (10 mL) and HCl (12 M, 5 mL) and stirred at 20 °C for 2 h. The mixture was adjusted to pH = 8 with NaHCO3 (aq) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica flash column chromatography (eluting with 0-50% ethyl acetate in petroleum ether) to give the title compound (600 mg, 45% yield). LCMS (ESI), [M+H] + =339.1.

[0183] Step 2: 4-((3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane [ka]

[0184] To a solution of (3S)-3-[2-isopropyl-5-[6-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]cyclopentanone (100.0 mg, 0.30 mmol) and homomorpholine HCl (122.0 mg, 0.89 mmol) in anhydrous methyl alcohol (5 mL) was added acetic acid (0.08 mL, 1.48 mmol) and sodium cyanoborohydride (93.0 mg, 1.48 mmol) at 20 °C. The reaction was stirred at 50 °C for 2 hours. The reaction was quenched with saturated sodium bicarbonate (10 mL) and extracted with dichloromethane (50 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-10% methanol in dichloromethane) to give the title compound (100 mg, 79.9% yield). LCMS (ESI), [M+H] + =424.2.

[0185] Step 3: 4-((1S,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane and 4-((1R,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane (Compounds 5 and 6) [ka] [ka]

[0186] 4-[rac-(3S)-3-[2-isopropyl-5-[6-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]cyclopentyl]-1,4-oxazepane (150.0 mg, 0.35 mmol) was separated using chiral SFC (phenomenex-cellulose-2 (250 mm x 30 mm, 10 μm); 0.1% NH₃HO; MeOH 25 / 25; 70 mL / min) to give the title compounds 5 (first peak in SFC, 25.68 mg, 16.9% yield) and 6 (second peak in SFC, 87.3 mg, 57.6% yield). The relative stereochemistry was determined by 2D-NMR.

[0187] Compound 5: 1 H NMR(400MHz,DMSO-d6)δ 9.26(s,1H),8.53(d,J=8.0Hz,1H),7.98(d,J=8.0Hz,1H),4.79-4.72(m,1H),3.70-3.56(m,6H),2.8 2-2.61(m,4H),2.13-2.02(m,4H),1.89-1.75(m,3H),1.59-1.49(m,1H),1.45(dd,J=4.0,6.4Hz,6H).

[0188] Compound 6: 1 H NMR(400MHz,DMSO-d6)δ 9.26(s,1H),8.54(dd,J=1.2,8.0Hz 1H),7.98(d,J=8.0Hz,1H),4.79-4.72(m,1H),3.67(t,J=6.0Hz,2H),3.62-3.60(m,2H),3.47-3.40(m,1H),3.16-3.07(m,1H),2.71-2. 68(m,4H),2.28-2.21(m,1H),2.08-2.03(m,1H),1.94-1.87(m,2H),1.81-1.73(m,3H),1.67-1.61(m,1H),1.44(dd,J=3.2,6.4Hz,6H).

[0189] Example D: 4-((1s,4s)-4-(1-ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-1,4-oxazepane and 4-((1r,4r)-4-(1-ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-1,4-oxazepane (Compounds 7* and 8*) [ka] The title compound was synthesized following a procedure similar to Examples E and F, compounds 5 and 6, but instead using 4-oxocyclohexane-1-carboxylic acid, ethylhydrazine HCl, and 6-(trifluoromethyl)nicotinimidamide HCl in step 1. The cis / trans mixture was separated by reverse-phase HPLC to give the title compounds 7* (first peak by LCMS, 26 mg, 13% yield) and 8* (second peak by LCMS, 39 mg, 20% yield). LCMS (ESI) [M+H] + =424.20. Relative stereochemistry arbitrarily assigned.

[0190] Compound 7*: 1 H NMR(400MHz,DMSO-d6)δ 9.26(d,J=2.1Hz,1H),8.56-8.49(m,1H),8.04-7.98(m,1H),4.27(q,J=7.2Hz,2H),3.93-3.64(m,4H),3.56-3 .33(m,6H),3.09-3.00(m,1H),2.17-2.11(m,2H),2.07-1.98(m,3H),1.80-1.68(m,4H),1.43(t,J=7.2Hz,3H).

[0191] Compound 8*: 1H NMR(400MHz,DMSO-d6)δ 9.35(d,J=2.0Hz,1H),8.61-8.54(m,1H),8.05-7.98(m,1H),4.25(q,J=7.2Hz,2H),3.99-3.66(m,4H ),3.55-3.34(m,7H),2.29-2.14(m,2H),2.07-1.96(m,3H),1.95-1.81(m,4H),1.42(t,J=7.2Hz,3H).

[0192] Example E: 4-((1S,3S)-3-(1-cyclopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane and 4-((1R,3S)-3-(1-cyclopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane (Compounds 9* and 10*) [ka] The title compound was synthesized following a procedure similar to that of Examples E and F, compounds 5 and 6, but using cycloproylhydrazine HCl and 6-(trifluoromethyl)picolinimidamide HCl instead in step 1. The cis / trans mixture was separated by chiral SFC [Chiralpak ID (150 × 21.2 mm, 5 μm); 0.1% NH OH in 30% isocratic methanol; 40° C.; 70 mL / min] to give the title compound 9* (first peak in SFC, 10 mg, 9% yield) and compound 10* (second peak in SFC, 47 mg, 42% yield). LCMS (ESI) [M+H] + =422.10. Relative stereochemistry arbitrarily assigned.

[0193] Compound 9*: 1H NMR(400MHz,DMSO-d6)δ 8.27(d,J=8.0Hz,1H),8.20-8.14(m,1H),7.94-7.88(m,1H),3.78-3.70(m,1H),3.70-3.59(m,5H),3.28-3 .20(m,1H),2.72-2.66(m,4H),2.23-1.97(m,4H),1.93-1.75(m,3H),1.62-1.50(m,1H),1.21-1.09(m,4H).

[0194] Compound 10*: 1 H NMR(400MHz,DMSO-d6)δ 8.28(d,J=8.0Hz,1H),8.21-8.13(m,1H),7.94-7.88(m,1H),3.79-3.59(m,5H),3.59-3.48(m,1H),3.20-3.08(m,1H),2.75-2 .67(m,4H),2.37-2.27(m,1H),2.17-2.05(m,1H),2.01-1.86(m,2H),1.85-1.73(m,3H),1.73-1.59(m,1H),1.26-1.06(m,4H).

[0195] Example F: 4-((1S,3R)-3-(1-cyclopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane and 4-((1R,3S)-3-(1-cyclopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane (Compounds 11* and 12*) [ka] The title compound was synthesized following a procedure similar to that of Examples C and D, compounds 3 and 4, but using cycloproylhydrazine HCl and 6-(trifluoromethyl)picolinimidamide HCl instead in step 1. The cis / trans mixture was separated by chiral SFC [Chiralpak IB-N (150 × 21.2 mm, 5 μm); 0.1% NH OH in 30% isocratic methanol, 30° C.; 70 mL / min] to give the title compounds 11* (first peak in SFC, 6 mg, 5% yield) and 12* (second peak in SFC, 41 mg, 33% yield). LCMS (ESI) [M+H] + =422.10. Relative stereochemistry arbitrarily assigned.

[0196] Compound 11*: 1 H NMR(400MHz,DMSO-d6)δ 8.27(d,J=7.9Hz,1H),8.20-8.14(m,1H),7.93-7.89(m,1H),3.78-3.71(m,1H),3.70-3.59(m,5H),3.27-3 .20(m,1H),2.75-2.64(m,4H),2.23-1.97(m,4H),1.92-1.76(m,3H),1.61-1.50(m,1H),1.21-1.09(m,4H).

[0197] Compound 12*: 1 H NMR(400MHz,DMSO-d6)δ 8.28(d,J=7.9Hz,1H),8.20-8.14(m,1H),7.93-7.89(m,1H),3.77-3.65(m,3H),3.65-3.59(m,2H),3.59-3.49(m,1H),3.19-3.09(m,1H) ),2.75-2.66(m,4H),2.37-2.27(m,1H),2.17-2.06(m,1H),1.99-1.88(m,2H),1.85-1.73(m,3H),1.73-1.59(m,1H),1.23-1.08(m,4H).

[0198] Example G: 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane and 4-((1R,3s,5S,6r)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (Compounds 13 and 14) [ka] Step 1: 5-((1R,5S)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazole [ka]

[0199] Following the general procedure in J. Org. Chem. 2011, 76, 1177, (1R,5S)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxylic acid, isopropylhydrazine HCl, and 3-(trifluoromethyl)benzimidamide HCl, the title compound (1.31 g, 84.5% yield) was obtained after silica flash column chromatography (IprOAc / heptane). LCMS (ESI) [M+H] + =590.3.

[0200] Step 2: (1R,5S)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-ol [ka]

[0201] To a mixture of 5-((1R,5S)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (1.31 g, 2.22 mmol) in THF (22 mL) was slowly added EtN.3HF (7.8 mL 44.4 mmol). The reaction mixture was then heated to 70° C. for 14 h. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO (200 mL), and then extracted with IprOAc (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO, filtered, concentrated, and purified by silica flash chromatography (0-100% heptane / IprOAc) to give the title compound (750 mg, 96% yield). LCMS (ESI) [M+H] + =352.2.

[0202] Step 3: (1R,5S,6r)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-one [ka]

[0203] To a stirred solution of (1R,5S)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-ol (750 mg, 2.13 mmol) in DCM (21 mL) was added Dess-Martin reagent (1.36 g, 3.2 mmol). The reaction mixture was stirred at room temperature for 2 h. Saturated aqueous NaHCO3 (100 mL) and sodium sulfite (100 mL) were slowly added to the reaction mixture, and the resulting reaction mixture was stirred at room temperature for 0.5 h. The organic layer was separated, and the aqueous layer was extracted with DCM (100 mL × 2). The combined organic layers were washed with brine over anhydrous Mg2SO4, filtered, concentrated, and purified by silica flash chromatography (IprOAc / heptane) to give the title compound (710 mg, 2 mmol). LCMS(ESI)[M+H] + =350.1.

[0204] Step 4: 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane and 4-((1R,3s,5S,6r)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (Compounds 13 and 14) [ka]

[0205] To a mixture of (1R,5S,6r)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-one (142 mg, 0.41 mmol) and homomorpholine (65 mg, 0.61 mmol) in MeOH (4.1 mL) was added acetic acid (203 μL, 3.54 mmol) and sodium cyanoborohydride (51 mg, 0.81 mmol). The reaction mixture was stirred at 50° C. for 2 h, cooled, then diluted with DCM, washed with saturated aqueous NaHCO, dried over anhydrous MgSO, filtered, and concentrated in vacuo. The cis / trans mixture was separated by reverse-phase HPLC (Interchim HPLC, 0.1% aqueous ammonium hydroxide, acetonitrile, XSelect CSH Prep C18, 50 x 30 mm x 5 μm, 40-80% B over 10 min at 60 mL / min) to give the title compounds 13 (trans isomer, 27 mg, 15% yield) and 14 (cis isomer, 26 mg, 15% yield). LCMS (ESI) [M+H] + = 435.2. The relative stereochemistry was determined by 2D-NMR analysis.

[0206] Compound 13: 1 H NMR (400 MHz, DMSO-d6) δ 8.23-8.16(m,1H),8.16-8.11(m,1H),7.78-7.71(m,1H),7.71-7.63(m,1H),4. 85(hept,J=6.6Hz,1H),3.66(t,J=5.9Hz,2H),3.63-3.56(m,2H),3.30-3.21(m ,1H),2.68-2.60(m,4H),2.21(t,J=3.2Hz,1H),2.20-2.12(m,2H),1.92-1.85( m,2H),1.82-1.71(m,2H),1.67(dd,J=13.6,7.1Hz,2H),1.48(d,J=6.5Hz,6H).

[0207] Compound 14: 1H NMR(400MHz,DMSO-d6)δ 8.23-8.17(m,1H),8.15(d,J=1.8Hz,1H),7.78-7.71(m,1H),7.71-7.63(m,1H),4.88(h,J=6.6Hz,1H),3.66(t,J=6.0Hz,2H),3.63- 3.56(m,2H),3.00-2.87(m,1H),2.66-2.57(m,4H),2.15-2.05(m,3H),1.95-1.86(m,2H),1.83-1.67(m,4H),1.45(d,J=6.6Hz,6H).

[0208] Example H: 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane and 4-((1R,3s,5S,6r)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (Compounds 15 and 16) [ka] The title compound was synthesized following a procedure similar to that of Examples C and D, compounds 13 and 14, but using 6-(trifluoromethyl)picolinimidamide HCl instead in step 1. The cis / trans mixture was separated by reverse-phase HPLC (Interchim HPLC, 0.1% ammonium hydroxide in water, Solvent B: acetonitrile, Column: XSelect CSH Prep C18, Column dimensions: 50 × 30 mm (5 μm), Column temperature: 25 °C, Method: 30-70% B over 10 min at 60 mL / min) to give the title compounds 15 (trans isomer; 17.5 mg, 11% yield) and 16 (cis isomer; 15 mg, 10% yield). LCMS (ESI) [M+H] + =436.2. The relative stereochemistry was determined by 2D-NMR.

[0209] Compound 15:1 H NMR(400MHz,DMSO-d6)δ 9.24-9.18(m,1H),8.51-8.44(m,1H),7.99-7.92(m,1H),4.88(h,J=6. 6Hz,1H),3.66(t,J=5.9Hz,2H),3.63-3.56(m,2H),3.30-3.19(m,1H), 2.68-2.60(m,4H),2.28-2.23(m,1H),2.23-2.12(m,2H),1.93-1.85(m ,2H),1.76(p,J=5.9Hz,2H),1.72-1.63(m,2H),1.49(d,J=6.6Hz,6H).

[0210] Compound 16: 1 H NMR(400MHz,DMSO-d6)δ 9.24-9.19(m,1H),8.52-8.44(m,1H),8.00-7.92(m,1H),4.93(hept,J=6.6Hz,1H),3.66(t,J=6.0Hz,2H),3.63-3.56(m,2H),2.95(p,J=8 .4Hz,1H),2.65-2.57(m,4H),2.16-2.06(m,3H),1.92(tt,J=1.9,1.0Hz,2H),1.82-1.75(m,2H),1.75-1.67(m,2H),1.46(d,J=6.6Hz,6H).

[0211] Example I: 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(3-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane and 4-((1R,3s,5S,6r)-6-(1-isopropyl-3-(3-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (Compounds 17 and 18) [ka] The title compound was synthesized following a procedure similar to that of Examples C and D, compounds 13 and 14, but using 3-(trifluoromethoxy)benzimidamide instead in step 1. The cis / trans mixture was separated by reverse-phase HPLC (Interchim HPLC, 0.1% aqueous ammonium hydroxide, acetonitrile, XSelect CSH Prep C18, 50 x 30 mm (5 μm), 25 °C, 40-80% B over 10 min, 60 mL / min) to give the title compounds 17 (trans isomer; 31.8 mg, 14.4% yield) and 18 (cis isomer; 33.7 mg, 15% yield). LCMS (ESI) [M+H] + =451.2. The relative stereochemistry was determined by 2D-NMR analysis.

[0212] Compound 17: 1 H NMR(400MHz,DMSO-d6)δ 7.97-7.89(m,1H),7.79-7.73(m,1H),7.61-7.52(m,1H),7.42-7.33(m ,1H),4.83(h,J=6.6Hz,1H),3.66(t,J=5.9Hz,2H),3.63-3.56(m,2H), 3.30-3.20(m,1H),2.65-2.61(m,4H),2.21-2.14(m,3H),1.91-1.82(m ,2H),1.76(p,J=5.9Hz,2H),1.71-1.61(m,2H),1.47(d,J=6.6Hz,6H).

[0213] Compound 18: 1 H NMR (400 MHz, DMSO-d6) δ 7.97-7.90(m,1H),7.79-7.73(m,1H),7.61-7.52(m,1H),7.41-7.33(m,1H) ,4.88(hept,J=6.6Hz,1H),3.66(t,J=6.0Hz,2H),3.62-3.56(m,2H),3.00- 2.87(m,1H),2.66-2.57(m,4H),2.15-2.07(m,2H),2.07-2.04(m,1H),1.94 -1.84(m,2H),1.82-1.75(m,2H),1.75-1.66(m,2H),1.44(d,J=6.5Hz,6H).

[0214] Example J: 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)morpholine and 4-((1R,3s,5S,6r)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)morpholine (Compounds 19* and 20*) [ka] The title compound was synthesized following a procedure similar to that of Examples C and D, compounds 13 and 14, but using morpholine instead in step 4. The cis / trans mixture was separated by reverse-phase HPLC (Interchim HPLC; 0.1% aqueous ammonium hydroxide, acetonitrile, XSelect CSH Prep C18, 50 x 30 mm x 5 μm) at 25 °C, 60 mL / min over 10 min (40-80%) to give the title compounds 19* (trans isomer, 31.9 mg, 17% yield) and 20* (cis isomer, 55.3 mg, 29% yield). LCMS (ESI) [M+H] + =421.1. Relative stereochemistry arbitrarily assigned.

[0215] Compound 19*: 1 H NMR(400MHz,DMSO-d6)δ 8.23-8.17(m,1H),8.17-8.11(m,1H),7.78-7.71(m,1H),7.71-7.63(m,1H),4.81(p,J=6.6Hz,1H),3.57(t,J=4.6Hz,4H),2.85-2 .74(m,1H),2.38-2.34(m,4H),2.34-2.28(m,1H),2.16-2.05(m,2H),1.96-1.86(m,2H),1.85-1.75(m,2H),1.48(d,J=6.6Hz,6H).

[0216] Compound 20*: 1H NMR(400MHz,DMSO-d6)δ 8.24-8.17(m,1H),8.17-8.13(m,1H),7.80-7.73(m,1H),7.73-7.65(m,1H),4.91-4.79(m,1H),4.05-3.98(m,2H),3.69-3.59 (m,3H),3.49-3.41(m,2H),3.04-2.99(m,2H),2.44-2.39(m,2H),2.14-2.08(m,1H),2.11-2.06(m,4H),1.47(d,J=6.6Hz,6H).

[0217] Example K: 4-((1R,3R)-3-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1S,3R)-3-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compounds 21* and 22*) [ka] The title compound was synthesized following a procedure similar to that of Examples C and D, compounds 3 and 4, but using 3-(trifluoromethyl)benzimidamide HCl in step 1 and morpholine in step 2 instead. The cis / trans mixture was separated by chiral SFC [PIC 200; cellulose-2 (250 × 21.2 mm, 5 μm); 15% isocratic 0.1% NHOH in MeOH (40 °C); 70 mL / min] to give the title compounds 21* (first peak in SFC, 27.6 mg, 13% yield) and 22* (second peak in SFC, 75.4 mg, 36% yield). LCMS (ESI) [M+H] + =409.2. Relative stereochemistry arbitrarily assigned.

[0218] Compound 21*: 1H NMR(400MHz,DMSO-d6)δ 8.26(d,J=7.7Hz,1H),8.20(s,1H),7.79(d,J=7.8Hz,1H),7.75-7.66(m ,1H),4.73(hept,J=6.6Hz,1H),4.05-3.99(m,1H),3.93(s,1H),3.60(s, 5H),3.19-3.13(m,1H),2.79(s,1H),2.45-2.39(m,2H),2.30-2.24(m,2 H),2.14(s,1H),2.05-1.99(m,1H),1.91-1.82(m,1H),1.49-1.41(m,6H)

[0219] Compound 22*: 1 H NMR(400MHz,DMSO-d6)δ 8.30-8.22(m,1H),8.22-8.16(m,1H),7.82-7.74(m,1H),7.74-7.65(m ,1H),4.72(h,J=6.6Hz,1H),3.62-3.54(m,4H),3.49-3.37(m,1H),2.72 -2.59(m,1H),2.43(s,4H),2.32-2.20(m,1H),2.12-1.99(m,1H),1.98 -1.84(m,2H),1.84-1.71(m,1H),1.71-1.61(m,1H),1.48-1.40(m,6H).

[0220] Example L: 4-((1S,3S)-3-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1S,3S)-3-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compounds 23* and 24*) [ka] The title compound was synthesized following a procedure similar to that of Examples E and F, compounds 5 and 6, but using 3-(trifluoromethyl)benzimidamide HCl in step 1 and morpholine in step 2 instead. The cis / trans mixture was separated by chiral SFC [cellulose-2 (250 × 21.2 mm × 5 μm); 15% isocratic 0.1% NH4OH in MeOH (40 °C); 70 mL / min] to give the title compounds 23* (first peak in SFC, 22.9 mg, 11% yield) and 24* (second peak in SFC, 68.9 mg, 32.4% yield). LCMS (ESI) [M+H] + =409.2. Relative stereochemistry arbitrarily assigned.

[0221] Compound 23*: 1 H NMR(400MHz,DMSO-d6)δ 8.30-8.22(m,1H),8.22-8.16(m,1H),7.82-7.74(m,1H),7.74-7.65(m,1 H),4.72(h,J=6.5Hz,1H),3.63-3.52(m,4H),3.56-3.44(m,1H),2.79(p,J =7.6Hz,1H),2.45-2.39(m,4H),2.20-2.07(m,1H),2.11-2.00(m,1H),2. 05-1.93(m,2H),1.93-1.77(m,1H),1.61-1.47(m,1H),1.47-1.40(m,6H).

[0222] Compound 24*: 1 H NMR(400MHz,DMSO-d6)δ 8.30-8.22(m,1H),8.22-8.16(m,1H),7.82-7.74(m,1H),7.74-7.65(m,1H),4.73(hept,J=6.5Hz,1H),3.58(t,J=4.6Hz,4H),3.51-3.37(m ,1H),2.73-2.59(m,1H),2.46-2.40(m,4H),2.32-2.20(m,1H),2.12- 1.99(m,1H),1.98-1.84(m,2H),1.89-1.60(m,2H),1.48-1.40(m,6H).

[0223] Example M: ​​4-((1R,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1S,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compounds 25* and 26*) [ka] The title compound was synthesized following a procedure similar to that of Examples C and D, compounds 3 and 4, but using 6-(trifluoromethyl)picolinimidamide HCl in step 1 and morpholine in step 2 instead. The cis / trans mixture was separated by chiral SFC [Chiracel OX (150 × 21.2 mm, 5 μm); 20% isocratic; 0.1% NH OH in MeOH (40° C.); 70 mL / min] to give the title compounds 24* (first peak in SFC, 28.2 mg, 13.3% yield) and 26* (second peak in SFC, 115.7 mg, 55% yield). LCMS (ESI) [M+H] + =410.2. Relative stereochemistry arbitrarily assigned.

[0224] Compound 25*: 1 H NMR(400MHz,DMSO-d6)δ 8.30(d,J=8.0Hz,1H),8.22-8.13(m,1H),7.92(d,J=7.7Hz,1H),4.76(hept,J=6.5Hz,1H),3.63-3.55(m,4H),3.58-3.46(m ,1H),2.80(p,J=7.5Hz,1H),2.46-2.38(m,4H),2.21-1.94(m,4H),1.93-1.78(m,1H),1.62-1.49(m,1H),1.54-1.41(m,6H).

[0225] Compound 26*: 1H NMR(400MHz,DMSO-d6)δ 8.31(d,J=8.0Hz,1H),8.22-8.13(m,1H),7.96-7.88(m,1H),4.76(hept,J=6.6Hz,1H),3.58(t,J=4.6Hz,4H),3.51-3.39(m,1H),2.72-2.63( m,1H),2.47-2.38(m,4H),2.33-2.21(m,1H),2.11-2.01(m,1H),1.98- 1.85(m,2H),1.89-1.75(m,1H),1.78-1.60(m,1H),1.49-1.41(m,6H).

[0226] Example N: 4-((1R,3R)-3-(1-isopropyl-3-(4-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1S,3R)-3-(1-isopropyl-3-(4-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and (Compounds 27* and 28*) [ka] The title compound was synthesized following a procedure similar to that of Examples C and D, compounds 3 and 4, but using 4-(trifluoromethyl)picolinimidamide HCl in step 1 and morpholine in step 2 instead. The cis / trans mixture was separated by chiral SFC [Chiralpak IC (150 x 21.2 mm x 5 μm); 20% isocratic 0.1% NHOH in MeOH; 40° C.; 70 mL / min] to give the title compounds 27* (SFC first peak, 1 mg, 3% yield) and 28* (SFC second peak, 4.1 mg, 19% yield). LCMS (ESI) [M+H] + =410.2. Relative stereochemistry arbitrarily assigned.

[0227] Compound 27: Not determined.

[0228] Compound 28: 1H NMR(400MHz,DMSO-d6)δ 8.96-8.89(m,1H),8.22-8.16(m,1H),7.84-7.76(m,1H),4.82-4.64(m,1H),3.58(t,J=4.6Hz,4H),3.46(p,J=8.1Hz,1H),2.74-2.61(m,1 H),2.47-2.40(m,4H),2.33-2.21(m,1H),2.15-2.00(m,1H),1.98-1.85(m,2H),1.89-1.73(m,1H),1.73-1.59(m,1H),1.48-1.41(m,6H).

[0229] Example O: 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane and 4-((1R,3s,5S,6r)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (Compounds 29 and 30) [ka] Step 1: (1R,5S,6r)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one [ka]

[0230] To a solution of (1R,5S,6r)-6-(3-iodo-1-isopropyl-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one (2.0 g, 6.1 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine (2.5 g, 9.2 mmol) in 1,4-dioxane (32 mL) and water (8 mL), CsCO (6 g, 18.4 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (460 mg, 0.65 mmol) were added. The reaction mixture was then placed under a nitrogen atmosphere and stirred at 100 °C for 4 h. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (2.1 g, 5.8 mmol, 96% yield). LCMS (ESI) [M+H] + =350.2.

[0231] Step 2: 4-((1R,3s,5S,6r)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane and 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (Compounds 29* and 30*) [ka]

[0232] To a solution of (1R,5S,6r)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one (100 mg, 0.28 mmol) and 1,4-oxazepane hydrochloride (60 mg, 0.44 mmol) in anhydrous methanol (4 mL) was added NaBHCN (90 mg, 1.44 mmol) at 20 °C. The reaction mixture was then heated to 70 °C and stirred for 2 h. The reaction was quenched with saturated NaHCO solution (5 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 preparative TLC (6% methanol in dichloromethane) to give a mixture of diastereomeric compounds (90 mg, 72% yield), which was separated by chiral SFC (Daicel Chiralcecl OJ-H (250 mm*30 mm, 5 μm); supercritical CO2 / EtOH+NH3·H2O=90 / 10; 60 mL / min) to give compound 29 (first peak of SFC, 14.8 mg, 16.3% yield) and compound 30 (second peak of SFC, 23.5 mg, 26% yield). LCMS (ESI) [M+H] + =435.4. Relative stereochemistry 1 Assignment was based on 1 H NMR.

[0233] Compound 29: 1 H NMR(400MHz,CDCl3)δ 9.11(s,1H),8.74(s,1H),8.29(s,1H),6.13(s,1H),4.80-4.60(m,1H),3.80(t,J=6.0Hz,2H),3.76(s,2H),3.39-3.33( m,1H),2.74-2.67(m,4H),2.39-2.32(m,2H),1.95-1.88(m,2H),1.82-1.79(m,1H),1.56(d,J=6.8Hz,6H),1.26(s,4H).

[0234] Compound 30: 1H NMR(400MHz,CDCl3)δ 9.11(s,1H),8.74(s,1H),8.29(s,1H),6.17(s,1H),4.76-4.69(m,1H),3.79(t,J=6.4Hz,2H),3.74(d,J=4.0Hz,2 H),2.90-2.62(m,5H),2.33-2.13(m,2H),1.98-1.91(m,J=10.8Hz,4H),1.70-1.65(m,3H),1.55(d,J=6.4Hz,6H).

[0235] Example P: 4-((1R,3s,5S,6r)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)morpholine (Compound 31) and 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)morpholine (Compound 32) [ka] [ka] The title compound was synthesized following a similar procedure to compound 29*, using 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine in step 1. The crude mixture was purified by silica flash chromatography (0-100% ethyl acetate in petroleum ether) to give compound 31 (second peak in HPLC (basic), 19.2 mg, 23% yield) and compound 32 (first peak in HPLC (basic), 18.7 mg, 22% yield). LCMS (ESI) [M+H] + =421.1. The relative stereochemistry was determined by 2D-NMR analysis.

[0236] Compound 31: 1H NMR(400MHz,CD3OD)δ 8.15(d,J=8.0Hz,1H),7.97(t,J=7.6Hz,1H),7.62(d,J=7.6Hz,1H),6.51(s,1H),4.84-4.76(m,1H),3.70(t,J=4. 4Hz,4H),2.61-2.40(m,5H),2.29(dd,J=13.2,7.2Hz,2H),1.89-1.78(m,2H),1.75(s,3H),1.53(d,J=6.4Hz,6H).

[0237] Compound 32: 1 H NMR(400MHz,DMSO-d6)δ 8.17-8.11(m,1H),8.10-8.02(m,1H),7.75(d,J=7.6Hz,1H),6.38(s,1H),4.79-4.73(m,1H),3.55(t,J=4.4Hz,4H),2.84-2. 72(m,1H),2.35-2.33(m,4H),2.19-2.05(m,2H),2.03-2.01(m,1H),1.76-1.71(m,2H),1.67(brs,2H),1.47(d,J=6.4Hz,6H).

[0238] Example Q: 4-((1R,3s,5S,6r)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-2,2-dimethylmorpholine (compound 33) and 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-2,2-dimethylmorpholine (compound 34) [ka] The title compound was synthesized according to a similar procedure to compound 29*, using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine in step 1. The crude mixture was purified by reverse phase chromatography (column: Phenomenex Gemini C18 250*50mm*10um; mobile phase: [water (0.05% ammonia hydroxide)]; acetonitrile; 60%-80%, 10 min) to give compound 33 (first peak in HPLC (basic), 24.4 mg, 23.5% yield) and compound 34 (second peak in HPLC (basic), 13.5 mg, 13% yield). LCMS (ESI) [M+H] + =449.3. The relative stereochemistry was determined by 2D-NMR.

[0239] Compound 33: 1 H NMR(400MHz,CD3OD)δ 9.15(s,1H),8.73(s,1H),8.41(s,1H),6.43(s,1H),4.82-4.75(m,1H),3.75-3.65(m,2H),2 .42-2.32(m,3H),2.29-2.18(m,4H),1.83-1.73(m,5H),1.53(d,J=6.0Hz,6H),1.24(s,6H).

[0240] Compound 34: 1 H NMR(400MHz,CD3OD)δ 9.15(s,1H),8.73(s,1H),8.41(s,1H),6.38(s,1H),4.82-4.75(m,1H),3.71(t,J=4.8Hz,2H),2.74-2.72(m,1H),2.42-2. 32(m,2H),2.25-2.19(m,2H),2.16-2.09(m,3H),1.93-1.89(m,2H),1.69-1.64(m,2H),1.54(d,J=6.8Hz,6H),1.24(s,6H).

[0241] Example R: (1R,4R)-5-((1R,3s,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane, (1S,4R)-5-((1R,3s,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane, (1R,4R)-5 -((1R,3r,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane and (1S,4R)-5-((1R,3r,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (Compounds 35*, 36*, 37*, and 38*) [ka] The title compound was synthesized following a procedure similar to that of compound 29*, using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine in step 1. The crude mixture was purified by reverse-phase chromatography (70-100% acetonitrile / (0.05% NH3H2O ​​in water + 10 mM NH4HCO3) to give a cis-diastereomeric mixture (first peak in HPLC (basic), 70 mg, 32.2% yield) and a trans-diastereomeric mixture (second peak in HPLC (basic), 100 mg, 49% yield). LCMS (ESI) [M+H] + =433.4.

[0242] The cis mixture (peak 1) was confirmed by 2D NMR (first peak in HPLC (basic), 70 mg) and separated by chiral SFC (Daicel Chiralcel OJ-H (250 mm x 30 mm, 5 μm); supercritical CO₂ / EtOH + NH₃·H₂O = 85 / 15; 60 mL / min) to give the cis title compound 35* (first peak in SFC, 13.9 mg, 18.9% yield) and the cis title compound 36* (second peak in SFC, 12.1 mg, 16.4% yield). LCMS (ESI) [M+H] + =433.4. Absolute stereochemistry arbitrarily assigned.

[0243] Compound 35*: 1 H NMR(400MHz,CDCl3)δ 9.12(d,J=1.6Hz,1H),8.76(s,1H),8.29(s,1H),6.20(s,1H),4.73-4.60(m,1H),4.54-4.48(m,1H),4.16-4.09(m,1H),3.76-3.68(m,1 H),3.19-2.97(m,1H),2.69-2.65(m,1H),2.32-2.15(m,4H),2.01-1.91(m,1H),1.84-1.80(m,4H),1.56(d,J=6.8Hz,6H),1.26(s,2H).

[0244] Compound 36*: 1 H NMR(400MHz,CDCl3)δ 9.12(s,1H),8.76(s,1H),8.29(s,1H),6.21(s,1H),4.66-4.58(m,2H),4.25-4.18(m,1H),3.79-3.72(m,1H),3.19-3.16(m ,1H),2.75-2.69(m,1H),2.35-2.15(m,4H),2.04-1.95(m,1H),1.86-1.82(m,4H),1.58-1.55(d,J=6.8Hz,6H),1.26(s,2H).

[0245] The trans stereochemistry was confirmed by 2D NMR (second peak in HPLC (basic), 100 mg), and the mixture was separated by chiral SFC (Daicel Chiralcel OJ-H (250 mm * 30 mm, 5 μm); supercritical CO2 / EtOH + NH3 · H2O = 75 / 25; 60 mL / min) to give the trans title compound 37* (first peak in SFC, 33.9% yield) and the trans title compound 38* (second peak in SFC, 49.4 mg, 48.4% yield). Absolute stereochemistry was arbitrarily assigned. LCMS (ESI) [M+H] + =433.4.

[0246] Compound 37*: 1 H NMR(400MHz,CDCl3)δ 9.11(s,1H),8.74(s,1H),8.29(s,1H),6.11(s,1H),4.75-4.69(m,1H),4.39-4.35(m,1H),4.06-3.98(m,1H),3.65-3.56(m,2H),3 .35-3.31(m,1H),2.93-2.88(m,1H),2.52-2.40(m,2H),2.16-1.93(m,3H),1.69-1.63(m,4H),1.56(d,J=6.8Hz,6H),1.26(s,1H).

[0247] Compound 38*: 1 H NMR(400MHz,CDCl3)δ 9.11(d,J=1.6Hz,1H),8.74(s,1H),8.29(s,1H),6.12(s,1H),4.72-4.68(m,1H), 4.44-4.37(m,1H),4.03-3.98(m,1H),3.74-3.62(m,2H),3.34-3.31(m,1H),2.93- 2.89(m,1H),2.54-2.51(m,1H),2.41-2.38(m,1H),2.20-2.17(m,1H),1.93-1.89 (m,2H),1.82-1.70(m,2H),1.69-1.65(m,2H),1.56(d,J=6.8Hz,6H),1.26(s,1H).

[0248] Example S: (S)-4-((1R,3s,5S,6S)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-2-methylmorpholine, (R)-4-((1R,3s,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-2-methylmorpholine, (S)-4-((1 (R,3r,5S,6S)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-2-methylmorpholine and (R)-4-((1R,3r,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-2-methylmorpholine (Compounds 39*, 40*, 41*, and 42*) [ka] The title compound was synthesized following a procedure similar to that of compound 29*, using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine in step 1. The crude residue was purified by reverse-phase chromatography (70-100% acetonitrile / (0.05% NH3H2O ​​in water + 10 mM NH4HCO3) to give a cis-diastereomeric mixture (first peak in HPLC (basic), 80 mg, 39.6% yield) and a trans-diastereomeric mixture (second peak in HPLC (basic), 73 mg, 36.1% yield). LCMS (ESI) [M+H] + =435.4.

[0249] The cis-diastereomeric stereochemistry was confirmed by 2D NMR (first peak in HPLC (basic), 80 mg) and separated by chiral SFC (SFC-17; DAICEL CHIRALCEL OJ-H (250 mm * 30 mm, 5 μm); supercritical CO2 / EtOH + NH3·H2O = 90 / 10; 60 mL / min) to give the title compound 39* (first peak in SFC, 21.9 mg, 27.4% yield) and the title compound 40* (second peak in SFC, 14.7 mg, 18.4% yield). LCMS (ESI) [M+H] + = 435.4. Absolute stereochemistry arbitrarily assigned.

[0250] Compound 39*: 1 H NMR(400MHz,CDCl3)δ 9.11(s,1H),8.75(s,1H),8.29(s,1H),6.18(s,1H),4.73-4.66(m,1H),3.90-3.87(m,1H),3.78-3.63(m,2H),2.86-2.77(m,2H),2. 46-2.42(m,1H),2.31-2.23(m,2H),2.20-1.82(m,4H),1.76-1.72(m,2H),1.55(d,J=6.8Hz,6H),1.26(s,1H),1.18(d,J=6.4Hz,3H).

[0251] Compound 40*: 1 H NMR(400MHz,CDCl3)δ 9.11(s,1H),8.74(s,1H),8.29(s,1H),6.12(s,1H),4.73-4.66(m,1H),3.91-3.88(m,1H),3.73-3.55(m,2H),2.91-2.72( m,4H),2.34-2.24(m,2H),2.14-1.97(m,1H),1.76-1.72(m,4H),1.55(d,J=6.8Hz,6H),1.26(s,1H),1.18(d,J=6.4Hz,3H).

[0252] The trans stereochemistry was confirmed by 2D NMR analysis, and the mixture (second peak of HPLC (basic), 73 mg) was separated by chiral SFC (Daicel Chiralcel OJ-H (250 mm * 30 mm, 5 μm); supercritical CO2 / EtOH + NH3 · HO = 90 / 10; 60 mL / min) to give the title compound 41* (first peak of SFC, 21.6 mg, 29.6% yield) and the title compound 42* (second peak of SFC, 18.5 mg, 25.3% yield). LCMS (ESI) [M+H] + = 435.4. Absolute stereochemistry arbitrarily assigned.

[0253] Compound 41*: 1 H NMR(400MHz,CDCl3)δ 9.11(s,1H),8.74(s,1H),8.29(s,1H),6.18(s,1H),4.74-4.62(m,1H),3.90-3.87(m,1H),3.80-3.65(m,2H),2.86-2.78(m,2H),2. 46-2.42(m,1H),2.30-2.23(m,2H),2.07-1.76(m,4H),1.75-1.74(m,2H),1.55(d,J=6.8Hz,6H),1.26(s,1H),1.17(d,J=6.4Hz,3H).

[0254] Compound 42*: 1 H NMR(400MHz,CDCl3)δ 9.10(s,1H),8.74(s,1H),8.29(s,1H),6.12(s,1H),4.73-4.66(m,1H),3.90-3.88(m,1H),3.67-3.61(m,2H),2.89-2.74( m,4H),2.34-2.28(m,2H),2.12-1.98(m,1H),1.72-1.66(m,4H),1.55(d,J=6.8Hz,6H),1.26(s,1H),1.18(d,J=6.4Hz,3H).

[0255] Example T: (S)-4-((1R,3s,5S,6S)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine, (R)-4-((1R,3s,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine, (S)-4-((1 (R,3r,5S,6S)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (R)-4-((1R,3r,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine (Compounds 43*, 44*, 45*, and 46*) [ka] The title compound was synthesized following a procedure similar to that of compound 29*, using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine in step 1. The crude residue was purified by reverse-phase chromatography (70-100% acetonitrile / (0.05% NH3H2O ​​in water + 10 mM NH4HCO3) to give the cis mixture (first peak in HPLC (basic), 75 mg, 36.8% yield) and the trans mixture (second peak in HPLC (basic), 100 mg, 49.5% yield). LCMS (ESI) [M+H] + =435.4.

[0256] The cis stereochemistry was confirmed by 2D NMR analysis, and the mixture (first peak of HPLC (basic), 75 mg) was separated by chiral SFC (Daicel Chiralcel OJ-H (250 mm * 30 mm, 5 μm); supercritical CO2 / EtOH + NH3 · HO = 90 / 10; 60 mL / min) to give the title compound 43* (first peak of SFC, 12.1 mg, 16.1% yield) and the title compound 44* (second peak of SFC, 14.4 mg, 19.2% yield). LCMS (ESI) [M+H] + = 435.4. Absolute stereochemistry arbitrarily assigned.

[0257] Compound 43*: 1 H NMR(400MHz,CDCl3)δ 9.11(d,J=1.6Hz,1H),8.75(s,1H),8.29(s,1H),6.20(s,1H),4.67-4.59(m,1H),4.11-3.59(m,4H),2.97- 2.82(m,3H),2.39-1.91(m,3H),1.77-1.74(m,3H),1.55(d,J=6.4Hz,6H),1.26(s,3H),1.19-1.13(m,2H).

[0258] Compound 44*: 1 H NMR(400MHz,CDCl3)δ 9.11(d,J=1.6Hz,1H),8.75(s,1H),8.29(s,1H),6.19(s,1H),4.61-4.59(m,1H),4.01-3.57(m,4H),3.10-2.72(m,3H),2.56-2 .50(m,1H),2.26-2.10(m,2H),2.03-1.88(m,1H),1.76-1.72(brs,2H),1.55(d,J=6.4Hz,6H),1.26(s,3H),1.18-1.157(m,2H).

[0259] The trans stereochemistry was confirmed by 2D NMR, and the mixture (second peak of HPLC (basic), 100 mg) was separated by chiral SFC (Daicel Chiralcel OJ-H (250 mm * 30 mm, 5 μm); supercritical CO2 / EtOH + NH3 · HO = 90 / 10; 60 mL / min) to give the title compound 45* (first peak of SFC, 27.7 mg, 27.4% yield) and the title compound 46* (second peak of SFC, 26.6 mg, 26.3% yield). LCMS (ESI) [M+H] + = 435.4. Absolute stereochemistry arbitrarily assigned.

[0260] Compound 45*: 1 H NMR(400MHz,CDCl3)δ 9.11(s,1H),8.74(s,1H),8.29(s,1H),6.13(s,1H),4.80-4.58(m,1H),3.90-3.61(m,3H),3.55-3.40(m,2H),2.85-2.81(m,1H),2.6 4-2.61(m,1H),2.49-2.42(m,1H),2.35-2.09(m,2H),1.88-1.72(m,2H),1.68-1.65(m,4H),1.56(d,J=6.8Hz,6H),1.09-1.07(m,2H).

[0261] Compound 46*: 1 H NMR(400MHz,CDCl3)δ 9.11(d,J=1.2Hz,1H),8.74(s,1H),8.29(s,1H),6.13(s,1H),4.78-4.60(m,1H),3.88-3.61(m,3H),3.58-3.42(m,2H),2.85-2.81(m,1H) ,2.64-2.61(m,1H),2.49-2.42(m,1H),2.34-2.13(m,2H),1.88-1.72(m,2H),1.69-1.65(m,4H),1.56(d,J=6.8Hz,6H),1.13-1.09(m,2H).

[0262] Example U: 4-((1R,3S,5S,6R)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (compound 47) and 4-((1R,3S,5S,6R)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (compound 48) [ka] The title compound was synthesized following a procedure similar to that of compound 29*, using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine in step 1. The crude residue was purified by reverse-phase chromatography (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, 70%-100%) to give title compound 47 (second peak in SFC, 57.9 mg, 31% yield) and title compound 48 (first peak in SFC, 46.1 mg, 25% yield). LCMS (ESI) [M+H] + =435.3. The relative stereochemistry was determined by 2D-NMR.

[0263] Compound 47: 1 H NMR(400MHz,CDCl3)δ 9.04(s,1H),8.24(d,J=8.8Hz,1H),7.67(d,J=8.0Hz,1H),6.20(s,1H),4.75-4.56(m,1H),3.86-3.76(m,4H),2.88-2.65(m, 4H),2.33-2.21(dd,J=12.4,7.2Hz,2H),2.05-1.92(m,4H),1.77-1.69(s,2H),1.60(d,J=3.2Hz,2H),1.56(d,J=6.8Hz,6H).

[0264] Compound 48: 1H NMR(400MHz,CDCl3)δ 9.02(s,1H),8.23(d,J=8.0Hz,1H),7.65(d,J=8.4Hz,1H),6.13(s,1H),4.69-4.62(m,1H),3.84-3.73(m,4H),3 .41-3.29(m,1H),2.83-2.67(m,4H),2.36(s,2H),1.91(s,2H),1.78(s,1H),1.67(s,2H),1.56(d,J=6.8Hz,6H).

[0265] Example V: 4-((1R,3s,5S,6r)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (Compound 49) and 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (Compound 50) [ka] [ka] The title compound was synthesized following a similar procedure to compound 29*, using 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine in step 1. The crude mixture was purified by reverse-phase chromatography (acetonitrile 30%-60% / 0.1% aqueous NH4OH) to give compound 49 (first peak in HPLC (basic), 20.1 mg, 16% yield) and compound 50 (second peak in HPLC (basic), 16.1 mg, 12.3% yield). LCMS (ESI) [M+H] + =435.3. The relative stereochemistry was determined by 2D-NMR.

[0266] Compound 49: 1H NMR(400MHz,CD3OD)δ 8.15(d,J=8.0Hz,1H),7.96(t,J=8.0Hz,1H),7.62(d,J=7.6Hz,1H),6.51(s,1H),4.83-4.74(m,1H),3.85-3.69(m,4H),3.06 -2.94(m,1H),2.90-2.77(m,4H),2.29(dd,J=12.4,7.2Hz,2H),2.00-1.83(m,4H),1.80-1.70(m,3H),1.53(d,J=6.4Hz,6H).

[0267] Compound 50: 1 H NMR(400MHz,CD3OD)δ 8.15(d,J=8.0Hz,1H),7.96(t,J=8.0Hz,1H),7.62(d,J=7.6Hz,1H),6.46(s,1H),4.85-4.76(m,1H),3.82-3.72(m,4H),3.54-3.39(m,1H) ,2.88-2.83(m,4H),2.51-2.35(m,2H),1.98-1.87(m,2H),1.84-1.79(m,1H),1.72-1.70(m,2H),1.62-1.61(m,2H),1.55(d,J=6.4Hz,6H).

[0268] Example W: 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (Compound 51) and 4-((1R,3s,5S,6r)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (Compound 52) [ka] Step 1: (E)-Benzyl (amino(methylthio)methylene)carbamate [ka]

[0269] To an ice-cooled mixture of 2-methylisothiourea sulfite (10 g, 58.06 mmol) and aqueous sodium hydroxide (34.8 mL, 69.6 mmol, 2N) in dichloromethane (100 mL) was added benzyl chloroformate (7.0 mL, 52.26 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was extracted with ethyl acetate (500 mL × 2) and washed with brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica flash chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (10 g, 77% yield).

[0270] Step 2: (Z)-benzyl ((3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxamido)(methylthio)methylene)carbamate [ka]

[0271] To a solution of 3-[tert-butyl(diphenyl)silyl]oxybicyclo[3.1.0]hexane-6-carboxylic acid (1.97 mL, 62.42 mmol), N,N-diisopropylethylamine (19.4 mL, 111.4 mmol), and (E)-benzyl(amino(methylthio)methylene)carbamate (10.0 g, 44.59 mmol) in tetrahydrofuran (80 mL) was added HATU (25.4 g, 66.88 mmol) at 20 °C. The reaction mixture was then stirred at 20 °C for 2 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with brine (50 mL). The organic layer was dried over Na SO , filtered, and concentrated. The residue was purified by silica flash chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (22 g, 84% yield).

[0272] Step 3: 5-[3-[Tert-butyl(diphenyl)silyl]oxy-6-bicyclo[3.1.0]hexanyl]-1-isopropyl-1,2,4-triazol-3-amine [ka]

[0273] To a stirred solution of (Z)-benzyl((3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxamide)(methylthio)methylene)carbamate (20.0 g, 34.08 mmol) in N,N-dimethylformamide (200 mL) was added isopropylhydrazine hydrochloride (18.9 g, 170.4 mmol) and trimethylamine (47.4 mL, 340.8 mmol). The reaction mixture was stirred at 160° C. for 2.5 hours. The reaction mixture was quenched with water (200 mL) and extracted with 10% methanol in ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (10 g, 64% yield). LCMS (ESI) [M+H] + =461.3.

[0274] Step 4: 5-(3-((Tert-butyldiphenylsilyl)oxy)bicycle[3.1.0]hexan-6-yl)-3-iodo-1-isopropyl-1H-1,2,4-triazole [ka]

[0275] To an ice-cold solution of 5-[3-[tert-butyl(diphenyl)silyl]oxy-6-bicyclo[3.1.0]hexanyl]-1-isopropyl-1,2,4-triazol-3-amine (5000.0 mg, 10.85 mmol) in acetonitrile (50 mL) and water (10 mL) was added 4-methylbenzenesulfonic acid (9331 mg, 54.3 mmol) and sodium nitrite (1498 mg, 21.71 mmol) in water (5 mL) and stirred at 0 °C for 30 minutes. Sodium iodide (4067.0 mg, 27.13 mmol) was then rapidly added to the solution and stirred at 0 °C for 3 hours. The reaction was poured into water (50 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na SO , filtered, and concentrated under reduced pressure. The crude product was purified by silica flash chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (3800 mg, 61% yield). LCMS (ESI) [M+H] + =572.0.

[0276] Step 5: 6-(3-iodo-1-isopropyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-ol [ka]

[0277] To a stirred solution of tert-butyl-[[6-(5-iodo-2-isopropyl-1,2,4-triazol-3-yl)-3-bicyclo[3.1.0]hexanyl]oxy]-diphenyl-silane (3800.0 mg, 6.65 mmol) in tetrahydrofuran (38 mL) was added triethylamine trihydrofluoride (21.7 mL, 132.97 mmol). The reaction mixture was stirred at 70 °C for 16 hours. The reaction was quenched with saturated NaHCO3 (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica flash chromatography (0-25% ethyl acetate in petroleum ether) to give the title compound (2000 mg, 83% yield). LCMS (ESI) [M+H] + =334.0.

[0278] Step 6: 6-(5-iodo-2-isopropyl-1,2,4-triazol-3-yl)bicyclo[3.1.0]hexan-3-one [ka]

[0279] To a stirred solution of 6-(5-iodo-2-isopropyl-1,2,4-triazol-3-yl)bicyclo[3.1.0]hexan-3-ol (2000 mg, 6 mmol) in dichloromethane (20 mL) was added Dess-Martin periodinane (3055 mg, 7.2 mmol) and stirred at 25 °C for 16 h. The reaction was quenched with saturated aqueous NaHCO3 (80 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (1200 mg, 59% yield). LCMS (ESI) [M+H] + =332.0.

[0280] Step 7: 6-[2-isopropyl-5-[5-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]bicyclo[3.1.0]hexan-3-one [ka]

[0281] A suspension of KCO (626 mg, 4.53 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (107 mg, 0.15 mmol), 6-(5-iodo-2-isopropyl-1,2,4-triazol-3-yl)bicyclo[3.1.0]hexan-3-one (500 mg, 1.51 mmol), and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine (495 mg, 1.81 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 80 °C for 2 h under a N atmosphere. The mixture was diluted with water (25 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (200 mg, 27% yield). LCMS (ESI) [M+H] + =351.1.

[0282] Step 8: 4-[(1R,5S)-6-[2-isopropyl-5-[5-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]-3-bicyclo[3.1.0]hexanyl]-1,4-oxazepane [ka]

[0283] To a solution of 6-[2-isopropyl-5-[5-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]bicyclo[3.1.0]hexan-3-one (80 mg, 0.23 mmol) and homomorpholine hydrochloride (94 mg, 0.69 mmol) in methanol (3 mL) at 25° C., NaBHCN (72 mg, 1.14 mmol) was added. The reaction mixture was then stirred at 80° C. for 16 hours. The reaction mixture was concentrated, and the crude product was purified by preparative TLC to give the title compound (60 mg, 60% yield) as a mixture of diastereomers.

[0284] Step 9: 4-((1R,3R,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (compound 51) and 4-((1R,3S,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (compound 52) [ka]

[0285] The mixture of diastereomers was purified by reverse phase chromatography (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, 65%-95%) to give compound 51 (first peak by HPLC, 22.2 mg, 19% yield) and compound 52 (second peak by HPLC, 32.6 mg, 27% yield). LCMS (ESI) [M+H] + =423.3. The relative stereochemistry was determined by 2D-NMR.

[0286] Compound 51:1H NMR(400MHz,CD3OD)δ 9.37(d,J=1.6Hz,1H),8.87(d,J=1.2Hz,1H),8.59(s,1H),4.94-4.90(m,1H),3.80-3.73(m,4H),3.50-3.31(m,1H),2.79-2.75( m,4H),2.43-2.36(m,2H),2.12(t,J=3.2Hz,1H),2.05-2.01(m,2H),1.90-1.87(m,2H),1.75-1.65(m,2H),1.58(d,J=6.8Hz,6H).

[0287] Compound 52: 1 H NMR(400MHz,CD3OD)δ 9.37(d,J=1.6Hz,1H),8.87(d,J=1.2Hz,1H),8.59(s,1H),4.94-4.90(m,1H),3.80-3.74(m,4H),3.43-3.31(m,1H),2 .79-2.73(m,4H),2.45-2.35(m,2H),2.04-2.02(m,1H),1.96-1.88(m,4H),1.75-1.65(m,2H),1.55(d,J=6.8Hz,6H).

[0288] Example X: 4-((1R,3s,5S,6r)-6-(1-ethyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (compound 53) and 4-((1R,3r,5S,6r)-6-(1-ethyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (compound 54) [ka] Step 1: 3-(5-((1R,5S,6r)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyridine [ka]

[0289] To a mixture of 5-((1R,5S,6r)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-3-iodo-1H-pyrazole (2.0 g, 3.78 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine (1.6 g, 5.86 mmol) in 1,4-dioxane (16 mL) and water (4 mL) was added KCO (1.6 g, 11.58 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.28 g, 0.40 mmol). The reaction mixture was then placed under a nitrogen atmosphere and stirred at 75 °C for 5 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica flash chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (2.0 g, 88% yield). LCMS (ESI) [M+H] + =548.1.

[0290] Step 2: 3-(5-((1R,5S,6r)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-ethyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyridine [ka]

[0291] N, N -3-(5-((1R,5S,6r)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1 in dimethylformamide (8 mL) HTo a stirred mixture of (-pyrazol-3-yl)-5-(trifluoromethyl)pyridine (1.2 g, 2.19 mmol) and Cs2CO3 (1.4 g, 4.3 mmol), iodoethane (0.9 mL, 11.25 mmol) was added dropwise, followed by stirring at 25 °C for 3 h. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica flash chromatography (0-15% ethyl acetate in petroleum ether) to give the title compound (890 mg, 71% yield). LCMS (ESI) [M+H] + =576.2.

[0292] Step 3: (1R,5S,6r)-6-(1-ethyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-ol [ka]

[0293] To 3-(5-((1R,5S,6r)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-ethyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyridine (870 mg, 1.51 mmol) in a flask was added tetrabutylammonium fluoride (12.0 mL, 12 mmol, 1 M) in tetrahydrofuran, and the mixture was stirred at 25 °C for 5 hours. The reaction was then quenched with saturated NH4Cl solution (15 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica flash chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (500 mg, 98% yield). LCMS (ESI) [M+H] + =338.1.

[0294] Step 4: (1R,5S,6r)-6-(1-ethyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one [ka]

[0295] To a solution of (1R,5S,6r)-6-(1-ethyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-ol (500 mg, 1.48 mmol) in anhydrous dichloromethane (12 mL) was added Dess-Martin periodinane (1000 mg, 2.36 mmol), and the reaction mixture was stirred at 25 °C for 4 hours. The mixture was then quenched with Na SO solution (20 mL), followed by saturated NaHCO solution (10 mL), and extracted with dichloromethane (100 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na SO , filtered, and concentrated. The residue was purified by silica flash chromatography (0-40% ethyl acetate in petroleum ether) to give the title compound (410 mg, 83% yield). LCMS(ESI)[M+H] + =336.3.

[0296] Step 5: 4-((1R,3s,5S,6r)-6-(1-ethyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (compound 53) and 4-((1R,3r,5S,6r)-6-(1-ethyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (compound 54) [ka]

[0297] To a solution of (1R,5S,6r)-6-(1-ethyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one (130 mg, 0.38 mmol) and 1,4-oxazepane hydrochloride (135 mg, 0.97 mmol) in anhydrous methanol (6 mL) was added NaBHCN (120 mg, 1.92 mmol) and acetic acid (0.02 mL, 0.35 mmol) dropwise at 20 °C. The reaction mixture was then heated to 70 °C and stirred for 4 h. The reaction was quenched with saturated NaHCO solution (5 mL) and extracted with dichloromethane (30 mL × 2). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography (70-100% acetonitrile / (0.05% NH3H2O ​​in water + 10 mM NH4HCO3) to give the title compound 53 (second peak in SFC, 32.4 mg, 24% yield) and compound 54 (first peak in SFC, 40.3 mg, 30% yield). LCMS (ESI) [M+H] + =421.4. The relative stereochemistry was determined by 2D-NMR.

[0298] Compound 53: 1 H NMR(400MHz,CDCl3)δ 9.10(d,J=1.6Hz,1H),8.76(d,J=1.2Hz,1H),8.28(s,1H),6.18(s,1H),4.28-4.20(m,2H),3.79-3.72(m,4H),2.55-2 .50(m,5H),2.32-2.20(m,2H),2.04-1.81(m,2H),1.76-1.70(brs,2H),1.57(t,J=3.2Hz,1H),1.51(t,J=7.2Hz,3H).

[0299] Compound 54: 1H NMR(400MHz,CDCl3)δ 9.11(s,1H),8.77(s,1H),8.29(s,1H),6.13(s,1H),4.32-4.20(m,2H),3.82-3.78(m,4H),3.35-3.30(m,1H),2.7 9-2.70(m,3H),2.39-2.35(m,2H),1.95-1.91(m,2H),1.85-1.81(m,2H),1.71-1.67(m,4H),1.53(t,J=7.2Hz,3H).

[0300] Example Y: 4-((1S,3S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine (Compound 58*) and 4-((1R,3R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine (Compound 59 *), 4-((1R,3S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine (Compound 60*) and 4-((1S,3R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine (Compound 61*) [ka] Step 1: 3-Bromocyclopent-2-enone [ka]

[0301] To a suspension of Ph3PBr2 (4.73 g, 11.2 mmol) in dichloromethane (10 mL) was added cyclopent-4-ene-1,3-dione (1.0 g, 10.2 mmol) and triethylamine (1.56 mL, 11.2 mmol) at 25 °C. The reaction mixture was then stirred at 25 °C for 18 hours. A yellow suspension formed. The reaction mixture was concentrated under vacuum, and then 2-methoxy-2-methylpropane (50 mL) was added to the above mixture, stirred, and filtered. The organic layer was concentrated under reduced pressure and purified by silica flash chromatography (10%-20% ethyl acetate in petroleum ether) to give the title compound (1.10 g, 67% yield). 1 H NMR(400MHz,DMSO-d6)δ 6.66-6.62(m,1H),3.01-2.94(m,2H),2.50-2.47(m,2H).

[0302] Step 2: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-enone [ka]

[0303] A mixture of 4-bromocyclopent-2-enone (1.10 g, 6.83 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2 dioxaborolane) (1.91 g, 7.52 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (500 mg, 0.68 mmol), and KOAc (2.01 g, 20.5 mmol) in 1,4-dioxane (10 mL) was degassed and purged with N2 three times. The reaction mixture was then stirred under N2 at 100 °C for 12 h. A brown suspension formed. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica flash chromatography (2%-3% methanol in dichloromethane) to give the title compound (1.30 g, 91% yield). 1 H NMR(400MHz,DMSO-d6)δ 6.45-6.40(m,1H),2.68-2.63(m,2H),2.28-2.23(m,2H),1.27(s,12H).

[0304] Step 3: 3-(3-bromo-1-isopropyl-1H-pyrazol-5-yl)cyclopent-2-enone [ka]

[0305] A suspension of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-enone (1.30 g, 6.25 mmol), 3,5-dibromo-1-isopropyl-1H-pyrazole (1.67 g, 6.25 mmol), CsCO (6.11 g, 18.7 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (457 mg, 0.62 mmol) in 1,4-dioxane (30 mL) and water (6 mL) was degassed and purged with N three times, then the reaction mixture was stirred under N at 100° C. for 1.5 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica flash chromatography (40%-50% ethyl acetate in petroleum ether) to give the title compound (1.0 g, 59% yield). 1 H NMR(400MHz,CDCl3)δ 6.85(s,1H),6.64(d,J=1.6Hz,1H),5.04-4.94(m,1H),3.31-3.28(m,2H),2.90-2.84(m,2H),1.85(d,J=6.4Hz,6H).LCMS(ESI)[M+H] + =269.2.

[0306] Step 4: 3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopent-2-enone [ka]

[0307] A suspension of 3-(3-bromo-1-isopropyl-1H-pyrazol-5-yl)cyclopent-2-enone (1.0 g, 3.7 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine (1.01 g, 3.7 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (270 mg, 0.4 mmol), and CsCO (3630 mg, 11.1 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was degassed and purged with N three times, then the reaction mixture was stirred under N at 100 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica flash chromatography (30%-50% ethyl acetate in petroleum ether) to give the title compound (1000 mg, 80% yield). LCMS (ESI) [M+H] + =336.1.

[0308] Step 5: 3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone [ka]

[0309] To a solution of 3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopent-2-enone (1.0 g, 2.98 mmol) in methanol (20 mL) was added 10% palladium on carbon (0.32 g, 0.30 mmol) at 25° C., and the reaction mixture was then stirred under H (15 psi) at 25° C. for 20 hours. The reaction mixture was filtered, and the filtrate cake was washed with methanol (10 mL×2). The combined organic layers were concentrated under vacuum. The residue was purified by silica flash chromatography (30%-50% ethyl acetate in petroleum ether) to give the title compound (700 mg, 70% yield). 1H NMR(400MHz,CDCl3)δ 9.47(s,1H),9.09(d,J=1.2Hz,1H),8.64(s,1H),6.72(s,1H),3.10-3.00(m,1H),2.88- 2.78(m,2H),2.73-2.61(m,2H),2.47-2.39(m,1H),1.93-1.86(m,6H).LCMS(ESI)[M+H] + =338.1.

[0310] Step 6: 4-(3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine [ka]

[0311] To a solution of 3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone (350 mg, 1.04 mmol), morpholine (225 mg, 2.59 mmol), and NaBHCN (130 mg, 2.08 mmol) in methanol (5 mL) was added acetic acid (0.03 mL), and the reaction mixture was then stirred at 50° C. for 2 hours. The reaction mixture was concentrated. The residue was then purified by silica flash chromatography (5%-10% methanol in dichloromethane) to afford the title compound (320 mg, 76% yield) as a mixture of diastereomers. LCMS (ESI) [M+H] + =409.2.

[0312] Step 7: 4-((1S,3S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine (Compound 58*) and 4-((1R,3R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine (Compound 59) *), 4-((1R,3S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine (Compound 60*) and 4-((1S,3R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine (Compound 61*) [ka]

[0313] The diastereomers of 4-(3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine (320 mg, 0.78 mmol) were purified by SFC (column: ChiralPak AD-3 150 × 4.6 mm) Purification by HPLC (ID, 3 μm, mobile phase: A:CO₂B:IPA (0.05% DEA) gradient: 5% to 40% B in 5.5 min, then 5% B in 1.5 min, flow rate: 2.5 mL / min, column temperature 40 °C, back pressure: 100 bar) gave title compound 58* (first peak in SFC, 20.1 mg, 6.2% yield), compound 59* (second peak in SFC, 27.3 mg, 8.4% yield), compound 60* (third peak in SFC, 41.7 mg, 12.2% yield), and compound 61* (fourth peak in SFC, 56.3 mg, 17.4% yield). LCMS (ESI) [M+H] + =409.2. Relative stereochemistry arbitrarily assigned.

[0314] Compound 58*: 11H NMR (400 MHz, CDCl3) δ 9.09 (d, J = 1.6 Hz, 1H), 8.69 (s, 1H), 8.25 (s, 1H), 6.30 (1H, s), 4.46 - 4.34 (m, 1H), 3.74 - 3.60 (m, 4H), 3.34 - 3.14 (m, 1H), 2.78 - 2.66 (m, 1H), 2.53 - 2.33 (m, 4H), 2.20 - 2.11 (m, 1H), 2.07 - 1.98 (m, 2H), 1.88 - 1.80 (m, 1H), 1.74 - 1.62 (m, 1H), 1.58 - 1.56 (m, 1H), 1.46 (d, J = 5.6 Hz, 6H).

[0315] Compound 59*: 1 1H NMR (400 MHz, CDCl3) δ 9.09 (d, J = 1.6 Hz, 1H), 8.69 (s, 1H), 8.25 (s, 1H), 6.30 (1H, s), 4.52 - 4.35 (m, 1H), 3.75 - 3.60 (m, 4H), 3.29 - 3.14 (m, 1H), 2.78 - 2.69 (m, 1H), 2.55 - 2.35 (m, 4H), 2.20 - 2.07 (m, 1H), 2.08 - 2.02 (m, 2H), 1.88 - 1.80 (m, 1H), 1.74 - 1.62 (m, 1H), 1.61 - 1.56 (m, 1H), 1.46 (d, J = 5.6 Hz, 6H).

[0316] Compound 60*: 1 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.75 (s, 1H), 8.31 (s, 1H), 6.42 (s, 1H), 4.53 - 4.40 (m, 1H), 3.78 - 3.70 (m, 4H), 3.22 - 3.09 (m, 1H), 2.79 - 2.70 (m, 1H), 2.65 - 2.44 (m, 4H), 2.37 - 2.22 (m, 1H), 2.19 - 2.10 (m, 1H), 2.04 - 1.96 (m, 1H), 1.82 - 1.69 (m, 3H), 1.53 (d, J = 6.4 Hz, 6H).

[0317] Compound 61*: 1H NMR(400MHz,CDCl3)δ 9.14(d,J=1.2Hz,1H),.8.75(s,1H),8.31(s,1H),6.42(s,1H),4.53-4.42(m,1H),3.78-3.70(m,4H),3.18-3.12(m,1H),2.79-2. 70(m,1H),2.65-2.44(m,4H),2.37-2.22(m,1H),2.19-2.10(m,1H),2.04-1.96(m,1H),1.82-1.69(m,3H),1.53(d,J=6.4Hz,6H).

[0318] Example Z: 4-((1S,3S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-1,4-oxazepane, 4-((1R,3R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-1,4-oxazepane, 4-((1R,3S )-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-1,4-oxazepane and 4-((1S,3R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-1,4-oxazepane (Compounds 62*, 63*, 64*, and 65*) [ka] Step 1: (R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone and (S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone [ka]

[0319] Following the procedure for Compound 58*, 800 mg of 3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone was prepared and purified by SFC (column: Chiral Pak AD-3 150 × 4.6 mm). Purification by ID, 3 μm, mobile phase: A:CO₂B:ethanol (0.05% DEA), gradient: 5% to 40% B in 5.5 min, then 5% B in 1.5 min, flow rate: 2.5 mL / min, column temperature: 40 °C, back pressure: 100 bar) afforded (R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone (first peak in SFC, 350 mg, 43.7% yield) and (S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone (second peak in SFC, 370 mg, 46.2% yield). Both were obtained as single unknown stereoisomers. Relative stereochemistry was arbitrarily assigned.

[0320] Step 2: 4-((1S,3S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-1,4-oxazepane (Compound 63*) and 4-((1R,3S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-1,4-oxazepane (Compound 64*) [ka]

[0321] To a solution of (S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone (second peak in SFC, 100 mg, 0.3 mmol), 1,4-oxazepane (60 mg, 0.59 mmol), and NaBHCN (37 mg, 0.59 mmol) in methanol (2 mL) was added acetic acid (0.01 mL). The reaction mixture was then stirred at 50° C. for 1 hour. A brown solution formed. The reaction mixture was concentrated, and the residue was purified by silica flash chromatography (5%-10% methanol in dichloromethane) to give a diastereomeric mixture compound (120 mg, 90% yield). This was purified by chiral SFC (Column: Chiral Pak AD-3 150 x 4.6 mm ID, 3 μm, Mobile phase: A:CO₂B:ethanol (0.05% DEA), Gradient: 5% to 40% B in 5.5 min, then 5% B in 1.5 min, Flow rate: 2.5 mL / min, Column temperature: 40 °C, Back pressure: 100 bar) to give Compound 63* (SFC first peak, 22.2 mg, 19% yield) and Compound 64* (SFC second peak, 32.6 mg, 27% yield). LCMS (ESI) [M+H] + =423.3. Relative stereochemistry arbitrarily assigned.

[0322] Compound 63*: 1 H NMR(400MHz,CDCl3)δ 9.14(d,J=1.6Hz,1H),8.75(s,1H),8.31(s,1H),6.35(s,1H),4.57-4.57(m,1H),3.87-3.82(m,4H),3.48-3.43(m,2H),3.11-3. 00(m,4H),2.41-2.35(m,1H),2.31-2.24(m,1H),2.20-2.05(m,3H),2.03-1.87(m,2H),1.84-1.74(m,1H),1.52(d,J=6.8Hz,6H).

[0323] Compound 64*: 1H NMR(400MHz,CDCl3)δ 9.15(d,J=2.0Hz,1H),8.75(d,J=1.2Hz,1H),8.31(s,1H),6.42(s,1H),4.54-4.43(m,1H),3.84-3.77(m,4H),3.21-3.09(m,2H),2.8 9-2.76(m,4H),2.38-2.29(m,1H),2.19-2.10(m,1H),2.04-1.93(m,3H),1.84-1.76(m,2H),1.75-1.65(m,1H),1.52(d,J=6.8Hz,6H).

[0324] Step 3: 4-((1R,3R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-1,4-oxazepane (Compound 65*) and 4-((1S,3R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-1,4-oxazepane (Compound 62*) [ka]

[0325] To a solution of (R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone (first peak in SFC, 100 mg, 0.3 mmol), 1,4-oxazepane (60 mg, 0.59 mmol), and NaBHCN (37 mg, 0.59 mmol) in methanol (2 mL) was added acetic acid (0.01 mL). The reaction mixture was then stirred at 50° C. for 1 hour. A brown solution formed. The reaction mixture was concentrated, and the residue was purified by silica flash chromatography (5%-10% methanol in dichloromethane) to give the racemic mixture compound (120 mg, 90% yield). The racemic mixture was purified by chiral SFC (Column: Chiral Pak AD-3 150 x 4.6 mm ID, 3 um, Mobile phase: A:CO₂B:ethanol (0.05% DEA), Gradient: 5% to 40% B in 5.5 min, then 5% B in 1.5 min, Flow rate: 2.5 mL / min, Column temperature: 40 °C, Back pressure: 100 bar) to give Compound 65* (first peak in SFC, 16.7 mg, 13.1% yield) and Compound 62* (second peak in SFC, 37.8 mg, 31.2% yield). LCMS (ESI) [M+H] + =423.3. Relative stereochemistry arbitrarily assigned.

[0326] Compound 65*: 1 H NMR(400MHz,CDCl3)δ 9.15(d,J=1.6Hz,1H),8.75(s,1H),8.31(s,1H),6.36(s,1H),4.52-4.44(m,1H),3.85-3.70(m,4H),3.40-3.10(m,2H),2.90-2 .65(m,4H),2.26-2.18(m,1H),2.13-2.10(m,1H),1.97-1.91(m,3H),1.90-1.83(m,2H),1.78-1.71(m,1H),1.56-1.47(m,6H).

[0327] Compound 62*: 1H NMR(400MHz,CDCl3)δ 9.16(d,J=1.6Hz,1H),8.75(s,1H),8.32(s,1H),6.46(s,1H),4.49-4.44(m,1H),3.85-3.80(m,4 H),3.34-3.23(m,1H),3.19-3.10(m,1H),2.98-2.90(m,4H),2.41-2.33(m,1H),2.19-2 .01(m,1H),2.11-1.98(m,3H),1.90-1.83(m,2H),1.81-1.75(m,1H),1.56-1.47(m,6H).

[0328] Example AA: (S)-4-((1R,3r,5S,6S)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (S)-4-((1R,3s,5S,6S)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine (Compounds 66 and 67) [ka] The title compound was synthesized according to a procedure similar to that for Compound 68, using 3-(trifluoromethyl)benzimidamide hydrochloride and (1R,5S)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxylic acid in Step 1. The crude mixture was purified by preparative TLC (10% methanol in dichloromethane) to give Compound 66 (first peak in SFC, 36.41 mg, 28.7% yield) and Compound 67 (second peak in SFC, 30.31 mg, 24% yield). LCMS (ESI) [M+H] + =435.2. The relative stereochemistry was determined by 2D-NMR.

[0329] Compound 66: 1H NMR(400MHz,CD3OD)δ 8.30(s,1H),8.21(d,J=7.6Hz,1H),7.58(d,J=6.8Hz,1H),7.52-7.48(m,1H),4.70-4.65(m,1H),3.79-3.58(m,5H),3.40-3.35 (m,1H),2.90-2.82(s,1H),2.61-2.48(m,3H),2.45-2.00(m,4H),1.58(d,J=2.0Hz,6H),1.30-1.22(m,1H),1.18-1.09(m,3H).

[0330] Compound 67: 1 H NMR(400MHz,CD3OD)δ 8.31(s,1H),8.22(d,J=7.6Hz,1H),7.59(d,J=6.8Hz,1H),7.52-7.49(m,1H),4.67-4.64(m,1H),3.80-3.70(m,3H),3.60-3.46(m,1H), 2.92-2.82(m,2H),2.69(s,1H),2.48(s,1H),2.20-2.08(m,4H),1.96(s,2H),1.58(d,J=2.0Hz,6H),1.26(s,1H),1.10(d,J=5.6Hz,3H).

[0331] Example AB: 4-((1R,3s,5S,6r)-6-(3-(5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane and 4-((1R,3r,5S,6r)-6-(3-(5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (Compounds 68 and 69) [ka] Step 1: 3-Bromo-5-(5-((1R,5S,6r)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-1,2,4-triazol-3-yl)pyridine [ka]

[0332] To a solution of (1R,5S,6r)-3-((tertbutyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxylic acid (2 g, 5.26 mmol) and 5-bromonicotinimidamide hydrochloride (1857 mg, 7.88 mmol) in N,N-dimethylformamide (20 mL) was added N,N-diisopropylethylamine (3 mL, 17.22 mmol) and HATU (2198 mg, 5.78 mmol). The reaction mixture was stirred at 20 °C for 1 hour. To the above mixture, isopropylhydrazine hydrochloride (872 mg, 7.88 mmol) and acetic acid (3 mL, 52.56 mmol) were added and stirred at 80 °C for an additional 1.5 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (30 mL × 3) and concentrated. The residue was purified by silica flash chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound (2.5 g, 79% yield). LCMS (ESI), [M+H] + =602.2.

[0333] Step 2: 3-(5-((1R,5S,6r)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-1,2,4-triazol-3-yl)-5-(difluoromethoxy)pyridine, (1R,5S)-6-[3-[5-(difluoromethoxy)-3-pyridyl]-1H-1,2,4-triazol-5-yl]bicyclo[3.1.0]hexan-3-ol [ka]

[0334] A solution of [(1S,5R)-6-[5-(5-bromo-3-pyridyl)-2-isopropyl-1,2,4-triazol-3-yl]-3-bicyclo[3.1.0]hexanyl]oxy-tert-butyl-diphenyl-silane (900 mg, 1.5 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (51 mg, 0.12 mmol), Pd(dba) (27 mg, 0.03 mmol), and KOH (168 mg, 2.99 mmol) in dioxane (4 mL) and water (2 mL) was stirred at 100 °C under N for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (6 mL). Then, KOH (2693 mg, 48 mmol) and difluoromethyl trifluoromethanesulfonate (891 mg, 4.45 mmol) were added to o The mixture was added at rt and stirred for 30 minutes. The reaction mixture was diluted with water (15 mL), and the resulting solution was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-100% ethyl acetate in petroleum ether) to give the title protected compound (600 mg, 68% yield), LCMS (ESI), [M+H] + = 589.3 and the title deprotected compound (200 mg, 38% yield). LCMS (ESI), [M+H] + =351.1.

[0335] Step 3: (1R,5S,6r)-6-(3-(5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-ol [ka]

[0336] To a stirred solution of tert-butyl-[[(1R,5S)-6-[5-[5-(difluoromethoxy)-3-pyridyl]-2-isopropyl-1,2,4-triazol-3-yl]-3-bicyclo[3.1.0]hexanyl]oxy]-diphenyl-silane (600 mg, 1.02 mmol) in THF (10 mL) was added triethylamine trihydrofluoride (8 mL, 49.08 mmol). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was quenched with saturated NaHCO3. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography (0-80% ethyl acetate in petroleum ether) to give the title compound (300 mg, 84% yield). LCMS(ESI), [M+H] + =351.1.

[0337] Step 4: (1R,5S,6r)-6-(3-(5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-one [ka]

[0338] To a solution of (1R,5S,6r)-6-(3-(5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-ol (500 mg, 1.43 mmol) in DCM (10 mL) was added Dess-Martin periodinane (908 mg, 2.14 mmol). The resulting solution was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (15 mL), and the resulting solution was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with NaSO (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-80% ethyl acetate in petroleum ether) to give the title compound (270 mg, 54% yield).

[0339] Step 5: 4-((1R,3s,5S,6r)-6-(3-(5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane and 4-((1R,3r,5S,6r)-6-(3-(5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (Compounds 68 and 69) [ka]

[0340] To a solution of (1R,5S,6r)-6-(3-(5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-one (130 mg, 0.37 mmol), homomorpholine hydrochloride (62 mg, 0.45 mmol), and acetic acid (22 mg, 0.37 mmol) in methyl alcohol (5 mL) was added sodium cyanoborohydride (117 mg, 1.87 mmol), and the mixture was stirred for 50 minutes. o The mixture was stirred at rt for 16 hours. The reaction mixture was diluted with water (10 mL) and the pH was adjusted to 9 with NaHCO3. The resulting solution was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse-phase chromatography (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, 50%-80%, 25 mL / min) to give compound 68 (second peak of SFC, 44.55 mg, 26% yield) and compound 69 (first peak of SFC, 35.38 mg, 22% yield). LCMS (ESI), [M+H] + =434.3. The relative stereochemistry was determined by 2D-NMR.

[0341] Compound 68: 1H NMR(400MHz,CD3OD)δ 9.01(d,J=1.6Hz,1H),8.43(d,J=2.8Hz,1H),8.14(s,1H),7.22-6.82(m ,1H),4.92-4.90(m,1H),3.79(t,J=6.0Hz,2H),3.77-3.74(m,2H),3.01 -2.92(m,1H),2.82-2.76(m,4H),2.29(dd,J=7.2,12.4Hz,2H),2.07-2. 05(m,2H),2.03-2.00(m,1H),1.95-1.88(m,4H),1.54(d,J=6.8Hz,6H).

[0342] Compound 69: 1 H NMR (400 MHz, CD3OD) δ 9.00(d,J=1.6Hz,1H),8.43(d,J=2.8Hz,1H),8.14(s,1H),7.22-6.81(m,1H) ,4.94-4.90(m,1H),3.79(t,J=6.0Hz,2H),3.77-3.73(m,2H),3.48-3.37(m, 1H),2.78-2.75(m,4H),2.43-2.36(m,2H),2.12-2.09(m,1H),2.04-2.01(m, 2H),1.93-1.88(m,2H),1.69(dd,J=8.4,14.0Hz,2H),1.57(d,J=6.4Hz,6H).

[0343] Example AC: (R)-4-((1R,3r,5S,6R)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (R)-4-((1R,3s,5S,6R)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine (Compounds 70* and 71*) [ka] The title compound was synthesized according to a procedure similar to that for Compound 68, using 3-(trifluoromethyl)benzimidamide hydrochloride and (1R,5S)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxylic acid in Step 1. The crude mixture was purified by preparative TLC (10% methanol in dichloromethane) to give Compound 70* (first peak of SFC, 41.35 mg, 33% yield) and Compound 71* (second peak of SFC, 43.68 mg, 35% yield). LCMS (ESI) [M+H] + =435.3. Relative stereochemistry arbitrarily assigned.

[0344] Compound 70*: 1 H NMR(400MHz,CDCl3)δ 8.30(s,1H),8.21(d,J=8.0Hz,1H),7.60-7.56(m,1H),7.52-7.47(m,1H),4.70-4.67(m,1H),3.82-3.56(m,4H),3.38-3.35(m,1H), 2.88-2.84(m,1H),2.72-2.44(m,2H),2.33-2.16(m,2H),2.05-2.00(m,3H),1.84-1.69(m,2H),1.58(d,J=6.4Hz,6H),1.09(s,3H).

[0345] Compound 71*: 1 H NMR(400MHz,CDCl3)δ 8.31(s,1H),8.22(d,J=8.0Hz,1H),7.61-7.57(m,1H),7.53-7.48(m,1H),4.68-4.63(m,1H),4.04- 3.41(m,4H),3.39-2.32(m,4H),2.21-1.90(m,6H),1.68(s,1H),1.57(d,J=6.4Hz,6H),1.16(s,3H).

[0346] Example AD: (R)-4-((1R,3s,5S,6R)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (R)-4-((1R,3r,5S,6R)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine (Compounds 72 and 73) [ka] The title compound was synthesized following a similar procedure to compound 51, using (R)-3-methylmorpholine in the final step. The crude mixture was purified by reverse-phase chromatography (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, 55%-85%) to give compound 72 (first peak by HPLC, 32.76 mg, 17.4% yield) and compound 73 (second peak by HPLC, 69.52 mg, 36.9% yield). LCMS (ESI), [M+H] + =436.2. The relative stereochemistry was determined by 2D-NMR.

[0347] Compound 72: 1 H NMR(400MHz,CD3OD)δ 8.25(d,J=7.6Hz,1H),7.91(t,J=8.0Hz,1H),7.64(d,J=7.6Hz,1H),4.75- 4.85(m,1H),3.77(brs,3H),3.53(dd,J=3.6,11.2Hz,1H),2.96-2.78(m,2H ),2.70(brs,1H),2.49(d,J=9.6Hz,1H),2.20-2.07(m,4H),1.98(brs,2H) ,1.70(t,J=3.2Hz,1H),1.59(dd,J=2.8,6.8Hz,6H),1.11(d,J=6.4Hz,3H).

[0348] Compound 73: 1H NMR(400MHz,CD3OD)δ 8.25(d,J=8.0Hz,1H),7.91(t,J=8.0Hz,1H),7.64(d,J=7.6Hz,1H),4.76-4.70(m,1H),3.79(d, J=11.2Hz,1H),3.70-3.62(m,2H),3.60-3.55(m,1H),3.35-3.32(m,1H),2.86(brs,1H),2.62-2 .57(m,1H),2.46(d,J=12.0Hz,1H),2.28-2.22(m,1H),2.21-2.14(m,1H),2.12-2.00(m,3H),1. 84(d,J=6.4Hz,1H),1.72(dd,J=6.4,13.2Hz,1H),1.60(d,J=6.8Hz,6H),1.08(d,J=6.4Hz,3H).

[0349] Example AE: 4-((1R,3s,5S,6r)-6-(3-(3-(difluoromethoxy)phenyl)-1-isopropyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane and 4-((1R,3r,5S,6r)-6-(3-(3-(difluoromethoxy)phenyl)-1-isopropyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1,4-oxazepane (Compounds 74 and 75) [ka] The title compound was synthesized following a procedure similar to that for Compound 68, using 3-bromobenzimidamide hydrochloride in step 1. The crude mixture was purified by reverse-phase chromatography (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, 60%-90%) to give Compound 74 (first peak in SFC, 35.84 mg, 28.2% yield) and Compound 75 (second peak in SFC, 35.65 mg, 27% yield). LCMS (ESI), [M+H] + =433.2. The relative stereochemistry was determined by 2D-NMR.

[0350] Compound 74: 1H NMR (400 MHz, CD3OD) δ 7.83(d,J=7.6Hz,1H),7.72(s,1H),7.44(t,J=8.0Hz,1H),7.15(dd,J=2.4,8.0 Hz,1H),7.06-6.66(m,1H),4.86-4.81(m,1H),3.79(t,J=6.0Hz,2H),3.77-3.7 3(m,2H),3.00-2.90(m,1H),2.81-2.74(m,4H),2.28(dd,J=7.2,12.4Hz,2H),2 .06-2.02(m,2H),1.99-1.96(m,1H),1.95-1.85(m,4H),1.54(d,J=6.8Hz,6H).

[0351] Compound 75: 1 H NMR (400 MHz, CD3OD) δ 7.82(d,J=8.0Hz,1H),7.71(s,1H),7.44(t,J=8.0Hz,1H),7.15(dd,J=2.0,8. 4Hz,1H),7.06-6.66(m,1H),4.86-4.83(m,1H),3.82-3.74(m,4H),3.51-3.39 (m,1H),2.86-2.74(m,4H),2.46-2.38(m,2H),2.09-2.07(m,1H),2.05-2.01( m,2H),1.97-1.88(m,2H),1.69(dd,J=8.4,13.6Hz,2H),1.56(d,J=6.4Hz,6H).

[0352] Example AF: (R)-4-((1R,3r,5S,6R)-6-(3-(3-(difluoromethoxy)phenyl)-1-isopropyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (R)-4-((1R,3s,5S,6R)-6-(3-(3-(difluoromethoxy)phenyl)-1-isopropyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine (Compounds 76 and 77) [ka] The title compound was synthesized following a procedure similar to that for Compound 74, using (3R)-3-methylmorpholine in the final step. The crude mixture was purified by preparative TLC (ethyl acetate / methanol = 10 / 1) to give Compound 76 (41 mg, 32% yield) and Compound 77 (35.76 mg, 28% yield). LCMS (ESI), [M+H] + =433.3. The relative stereochemistry was determined by 2D-NMR.

[0353] Compound 76: 1 H NMR(400MHz,CD3OD)δ 7.83(d,J=8.0Hz,1H),7.72(s,1H),7.44(t,J=8.0Hz,1H),7.15(dd,J=2.4,8.0Hz,1H),7. 06-6.67(m,1H),4.86-4.80(m,1H),3.78-3.71(m,1H),3.71-3.62(m,2H),3.54-3.43(m,2H ),2.89-2.81(m,1H),2.69-2.61(m,1H),2.54-2.46(m,1H),2.34-2.19(m,2H),2.12-2.08( m,1H),2.05-1.98(m,2H),1.84-1.70(m,2H),1.56(d,J=6.4Hz,6H),1.09(d,J=6.4Hz,3H).

[0354] Compound 77: 1 H NMR(400MHz,CD3OD)δ 7.83(d,J=7.2Hz,1H),7.72(s,1H),7.44(t,J=8.0Hz,1H),7.15(dd,J=2.4,8.0Hz ,1H),7.06-6.67(m,1H),4.86-4.83(m,1H),3.78-3.66(m,3H),3.55-3.45(m,1H) ,3.12(brs,1H),2.89-2.70(m,2H),2.55-2.45(m,1H),2.24-2.12(m,2H),2.09-2 .01(m,3H),1.97-1.88(m,2H),1.54(dd,J=2.4,6.4Hz,6H),1.13(d,J=6.4Hz,3H).

[0355] Example AG: (S)-4-((1R,4S)-4-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-3-methylmorpholine and (S)-4-((1S,4R)-4-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-3-methylmorpholine (Compounds 78* and 7 9*), (R)-4-((1R,4R)-4-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-3-methylmorpholine and (R)-4-((1S,4S)-4-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-3-methylmorpholine (compounds 80* and 81*). [ka] Step 1: 2-(1-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-1,2,4-triazol-3-yl)-6-(trifluoromethyl)pyridine [ka]

[0356] To a solution of 6-(trifluoromethyl)pyridine-2-carboxamidine hydrochloride (300.0 mg, 1.33 mmol) and 1,4-dioxaspiro[4.5]decane-8-carboxylic acid (371.43 mg, 1.99 mmol) in N,N-dimethylformamide (12 mL) was added HATU (556 mg, 1.46 mmol) and N,N-diisopropylethylamine (0.68 mL, 3.99 mmol) and stirred at 20°C for 1 hour. Isopropylhydrazine hydrochloride (221 mg, 1.99 mmol) and acetic acid (0.76 mL, 13.3 mmol) were then added and stirred at 80°C for 1.5 hours. The mixture was diluted with ethyl acetate (500 mL) and washed with water and brine (50 mL x 3). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the title compound (520 mg, 98.6% yield). LCMS (ESI) [M+H]+ = 397.2.

[0357] Step 2: 4-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclohexanone [ka]

[0358] To a solution of 2-[5-(1,4-dioxaspiro[4.5]decan-8-yl)-1-isopropyl-1,2,4-triazol-3-yl]-6-(trifluoromethyl)pyridine (520.0 mg, 1.31 mmol) in tetrahydrofuran (2 mL) was added hydrochloric acid (7.44 mL, 7.44 mmol, 1.0 M) at 25 °C and stirred at 25 °C for 16 hours. The mixture was adjusted to pH = 9 with Na2CO3 and diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (30 mL × 2). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica flash chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (270 mg, 58.4% yield). LCMS (ESI) [M+H]+ = 353.2.

[0359] Step 3: (S)-4-((1R,4S)-4-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-3-methylmorpholine and (S)-4-((1s,4R)-4-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-3-methylmorpholine (Compounds 78* and 79*) [ka]

[0360] To a solution of 4-[2-isopropyl-5-[6-(trifluoromethyl)-2-pyridyl]-1,2,4-triazol-3-yl]cyclohexanone (100 mg, 0.28 mmol) in methyl alcohol (4 mL) was added (S)-3-methylmorpholine (287 mg, 2.84 mmol), acetic acid (17 mg, 0.28 mmol), and sodium cyanoborohydride (54 mg, 0.85 mmol), and the mixture was stirred at 70° C. for 30 hours. The reaction mixture was diluted with water (20 mL) and adjusted to pH 9 with saturated Na2CO3. 。 The resulting solution was extracted with dichloromethane (30 mL × 3), and the combined organic layers were concentrated under vacuum. The residue was purified by reverse-phase chromatography (30%-60% acetonitrile / 0.05% aqueous ammonia hydroxide) to give compound 78* (second peak in SFC, 37.54 mg, 29% yield) and compound 79* (first peak in SFC, 14.25 mg, 11% yield). The relative stereochemistry was arbitrarily assigned.

[0361] Compound 78*: 1H NMR(400MHz,CD3OD)δ 8.33(d,J=7.6Hz,1H),8.12(t,J=8.0Hz,1H),7.82(d,J=7.6Hz,1H),4.86-4.76(m,1H),3 .87-3.77(m,1H),3.70(dd,J=2.8,11.2Hz,1H),3.67-3.56(m,1H),3.04-2.93(m,2H),2. 89-2.81(m,1H),2.80-2.78(m,1H),2.65-2.52(m,1H),2.10-1.99(m,3H),1.99-1.79(m, 3H),1.78-1.66(m,1H),1.56(d,J=6.8Hz,6H),1.53-1.38(m,1H),1.05(d,J=6.0Hz,3H).

[0362] Compound 79*: 1 H NMR(400MHz,CD3OD)δ 8.36(d,J=8.0Hz,1H),8.12(t,J=8.0Hz,1H),7.81(d,J=7.6Hz,1H),4.82-4.71(m,1H),3 .79-3.65(m,3H),3.42(dd,J=6.4,10.8Hz,1H),3.29-3.23(m,1H),2.95-2.91(m,1H),2. 85-2.79(m,1H),2.75-2.67(m,1H),2.66-2.58(m,1H),2.25-2.04(m,4H),1.89-1.74(m, 2H),1.74-1.65(m,1H),1.64-1.58(m,1H),1.55(d,J=6.4Hz,6H),1.05(d,J=6.4Hz,3H).

[0363] Step 4: (R)-4-((1R,4R)-4-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-3-methylmorpholine and (R)-4-((1s,4S)-4-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclohexyl)-3-methylmorpholine (Compounds 80* and 81*) [ka]

[0364] To a solution of 4-[2-isopropyl-5-[6-(trifluoromethyl)-2-pyridyl]-1,2,4-triazol-3-yl]cyclohexanone (130 mg, 0.37 mmol) in methanol (6 mL), (R)-3-methylmorpholine (373 mg, 3.69 mmol), acetic acid (22 mg, 0.37 mmol), and sodium cyanoborohydride (70 mg, 1.11 mmol) were added and stirred at 70 °C for 30 hours. The reaction mixture was diluted with water (20 mL) and adjusted to pH = 9 with saturated Na2CO3. The resulting solution was extracted with dichloromethane (30 mL × 3), and the combined organic layers were concentrated in vacuo. The resulting residue was purified by reverse-phase chromatography (30%-60% acetonitrile / 0.05% aqueous ammonia hydroxide) to give compound 80* (second peak in SFC, 7.79 mg, 5% yield) and compound 81* (first peak in SFC, 32.82 mg, 20% yield). LCMS (ESI) [M+H] + =438.1. Relative stereochemistry arbitrarily assigned.

[0365] Compound 80*: 1 H NMR(400MHz,CD3OD)δ 8.33(d,J=8.0Hz,1H),8.12(t,J=8.0Hz,1H),7.83(d,J=7.6Hz,1H),4.84-4.82(m,1H),3.86(d,J=11.6Hz,1H),3.76(d,J=11.2Hz,1H),3. 71-3.60(m,1H),3.40-3.32(m,1H),3.25-2.56(m,5H),2.12-1.67(m,7H),1.56(d,J=6.8Hz,6H),1.52-1.49(m,1H),1.11(d,J=5.6Hz,3H).

[0366] Compound 81*: 1H NMR(400MHz,CD3OD)δ 8.36(d,J=8.0Hz,1H),8.12(t,J=7.6Hz,1H),7.82(d,J=7.6Hz,1H),4.77-4.71(m,1H),3 .75-3.68(m,3H),3.42(dd,J=6.4,11.2Hz,1H),3.31-3.28(m,1H),2.95-2.91(m,1H),2. 85-2.80(m,1H),2.75-2.67(m,1H),2.67-2.59(m,1H),2.19-2.08(m,4H),1.90-1.78(m, 2H),1.74-1.66(m,1H),1.65-1.58(m,1H),1.55(d,J=6.4Hz,6H),1.05(d,J=6.0Hz,3H).

[0367] Example AH: 1-((1R,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-4-(2-methoxyethyl)piperazine and 1-((1S,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-4-(2-methoxyethyl)piperazine (Compounds 82 and 83) [ka] The title compound was synthesized following a procedure similar to that for Compound 68, using 6-(trifluoromethyl)nicotinimidamide hydrochloride and (R)-3-oxocyclopentanecarboxylic acid in Step 1. The crude mixture was purified by silica flash chromatography (0-10% methanol in dichloromethane) to give the title compound (50 mg, 68.2% yield) as a mixture of diastereomers. The mixture of diastereomers was separated using chiral SFC (Daicel Chiralpak SFC-21; DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); 0.1% NH3 in ETOH; 15 / 15; 60 mL / min) to give Compound 82 (first peak in SFC, 3.65 mg, 6.9% yield) and Compound 83 (second peak in SFC, 30.03 mg, 59.5% yield). LCMS (ESI), [M+H] + =467.3. The relative stereochemistry was determined by 2D-NMR.

[0368] Compound 82: 1 H NMR(400MHz,CD3OD)δ 9.32(s,1H),8.61(dd,J=1.6,8.4Hz,1H),7.90(d,J=8.0Hz,1H),4.80-4.73(m,1H),3.65-3.56(m,3H),3.35(s,3H),3.18-3.06( m,1H),2.73(brs,9H),2.37-2.19(m,4H),2.13-2.08(m,1H),2.02-1.93(m,1H),1.74-1.67(m,1H),1.54(dd,J=2.4,6.4Hz,6H).

[0369] Compound 83: 1H NMR (400 MHz, CD3OD) δ 9.32(s,1H),8.60(dd,J=1.6,8.4Hz,1H),7.90(d,J=8.4Hz,1H),4.79-4.72 (m,1H),3.55(t,J=5.2Hz,2H),3.51-3.44(m,1H),3.34(s,3H),2.89-2.83( m,1H),2.63-2.60(m,10H),2.41-2.35(m,1H),2.20-2.13(m,1H),2.10-2.0 3(m,2H),2.01-1.92(m,1H),1.87-1.80(m,1H),1.53(dd,J=2.8,6.8Hz,6H).

[0370] Example AI: 1-Cyclobutyl-4-((1R,3s,5S,6r)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)piperazine and 1-cyclobutyl-4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)piperazine (Compounds 84 and 85) [ka] The title compound was synthesized following a procedure similar to that for compound 29*, using (1R,5S,6r)-6-(3-iodo-1-isopropyl-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine in step 1. The crude mixture was purified by reverse-phase chromatography (Phenomenex Gemini-NX C18 75*30 mm*3 um water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-CAN; 57%-87%) to give compound 84 (second peak of SFC, 33.71 mg, 25% yield) and compound 85 (first peak of SFC, 35.5 mg, 26% yield). LCMS (ESI) [M+H] +=474.3. The relative stereochemistry was determined by 2D-NMR.

[0371] Compound 84: 1 H NMR(400MHz,CD3OD)δ 8.15(d,J=8.0Hz,1H),7.97(t,J=8.0Hz,1H),7.62(d,J=7.6Hz,1H),6.51(s,1H),4.84-4.74(m,1H),2.80-2.76(m, 1H),2.73-2.33(m,8H),2.29(dd,J=7.2,12.4Hz,3H),2.08-2.04(m,2H),1.96-1.68(m,9H),1.53(d,J=6.8Hz,6H).

[0372] Compound 85: 1 H NMR(400MHz,CD3OD)δ 8.15(d,J=8.0Hz,1H),7.97(t,J=8.0Hz,1H),7.62(d,J=7.6Hz,1H),6.46(s,1H),4.85-4.78(m,1H),3.00(q,J=8.4Hz,1H),2. 81-2.76(m,1H),2.73-2.10(m,9H),2.08-2.01(m,2H),1.96-1.67(m,8H),1.61(dd,J=8.4,13.6Hz,2H),1.55(d,J=6.4Hz,6H).

[0373] Example AJ: 2-(4-((1R,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)piperazin-1-yl)ethanol and 2-(4-((1S,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)piperazin-1-yl)ethanol (compounds 86* and 87*), [ka] Step 1: (R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone and (S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone [ka]

[0374] Following the procedure for compound 58*, 2400 mg of 3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone was prepared, which was purified by SFC (SFC-11, Phenomenex-Cellulose-2 (250 mm*50 mm, 10 μm, 0.1% NH3HO ETOH, 25 / 25, 200 ml / min) to give title compound-1 (first peak in SFC, 1 g, 42% yield) and title compound-2 (second peak in SFC, 1 g, 42% yield). LCMS (ESI), [M+H]+ = 338.1. Relative stereochemistry was arbitrarily assigned.

[0375] Step 2: 2-(4-((3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)piperazin-1-yl)ethanol [ka]

[0376] A solution of (R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone (100 mg, 0.30 mmol), 2-(piperazin-1-yl)ethanol (116 mg, 0.89 mmol), acetic acid (36 mg, 0.59 mmol), and 4AMS in anhydrous 1,2-dichloroethane (3 mL) was stirred at 25 °C for 2 hours. NaBH(OAc) (314 mg, 1.48 mmol) was then added and stirred at 25 °C for 16 hours. The mixture was diluted with water (15 mL), and the pH was adjusted to 9 with aqueous NaHCO solution. The resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica flash chromatography (0-5% methanol in dichloromethane) to give the title compound (100 mg, 75% yield) as a mixture of diastereomers. LCMS (ESI), [M+H]+ = 452.2.

[0377] Step 3: 2-(4-((1R,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)piperazin-1-yl)ethanol and 2-(4-((1S,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)piperazin-1-yl)ethanol (Compounds 86* and 87*) [ka]

[0378] The diastereomeric mixture (120 mg, 0.27 mmol) was separated using chiral SFC (SFC-17, DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 μm), 0.1% NH₃H₂O / ETOH, 40 / 40, 70 ml / min) to give compound 86* (anti isomer, first peak in SFC, 17.76 mg, 15% yield) and compound 87* (syn isomer, second peak in SFC, 75.74 mg, 63% yield). Relative stereochemistry was arbitrarily assigned.

[0379] Compound 86*: 1 H NMR (400 MHz, CD3OD) δ 9.10(d,J=1.2Hz,1H),8.37(dd,J=1.6,8.0Hz,1H),7.82(d,J=8.4Hz,1H),6 .69(s,1H),4.69-4.60(m,1H),3.70(t,J=6.0Hz,2H),3.30-3.24(m,1H),2. 88-2.47(m,1H),3.05-2.44(m,11H),2.44-2.33(m,1H),2.24-2.15(m,1H), 2.11-1.99(m,1H),1.86-1.73(m,2H),1.68-1.55(m,1H),1.53-1.45(m,6H).

[0380] Compound 87*: 1 H NMR(400MHz,CD3OD)δ 9.10(d,J=1.6Hz,1H),8.37(dd,J=1.6,8.4Hz,1H),7.82(d,J=8.4Hz,1H),6.69(s,1H),4.69-4.59(m,1H),3.35(s,3H),3.29-3.23(m,1H) ),2.96-2.77(m,3H),2.44-2.26(m,3H),2.23-2.15(m,1H),2.10-2.02(m,1H),2.00-1.92(m,2H),1.90-1.54(m,6H),1.53-1.45(m,6H).

[0381] Example AK: 2-(4-((1S,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)piperazin-1-yl)ethanol and 2-(4-((1R,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)piperazin-1-yl)ethanol (Compounds 88* and 89*) [ka] Step 1: 2-(4-((3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)piperazin-1-yl)ethanol [ka]

[0382] A solution of (S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone (120.0 mg, 0.36 mmol), 2-(piperazin-1-yl)ethanol (139 mg, 1.07 mmol), acetic acid (43 mg, 0.71 mmol), and 4AMS in anhydrous 1,2-dichloroethane (3 mL) was stirred at 25 °C for 2 hours. NaBH(OAc) (377 mg, 1.78 mmol) was then added and stirred at 25 °C for 16 hours. The mixture was diluted with water (25 mL), and the pH was adjusted to 9 with aqueous NaHCO solution. The resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-5% methanol in dichloromethane) to give the title compound (120 mg, 74% yield) as a mixture of diastereomers. LCMS (ESI), [M+H]+ = 452.2.

[0383] Step 2: 2-(4-((1S,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)piperazin-1-yl)ethanol and 2-(4-((1R,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)piperazin-1-yl)ethanol [ka]

[0384] The mixture of diastereomers (120 mg, 0.27 mmol) was separated using chiral SFC (SFC-13, Phenomenex-Cellulose-2 (250 mm x 50 mm, 10 μm), 0.1% NH₃HO / ETOH, 35 / 35, 60 ml / min) to give compound 88* (anti isomer, first peak in SFC, 13.53 mg, 11% yield) and compound 89* (syn isomer, second peak in SFC, 75.77 mg, 63% yield). Relative stereochemistry was arbitrarily assigned.

[0385] Compound 88*: 1 H NMR(400MHz,CD3OD)δ 9.10(s,1H),8.39-8.31(m,1H),7.82(d,J=8.4Hz,1H),6.65(s,1H),4. 77-4.55(m,1H),3.71(t,J=6.0Hz,2H),3.46-3.36(m,1H),3.02-2.93( m,1H),2.90-2.59(m,10H),2.30-2.23(m,1H),2.20-2.10(m,2H),2.02 -1.96(m,1H),1.84-1.73(m,1H),1.71-1.60(m,1H),1.55-1.45(m,6H).

[0386] Compound 89*: 1 H NMR(400MHz,CD3OD)δ 9.10(d,J=1.6Hz,1H),8.37(dd,J=1.2,8.4Hz,1H),7.82(d,J=8.4Hz,1H),6.69(s,1H),4.69-4.56(m,1H),3.70(t,J=6.0Hz,2H),3. 30-3.24(m,1H),2.88-2.45(m,11H),2.44-2.36(m,1H),2.22-2.03(m,2H),1.85-1.72(m,2H),1.69-1.61(m,1H),1.55-1.43(m,6H).

[0387] Example AL: 1-((1R,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-4-(2-methoxyethyl)piperazine and 1-((1S,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-4-(2-methoxyethyl)piperazine (Compounds 90* and 91*) [ka] The title compound was synthesized according to a similar procedure to compound 86* using 1-(2-methoxyethyl)piperazine and 3-[2-isopropyl-5-[6-(trifluoromethyl)-3-pyridyl]pyrazol-3-yl]cyclopentanone (first peak in SFC) in the reductive amination step. The crude mixture was purified by prep-TLC (10% methanol in dichloromethane) to give the title compound (100 mg, 95% yield) as a mixture of diastereomers. The mixture of diastereomers (100 mg, 0.21 mmol) was separated using chiral SFC (SFC-11; Daicel Chiralpak AD (250 mm * 30 mm, 10 μm)); 0.1% NH3HO; ETOH; 20 / 20; 60 mL / min) to give compound 90* (first peak of SFC, 12.48 mg, 12% yield) and compound 91* (second peak of SFC, 53.25 mg, 52% yield). LCMS (ESI) [M+H] + =466.3. Relative stereochemistry arbitrarily assigned.

[0388] Compound 90*: 1H NMR(400MHz,CD3OD)δ 9.06(s,1H),8.26(dd,J=1.6,8.0Hz,1H),7.66(d,J=8.0Hz,1H),6.36(s,1H),4.53-4.45(m,1H),3.54(t,J=5.6Hz,2H),3.3 6(s,3H),2.95(s,1H),2.88-2.60(m,10H),2.38-2.16(m,4H),1.94-1.90(m,1H),1.82-1.68(m,2H),1.52(t,J=6.8Hz,6H).

[0389] Compound 91*: 1 H NMR(400MHz,CD3OD)δ 9.07(d,J=1.6Hz,1H),8.25(dd,J=1.6,8.0Hz,1H),7.67(d,J=8.0Hz,1H),6.43(s,1H),4.52-4.45(m,1H),3.55(t,J=5.2Hz,2H),3.36(s,3H) ),3.16-3.14(m,1H),2.83-2.50(m,10H),2.36-2.33(m,1H),2.17-2.1 4(m,1H),2.03-2.01(m,1H),1.87-1.64(m,4H),1.54(d,J=6.8Hz,6H).

[0390] Example AM: 1-((1S,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-4-(2-methoxyethyl)piperazine and 1-((1R,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)-4-(2-methoxyethyl)piperazine (Compound 92* and Compound 93*) [ka] The title compound was synthesized following a similar procedure to Compound 86*, using 1-(2-methoxyethyl)piperazine and 3-[2-isopropyl-5-[6-(trifluoromethyl)-3-pyridyl]pyrazol-3-yl]cyclopentanone (SFC second peak) in the final reductive amination step. The crude mixture was purified by prep-TLC (10% methanol in dichloromethane) to give the title compound (90 mg, 90% yield) as a mixture of diastereomers. The diastereomeric mixture (90 mg, 0.19 mmol) was separated using chiral SFC (Daicel Chiralpak AD (250 mm * 30 mm, 10 μm); 0.1% NH3HO; IPA; 15 / 15; 60 mL / min) to give Compound 92* (SFC first peak, 7.54 mg, 7% yield) and Compound 93* (SFC second peak, 53.51 mg, 52% yield). LCMS(ESI)[M+H] + =466.3. Relative stereochemistry arbitrarily assigned.

[0391] Compound 92*: 1 H NMR(400MHz,CD3OD)δ 9.06(s,1H),8.26(d,J=8.8Hz,1H),7.67(d,J=8.0Hz,1H),6.37(s,1H),4.54-4.47(m,1H),3.54(t,J=5.2Hz,2H), 3.36(s,4H),2.98-2.59(m,10H),2.25-2.15(m,4H),1.96-1.91(m,1H),1.89-1.77(m,2H),1.53(d,J=6.8Hz,6H).

[0392] Compound 93*: 1H NMR(400MHz,CD3OD)δ 9.06(s,1H),8.24(dd,J=1.6,8.4Hz,1H),7.66(d,J=8.0Hz,1H),6.42(s,1H),4.53-4.47(m,1H),3.52(t,J=5.6Hz,2H),3.35(s,3H),3. 19-3.07(m,1H),2.72-2.61(m,2H),2.60-2.50(m,8H),2.33-2.30(m,1H),2.21-1.96(m,2H),1.88-1.60(m,4H),1.52(d,J=6.8Hz,6H).

[0393] Example AN: 4-((1S,3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1R,3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compounds 94 and 95) [ka] The title compound was synthesized using 2-(trifluoromethyl)pyrimidine-5-carboximidamide hydrochloride and (S)-3-oxocyclopentanecarboxylic acid in step 1, following a procedure similar to that for compound 68. The crude mixture was purified by silica flash chromatography (0-10% methanol in dichloromethane) to give the title compound (150 mg, 73% yield) as a mixture of diastereomers. The diastereomeric mixture (150 mg, 0.37 mmol) was separated using chiral SFC (DAICEL CHIRALPAAD (250 mm x 30 mm, 10 μm); 0.1% NH3HO + MEOH, 20 / 20; 60 mL / min) to give compound 94 (first peak in SFC, 33.31 mg, 20.4% yield) and compound 95 (second peak in SFC, 73.33 mg, 46% yield) as colorless oils. LCMS (ESI) [M+H]+ = 411.2. The relative stereochemistry was determined by 2D-NMR.

[0394] Compound 94: 1 H NMR(400MHz,CD3OD)δ 9.51(s,2H),4.84-4.74(m,1H),3.74(t,J=4.8Hz,4H),3.65-3.57(m,1H),3.02-2.94(m,1H),2.64-2.53(m,4H),2.29- 2.23(m,2H),2.21-2.16(m,1H),2.11-2.04(m,1H),2.01-1.91(m,1H),1.71-1.61(m,1H),1.54(dd,J=2.0,6.8Hz,6H).

[0395] Compound 95: 1 H NMR(400MHz,CD3OD)δ 9.51(s,2H),4.83-4.73(m,1H),3.73(t,J=4.8Hz,4H),3.54-3.46(m,1H),2.88-2.79(m,1H),2.64-2.52(m,4H),2.42-2.36(m,1) H),2.23-2.14(m,1H),2.12-2.01(m,2H),1.98-1.93(m,1H),1.91-1.90(m,1H),1.88-1.78(m,1H),1.54(dd,J=2.4,6.8Hz,6H).

[0396] Example AO: (R)-4-((1R,3s,5S,6R)-6-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (R)-4-((1R,3r,5S,6R)-6-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine (Compounds 96 and 97) [ka] The title compound was synthesized following a procedure similar to that for compound 29*, using (1R,5S,6r)-6-(3-iodo-1-isopropyl-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine in step 1. The crude mixture was purified by reverse-phase chromatography (Boston Prime C18 150*30 mm×5 μm; water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN; 65%-95%) to give compound 96 (first peak of SFC, 28.44 mg, 22% yield) and compound 97 (second peak of SFC, 56.2 mg, 45% yield). LCMS (ESI), [M+H] + =436.2. The relative stereochemistry was determined by 2D-NMR.

[0397] Compound 96: 1 H NMR(400MHz,CD3OD)δ 9.27(s,2H),6.50(s,1H),4.83-4.79(m,1H),3.73-3.69(m,3H),3.48(dd,J=4.4,11.2Hz,1H),3.10-3.01(m,1H),2.8 8-2.68(m,2H),2.50(d,J=11.6Hz,1H),2.32-2.18(m,2H),1.93-1.75(m,5H),1.53(d,J=6.8Hz,6H),1.12(t,J=6.0Hz 3H).

[0398] Compound 97: 1 H NMR(400MHz,CD3OD)δ 9.26(s,2H),6.46(s,1H),4.85-4.82(m,1H),3.72-3.66(m,3H),3.51-3.47(m,2H),2.82(s,1H),2.70-2.64(m,1H),2.51 -2.47(m,1H),2.35-2.18(m,2H),1.86(t,J=2.8Hz,1H),1.76-1.67(m,4H),1.55(d,J=6.4Hz,6H),1.09(d,J=6.4Hz,3H).

[0399] Example AP: 4-((1R,3s,5S,6r)-6-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)morpholine and 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)morpholine (Compounds 98 and 99) [ka] Step 1: 1-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-3-(2-(trifluoromethyl)pyrimidin-4-yl)propane-1,3-dione [ka]

[0400] To a solution of 1-[3-[tert-butyl(diphenyl)silyl]oxy-6-bicyclo[3.1.0]hexanyl]ethanone (1.6 g, 4.23 mmol) in tetrahydrofuran (30 mL) was added NaH (254 mg, 6.34 mmol, 60% in mineral oil) in portions at 0 °C under N and stirred for 0.5 h. A solution of methyl 2-(trifluoromethyl)pyrimidine-4-carboxylate (1.05 g, 5.07 mmol) in THF (5 mL) was added at 0 °C under N. The reaction mixture was then stirred at 20 °C for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (2 g, 74% yield). LCMS (ESI) [M+H] + =553.0.

[0401] Step 2: 4-(5-((1R,5S,6r)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazol-3-yl)-2-(trifluoromethyl)pyrimidine [ka]

[0402] To a solution of 1-[3-[tert-butyl(diphenyl)silyl]oxy-6-bicyclo[3.1.0]hexanyl]-3-[2-(trifluoromethyl)pyrimidin-4-yl]propane-1,3-dione (2 g, 3.62 mmol) in ethanol (20 mL) was added isopropylhydrazine hydrochloride (424 mg, 3.83 mmol) and triethylamine (0.55 mL, 3.83 mmol) and stirred at 25 °C for 15 h. The mixture was concentrated in vacuo, and the residue was purified by silica flash chromatography (0-5% ethyl acetate in petroleum ether) to give the title compound (1.5 g, 70% yield). LCMS (ESI) [M+H] + =591.6.

[0403] Step 3: (1R,5S,6r)-6-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-ol [ka]

[0404] To a solution of tert-butyl-[[(1S,5R)-6-[2-isopropyl-5-[2-(trifluoromethyl)pyrimidin-4-yl]pyrazol-3-yl]-3-bicyclo[3.1.0]hexanyl]oxy]-diphenyl-silane (1.5 g, 2.54 mmol) in tetrahydrofuran (10 mL), TABF (5 mL, 30.4 mmol, 1 M in THF) was added and stirred at 70 °C for 15 hours. The reaction mixture was concentrated under reduced pressure. The crude residue was diluted with water (10 mL) and then adjusted to pH = 7 with NaOH (2 M). The resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (680 mg, 74% yield). LCMS(ESI)[M+H] + =352.9.

[0405] Step 4: (1R,5S,6r)-6-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one [ka]

[0406] To a solution of (1R,5S)-6-[2-isopropyl-5-[2-(trifluoromethyl)pyrimidin-4-yl]pyrazol-3-yl]bicyclo[3.1.0]hexan-3-ol (680 mg, 1.93 mmol) in anhydrous dichloromethane (5 mL) was added Dess-Martin periodinane (1.22 g, 2.89 mmol) and stirred at 25 °C for 16 h. The mixture was then diluted with HO (5 mL), followed by aqueous NaSO (10 mL), and aqueous NaHCO (10 mL). The resulting mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography (0–40% ethyl acetate in petroleum ether) to give the title compound (430 mg, 62% yield). LCMS (ESI) [M+H] + =351.2.

[0407] Step 5: 4-((1R,3s,5S,6r)-6-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)morpholine and 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)morpholine (Compounds 98 and 99) [ka]

[0408] To a mixture of (1R,5S)-6-[2-isopropyl-5-[2-(trifluoromethyl)pyrimidin-4-yl]pyrazol-3-yl]bicyclo[3.1.0]hexan-3-one (80 mg, 0.23 mmol) in methyl alcohol (8 mL), morpholine (0.1 mL, 1.14 mmol), acetic acid (0.06 mL, 0.69 mmol), and NaBHCN (43 mg, 0.69 mmol) were added and stirred at 60 °C for 16 hours. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (50 mL × 3). The combined organics were washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase chromatography (Boston Prime C18 150*30 mm×5 μm; water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN; 60%-90%) to give compound 98 (first peak of SFC, 43.49 mg, 45% yield) and compound 99 (second peak of SFC, 26.71 mg, 27% yield). LCMS (ESI) [M+H]+ = 422.1. The relative stereochemistry was determined by 2D-NMR.

[0409] Compound 98: 1 H NMR(400MHz,CD3OD)δ 8.83(d,J=5.6Hz,1H),8.12(d,J=5.2Hz,1H),6.64(s,1H),4.84-4.77(m,1H),3.70(t,J=4.8Hz, 4H),2.51-2.49(m,5H),2.29(dd,J=7.2,12.4Hz,2H),1.78-1.76(m,5H),1.53(d,J=6.8Hz,6H).

[0410] Compound 99: 1 H NMR(400MHz,CD3OD)δ 8.84(d,J=5.2Hz,1H),8.13(d,J=5.2Hz,1H),6.59(s,1H),4.86-4.77(m,1H),3.69(t,J=4.8Hz,4H),2.97-2. 94(m,1H),2.48(brs,4H),2.36-2.34(m,2H),1.90(t,J=2.8Hz,1H),1.74-1.67(m,4H),1.56(d,J=6.8Hz,6H).

[0411] Example AQ: (S)-4-((1R,3s,5S,6S)-6-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (S)-4-((1R,3r,5S,6S)-6-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine (Compounds 100 and 101) [ka] The title compound was synthesized following a procedure similar to that for compound 98, using (1R,5S,6r)-6-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one and (S)-3-methylmorpholine in the final reductive amination step. The crude mixture was purified by reverse-phase chromatography (Boston Prime C18 150*30 mm×5 μm; water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN; 65%-95%) to give compound 100 (second peak of SFC, 33.93 mg, 27% yield) and compound 101 (first peak of SFC, 34.36 mg, 28% yield). LCMS (ESI) [M+H] + =436.3. The relative stereochemistry was determined by 2D-NMR.

[0412] Compound 100: 1H NMR(400MHz,CD3OD)δ 8.84(d,J=5.2Hz,1H),8.12(d,J=5.6Hz,1H),6.64(s,1H),4.86-4.83(m,1H),3.7 2-3.68(m,3H),3.47(dd,J=4.4,11.2Hz,1H),3.08-3.00(m,1H),2.79(t,J=6.8Hz, 1H),2.75-2.67(m,1H),2.51-2.45(m,1H),2.24-2.16(m,2H),1.95-1.88(m,2H),1 .83-1.80(m,1H),1.77-1.63(m,2H),1.54(d,J=6.0Hz,6H),1.10(d,J=6.4Hz,3H).

[0413] Compound 101: 1 H NMR(400MHz,CD3OD)δ 8.84(d,J=5.6Hz,1H),8.13(d,J=5.2Hz,1H),6.60(s,1H),4.87-4.83(m,1H),3.81-3.66(m,3H),3.50-3.46(m,2H),2.92-2.88(m,1H),2.68 -2.64(m,1H),2.50-2.48(m,1H),2.35-2.20(m,2H),1.86(t,J=3.2Hz,1H),1.74-1.69(m,4H),1.56(d,J=6.8Hz,6H),1.09(d,J=6.4Hz,3H).

[0414] Example AR: (R)-4-((1R,3s,5S,6S)-6-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (R)-4-((1R,3r,5S,6S)-6-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine (Compounds 102 and 103) [ka] The title compound was synthesized following a procedure similar to that for compound 98, using (1R,5S,6r)-6-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one and (R)-3-methylmorpholine in the final reductive amination step. The crude mixture was purified by reverse-phase chromatography (Boston Prime C18 150*30 mm×5 μm; water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN; 65%-95%) to give compound 102 (second peak of SFC, 27.8 mg, 18% yield) and compound 103 (first peak of SFC, 34.53 mg, 22% yield). LCMS (ESI) [M+H] + =436.3. The relative stereochemistry was determined by 2D-NMR.

[0415] Compound 102: 1 H NMR(400MHz,CD3OD)δ 8.83(d,J=5.2Hz,1H),8.12(d,J=5.6Hz,1H),6.64(s,1H),4.84-4.81(m,1H),3.82-3.68(m,2H),3.47(dd,J=4.4,11.2Hz,1H),3.10-3.00(m, 1H),2.88-2.75(m,1H),2.74-2.68(m,1H),2.50-2.41(m,1H),2.33-2. 16(m,2H),1.94-1.76(m,5H),1.54(d,J=6.8Hz,6H),1.13-1.09(m,3H).

[0416] Compound 103: 1H NMR(400MHz,CD3OD)δ 8.84(d,J=5.6Hz,1H),8.12(d,J=5.2Hz,1H),6.59(s,1H),4.85-4.83(m ,1H),3.72-3.66(m,3H),3.49(dd,J=4.4,11.2Hz,2H),2.85-2.80(m,1H) ,2.68-2.64(m,1H),2.50-2.46(m,1H),2.36-2.20(m,2H),1.86(t,J=3.2 Hz,1H),1.77-1.69(m,4H),1.56(d,J=6.8Hz,6H),1.09(d,J=6.4Hz,3H).

[0417] Example AS: 4-((1R,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1S,3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compounds 104 and 105) [ka] [ka] The title compound was synthesized following a procedure similar to that for Compound 68, using 6-(trifluoromethyl)nicotinimidamide hydrochloride and (S)-3-oxocyclopentanecarboxylic acid in Step 1. The crude mixture was purified by silica flash chromatography (0-65% ethyl acetate in petroleum ether) to give the title compound (90 mg, 73.6% yield) as a mixture of diastereomers. The diastereomeric mixture (90.0 mg, 0.22 mmol) was separated using chiral SFC (DAICEL CHIRALPAK OD (250 mm*30 mm, 10 μm); 0.1% NH3HO ETOH 15 / 15; 60 mL / min) to give Compound 104 (first peak in SFC, 14.39 mg, 15.3% yield) and Compound 105 (second peak in SFC, 41.4 mg, 45.5% yield). LCMS (ESI) [M+H]+ = 410.2. The relative stereochemistry was determined by 2D-NMR.

[0418] Compound 104: 1 H NMR(400MHz,CD3OD)δ 9.32(s,1H),8.60(d,J=8.4Hz,1H),7.90(d,J=8.4Hz,1H),4.80-4.73(m,1H),3.73(t,J=4.8Hz,4H),3.63-3.55(m,1H),3.01-2.9 3(m,1H),2.59(brs,4H),2.26-2.15(m,3H),2.11-2.03(m,1H),2.00-1.91(m,1H),1.70-1.60(m,1H),1.54(dd,J=2.0,6.4Hz,6H).

[0419] Compound 105: 1H NMR(400MHz,CD3OD)δ 9.32(s,1H),8.60(d,J=8.4Hz,1H),7.90(d,J=8.4Hz,1H),4.79-4.73( m,1H),3.73(t,J=4.8Hz,4H),3.53-3.44(m,1H),2.88-2.80(m,1H),2.6 1(d,J=4.0Hz,4H),2.42-2.35(m,1H),2.20-2.16(m,1H),2.11-2.03(m, 2H),2.00-1.93(m,1H),1.87-1.82(m,1H),1.54(dd,J=2.0,6.8Hz,6H).

[0420] Example AT: (R)-4-((1R,3s,5S,6R)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (R)-4-((1R,3r,5S,6R)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine (Compounds 202 and 106) [ka] Step 1: 1-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-3-(6-(trifluoromethyl)pyrimidin-4-yl)propane-1,3-dione [ka]

[0421] To a solution of 1-[3-[tert-butyl(diphenyl)silyl]oxy-6-bicyclo[3.1.0]hexanyl]ethanone (1.0 g, 2.64 mmol) in tetrahydrofuran (10 mL) was added NaH (0.16 g, 3.96 mmol, 60% in mineral oil) under N at 0 °C and stirred at 0 °C for 1 h. Then, methyl 6-(trifluoromethyl)pyrimidine-4-carboxylate (0.82 g, 3.96 mmol) was added to the above reaction mixture and stirred at 20 °C for 2 h. The reaction was quenched with aqueous NH Cl (20 mL) and extracted with dichloromethane (50 mL × 3). The combined organic layers were dried over anhydrous Na SO , filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-5% ethyl acetate in petroleum ether) to give the title compound (1200 mg, 95.7% yield). LCMS (ESI), [M+H]+ = 553.2.

[0422] Step 2: 4-(5-((1R,5S,6r)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazol-3-yl)-6-(trifluoromethyl)pyrimidine [ka]

[0423] To a solution of 1-[3-[tert-butyl(diphenyl)silyl]oxy-6-bicyclo[3.1.0]hexanyl]-3-[6-(trifluoromethyl)pyrimidin-4-yl]propane-1,3-dione (1200.0 mg, 2.17 mmol) and isopropylhydrazine hydrochloride (480.0 mg, 4.34 mmol) in ethanol (20 mL) was added triethylamine (0.6 mL, 4.34 mmol) and stirred at 25 °C for 15 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica flash chromatography (0-25% ethyl acetate in petroleum ether) to give the title compound (1000 mg, 78% yield). LCMS (ESI), [M+H]+ = 591.2.

[0424] Step 3: 4-(5-((1R,5S,6r)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazol-3-yl)-6-(trifluoromethyl)pyrimidine [ka]

[0425] To a stirred solution of tert-butyl-diphenyl-[[rac-(1R,5S)-6-[2-isopropyl-5-[6-(trifluoromethyl)pyrimidin-4-yl]pyrazol-3-yl]-3-bicyclo[3.1.0]hexanyl]oxy]silane (1000.0 mg, 1.69 mmol) in tetrahydrofuran (5 mL) was added triethylamine trihydrofluoride (10.0 mL, 61.45 mmol) and stirred at 70 °C for 8 h. The reaction mixture was adjusted to pH = 9 with aqueous NaOH (4 M). The resulting solution was extracted with dichloromethane (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (550 mg, 91.3% yield). LCMS(ESI), [M+H]+=353.2.

[0426] Step 4: (1R,5S,6r)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicycle[3.1.0]hexan-3-one [ka]

[0427] To a solution of (1R,5S)-6-[2-isopropyl-5-[6-(trifluoromethyl)pyrimidin-4-yl]pyrazol-3-yl]bicyclo[3.1.0]hexan-3-ol (550.0 mg, 1.56 mmol) in anhydrous dichloromethane (10 mL) was added Dess-Martin periodinane (993.0 mg, 2.34 mmol) at 0 °C under N. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with aqueous NaSO (10 mL) and extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with aqueous NaHCO (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0–25% ethyl acetate in petroleum ether) to give the title compound (350 mg, 63.4% yield). LCMS(ESI), [M+H]+=351.3. 1 H NMR(400MHz,CD3OD)δ 9.24(s,1H),8.27(d,J=1.2Hz,1H),6.77(s,1H),4.85-4.80(m,1H),2.81-2.74(m,2H ),2.43-2.38(m,2H),2.04-2.00(m,2H),1.65(t,J=3.6Hz,1H),1.55(d,J=6.4Hz,6H).

[0428] Step 5: (R)-7-(1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide and (S)-7-(1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide (Compounds 202 and 106) [ka]

[0429] To a solution of rac-(1R,5S)-6-[2-isopropyl-5-[6-(trifluoromethyl)pyrimidin-4-yl]pyrazol-3-yl]bicyclo[3.1.0]hexan-3-one (100 mg, 0.29 mmol) in methyl alcohol (4 mL), (3R)-3-methylmorpholine (0.09 mL, 0.86 mmol), acetic acid (0.08 mL, 1.43 mmol), and sodium cyanoborohydride (54 mg, 0.86 mmol) were added and stirred at 60 °C for 16 hours. The reaction mixture was adjusted to pH = 8 with saturated NaHCO (10 mL) at 0 °C and extracted with ethyl acetate (40 mL × 2). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, 65%-95%) to give compound 202 (first peak by HPLC, 21.28 mg, 15.7% yield) and compound 106 (second peak by HPLC, 27.83 mg, 28.3% yield). LCMS (ESI) [M+H]+ = 436.2. The relative stereochemistry was determined by 2D-NMR.

[0430] Compound 202: 1 H NMR (400 MHz, CD3OD) δ 9.22(s,1H),8.25(d,J=1.2Hz,1H),6.67(s,1H),4.85-4.81(m,1H),3.75-3. 65(m,3H),3.50-3.46(m,1H),3.06-3.04(m,1H),2.81(brs,1H),2.73-2.67(m ,1H),2.49(d,J=12.0Hz,1H),2.23-2.12(m,2H),1.93-1.86(m,2H),1.83(t,J =3.2Hz,1H),1.79-1.70(m,2H),1.55(d,J=6.8Hz,6H),1.11(d,J=6.8Hz,3H).

[0431] Compound 106: 1H NMR(400MHz,CD3OD)δ 9.22(s,1H),8.25(d,J=1.2Hz,1H),6.63(s,1H),4.85-4.81(m,1H),3.75-3.64(m,3H),3.51-3.47(m,2H),2.85(brs,1H),2.69-2.63 (m,1H),2.52-2.47(m,1H),2.34-2.21(m,2H),1.88(t,J=2.8Hz,1H),1.76-1.65(m,4H),1.57(d,J=6.8Hz,6H),1.11(d,J=6.4Hz,3H).

[0432] Example AU: 4-((1R,3s,5S,6r)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyrazin-2-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)morpholine and 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyrazin-2-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)morpholine (Compounds 107 and 108) [ka] The title compound was synthesized following a procedure similar to that for compound 202, using methyl 6-(trifluoromethyl)pyrazine-2-carboxylate and 1-[3-[tert-butyl(diphenyl)silyl]oxy-6-bicyclo[3.1.0]hexanyl]ethanone in step 1. The crude mixture was purified by reverse-phase chromatography (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, 55%-80%) to give title compound 107 (first peak by HPLC, 8.8 mg, 6.9% yield) and title compound 108 (second peak by HPLC, 11 mg, 8.8% yield). LCMS (ESI) [M+H] + =422.3. The relative stereochemistry was determined by 2D-NMR.

[0433] Compound 107: 1H NMR(400MHz,CD3OD)δ 9.38(s,1H),8.83(s,1H),6.57(s,1H),4.84-4.78(m,1H),3.71(t,J=4.4Hz,3H),2.55-2. 45(m,5H),2.33-2.29(m,2H),1.89-1.83(m,2H),1.81-1.75(m,3H),1.55(d,J=6.8Hz,6H).

[0434] Compound 108: 1 H NMR (400 MHz, CD3OD) δ 9.38(s,1H),8.83(s,1H),6.58(s,1H),4.84-4.78(m,1H),3.69(t,J=4.4Hz,4H),3.04-2.90(m,1H) ,2.48(brs,4H),2.38-2.29(m,2H),1.85(t,J=3.2Hz,1H),1.76-1.65(m,4H),1.57(d,J=6.8Hz,6H).

[0435] Example AV: (R) 2-ethyl-4-((1R,3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and (S)-2-ethyl-4-((1R,3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compounds 109* and 110*) [ka] The title compound was synthesized according to a procedure similar to that for Compound 68, using 2-(trifluoromethyl)pyrimidine-5-carboximidamide hydrochloride and (S)-3-oxocyclopentanecarboxylic acid in Step 1. The crude mixture was purified by silica flash chromatography (0-10% methanol in dichloromethane) to afford the title compound (300 mg, 56.3% yield) as a mixture of diastereomers.

[0436] The mixture of diastereomers (300 mg, 0.68 mmol) was separated using chiral SFC (DAICEL CHIRALPAIE (250 mm * 30 mm, 10 μm); hexane-IPA (0.1% NH4OH), 10 / 10; 25 mL / min) to give compound 109* (first peak in SFC, 50.08 mg, 16% yield) and compound 110* (second peak in SFC, 45.7 mg, 14% yield). LCMS (ESI), [M+H] + =439.3. Relative stereochemistry arbitrarily assigned.

[0437] Compound 109*: 1 H NMR(400MHz,CD3OD)δ 9.51(s,2H),4.81-4.74(m,1H),3.88(dd,J=2.0,11.6Hz,1H),3.69-3. 63(m,1H),3.54-3.40(m,2H),2.99-2.81(m,3H),2.42-2.36(m,1H),2.2 8-2.14(m,2H),2.12-2.04(m,2H),2.02-1.88(m,2H),1.86-1.81(m,1H) ,1.54(dd,J=2.4,6.4Hz,6H),1.51-1.42(m,2H),0.96(t,J=7.6Hz,3H).

[0438] Compound 110*: 1 H NMR (400 MHz, CD3OD) δ 9.51(s,2H),4.81-4.75(m,1H),3.88(dd,J=2.0,11.6Hz,1H),3.69-3.64(m, 1H),3.55-3.40(m,2H),2.93(t,J=11.2Hz,2H),2.87-2.79(m,1H),2.42-2.36 (m,1H),2.25-2.14(m,2H),2.11-2.00(m,2H),1.99-1.91(m,2H),1.88-1.79( m,1H),1.54(dd,J=3.6,6.4Hz,6H),1.50-1.42(m,2H),0.95(t,J=7.6Hz,3H).

[0439] Example AW: 4-((1R,3S)-3-(3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1S,3S)-3-(3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compounds 111* and 112*) [ka] The title compound was synthesized following a procedure similar to that for Compound 68, using 3-fluoro-4-(trifluoromethyl)benzimidamide and (S)-3-oxocyclopentanecarboxylic acid in step 1. The crude mixture was purified by reverse phase chromatography (BostonPrime C18 150*30mm*5um / water (NH3H2O+NH4HCO3)-ACN), 35%-65%) to give Compound 111* (second peak of SFC, 18.1 mg, 12.4% yield) and Compound 112* (first peak of SFC, 11.91 mg, 8.2% yield). LCMS (ESI), [M+H] + =427.1. Relative stereochemistry arbitrarily assigned.

[0440] Compound 111*: 1 H NMR(400MHz,CDCl3)δ 7.97-7.91(m,2H),7.62(t,J=8.0Hz,1H),4.56-4.49(m,1H),3.85-3.75(m,4H),3.29-3.2 4(m,1H),2.82-2.42(m,4H),2.37-2.31(m,1H),2.14-2.04(m,4H),1.54(d,J=6.8Hz,8H).

[0441] Compound 112*: 1H NMR(400MHz,CDCl3)7.97-7.91(m,2H),7.62(t,J=8.0Hz,1H),4.56-4.53(m,1H),3.93-3.79(m,4H) ,3.45-3.38(m,1H),2.97-2.92(m,1H),2.62-2.54(m,3H),2.21-1.99(m,5H),1.54(d,J=6.4Hz,8H).

[0442] Example AX: 4-((1S,3R)-3-(3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1R,3R)-3-(3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compounds 113* and 114*) [ka] The title compound was synthesized following a procedure similar to that for compound 68, using 3-fluoro-4-(trifluoromethyl)benzimidamide and (R)-3-oxocyclopentanecarboxylic acid in step 1. The crude mixture was purified by reverse phase chromatography (Boston Prime C18 150*30mm*5um / water (0.5% NH3H2O+NH4HCO3)-CAN, 35%-65%) to give title compound 113* (second peak of SFC, 11.65mg, 16% yield) and compound 114* (first peak of SFC, 6.71mg, 8.9% yield). LCMS (ESI), [M+H] + =427.2. Relative stereochemistry arbitrarily assigned.

[0443] Compound 113*: 1H NMR(400MHz,CDCl3)δ 7.97-7.91(m,2H),7.62(t,J=7.6Hz,1H),4.58-4.49(m,1H),3.80(s,4H),3.30-3.2 1(m,1H),2.61(s,5H),2.34-2.31(m,1H),2.14-1.90(m,5H),1.54(d,J=6.8Hz,6H).

[0444] Compound 114*: 1 H NMR(400MHz,CDCl3)δ 7.97-7.91(m,2H),7.62(t,J=7.8Hz,1H),4.57-4.50(m,1H),3.80(s,4H),3.42-3.39(m,1H),2.99-2.98(m 1H),2.61(s,4H),2.33-1.96(m,5H),1.53(d,J=6.8Hz,6H),1.26(s,1H).

[0445] Example AY: 4-((1R,3R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1S,3S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1S,3R) -3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1R,3S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compounds 115* and 116* and 117* and 118*) [ka] Step 1: 3-(5-Bromo-1-isopropyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)pyridine. [ka]

[0446] To a solution of 3,5-dibromo-1-isopropyl-1H-1,2,4-triazole (2.0 g, 7.44 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine (1.83 g, 6.69 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was added Pd(dppf)Cl (544.0 mg, 0.74 mmol) and KCO (3.08 g, 22.31 mmol). The reaction mixture was degassed, purged with N three times, and stirred under N at 90 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (0–10% ethyl acetate in petroleum ether) to give the title compound (600 mg, 24.1% yield). LCMS(ESI), [M+H] + =335.0.

[0447] Step 2: 3-(1-Isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopent-2-enone. [ka]

[0448] To a solution of 3-(5-bromo-1-isopropyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)pyridine (600.0 mg, 1.79 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-enone (559 mg, 2.69 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added Pd(dppf)Cl (131.0 mg, 0.18 mmol) and KCO (742 mg, 5.37 mmol). The reaction mixture was degassed, purged with N three times, and stirred under N at 100 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (350 mg, 58.1% yield). LCMS (ESI), [M+H] + =337.2.

[0449] Step 3: 3-(1-Isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentanone. [ka]

[0450] To a solution of 3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopent-2-enone (300.0 mg, 0.89 mmol) in ethyl acetate (10 mL) was added Rh / C (367 mg). The reaction mixture was degassed, purged with H2 three times, and stirred under H2 (15 psi) at 25 °C for 1 h. The mixture was filtered, and the filtrate was concentrated to give the title compound (280 mg, 92.8% yield). LCMS (ESI), [M+H] + =339.1.

[0451] Step 4: 4-(3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine [ka]

[0452] To a solution of 3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentanone (260.0 mg, 0.77 mmol) and morpholine (0.2 mL, 2.31 mmol) in methyl alcohol (4 mL) was added acetic acid (0.18 mL, 3.07 mmol) and sodium cyanoborohydride (242 mg, 3.84 mmol). The mixture was stirred at 60 °C for 1 h. The mixture was then adjusted to pH 7-8 with NaHCO (aq) and extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash chromatography (0-10% methanol in dichloromethane) to give the title compound (200 mg, 64% yield). LCMS(ESI), [M+H] + =410.1.

[0453] Step 5: 4-((1R,3R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1S,3S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1S,3R)- 3-(1-Isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1R,3S)-3-(1-Isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compounds 115* and 116* and 117* and 118*) [ka]

[0454] The mixture of diastereomers (200.0 mg, 0.49 mmol) was separated using chiral SFC (Daicel Chiralcel OD-H (250 mm * 30 mm, 5 μm) / 0.1% NH₃H₂O IPA, 15 / 15) to give compound 115* (first peak in SFC, 10.22 mg, 5.1% yield), compound 116* (second peak in SFC, 9.39 mg, 4.7% yield), compound 117* (third peak in SFC, 19.62 mg, 9.8% yield), and compound 118* (fourth peak in SFC, 31.73 mg, 15.9% yield). LCMS (ESI), [M+H] + =410.1. Relative stereochemistry arbitrarily assigned.

[0455] Compound 115*: 1 H NMR(400MHz,CD3OD)δ 9.43(d,J=1.6Hz,1H),8.90(s,1H),8.65(s,1H),4.81-4.74(m,1H),3.73(t,J=4.8Hz,4H),3.64-3.55(m,1H),3.0 1-2.93(m,1H),2.59(s,4H),2.28-2.16(m,3H),2.11-1.93(m,2H),1.70-1.60(m,1H),1.54(dd,J=2.0,6.4Hz,6H).

[0456] Compound 116*: 1 H NMR(400MHz,CD3OD)δ 9.43(s,1H),8.90(s,1H),8.65(s,1H),4.81-4.74(m,1H),3.73(t,J=4.4Hz,4H),3.64-3.55(m,1H),3.01-2.93(m,1H) ,2.59(s,4H),2.28-2.16(m,3H),2.11-2.04(m,1H),2.01-1.92(m,1H),1.70-1.60(m,1H),1.54(dd,J=2.0,6.8Hz,6H).

[0457] Compound 117*: 1H NMR(400MHz,CD3OD)δ 9.43(d,J=1.6Hz,1H),8.90(s,1H),8.65(s,1H),4.80-4.73(m,1H),3.73(t,J=4.8Hz,4H),3.53-3.44(m,1H),2.87-2.79(m,1H),2.61-2 .60(m,4H),2.42-2.36(m,1H),2.23-2.14(m,1H),2.11-2.03(m,2H),1.99-1.93(m,1H),1.88-1.79(m,1H),1.54(dd,J=2.0,6.4Hz,6H).

[0458] Compound 118*: 1 H NMR(400MHz,CD3OD)δ 9.43(d,J=1.6Hz,1H),8.89(s,1H),8.65(s,1H),4.80-4.73(m,1H),3.73(t,J=4.8Hz,4H),3.53-3.44(m,1H),2.87-2.79(m,1H),2.61-2 .60(m,4H),2.42-2.36(m,1H),2.21-2.14(m,1H),2.11-2.05(m,2H),1.99-1.93(m,1H),1.88-1.79(m,1H),1.54(dd,J=2.0,6.4Hz,6H).

[0459] Examples AZ: (R)-4-((1R,3s,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (R)-4-((1R,3r,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine (Compounds 119 and 120) [ka] The title compound was synthesized according to a procedure similar to that for Compound 68, using 5-(trifluoromethyl)nicotinimidamide hydrochloride and (1R,5S)-3-[tert-butyl(diphenyl)silyl]oxybicyclo[3.1.0]hexane-6-carboxylic acid in Step 1. The crude mixture was purified by reverse-phase chromatography (water (NNH3H2O ​​+ NH4HCO3)-ACN, 55%-85%, 25 ml / min) to give Compound 119 (first peak in HPLC, 15.3 mg, 20.3% yield) and Compound 120 (second peak in HPLC, 23.5 mg, 31.2% yield). LCMS (ESI), [M+H] + =436.2. The relative stereochemistry was determined by 2D-NMR.

[0460] Compound 119: 1 H NMR(400MHz,CD3OD)δ 9.38(s,1H),8.88(s,1H),8.60(s,1H),4.93(s,1H),3.74-3.71(m,3H),3.50-3.46(m,1H),3.18-3.04(m,1H),2.87-2.73(m,2H) ,2.52-2.46(m,1H),2.32-2.14(m,2H),2.09-2.04(m,3H),1.96-1.87(m,2H),1.56(dd,J=2.8,6.4Hz,6H),1.12(d,J=6.4Hz,3H).

[0461] Compound 120: 1 H NMR(400MHz,CD3OD)δ 9.38(s,1H),8.88(s,1H),8.60(s,1H),4.92(s,1H),3.89-3.59(m,3H),3.48-3.43(m,1H),3.18-3.04(m,1H),2.90-2. 63(m,2H),2.58-2.46(m,1H),2.36-2.05(m,5H),1.99-1.86(m,2H),1.56(dd,J=2.8,6.8Hz,6H),1.12(d,J=6.4Hz,3H).

[0462] Example BA: (S)-4-((1R,3s,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (S)-4-((1R,3r,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine (Compounds 121 and 122) [ka] The title compound was synthesized according to a procedure similar to that for Compound 68, using 5-(trifluoromethyl)nicotinimidamide hydrochloride and (1R,5S)-3-[tert-butyl(diphenyl)silyl]oxybicyclo[3.1.0]hexane-6-carboxylic acid in Step 1. The crude mixture was purified by reverse-phase chromatography (water (NH3H2O ​​+ NH4HCO3)-ACN, 50%-80%, 25 ml / min) to give Compound 121 (first peak in HPLC, 22.04 mg, 27.8% yield) and Compound 122 (second peak in HPLC, 26 mg, 34.5% yield). LCMS (ESI), [M+H] + =436.2. The relative stereochemistry was determined by 2D-NMR.

[0463] Compound 121: 1 H NMR(400MHz,CD3OD)δ 9.38(s,1H),8.88(s,1H),8.60(s,1H),4.92(s,1H),3.85-3.62(m,3H),3.49-3.45(m,1H),3.13-3.09(m,1H),2.87-2. 71(m,2H),2.55-2.48(m,1H),2.35-2.05(m,5H),1.97-1.87(m,2H),1.56(dd,J=2.8,6.8Hz,6H),1.12(d,J=6.8Hz,3H).

[0464] Compound 122: 1H NMR(400MHz,CD3OD)δ 9.37(s,1H),8.87(s,1H),8.59(s,1H),4.93(s,1H),3.77-3.63(m,3H),3.54-3.45(m,2H),2.88-2.85(m,1H),2.69-2.63(m,1H),2.5 3-2.49(m,1H),2.33-2.20(m,2H),2.16-2.15(m,1H),2.04(brs,2H),1.85-1.72(m,2H),1.58(d,J=6.4Hz,6H),1.09(d,J=6.4Hz,3H).

[0465] Example BB: (S)-2-ethyl-4-((1R,3S)-3-(3-(5-fluoropyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compound 123) [ka] The title compound was synthesized following a procedure similar to that for Compound 68, using 5-fluoronicotinimidamide and (S)-3-oxocyclopentanecarboxylic acid in Step 1. The crude mixture was purified by silica flash chromatography (0-10% methanol in dichloromethane) to give the title compound as a mixture of diastereomers (80 mg), which was purified using chiral SFC (SFC-16; DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 μm); 0.1% NH3HO MEOH, 35 / 35; 70 mL / min) to give Compound 123 (59.61 mg, 75% yield). LCMS (ESI) [M+H] + =388.3. The relative stereochemistry was determined by 2D-NMR.

[0466] Compound 123: 1H NMR(400MHz,CDCl3)δ 9.11(s,1H),8.43(d,J=2.8Hz,1H),8.05(dd,J=1.6,10.8Hz,1H),4.68-4.52(m,1H),3. 94(dd,J=1.6,11.2Hz,1H),3.75-3.65(m,1H),3.52-3.47(m,1H),3.30-3.20(m,1H),2.9 2-2.89(m,2H),2.88-2.85(m,1H),2.36-2.22(m,2H),2.15-2.10(m,2H),2.08-2.05(m, 2H),1.95-1.90(m,2H),1.54(d,J=6.4Hz,6H),1.53-1.46(m,2H),0.91(t,J=7.6Hz,3H).

[0467] Example BC: (R)-2-ethyl-4-((1R,3S)-3-(3-(5-fluoropyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compound 124) [ka] The title compound was synthesized following a procedure similar to that for Compound 68, using 5-fluoronicotinimidamide and (S)-3-oxocyclopentanecarboxylic acid in Step 1. The crude mixture was purified by silica flash chromatography (0-10% methanol in dichloromethane) to give the title compound as a mixture of diastereomers (80 mg), which was purified using chiral SFC (SFC-16; DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 μm); 0.1% NH3HO MEOH, 35 / 35; 70 mL / min) to give Compound 124 (48.82 mg, 61% yield). LCMS (ESI) [M+H] + =388.3. The relative stereochemistry was determined by 2D-NMR.

[0468] Compound 124: 1H NMR(400MHz,CDCl3)δ 9.11(s,1H),8.47(s,1H),8.06(d,J=8.8Hz,1H),4.55-4.52(m,1H),3.92-3.90(m ,1H),3.77-3.74(m,1H),3.55-3.51(m,1H),3.31-3.24(m,1H),2.95(d,J=11.6Hz, 1H),2.88-2.85(m,2H),2.33-2.29(m,2H),2.12-2.08(m,3H),2.03-1.96(m,1H),1 .93-1.90(m,2H),1.55(d,J=6.4Hz,6H),1.51-1.50(m,2H),1.01(t,J=7.6Hz,3H).

[0469] Example BD: (S)-4-((1S,3S)-3-(3-(5-chloropyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)-3-methylmorpholine, (S)-4-((1R,3S)-3-(3-(5-chloropyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)-3-methylmorpholine (Compounds 125 and 126) [ka] The title compound was synthesized using 5-chloronicotinimidamide and (S)-3-oxocyclopentanecarboxylic acid in step 1 following a procedure similar to that for compound 68. The crude mixture was purified by silica flash chromatography (0-10% methanol in dichloromethane) to give the title compound (110 mg, 83% yield) as a mixture of diastereomers. The diastereomers were separated using chiral SFC (SFC-16; DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 μm); 0.1% NH₃H₂O MEOH, 35 / 35; 70 mL / min) to give compound 125 (first peak in SFC, 6.7 mg, 6% yield) and compound 126 (second peak in SFC, 62.8 mg, 57% yield). LCMS (ESI) [M+H]+ = 390.2. The relative stereochemistry was determined by 2D-NMR.

[0470] Compound 125: 1 H NMR(400MHz,CD3OD)δ 9.09(d,J=1.6Hz,1H),8.57(s,1H),8.42(t,J=2.4Hz,1H),4.80-4.72(1H),3.75-3.72(m,3H),3.57-3.45(m,3H),2.94-2.76(m,2H),2.6 2-2.59(m,1H),2.24-2.20(m,2H),2.10-2.04(m,2H),2.00-1.89(m,1H),1.80-1.67(m,1H),1.53(d,J=6.8Hz,6H),1.15(d,J=6.4Hz,3H).

[0471] Compound 126: 1 H NMR(400MHz,CD3OD)δ 9.10(d,J=1.6Hz,1H),8.57(d,J=2.4Hz,1H),8.43(t,J=2.0Hz,1H),4.78-4.76(m,1H),3.82-3.72(m,3H),3.48-3.42(m,3H),2.83-2.81 (m,2H),2.67-2.55(m,1H),2.27-2.10(m,2H),2.08-1.98(m,3H),1.94-1.85(m,1H),1.54(dd,J=3.2,6.4Hz,6H),1.13(d,J=6.4Hz,3H).

[0472] Example BE: (R)-2-Ethyl-4-((1R,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compound 127) [ka] The title compound was synthesized following a procedure similar to that for Compound 68, using 6-(trifluoromethyl)nicotinimidamide hydrochloride and (S)-3-oxocyclopentanecarboxylic acid in Step 1. The crude mixture was purified by silica flash chromatography (0-10% methanol in dichloromethane) to give the title compound (100 mg) as a mixture of diastereomers. The diastereomers were separated using chiral SFC (DAICEL CHIRALPAAD (250 mm * 30 mm, 10 μm); 0.1% NH4OH; IPA, 15 / 15, 70 mL / min) to give Compound 127 (76.74 mg, 77% yield). LCMS (ESI), [M+H] + =438.2. The relative stereochemistry was determined by 2D-NMR.

[0473] Compound 127: 1 H NMR(400MHz,CD3OD)δ 9.32(s,1H),8.61(dd,J=1.6,8.0Hz,1H),7.90(d,J=8.4Hz,1H),4.77-4.76(m,1H),3.88 (dd,J=2.0,12.0Hz,1H),3.70-3.63(m,1H),3.52-3.40(m,2H),2.95-2.89(m,2H),2.87-2 .79(m,1H),2.41-2.35(m,1H),2.25-2.14(m,2H),2.11-2.01(m,2H),2.00-1.90(m,2H), 1.88-1.79(m,1H),1.54(dd,J=3.2,6.4Hz,6H),1.50-1.44(m,2H),0.95(t,J=7.6Hz,3H).

[0474] Example BF: (S)-2-ethyl-4-((1R,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compound 128) [ka] The title compound was synthesized following a procedure similar to that for Compound 68, using 6-(trifluoromethyl)nicotinimidamide hydrochloride and (S)-3-oxocyclopentanecarboxylic acid in Step 1. The crude mixture was purified by silica flash chromatography (0-10% methanol in dichloromethane) to give the title compound (100 mg) as a mixture of diastereomers. The mixture of diastereomers was separated using chiral SFC (DAICEL CHIRALPAAD (250 mm * 30 mm, 10 μm); 0.1% NH4OH; EtOH, 10 / 10, 70 mL / min) to give Compound 128 (76.8 mg, 77% yield). LCMS (ESI), [M+H] + =438.2. The relative stereochemistry was determined by 2D-NMR.

[0475] Compound 128: 1 H NMR(400MHz,CD3OD)δ 9.32(d,J=1.2Hz,1H),8.61(dd,J=1.6,8.0Hz,1H),7.90(d,J=8.0Hz,1H),4.78-4.74(m,1H ),3.88(dd,J=2.0,12.0Hz,1H),3.70-3.63(m,1H),3.52-3.41(m,2H),2.98-2.95(m,2H),2. 89-2.79(m,1H),2.41-2.35(m,1H),2.28-2.14(m,2H),2.11-2.02(m,2H),1.98-1.88(m,2H ),1.86-1.78(m,1H),1.54(dd,J=2.4,6.4Hz,6H),1.50-1.44(m,2H),0.96(t,J=7.6Hz,3H).

[0476] Example BG: (R)-4-((1R,3S)-3-(3-(5-chloropyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-ethylmorpholine (Compound 129) [ka] The title compound was synthesized following a procedure similar to that for Compound 68, using 5-chloronicotinimidamide and (S)-3-oxocyclopentanecarboxylic acid in Step 1. The crude mixture was purified by silica flash chromatography (0-10% methanol in dichloromethane) to give the title compound (120 mg, 91% yield) as a mixture of diastereomers. The diastereomers (100 mg) were separated using chiral SFC (SFC-16; DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); 0.1% NH₃H₂O ETOH, 40 / 40, 80 mL / min) to give Compound 129 (62.9 mg, 63% yield). LCMS (ESI), [M+H]⁺ = 404.2. The relative stereochemistry was determined by 2D-NMR.

[0477] Compound 129:1H NMR(400MHz,CD3OD)δ 9.10(d,J=1.6Hz,1H),8.57(d,J=2.4Hz,1H),8.42(t,J=2.0Hz,1H),4.76 ~4.73(m,1H),3.88(dd,J=2.4,11.6Hz,1H),3.67~3.64(m,1H),3.5~3.36 (m,2H),3.01~2.80(m,3H),2.44~2.36(m,1H),2.24~2.12(m,2H),2.12~1 .95(m,2H),1.89~1.78(m,1H),1.58~1.48(m,8H),0.96(t,J=7.6Hz,3H).

[0478] Example BH: (R)-2-(fluoromethyl)-4-((1S,3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine and (R)-2-(fluoromethyl)-4-((1R,3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine (Compounds 130* and 131*) [ka] Step 1: (S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentanone [ka]

[0479] A mixture of (S)-3-(3-bromo-1-isopropyl-1H-pyrazol-5-yl)cyclopentanone (500 mg, 1.84 mmol, second peak in SFC), (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (708 mg, 3.69 mmol), K2CO3 (765 mg, 5.53 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (131 mg, 0.18 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was placed under a nitrogen atmosphere and stirred at 100 °C for 4 h. The reaction mixture was filtered and concentrated. The residue was purified by silica flash chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound (600 mg, 93% yield). LCMS (ESI), [M+H]+ = 338.9.

[0480] Step 2: ((2R)-4-((3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholin-2-yl)methanol [ka]

[0481] To a mixture of (S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentanone (300 mg, 0.89 mmol) in dichloromethane (3 mL), (R)-morpholin-2-ylmethanol hydrochloride (272 mg, 1.77 mmol) and N,N-diisopropylethylamine (344 mg, 2.66 mmol) were added and stirred at 25 °C for 16 hours. NaBH(OAc) (564 mg, 2.66 mmol) was then added and stirred at 25 °C for 16 hours. The mixture was diluted with water (10 mL) and the pH was adjusted to 9 with aqueous NaHCO solution. The resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-2% methanol in dichloromethane) to give the title compound (300 mg, 77% yield) as a mixture of diastereomers. LCMS (ESI), [M+H]+ = 440.2.

[0482] Step 3: (2R)-2-(fluoromethyl)-4-((3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine [ka]

[0483] To a solution of ((2R)-4-((3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholin-2-yl)methanol (150 mg, 0.34 mmol) in dichloromethane (5 mL) was added (bis-(2-methoxyethyl)amino)sulfur trifluoride (240 mg, 1.08 mmol) at 0° C. and stirred at 25° C. for 16 hours. The mixture was diluted with water (25 mL) and the pH was adjusted to 9 with aqueous NaHCO. The resulting mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate / ethanol = 4 / 3 / 1) to give the title compound (100 mg, 66% yield) as a mixture of diastereomers. LCMS(ESI), [M+H]+=442.3.

[0484] Step 4: (R)-2-(Fluoromethyl)-4-((1S,3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine and (R)-2-(Fluoromethyl)-4-((1R,3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine (Compounds 130* and 131*) [ka]

[0485] The diastereomers (100 mg, 0.23 mmol) were separated using chiral SFC (SFC-22, DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm), 0.1% NH₃H₂O ETOH, 15 / 15, 80 ml / min) to give compound 130* (anti isomer, first peak in SFC, 8.34 mg, 8% yield) and compound 131* (syn isomer, second peak in SFC, 28.78 mg, 28% yield). LCMS (ESI), [M+H]+ = 442.3. Relative stereochemistry was arbitrarily assigned.

[0486] Compound 130*: 1 H NMR(400MHz,CD3OD)δ 9.31(s,2H),6.74(s,1H),4.70-4.64(m,1H),4.46(d,J=4.0Hz,1H),4.34(d,J=4.0Hz,1H),3.97-3.91(m,1H),3.84-3.64(m ,2H),3.52-3.36(m,1H),3.03-2.85(m,3H),2.29-2.11(m,4H),2.10-1.95(m,2H),1.84-1.62(m,2H),1.52(t,J=6.4Hz,6H).

[0487] Compound 131*: 1 H NMR(400MHz,CD3OD)δ 9.31(s,2H),6.78(s,1H),4.70-4.63(m,1H),4.47(d,J=4.0Hz,1H),4.35(d,J=4 .4Hz,1H),3.96-3.88(m,1H),3.84-3.74(m,1H),3.73-3.66(m,1H),3.38-3.32(m ,1H),3.01-2.96(m,1H),2.92-2.77(m,2H),2.44-2.37(m,1H),2.31-2.16(m,2H) ,2.11-2.01(m,2H),1.86-1.74(m,2H),1.72-1.63(m,1H),1.52(d,J=6.4Hz,6H).

[0488] Example BI: (S)-2-(Fluoromethyl)-4-((1S,3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine and (S)-2-(Fluoromethyl)-4-((1R,3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine (Compounds 132* and 133*) [ka] Step 1: ((2S)-4-((3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholin-2-yl)methanol [ka]

[0489] To a mixture of (S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentanone (300 mg, 0.89 mmol) in dichloromethane (3 mL), (S)-morpholin-2-ylmethanol hydrochloride (272 mg, 1.77 mmol) and N,N-diisopropylethylamine (344 mg, 2.66 mmol) were added and stirred at 25 °C for 16 hours. NaBH(OAc) (564 mg, 2.66 mmol) was then added and stirred at 25 °C for 16 hours. The mixture was diluted with water (25 mL) and the pH was adjusted to 9 with aqueous NaHCO solution. The resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-2% methanol in dichloromethane) to give the title compound (350 mg, 90% yield) as a mixture of diastereomers. LCMS (ESI), [M+H]+ = 440.3.

[0490] Step 2: (2S)-2-(fluoromethyl)-4-((3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine [ka]

[0491] To ((2S)-4-((3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholin-2-yl)methanol (150 mg, 0.34 mmol) in dichloromethane (5 mL) was added (bis-(2-methoxyethyl)amino)sulfur trifluoride (240 mg, 1.08 mmol) at 0° C. and stirred at 25° C. for 16 hours. The mixture was diluted with water (25 mL) and the pH was adjusted to 9 with aqueous NaHCO. The resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate / ethanol = 4 / 3 / 1) to give the title compound (100 mg, 66% yield) as a mixture of diastereomers. LCMS(ESI), [M+H]+=442.3.

[0492] Step 3: (S)-2-(Fluoromethyl)-4-((1S,3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine and (S)-2-(Fluoromethyl)-4-((1R,3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine (Compounds 132* and 133*) [ka]

[0493] The diastereomers (100 mg, 0.23 mmol) were separated using chiral SFC (SFC-11, DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm), 0.1% NH₃H₂O MEOH, 20 / 20, 70 ml / min) to give compound 132* (anti isomer, first peak in SFC, 11.93 mg, 12% yield) and compound 133* (syn isomer, second peak in SFC, 37.02 mg, 37% yield). LCMS (ESI), [M+H]+ = 442.3.

[0494] Compound 132*: 1 H NMR(400MHz,CD3OD)δ 9.31(s,2H),6.74(s,1H),4.71-4.64(m,1H),4.47(d,J=4.0Hz,1H),4. 35(d,J=4.0Hz,1H),3.96-3.92(m,1H),3.81-3.66(m,2H),3.47-3.38( m,1H),2.99-2.97(m,1H),2.93-2.85(m,2H),2.29-2.11(m,4H),2.10- 1.94(m,2H),1.84-1.73(m,1H),1.71-1.62(m,1H),1.54-1.51(m,6H).

[0495] Compound 133*: 1 H NMR(400MHz,CD3OD)δ 9.31(s,2H),6.78(s,1H),4.70-4.64(m,1H),4.46(d,J=4.4Hz,1H),4.35(d,J=4.4Hz,1H),3.95-3.90(m,1H),3.83-3.66(m,2H),3. 36-3.32(m,1H),3.00-2.76(m,3H),2.43-2.37(m,1H),2.27-2.15(m,2H),2.12-2.01(m,2H),1.86-1.62(m,3H),1.54-1.51(m,6H).

[0496] Example BJ: (R)-4-((1R,3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-methylmorpholine and (R)-4-((1S,3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-methylmorpholine (Compounds 134 and 135) [ka] The title compound was synthesized using 2-(trifluoromethyl)pyrimidine-5-carboximidamide and (S)-3-oxocyclopentanecarboxylic acid in step 1, following a procedure similar to that for compound 68. The crude mixture was purified by silica flash chromatography (0-5% methanol in dichloromethane) to give the title compound (100.0 mg, 80% yield) as a mixture of diastereomers. The diastereomers were separated using chiral SFC (Daicel Chiralpak AS (250 mm*30 mm, 10 μm); 0.1% NHOH; EtOH, 25 / 25, 70 ml / min) to give compound 134 (second peak in SFC, 43.96 mg, 44% yield) and compound 135 (first peak in SFC, 4.53 mg, 4.5% yield). LCMS (ESI), [M+H] = 425.2. The relative stereochemistry was determined by 2D-NMR.

[0497] Compound 134: 1 H NMR (400 MHz, CD3OD) δ 9.51(s,2H),4.81-4.76(m,1H),3.87-3.85(m,1H),3.71-3.68(m,1H),3.65-3 .63(m,1H),3.54-3.45(m,1H),2.96-2.90(m,2H),2.88-2.79(m,1H),2.42-2.3 6(m,1H),2.25-2.22(m,1H),2.19-2.14(m,1H),2.10-2.04(m,2H),1.95-1.92 (m,2H),1.88-1.81(m,1H),1.54(dd,J=3.2,6.8Hz,6H),1.14(d,J=6.4Hz,3H).

[0498] Compound 135: 1H NMR(400MHz,CD3OD)δ 9.51(s,2H),4.80-4.79(m,1H),3.87-3.85(m,1H),3.70-3.67(m,1H),3.66-3.56(m,2H),2.98-2.95(m,2H),2.89-2.87(m,1H),2.26-2.1 7(m,4H),2.12-2.04(m,1H),1.99-1.93(m,1H),1.91-1.85(m,1H),1.71-1.60(m,1H),1.54(dd,J=2.4,6.8Hz,6H),1.16(d,J=6.4Hz,3H).

[0499] Example BK: (R)-2-ethyl-4-((1R,3S)-3-(3-(5-fluoro-6-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compound 146) [ka] The title compound was synthesized following a procedure similar to that for compound 68, using 5-fluoro-6-(trifluoromethyl)nicotinimidamide and (S)-3-oxocyclopentanecarboxylic acid in step 1. The crude mixture was purified by silica flash chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound 146 (25.0 mg, 45% yield). LCMS (ESI), [M+H] = 456.2. The relative stereochemistry was determined by 2D-NMR.

[0500] Compound 146: 1H NMR(400MHz,CD3OD)δ 9.14(s,1H),8.36(d,J=11.2Hz,1H),4.78-4.73(m,1H),3.89-3.86(m,1H),3.69 -3.64(m,1H),3.50-3.40(m,2H),2.92(t,J=11.6Hz,2H),2.86-2.78(m,1H),2.41 -2.35(m,1H),2.25-2.13(m,2H),2.11-2.04(m,2H),2.01-1.89(m,2H),1.88-1. 82(m,1H),1.53(dd,J=3.6,6.4Hz,6H),1.50-1.44(m,2H),0.95(t,J=7.6Hz,3H).

[0501] Example BL: (S)-2-Ethyl-4-((1R,3S)-3-(3-(5-fluoro-6-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compound 147) [ka] The title compound was synthesized following a procedure similar to that for compound 68, using 5-fluoro-6-(trifluoromethyl)nicotinimidamide and (S)-3-oxocyclopentanecarboxylic acid in step 1. The crude mixture was purified by silica flash chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound 147 (23.9 mg, 13.5% yield). LCMS (ESI), [M+H] = 456.2. The relative stereochemistry was determined by 2D-NMR.

[0502] Compound 147: 1H NMR(400MHz,CD3OD)δ 9.14(s,1H),8.36(d,J=11.2Hz,1H),4.80-4.73(m,1H),3.90-3.86(m,1H),3.69-3. 63(m,1H),3.53-3.41(m,2H),3.00-2.87(m,2H),2.84-2.79(m,1H),2.44-2.35(m,1H ),2.29-2.22(m,1H),2.21-2.12(m,1H),2.11-2.01(m,2H),1.99-1.92(m,2H),1.89 -1.82(m,1H),1.53(dd,J=2.4,6.4Hz,6H),1.51-1.45(m,2H),0.96(t,J=7.2Hz,3H).

[0503] Example BM: (R)-4-((1S,3R)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-methylmorpholine and (R)-4-((1R,3R)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-methylmorpholine (Compounds 148 and 149) [ka] The title compound was synthesized according to the same procedure as Compound 68 using 2-(trifluoromethyl)pyrimidine-5-carboximidamide and (R)-3-oxocyclopentanecarboxylic acid in Step 1. The crude mixture was purified by reverse phase chromatography (BostonPrime C18 150*30mm*5um / water (NH3H2O+NH4HCO3)-CAN, 35%-65%) to give Compound 148 (SFC second peak, 54.48mg, 43.1% yield) and Compound 149 (SFC first peak, 7.18mg, 4.7% yield). LCMS (ESI), [M+H] + = 425.2. The relative stereochemistry was determined by 2D-NMR.

[0504] Compound 148:1 H NMR(400MHz,CD3OD)δ 9.51(s,2H),4.81-4.73(m,1H),3.87-3.84(m,1H),3.71-3.62(m,2H),3.54-3.45(m,1H),2.99-2.96(m,1H),2.90-2.79(m,2H), 2.42-2.36(m,1H),2.27-2.14(m,2H),2.10-2.02(m,2H),1.99-1.81(m,3H),1.54(dd,J=2.4,6.4Hz,6H),1.15(d,J=6.4Hz,3H).

[0505] Compound 149: 1 H NMR(400MHz,CD3OD)δ 9.51(s,2H),4.80-4.77(m,1H),3.90-3.85(m,1H),3.71-3.59(m,3H),3.03-2.91(m,1H),2.28-2.18(m,4H),2.12-2. 05(m,1H),1.99-1.95(m,1H),1.92-1.88(m,2H),1.72-1.62(m,1H),1.54(dd,J=3.2,6.8Hz,6H),1.14(d,J=6.4Hz,3H)

[0506] Example BN: (S)-4-((1S,3R)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-methylmorpholine and (S)-4-((1R,3R)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-methylmorpholine (Compounds 150 and 151) [ka] The title compound was synthesized according to the same procedure as Compound 68 using 2-(trifluoromethyl)pyrimidine-5-carboximidamide and (R)-3-oxocyclopentanecarboxylic acid in Step 1. The crude mixture was purified by reverse phase chromatography (BostonPrime C18 150*30mm*5um / water (NH3H2O+NH4HCO3)-CAN, 35%-65%) to give Compound 150 (SFC second peak, 68.53mg, 44.7% yield) and Compound 151 (SFC first peak, 16.03mg, 10.4% yield). LCMS (ESI), [M+H] + =425.1. The relative stereochemistry was determined by 2D-NMR.

[0507] Compound 150: 1 H NMR(400MHz,CD3OD)δ 9.51(s,2H),4.90-4.73(m,1H),3.87-3.84(m,1H),3.71-3.62(m,2H),3.54-3.45(m,1H),2.97-2.91(m,2H),2.84-2.82(m,1H),2.43-2.3 6(m,1H),2.25-2.14(m,2H),2.10-2.02(m,2H),1.99-1.90(m,2H),1.88-1.82(m,1H),1.54(dd,J=3.2,6.8Hz,6H),1.14(d,J=6.4Hz,3H).

[0508] Compound 151: 1 H NMR(400MHz,CD3OD)δ 9.51(s,2H),4.86-4.77(m,1H),3.88-3.84(m,1H),3.71-3.58(m,3H),2.98-2.95(m,2H),2.88(dd,J=1.6,11.6Hz,1H),2.28-2.16(m,4H), 2.12-2.04(m,1H),1.99-1.93(m,1H),1.89(dd,J=10.8,11.2Hz,1H),1.71-1.63(m,1H),1.54(dd,J=2.4,6.8Hz,6H),1.16(d,J=6.4Hz,3H).

[0509] Example BO: (R) 2-ethyl-4-((1S,3R)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and (R)-2-ethyl-4-((1R,3R)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compounds 152 and 153) [ka] The title compound was synthesized following a procedure similar to that for Compound 68, using 2-(trifluoromethyl)pyrimidine-5-carboximidamide and (R)-3-oxocyclopentanecarboxylic acid in step 1. The crude mixture was purified by reverse phase chromatography (Boston Prime C18 150*30mm*5um / water (NH3H2O+NH4HCO3)-CAN, 30%-70%) to give Compound 152 (SFC second peak, 48.92mg, 37.5% yield) and Compound 153 (SFC first peak, 5.59mg, 3.2% yield). LCMS (ESI), [M+H] + =439.2. The relative stereochemistry was determined by 2D-NMR.

[0510] Compound 152: 1 H NMR(400MHz,CD3OD)δ 9.51(s,2H),4.81-4.75(m,1H),3.88-3.84(m,1H),3.69-3.62(m,1H),3.54-3.47(m,1H ),3.45-3.40(m,1H),2.98-2.95(m,1H),2.89-2.86(m,1H),2.84-2.78(m,1H),2.42-2.3 6(m,1H),2.27-2.20(m,1H),2.19-2.14(m,1H),2.11-2.03(m,2H),2.01-1.96(m,1H),1 .93-1.80(m,2H),1.54(dd,J=2.4,6.4Hz,6H),1.50-1.42(m,2H),0.96(t,J=7.6Hz,3H).

[0511] Compound 153: 1 H NMR(400MHz,CD3OD)δ 9.51(s,2H),4.80-4.77(m,1H),3.92-3.89(m,1H),3.69-3.57(m,2H),3.43-3.42(m,1H),2.99-2.90(m,3H),2.30-2.16(m,4H) ),2.09-2.04(m,1H),1.97-1.88(m,2H),1.71-1.61(m,1H),1.54(dd,J=3.6,6.4Hz,6H),1.50-1.46(m,2H),0.97-0.94(m,3H).

[0512] Example BP: (S)-2-ethyl-4-((1S,3R)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and (S)-2-ethyl-4-((1R,3R)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compounds 154 and 155) [ka] The title compound was synthesized following a procedure similar to that for Compound 68, using 2-(trifluoromethyl)pyrimidine-5-carboximidamide and (R)-3-oxocyclopentanecarboxylic acid in step 1. The crude mixture was purified by reverse phase chromatography (Boston Prime C18 150*30mm*5um / water (NH3H2O+NH4HCO3)-CAN, 30%-70%) to give Compounds 154 (SFC second peak, 43.92mg, 33.6% yield) and 155 (SFC first peak, 4.71mg, 2.9% yield). LCMS (ESI), [M+H] + =439.2. The relative stereochemistry was determined by 2D-NMR.

[0513] Compound 154: 1H NMR(400MHz,CD3OD)δ 9.51(s,2H),4.81-4.75(m,1H),3.88-3.84(m,1H),3.69-3.63(m,1H),3. 54-3.39(m,2H),2.95-2.90(m,2H),2.87-2.78(m,1H),2.42-2.36(m,1H), 2.25-2.14(m,2H),2.10-2.02(m,2H),1.99-1.90(m,2H),1.88-1.81(m,1 H),1.54(dd,J=3.2,6.4Hz,6H),1.50-1.44(m,2H),0.95(t,J=7.6Hz,3H).

[0514] Compound 155: 1 H NMR(400MHz,CD3OD)δ 9.51(s,2H),4.80-4.75(m,1H),3.89-3.86(m,1H),3.69-3.59(m,2H),3.41-3.40(m,1H),2.98-2.95(m,2H),2.90-2.87(m,1H),2.26-2.1 7(m,4H),2.09-2.04(m,1H),1.96-1.87(m,2H),1.71-1.64(m,1H),1.54(dd,J=2.4,6.8Hz,6H),1.52-1.47(m,2H),0.97(t,J=7.6Hz,3H).

[0515] Example BQ: (R)-4-((1R,3S)-3-(3-(6-(difluoromethyl)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-ethylmorpholine (compound 156) [ka] The title compound was synthesized following a procedure similar to that for Compound 68, using 6-(difluoromethyl)nicotinimidamide and (S)-3-oxocyclopentanecarboxylic acid in Step 1. The crude mixture was purified by silica flash chromatography (0-10% methanol in dichloromethane) to give the title compound (60 mg, 0.13 mmol, 70% yield) as a mixture of diastereomers. The mixture of diastereomers (60 mg, 0.13 mmol) was separated using chiral SFC (Daicel Chiralpak AD (250 mm*30 mm, 10 μm); 0.1% NH3HO; IPA; 60 / 60, 60 mL / min) to give Compound 156 (first peak in SFC, 25.39 mg, 41% yield). LCMS (ESI) [M+H] + =420.3. The relative stereochemistry was determined by 2D-NMR.

[0516] Compound 156: 1 H NMR(400MHz,CD3OD)δ 9.25(s,1H),8.56(d,J=8.4Hz,1H),7.78(d,J=8.0Hz,1H),6.76(t,J=15.2Hz,1H),4.76-4.73( m,1H),3.88(dd,J=2.4,12.0Hz,1H),3.67-3.65(m,1H),3.55-3.43(m,2H),2.93(t,J=12.4Hz, 2H),2.88-2.80(m,1H),2.43-2.35(m,1H),2.28-2.15(m,2H),2.11-2.00(m,2H),1.99-1.90(m ,2H),1.89-1.80(m,1H),1.53(dd,J=3.6,6.4Hz,6H),1.48-1.46(m,1H),0.95(t,J=7.6Hz,3H).

[0517] Example BR*: 4-((1S,3R)-3-(3-(6-fluoro-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine, 4-((1R,3S)-3-(3-(6-fluoro-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1S,3S)-3-(3-(6-fluoro-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compounds 157*, 158* and 159*) [ka] Step 1: 5-(5-bromo-1-isopropyl-1H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine [ka]

[0518] A suspension of 3,5-dibromo-1-isopropyl-1,2,4-triazole (2 g, 7.44 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (1.9 g, 6.69 mmol), potassium carbonate (3 g, 22.31 mmol), and 1,1′-bis(diphenylphosphino)ferrocenepalladium dichloride (540 mg, 0.74 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was degassed and purged with N three times, then the reaction mixture was stirred under N at 90° C. for 1 hour. A black suspension formed. The reaction mixture was concentrated in vacuo. The residue was purified by silica flash chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (850 mg, 32.6% yield). LCMS (ESI) [M+H] + =350.2.

[0519] Step 2: 3-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopent-2-enone [ka]

[0520] A suspension of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (177 mg, 0.24 mmol), potassium carbonate (1 g, 7.27 mmol), 5-(5-bromo-1-isopropyl-1,2,4-triazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine (850 mg, 2.43 mmol), and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one (757 mg, 3.64 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was degassed and purged with N three times, then the reaction mixture was stirred under N at 90 °C for 4 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica flash chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound (500 mg, 58.6% yield). LCMS (ESI) [M+H] + =352.1.

[0521] Step 3: 3-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentanone [ka]

[0522] To a solution of 3-[5-[6-amino-5-(trifluoromethyl)-3-pyridyl]-2-isopropyl-1,2,4-triazol-3-yl]cyclopent-2-en-1-one (200 mg, 0.57 mmol) in ethanol (3 mL) was added 10% palladium on carbon (242 mg, 0.11 mmol) at 25° C. and stirred under H (15 psi) at 20° C. for 12 hours. The reaction mixture was filtered, and the filter cake was washed with methyl alcohol (10 mL × 2). The combined organic layers were concentrated in vacuo to give the title compound (200 mg, 99.4% yield). LCMS (ESI) [M+H] + =354.1.

[0523] Step 4: 5-(1-isopropyl-5-(3-morpholinocyclopentyl)-1H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine [ka]

[0524] To a solution of 3-[5-[6-amino-5-(trifluoromethyl)-3-pyridyl]-2-isopropyl-1,2,4-triazol-3-yl]cyclopentanone (670 mg, 1.9 mmol) in acetonitrile (10 mL) was added morpholine (1.6 mL, 18.96 mmol), acetic acid (0.6 mL, 11.3 mmol), and NaBH(OAc) (1607 mg, 7.58 mmol). The mixture was stirred at 60 °C for 2 h. The reaction mixture was diluted with ethyl acetate (60 mL), and the resulting mixture was washed with brine (30 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-10% methanol in dichloromethane) to give the title compound (570 mg, 70.8% yield). LCMS (ESI) [M+H] + =425.2.

[0525] Step 5: 5-(1-isopropyl-5-((1R,3S)-3-morpholinocyclopentyl)-1H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-isopropyl-5-((1S,3S)-3-morpholinocyclopentyl)-1H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine [ka]

[0526] 5-[1-Isopropyl-5-(3-morpholinocyclopentyl)-1,2,4-triazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine (570 mg, 1.34 mmol) was separated using chiral SFC (SFC-14; DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm)); 0.1% NH3HO+ETOH, 30 / 30; 60 mL / min) to give title compound-1 (first peak of SFC (mixture of diastereomers, 175 mg, 30.7% yield) and title compound-2 (second peak of SFC, 170 mg, 29.8% yield).

[0527] Step 4: 4-((1S,3R)-3-(3-(6-fluoro-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 5-(1-isopropyl-5-((1S,3R)-3-morpholinocyclopentyl)-1H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine (Compounds 157* and 158*) [ka]

[0528] To a mixture of 5-[1-isopropyl-5-[rac-(1R,5S)-3-morpholino-6-bicyclo[3.1.0]hexanyl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine (140 mg, 0.33 mmol) in pyridine (1 mL) was added hydrogen fluoride-pyridine (2 mL, 0.52 mmol) at 0° C., followed by sodium nitrite (14 mg, 0.21 mmol). The mixture was stirred at 0° C. for 60 minutes and then at 25° C. for 1 hour. The reaction mixture was quenched with sodium bicarbonate (10 mL) and extracted with dichloromethane (20 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase chromatography (water (NH3H2O ​​+ NH4HCO3)-CAN, 25%-55%). The mixture of diastereomers (70 mg) was separated using chiral SFC (Daicel Chiralpak AD (250 mm * 30 mm, 10 μm)); 0.1% NH4OH + MeOH; 40 / 40; 60 mL / min) to give compound 157* (first peak in SFC, 11.5 mg, 16% yield) and compound 158* (second peak in SFC, 49 mg, 70% yield). LCMS (ESI), [M+H] + =428.3. Relative stereochemistry arbitrarily assigned.

[0529] Compound 157*: 1 H NMR(400MHz,CD3OD)δ 8.79(d,J=1.6Hz,1H),8.34(d,J=1.6Hz,1H),4.73-4.66(m,1H),3.72(t,J=4.8Hz,4H),3.50-3.38(m ,1H),2.89-2.75(m,1H),2.59-2.49(m,4H),2.39-2.31(m,1H),2.21-1.80(m,5H),1.52-1.50(m,6H).

[0530] Compound 158*: 1H NMR(400MHz,CD3OD)δ 9.06(s,1H),8.84-8.65(m,1H),4.78-4.72(m,1H),3.74(t,J=4.4Hz,4H),3.54-3.44(m, 1H),2.89(s,1H),2.66(s,4H),2.48-2.35(m,1H),2.22-1.86(m,5H),1.59-1.50(m,6H).

[0531] Step 6: 4-((1S,3S)-3-(3-(6-fluoro-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compound 159*) [ka]

[0532] To a mixture of 5-[1-isopropyl-5-(3-morpholinocyclopentyl)-1,2,4-triazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine (50 mg, 0.12 mmol) in pyridine (1 mL) was added hydrogen fluoride-pyridine (2 mL, 0.12 mmol) at 0 °C, followed by sodium nitrite (10 mg, 0.15 mmol). The mixture was stirred at 0 °C for 60 minutes and then at 25 °C for 1 hour. The reaction mixture was quenched with sodium bicarbonate (10 mL), and the resulting solution was extracted with dichloromethane (20 mL × 3). The combined organics were dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase chromatography (water (NH3H2O ​​+ NH4HCO3) - CAN, 25%-55%) to give compound 159 (20 mg, 38.1% yield). LCMS(ESI), [M+H] + =428.2. Relative stereochemistry arbitrarily assigned.

[0533] Compound 159*: 1H NMR(400MHz,CD3OD)δ 9.06(s,1H),8.75(d,J=7.2Hz,1H),4.79-4.72(m,1H),3.78(t,J=4.4Hz,4H),3.58-3.48(m,1H) ,3.12-3.01(m,1H),2.82-2.78(m,4H),2.51-2.38(m,1H),2.19-1.89(m,5H),1.55-1.50(m,6H).

[0534] Example BS: (S)-4-((1R,3S)-3-(3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentyl)-2-(fluoromethyl)morpholine (Compound 160) [ka] The title compound was synthesized following a procedure similar to that of Compound 130*, using 3-fluoro-4-(trifluoromethyl)benzimidamide and (S)-3-oxocyclopentanecarboxylic acid in step 1. The crude mixture was purified by preparative TLC (10% methanol in dichloromethane) to give Compound 160 (23.67 mg, 25.9% yield). LCMS (ESI), [M+H] + =459.1. The relative stereochemistry was determined by 2D-NMR.

[0535] Compound 160: 1H NMR(400MHz,CD3OD)δ 8.01(d,J=8.4Hz,1H),7.93(d,J=11.6Hz,1H),7.75(t,J=8.0Hz,1H),4.77-4.71(m,1H),4.46 (d,J=4.0Hz,1H),4.35(d,J=4.0Hz,1H),3.92-3.86(m,1H),3.78-3.67(m,2H),3.51-3.43(m, 1H),2.99-2.90(m,2H),2.88-2.81(m,1H),2.41-2.34(m,1H),2.28-2.22(m,1H),2.20-2.12( m,2H),2.09-2.04(m,2H),2.01-1.93(m,1H),1.89-1.82(m,1H),1.53(dd,J=2.8,6.8Hz,6H).

[0536] Example BT: (S)-2-(fluoromethyl)-4-((1R,3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compound 161) [ka] The title compound was synthesized according to the same procedure as for compound 130*, using 2-(trifluoromethyl)pyrimidine-5-carboximidamide and (S)-3-oxocyclopentanecarboxylic acid in step 1. The crude mixture was purified by preparative TLC [(petroleum ether / (ethyl acetate / ethanol=3 / 1)]=1 / 1] to give the title compound 161 (25.23 mg, 58.4% yield). LCMS (ESI), [M+H] + =443.2. The relative stereochemistry was determined by 2D-NMR.

[0537] Compound 161: 1H NMR(400MHz,CD3OD)δ 9.51(s,2H),4.81-4.75(m,1H),4.46(d,J=4.4Hz,1H),4.35(d,J=4.4Hz,1H),3.96-3.93(m,1H),3.73-3.64(m,1H),3.55-3.42(m,2H),2.9 9-2.89(m,2H),2.87-2.81(m,1H),2.43-2.36(m,1H),2.28-2.21(m,1H),2.19-1.96(m,5H),1.89-1.82(m,1H),1.54(dd,J=3.2,6.4Hz,6H).

[0538] Example BU: (R)-4-((1R,3s,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-2-methylmorpholine and (R)-4-((1R,3r,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-2-methylmorpholine (Compounds 162 and 163) [ka] The title compound was synthesized according to a procedure similar to that for compound 51, using (1R,5S,6r)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-one and (2R)-2-methylmorpholine in the final step. The crude mixture was purified by reverse-phase chromatography (water (NH3HO+NH4HCO3)-CAN, 20%-50%) to give title compound 162 (first peak in HPLC (basic), 20.1 mg, 22.9% yield) and title compound 163 (second peak in HPLC (basic), 27.1 mg, 30.8% yield). LCMS (ESI) [M+H] + =436.1. The relative stereochemistry was determined by 2D-NMR.

[0539] Compound 162: 1 H NMR(400MHz,CD3OD)δ 9.37(d,J=1.6Hz,1H),8.87(d,J=1.2Hz,1H),8.59(s,1H),4.87-4.85(m,1H),3.92-3.80(m,1H),3.71-3.56(m,2H),2.91-2.76(m,2H),2. 61-2.46(m,1H),2.37-2.25(m,2H),2.17-2.06(m,3H),2.03-1.99(m,1H),1.90-1.78(m,3H),1.55(d,J=6.4Hz,6H),1.13(d,J=6.4Hz,3H)

[0540] Compound 163: 1 H NMR(400MHz,CD3OD)δ 9.37(d,J=1.6Hz,1H),8.88(d,J=1.2Hz,1H),8.59(s,1H),4.87-4.80(m,1H),3.93-3.81(m,1H),3.68-3.56(m,2H),3.02-2.81(m, 3H),2.41-2.30(m,2H),2.17(t,J=3.2Hz,1H),2.10-1.99(m,3H),1.83-1.70(m,3H),1.58(d,J=6.4Hz,6H),1.14(d,J=6.4Hz,3H).

[0541] Example BV: (R)-4-((1R,3R,5S,6R)-6-(1-isopropyl-3-((1R,4R)-4-(trifluoromethyl)cyclohexyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (R)-4-((1R,3S,5S,6R)-6-(1-isopropyl-3-((1R,4R)-4-(trifluoromethyl)cyclohexyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (R)-4-( (1R,3R,5S,6R)-6-(1-isopropyl-3-((1s,4S)-4-(trifluoromethyl)cyclohexyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (R)-4-((1R,3S,5S,6R)-6-(1-3-((1s,4S)-4-(trifluoromethyl)cyclohexyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine (Compounds 164* and 165* and 166* and 167*) [ka] Step 1: 5-((1R,5S,6r)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-isopropyl-3-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-1,2,4-triazole [ka]

[0542] A suspension of tert-butyl-diphenyl-[[rac-(1R,5S)-6-(5-iodo-2-isopropyl-1,2,4-triazol-3-yl)-3-bicyclo[3.1.0]hexanyl]oxy]silane (synthesized in Example BY, compound 51) (720 mg, 1.26 mmol), potassium carbonate (522 mg, 3.78 mmol), 4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)-1-cyclohexen-1-yl]-1,3,2-dioxaborolane (540 mg, 1.96 mmol), and Pd(dppf)Cl (92 mg, 0.13 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was degassed, purged with N three times, and stirred under N at 90 °C for 4 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica flash chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound (700 mg, 93.6% yield). LCMS (ESI) [M+H] + =594.4.

[0543] Step 2: (Z)-benzyl (((1R,5S)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxamido)(methylthio)methylene)carbamate [ka]

[0544] To a solution of tert-butyl-[[(1S,5R)-6-[2-isopropyl-5-[4-(trifluoromethyl)cyclohexen-1-yl]-1,2,4-triazol-3-yl]-3-bicyclo[3.1.0]hexanyl]oxy]-diphenyl-silane (700 mg, 1.18 mmol) in ethanol (10 mL) was added 10% palladium on carbon (250 mg, 0.24 mmol) at 25 °C, and the reaction mixture was then stirred under H (15 psi) at 25 °C for 12 hours. The reaction mixture was filtered, and the filter cake was washed with methyl alcohol (10 mL × 2). The combined organic layers were concentrated in vacuo to give the title compound (700 mg, 99.4% yield).

[0545] Step 3: (1R,5S,6r)-6-(1-isopropyl-3-(4-(trifluoromethyl)cyclohexyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-ol [ka]

[0546] To a stirred solution of tert-butyl-diphenyl-[[rac-(1R,5S)-6-[2-isopropyl-5-[4-(trifluoromethyl)cyclohexyl]-1,2,4-triazol-3-yl]-3-bicyclo[3.1.0]hexanyl]oxy]silane (700 mg, 1.17 mmol) in THF (5 mL) was added triethylamine trihydrofluoride (4 mL, 23.6 mmol). The reaction mixture was stirred at 70 °C for 8 h. The reaction mixture was adjusted to pH = 9 with aqueous NaOH (4 M). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica flash chromatography (0 to 50% ethyl acetate in petroleum ether) to give the title compound (280 mg, 66.7% yield). LCMS(ESI)[M+H] + =358.3.

[0547] Step 4: (1R,5S,6r)-6-(1-isopropyl-3-(4-(trifluoromethyl)cyclohexyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-one [ka]

[0548] To a solution of rac-(1R,5S)-6-[2-isopropyl-5-[4-(trifluoromethyl)cyclohexyl]-1,2,4-triazol-3-yl]bicyclo[3.1.0]hexan-3-ol (280 mg, 0.78 mmol) in dichloromethane (5 mL) was added Dess-Martin periodinane (665 mg, 1.58 mmol) at 0 °C and stirred at 25 °C for 2 h. The mixture was then diluted with dichloromethane (30 mL) and washed with Na2SO3 solution (20 mL) and NaHCO3 solution (10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica flash chromatography (0–50% ethyl acetate in petroleum ether) to give the title compound (220 mg, 76% yield). LCMS (ESI) [M+H] + =356.2.

[0549] Step 5: 1R,5S,6r)-6-(1-isopropyl-3-((1R,4R)-4-(trifluoromethyl)cyclohexyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-one and (1R,5S,6r)-6-(1-isopropyl-3-((1s,4S)-4-(trifluoromethyl)cyclohexyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-one [ka]

[0550] 5-[1-Isopropyl-5-(3-morpholinocyclopentyl)-1,2,4-triazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine (220 mg, 0.52 mmol) was separated using chiral SFC (SFC-13; Phenomenex-Cellulose-2 (250 mm * 30 mm, 10 μm); 0.1% NH3HO / IPA = 30 / 30; 60 mL / min) to give the title compound-1 (first peak of SFC, 50 mg, 22.7% yield) and the title compound-2 (second peak of SFC, 95 mg, 43% yield). LCMS (ESI) [M+H] +=356.2. Relative stereochemistry arbitrarily assigned.

[0551] Step 6: (R)-4-((1R,3R,5S,6R)-6-(1-isopropyl-3-((1R,4R)-4-(trifluoromethyl)cyclohexyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (R)-4-((1R,3S,5S,6R)-6-(1-isopropyl-3-((1R,4R)-4-(trifluoromethyl)cyclohexyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine (Compounds 164* and 165*) [ka]

[0552] To (3R)-3-methylmorpholine hydrochloride (155 mg, 1.13 mmol) and (1R,5S,6r)-6-(1-isopropyl-3-((1R,4R)-4-(trifluoromethyl)cyclohexyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-one (50 mg, 0.14 mmol) in anhydrous 1,2-dichloroethane (2 mL), molecular sieves and N,N-diisopropylethylamine (0.12 mL, 0.7 mmol) were added at 25 °C and stirred at 25 °C for 16 h. NaBH(OAc) (149 mg, 0.7 mmol) was then added and stirred at 65 °C for 16 h. Ethyl acetate (40 mL) was added, and the resulting mixture was washed with brine (30 mL × 3). The organics were concentrated in vacuo. The residue was purified by reverse phase chromatography (water (NH3H2O ​​+ NH4HCO3) - CAN, 20%-50%) to give compound 164* (first peak in HPLC (basic), 5.98 mg, 9.6% yield) and compound 165* (second peak in HPLC (basic), 4.9 mg, 7.9% yield). LCMS (ESI) [M+H] + =441.2. Relative stereochemistry arbitrarily assigned.

[0553] Compound 164*: 1 H NMR(400MHz,CD3OD)δ 4.79-4.72(m,1H),3.80-3.64(m,3H),3.54-3.42(m,1H),3.15-3.02(m,1H),2.86-2.68(m,2H),2.65-2.56(m,1H),2.50-2.48 (m,1H),2.26-2.08(m,3H),2.05-2.03(m,4H),1.98-1.71(m,5H),1.65-1.52(m,2H),1.42-1.29(m,8H),1.11(d,J=6.4Hz,3H)

[0554] Compound 165*: 1 H NMR(400MHz,CD3OD)δ 4.77-4.70(m,1H),3.77-3.70(m,1H),3.69-3.58(m,2H),3.54-3.40(m,2H),2.87-2.78(m,1H),2.70-2.55(m,2H),2.54-2.44(m,1H),2 .32-2.10(m,3H),2.08-1.96(m,5H),1.89-1.88(m,2H),1.82-1.64(m,2H),1.63-1.51(m,2H),1.43-1.35(m,8H),1.08(d,J=6.4Hz,3H).

[0555] Step 7: (R)-4-((1R,3R,5S,6R)-6-(1-isopropyl-3-((1s,4S)-4-(trifluoromethyl)cyclohexyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine and (R)-4-((1R,3S,5S,6R)-6-(1-isopropyl-3-((1s,4S)-4-(trifluoromethyl)cyclohexyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-3-methylmorpholine (Compounds 166* and 167*) [ka]

[0556] To (3R)-3-methylmorpholine hydrochloride (310 mg, 2.25 mmol) and (1R,5S,6r)-6-(1-isopropyl-3-((1s,4S)-4-(trifluoromethyl)cyclohexyl)-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-one (95 mg, 0.28 mmol) in anhydrous 1,2-dichloroethane (4 mL), molecular sieves and N,N-diisopropylethylamine (0.25 mL, 1.41 mmol) were added at 25 °C and stirred at 25 °C for 16 h. NaBH(OAc) (149 mg, 0.7 mmol) was then added and stirred at 65 °C for 16 h. Ethyl acetate (40 mL) was added, and the resulting mixture was washed with brine (30 mL × 3). The organics were concentrated in vacuo. The residue was purified by reverse phase chromatography (water (NH3H2O ​​+ NH4HCO3) - CAN, 20%-50%) to give compound 166* (first peak in HPLC (basic), 14.1 mg, 11.4% yield) and compound 167* (second peak in HPLC (basic), 10.9 mg, 8.8% yield). LCMS (ESI) [M+H] + =441.2. Relative stereochemistry arbitrarily assigned.

[0557] Compound 166*: 1 H NMR(400MHz,CD3OD)δ 4.78-4.71(m,1H),3.76-3.63(m,3H),3.51-3.44(m,1H),3.12-3.01(m,1H),3.00-2.92(m,1H),2.83-2.66(m,2H),2 .52-2.43(m,1H),2.30-2.07(m,5H),1.99-1.84(m,5H),1.75-1.65(m,6H),1.50-1.44(m,6H),1.10(d,J=6.4Hz,3H).

[0558] Compound 167*: 1H NMR(400MHz,CD3OD)δ 4.75-4.69(m,1H),3.79-3.59(m,3H),3.56-3.40(m,2H),2.96-2.95(m,1H),2.88-2.77(m,1H),2.69-2.59(m,1H),2.54-2.44 (m,1H),2.34-2.10(m,5H),2.01-2.00(m,1H),1.89(brs,2H),1.76-1.63(m,8H),1.48(d,J=6.4Hz,6H),1.08(d,J=6.4Hz,3H).

[0559] Example BW: (S)-2-(fluoromethyl)-4-((1S,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and (S)-2-(fluoromethyl)-4-((1R,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (compounds 168* and 169*): [ka] [ka] Step 1: ((S)-4-((1S,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholin-2-yl)methanol and ((S)-4-((1R,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholin-2-yl)methanol [ka]

[0560] To a solution of (S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentanone (120.0 mg, 0.35 mmol) in dichloromethane (3 mL) was added [(2S)-morpholin-2-yl]methanol hydrochloride (109 mg, 0.71 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.42 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours. Then, NaBH(OAc) (376 mg, 1.77 mmol) was added to the above mixture and stirred at 60 °C for another 2 hours. The reaction mixture was quenched with water (5 mL) and extracted with dichloromethane (10 mL × 3). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica flash chromatography (0-10% methanol in dichloromethane) to give the title compound (150 mg, 96% yield) as a mixture of diastereomers. LCMS (ESI), [M+H] + =440.3.

[0561] Step 2: (S)-2-(fluoromethyl)-4-((1S,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and (S)-2-(fluoromethyl)-4-((1R,3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine. (Compounds 168 and 169) [ka]

[0562] To a solution of ((2S)-4-((3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholin-2-yl)methanol (150.0 mg, 0.34 mmol) in dichloromethane (3 mL) was added Deoxo-Fluor (226.54 mg, 1.02 mmol) at 25 °C and stirred at 25 °C for 6 h. The mixture was adjusted to pH 7-8 with NaHCO (aq) and extracted with dichloromethane (20 mL × 3). The combined organics were washed with brine (20 mL × 2), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica flash chromatography (0-10% methanol in dichloromethane solution) to give the title compound (70 mg, 0.16 mmol, 49%), which was obtained as a mixture of diastereoisomers. LCMS (ESI) [M+H] + = 442.2. The mixture of diastereoisomers (70 mg, 0.16 mmol) was separated using chiral SFC (Daicel Chiralcel OD-H (250 mm * 30 mm, 5 um); 0.1% NH in HO; ETOH; 15 / 15; 60 mL / min) to give compound 168* (first peak in SFC, 11.07 mg, 15.3% yield) and title compound 169* (second peak in SFC, 54.16 mg, 76.6% yield). Relative stereochemistry was arbitrarily assigned.

[0563] Compound 168*: 1 H NMR (400 MHz, CD3OD) δ 9.32(s,1H),8.61(dd,J=1.6,8.0Hz,1H),7.90(d,J=8.0Hz,1H),4.82-4.74(m ,1H),4.46(d,J=4.4Hz,1H),4.34(d,J=4.0Hz,1H),3.94-3.90(m,1H),3.82-3 .66(m,2H),3.64-3.56(m,1H),3.03-2.91(m,3H),2.29-2.16(m,4H),2.12-2. 04(m,2H),2.01-1.91(m,1H),1.72-1.62(m,1H),1.54(dd,J=2.8,6.4Hz,6H),

[0564] Compound 169*: 1 H NMR(400MHz,CD3OD)δ 9.32(s,1H),8.61(dd,J=1.2,8.0Hz,1H),7.90(d,J=8.4Hz,1H),4.80-4.73(m,1H),4.47(d, J=4.4Hz,1H),4.35(d,J=4.0Hz,1H),3.94-3.91(m,1H),3.82-3.66(m,2H),3.53-3.45(m,1H) ),3.01-2.98(m,1H),2.90-2.81(m,2H),2.42-2.36(m,1H),2.30-2.24(m,1H),2.21-2.14(m ,1H),2.11-2.03(m,3H),2.02-1.94(m,1H),1.90-1.80(m,1H),1.54(dd,J=2.4,6.8Hz,6H).

[0565] Example BX: 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)morpholine (Compound 170): [ka] Step 1: (1R,5S,6r)-6-(3-iodo-1-isopropyl-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one [ka]

[0566] The title compound was synthesized according to the procedures described in WO2015091889.

[0567] Step 2: (1R,5S,6r)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one [ka]

[0568] A solution of (1R,5S,6r)-6-(3-iodo-1-isopropyl-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one (66 mg, 0.20 mmol), potassium phosphate (85 mg, 0.40 mmol), SPhos Pd G3 (7.8 mg, 0.010 mmol), and (3-(trifluoromethyl)phenyl)boronic acid (57 mg, 0.30 mmol) in 1,4-dioxane (1.0 mL) and water (0.25 mL) was stirred at 60 °C for 18 h. The reaction mixture was diluted with 1 N aqueous NH4Cl (1 mL) and dichloromethane (5 mL). The aqueous layer was extracted with dichloromethane (2 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude title compound (170 mg, 100% yield). LCMS (ESI) [M+H] + =349.2.

[0569] Step 3: 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)morpholine (Compound 170) [ka]

[0570] To ((1R,5S,6r)-6-(1-isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one (69 mg, 0.20 mmol) in toluene (1.0 mL) was added morpholine (52 mg, 0.60 mmol), sodium cyanoborohydride (19 mg, 0.30 mmol), and acetic acid (0.12 mL, 2.0 mmol) slowly. The reaction mixture was stirred at 80° C. for 3 h to give a 1N The mixture was diluted with aqueous NH4Cl (1 mL) and 10% methanol in dichloromethane (5 mL). The aqueous layer was extracted with 10% methanol in dichloromethane (2 x 5 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative HPLC (acetonitrile / water gradient + 0.1% NH4OH) to give the title compound (29 mg) as a pure single stereoisomer. LCMS (ESI) [M+H] + =420.3.

[0571] Compound 170: 1 H NMR(400MHz,DMSO-d6)δ 8.05-7.97(m,2H),7.65-7.55(m,2H),6.45(s,1H),4.79-4.64(m,1H),3.56(t,J=4.6Hz,4H),2.85-2.73(m,1H),2.39-2.31(m, 4H),2.17-2.06(m,2H),2.01(t,J=3.4Hz,1H),1.74(dd,J=13.7,6.1Hz,2H),1.69-1.61(m,2H),1.46(d,J=6.6Hz,6H).The relative stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0572] Example BY: 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)morpholine (Compound 171) [ka] The title compound was synthesized according to a procedure similar to that for Compound 170, using (5-(trifluoromethyl)pyridin-3-yl)boronic acid in Step 2. The residue was purified by preparative HPLC (acetonitrile / water gradient + 0.1% NH4OH) to give the title compound. LCMS (ESI) [M+H] + =421.3.

[0573] Compound 171: 1 H NMR(400MHz,DMSO-d6)δ 9.22(d,J=2.0Hz,1H),8.84(s,1H),8.36(s,1H),6.60(s,1H),4.81-4.67(m,1H),3.56(t,J=4.6Hz,4H),2.85-2.74(m,1H),2.39-2.3 1(m,4H),2.17-2.07(m,2H),2.04(t,J=3.3Hz,1H),1.75(dd,J=13.8,6.1Hz,2H),1.69-1.61(m,2H),1.47(d,J=6.6Hz,6H).The relative stereochemistry is 1 Assignment was based on 1 H NMR analysis.

[0574] Example BZ: 4-((1R,3r,5S,6r)-6-(1-isopropyl-3-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)morpholine (Compound 172) [ka] The title compound was synthesized according to a procedure similar to that for compound 170, using (2-(trifluoromethyl)py...

Claims

1. Compounds of Formula I: 【Chemistry 250】 or a pharmaceutically acceptable salt thereof, During the ceremony, n is 0 or 1; p is 1 or 2; Ring A is a saturated 5- or 6-membered monocyclic or bicyclic carbocyclyl; Ring B is phenyl, a 6-membered heteroaryl, or a 6-membered saturated or partially saturated cycloalkyl, said heteroaryl containing 1 or 2 heteroatoms; R ３ In each case, C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, hydroxy, C １ -C ６ Alkoxy, halo-C １ -C ６ independently selected from the group consisting of alkoxy, halo, and cyano; G is N or CR Ｇ and R Ｇ is hydrogen, C １ -C ６ Alkyl, and halo-C １ -C ６ selected from the group consisting of alkyl; R Ｎ１ is hydrogen, C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, and C ３ -C ５ cycloalkyl; R ２ is C １ -C ６ Alkyl, halo and halo-C １ -C ６ selected from the group consisting of alkyl; y is 1 or 2; m is 0, 1, 2, or 3; X is O or NR Ｈ and R Ｈ is hydrogen, C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, C ３ -C ５ Cycloalkyl, hydroxy-C １ -C ６ Alkyl, and C １ -C ６ Alkoxy-C １ -C ６ selected from the group consisting of alkyl; and, R １ In each case, C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, C １ -C ６ Alkoxy, hydroxy, NR Ｅ R Ｆ , Halo-C １ -C ６ Alkoxy, hydroxy-C １ -C ６ Alkyl, and C １ -C ６ Alkoxy-C １ -C ６ alkyl; or two R １ The groups together form -CH ２ - or -CH ２ CH ２ - forming crosslinks; R Ｅ and R Ｆ are each independently hydrogen, C １ -C ６ Alkyl, halo-C １ -C ６ Alkyl, C ３ -C ５ Cycloalkyl, hydroxy-C １ -C ６ Alkyl, and C １ -C ６ Alkoxy-C １ -C ６ or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkyl.

2. 2. The compound of claim 1, wherein Ring A is selected from the group consisting of cyclopentyl, cyclohexyl, and bicyclo[3.1.0]hexanyl.

3. 2. The compound of claim 1, wherein Ring A is cyclopentyl or bicyclo[3.1.0]hexanyl.

4. Ring A is cyclopentyl, and the compound has the following formula: 【Chemistry 251】 4. The compound of claim 3 having the formula:

5. Ring A is bicyclo[3.1.0]hexanyl and has the following formula: 【Chemical 252】 4. The compound of claim 3 having the formula:

6. The compound according to any one of claims 1 to 5, wherein n is 0.

7. n is 1 and R ２ is C １ -C ３ Alkyl, halo and halo-C １ -C ３ alkyl, or n is 1 and R ２ is methyl, fluoro, -CF ３ , -CHF ２ The compound according to any one of claims 1 to 5, selected from the group consisting of:

8. The compound of any one of claims 1 to 7, wherein Ring B is selected from the group consisting of cyclohexyl, phenyl, pyridinyl, pyrimidinyl, and pyrazinyl.

9. The compound according to any one of claims 1 to 8, wherein Ring B is cyclohexyl or phenyl.

10. The compound of any one of claims 1 to 9, wherein Ring B is phenyl.

11. A compound of the formula: 【Chemical 253】 or 【Chemical 254】 11. The compound of claim 10, wherein:

12. The compound of any one of claims 1 to 7, wherein Ring B is pyridinyl, pyrimidinyl, or pyrazinyl.

13. 13. The compound of claim 12, wherein Ring B is pyridinyl or pyrimidinyl.

14. The compound is a compound of formula Ia or Ia′: 【Chemistry 255】 or a pharmaceutically acceptable salt thereof [In the formula, Y １ , Y ２ , Y ３ , Y ４ and Y ５ are each independently N, C, or CH, with the proviso that Y １ , Y ２ , Y ３ , Y ４ and Y ５ and only one or two of these may be N; or 【256】 or a pharmaceutically acceptable salt thereof 2. The compound of claim 1, wherein:

15. The compound is a compound of formula Ib: 【Chemistry 257】 or a pharmaceutically acceptable salt thereof, During the ceremony, Y １ , Y ２ , Y ３ , Y ４ and Y ５ are each independently N, C, or CH, with the proviso that Y １ , Y ２ , Y ３ , Y ４ and Y ５ can be N; and 2. The compound of claim 1, wherein u is 1 or 2.

16. Y １ is CH and Y ２ is CR ３ and Y ３ is CH and Y ４ is N and Y ５ 16. The compound of claim 14 or claim 15, wherein is CH.

17. Y １ is CH and Y ２ is N and Y ３ is CR ３ and Y ４ is CH and Y ５ 16. The compound of claim 14 or claim 15, wherein is CH.

18. Y １ is N and Y ２ is CR ３ and Y ３ is CH and Y ４ is CH and Y ５ 16. The compound of claim 14 or claim 15, wherein is CH.

19. Y １ is CH and Y ２ is CR ３ and Y ３ is CH and Y ４ is CH and Y ５ 16. The compound of claim 14 or claim 15, wherein is CH.

20. Y １ is CH and Y ２ is CR ３ and Y ３ is CH and Y ４ is CH and Y ５ 16. The compound of claim 14 or claim 15, wherein is N.

21. Y １ is CH and Y ２ is N and Y ３ is CR ３ and Y ４ is N and Y ５ 16. The compound of claim 14 or claim 15, wherein is CH.

22. Y １ is N and Y ２ is CR ３ and Y ３ is N and Y ４ is CH and Y ５ 16. The compound of claim 14 or claim 15, wherein is CH.

23. Y １ is CH and Y ２ is CR ３ and Y ３ is N and Y ４ is CH and Y ５ 16. The compound of claim 14 or claim 15, wherein is N.

24. Y １ is N and Y ２ is CR ３ and Y ３ is CH and Y ４ is N and Y ５ 16. The compound of claim 14 or claim 15, wherein is CH.

25. Y １ is CH and Y ２ is CR ３ and Y ３ is CR ３ and Y ４ is CH and Y ５ 16. The compound of claim 14 or claim 15, wherein is CH.

26. Y １ is CH and Y ２ is N and Y ３ is CR ３ and Y ４ is CR ３ and Y ５ 16. The compound of claim 14 or claim 15, wherein is CH.

27. Y １ is CH and Y ２ is CR ３ and Y ３ is N and Y ４ is CH and Y ５ 16. The compound of claim 14 or claim 15, wherein is CH.

28. Y １ is CH and Y ２ is CH and Y ３ is CR ３ and Y ４ is CH and Y ５ 16. The compound of claim 14 or claim 15, wherein is CH.

29. Y １ is N and Y ２ is CH and Y ３ is CR ３ and Y ４ is CH and Y ５ 16. The compound of claim 14 or claim 15, wherein is CH.

30. Y １ is CR ３ and Y ２ is CH and Y ３ is CH and Y ４ is CH and Y ５ 16. The compound of claim 14 or claim 15, wherein is CH.

31. The compound is a compound of formula Ib': 【Chemical 258】 or a pharmaceutically acceptable salt thereof.

32. The compound of any one of claims 15 to 31, wherein u is 1.

33. The compound of any one of claims 15 to 31, wherein u is 2.

34. The compound of any one of claims 1 to 33, wherein p is 1.

35. The compound of any one of claims 1 to 33, wherein p is 2.

36. R ３ At least one of the following is halo-C １ -C ６ Alkyl, halo, cyano, C １ -C ６ Alkyl, and halo-C １ -C ６ The compound of any one of claims 1 to 35, selected from the group consisting of alkoxy.

37. R ３ At least one of the following is -CF ３ , -CHF ２ , methyl, fluoro, chloro, cyano, -OCF ３ and -OCHF ２ 37. The compound of claim 36, selected from the group consisting of:

38. R ３ At least one of the following is -CF ３ 38. The compound of claim 37, wherein:

39. At least one R ３ The compound of any one of claims 1 to 36, wherein is halo.

40. R ３ 40. The compound of claim 39, wherein at least one of is fluoro.

41. 41. The compound of any one of claims 1 to 40, wherein G is N.

42. The following formula: 【Chemical 259】 or 【Chemistry 260】 42. The compound of claim 41, having the formula:

43. 43. The compound of claim 42, wherein Ring B is cyclohexyl, phenyl, pyridinyl, pyrimidinyl, or pyrazinyl.

44. 41. The compound of any one of claims 1 to 40, wherein G is CH.

45. The following formula: 【Chemical 261】 or 【Chemical 262】 45. The compound of claim 44, having the formula:

46. 46. ​​The compound of claim 45, wherein Ring B is cyclohexyl, phenyl, pyridinyl, pyrimidinyl, or pyrazinyl.

47. R Ｎ１ But C １ -C ６ Alkyl and C ３ -C ５ 47. The compound of any one of claims 1 to 46, wherein the compound is selected from the group consisting of cycloalkyl.

48. R Ｎ１ 48. The compound of claim 47, wherein is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and cyclopropyl.

49. R Ｎ１ 49. The compound of claim 48, wherein is propyl.

50. R Ｎ１ 49. The compound of claim 48, wherein is isopropyl.

51. 51. The compound of any one of claims 1 to 50, wherein X is O.

52. 52. The compound of any one of claims 1 to 51, wherein y is 1.

53. 52. The compound of any one of claims 1 to 51, wherein y is 2.

54. 54. The compound of any one of claims 1 to 53, wherein m is 1.

55. 54. The compound of any one of claims 1 to 53, wherein m is 2.

56. R １ But in each case, C １ -C ６ Alkyl and halo-C １ -C ６ 56. The compound of any one of claims 1 to 55, independently selected from the group consisting of alkyl.

57. R １ In each case, methyl, ethyl and —CH ２ 57. The compound of claim 56, wherein the compound is selected from the group consisting of:

58. R １ 58. The compound of claim 57, wherein, in each instance, is methyl.

59. Two R's １ The groups together form -CH ２ - or -CH ２ CH ２ - forming a bridge,

60. 54. The compound of any one of claims 1 to 53, wherein m is 0.

61. X and R in the ring １ , m and y are: 【Chemical 263】 61. The compound of any one of claims 1 to 60, wherein the compound forms:

62. X is NR Ｈ 51. The compound according to any one of claims 1 to 50,

63. R Ｈ But C ３ -C ５ Cycloalkyl, hydroxy-C １ -C ６ Alkyl, and C １ -C ６ Alkoxy-C １ -C ６ 63. The compound of claim 62, wherein the compound is selected from the group consisting of alkyl.

64. R Ｈ But -CH ２ CH ２ OCH ３ , cyclobutyl and —CH ２ CH ２ 63. The compound of claim 62, wherein the compound is selected from the group consisting of: OH.

65. 65. The compound of any one of claims 62 to 64, wherein m is 0.

66. X and R in the ring １ , m and y are: 【Chemical 264】 66. The compound according to any one of claims 62 to 65, which forms:

67. The compound is a compound of formula Ia1 or 1b1: 【Chemical 265】 【Chemical 266】 or a pharmaceutically acceptable salt thereof, During the ceremony, u is 1 or 2; m is 0, 1 or 2; Y １ , Y ２ , Y ３ , Y ４ , and Y ５ are each independently CH, CR ３ , or N, where Y １ , Y ２ , Y ３ , Y ４ , and Y ５ Only one or two of may be N; G is N or CH; and R １ is, if present, in each instance C １ -C ６ Alkyl and halo-C １ -C ６ alkyl; or two R １ The groups together form -CH ２ - or -CH ２ CH ２ - forming a bridge, the compound according to claim 1.

68. R Ｎ１ But C １ -C ６ Alkyl and C ３ -C ５ 68. The compound of claim 67, wherein the compound is selected from the group consisting of cycloalkyl.

69. R Ｎ１ 68. The compound of claim 67, wherein is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and cyclopropyl.

70. R Ｎ１ 70. The compound of claim 69, wherein is propyl.

71. R Ｎ１ 70. The compound of claim 69, wherein is isopropyl.

72. 72. The compound of any one of claims 67 to 71, wherein y is 1.

73. 72. The compound of any one of claims 67 to 71, wherein y is 2.

74. R １ In each case, methyl, ethyl and —CH ２ 74. The compound of any one of claims 67 to 73, selected from the group consisting of F.

75. 74. The compound of any one of claims 67 to 73, wherein m is 0.

76. 75. The compound of any one of claims 67 to 74, wherein m is 1.

77. 77. The compound of any one of claims 67 to 76, wherein u is 1.

78. 77. The compound of any one of claims 67 to 76, wherein u is 2.

79. Y １ is CH and Y ２ is CR ３ and Y ３ is CH and Y ４ is N and Y ５ is CH; Y １ is CH and Y ２ is N and Y ３ is CR ３ and Y ４ is CH and Y ５ is CH; Y １ is N and Y ２ is CR ３ and Y ３ is CH and Y ４ is CH and Y ５ is CH; Y １ is CH and Y ２ is CR ３ and Y ３ is CH and Y ４ is CH and Y ５ is CH; Y １ is CH and Y ２ is CR ３ and Y ３ is CH and Y ４ is CH and Y ５ is N; Y １ is CH and Y ２ is N and Y ３ is CR ３ and Y ４ is N and Y ５ is CH; Y １ is N and Y ２ is CR ３ and Y ３ is N and Y ４ is CH and Y ５ is CH; Y １ is CH and Y ２ is CR ３ and Y ３ is N and Y ４ is CH and Y ５ is N; Y １ is N and Y ２ is CR ３ and Y ３ is CH and Y ４ is N and Y ５ is CH; Y １ is CH and Y ２ is CR ３ and Y ３ is CR ３ and Y ４ is CH and Y ５ is CH; Y １ is CH and Y ２ is N and Y ３ is CR ３ and Y ４ is CR ３ and Y ５ is CH; Y １ is CH and Y ２ is CR ３ and Y ３ is N and Y ４ is CH and Y ５ is CH; Y １ is CH and Y ２ is CH and Y ３ is CR ３ and Y ４ is CH and Y ５ is CH; Y １ is N and Y ２ is CH and Y ３ is CR ３ and Y ４ is CH and Y ５ is CH; or Y １ is CR ３ and Y ２ is CH and Y ３ is CH and Y ４ is CH and Y ５ is CH, The compound according to any one of claims 67 to 78.

80. R ３ but in each case halo-C １ -C ６ Alkyl, halo, cyano, C １ -C ６ Alkyl and halo-C １ -C ６ 80. The compound of any one of claims 67-79, independently selected from the group consisting of alkoxy.

81. R ３ In each case, -CF ３ , -CHF ２ , methyl, fluoro, chloro, cyano, -OCF ３ and -OCHF ２ 81. The compound of claim 80, independently selected from the group consisting of:

82. At least one R ３ Ga-CF ３ 82. The compound of claim 81, wherein:

83. At least one R ３ The compound of any one of claims 67 to 80, wherein is halo.

84. 84. The compound of claim 83, wherein said halo is fluoro.

85. The compound is a compound of formula Ia2 or 1b2: 【Chemical 267】 【Chemical 268】 or a pharmaceutically acceptable salt thereof, wherein: u is 1 or 2; Y １ , Y ２ , Y ３ , Y ４ , and Y ５ are each independently CH, CR ３ , or N, where Y １ , Y ２ , Y ３ , Y ４ , and Y ５ and 2. The compound of claim 1, wherein G is N or CH.

86. 86. The compound of claim 85, wherein u is 1.

87. 87. The compound of claim 85 or 86, wherein y is 1.

88. R Ｈ But C ３ -C ５ Cycloalkyl, hydroxy-C １ -C ６ Alkyl, and C １ -C ６ Alkoxy-C １ -C ６ 88. The compound of any one of claims 85 to 87, wherein the compound is selected from the group consisting of alkyl.

89. R Ｈ But -CH ２ CH ２ OCH ３ , cyclobutyl and —CH ２ CH ２ 89. The compound of claim 88, wherein the compound is selected from the group consisting of: OH.

90. R Ｎ１ But C １ -C ６ 90. The compound of any one of claims 85 to 89, which is alkyl.

91. R Ｎ１ 91. The compound of claim 90, wherein is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and butyl.

92. R Ｎ１ 92. The compound of claim 91, wherein is propyl.

93. R Ｎ１ 93. The compound of claim 92, wherein is isopropyl.

94. Y １ is CH and Y ２ is N and Y ３ is CR ３ and Y ４ is CH and Y ５ is CH; or Y １ is N and Y ２ is CR ３ and Y ３ is CH and Y ４ is CH and Y ５ 94. The compound of any one of claims 85 to 93, wherein is CH.

95. R ３ Halo-C １ -C ６ 95. The compound of claim 94, which is alkyl.

96. R ３ Ga-CF ３ 96. The compound of claim 95, wherein:

97. Ring A is bicyclo[3.1.0]hexanyl having the structure: 【Chemical 269】 and 96. The compound of any one of claims 1, 5, 11, 14, 42, 45, 67 or 85, wherein * indicates a bond to the N atom and # indicates a bond to a C atom on the triazole or pyrazole moiety.

98. Ring A is bicyclo[3.1.0]hexanyl having the structure: 【Chemistry 270】 and 98. The compound of claim 97, wherein * indicates a bond to the N atom and # indicates a bond to a C atom on the triazole or pyrazole moiety.

99. Ring A is bicyclo[3.1.0]hexanyl having the structure: 【Chemical 271】 and 98. The compound of claim 97, wherein * indicates a bond to the N atom and # indicates a bond to a C atom on the triazole or pyrazole moiety.

100. Ring A is bicyclo[3.1.0]hexanyl having the structure: 【Chemical 272】 and 98. The compound of claim 97, wherein * indicates a bond to the N atom and # indicates a bond to a C atom on the triazole or pyrazole moiety.

101. Ring A is bicyclo[3.1.0]hexanyl having the structure: 【Chemical 273】 and 98. The compound of claim 97, wherein * indicates a bond to the N atom and # indicates a bond to a C atom on the triazole or pyrazole moiety.

102. Ring A is a cyclohexyl having the following structure: 【Chemical 274】 and 96. The compound of any one of claims 1, 15, 31, 67, or 85, wherein * indicates a bond to the N atom and # indicates a bond to a C atom on the triazole or pyrazole moiety.

103. Ring A is a cyclohexyl having the following structure: 【Chemistry 275】 and 103. The compound of claim 102, wherein * indicates a bond to the N atom and # indicates a bond to a C atom on the triazole or pyrazole moiety.

104. Ring A is a cyclohexyl having the following structure: 【Chemical 276】 and 103. The compound of claim 102, wherein * indicates a bond to the N atom and # indicates a bond to a C atom on the triazole or pyrazole moiety.

105. Ring A is a cyclohexyl having the following structure: 【Chemical 277】 and 103. The compound of claim 102, wherein * indicates a bond to the N atom and # indicates a bond to a C atom on the triazole or pyrazole moiety.

106. Ring A is a cyclohexyl having the following structure: 【Chemical 278】 and 103. The compound of claim 102, wherein * indicates a bond to the N atom and # indicates a bond to a C atom on the triazole or pyrazole moiety.

107. Ring A is a cyclopentyl having the structure: 【Chemical 279】 86. The compound of any one of claims 1, 4, 11, 15, 31, 42, 45, 67, or 85, wherein

108. Ring A is a cyclopentyl having the structure: 【Chemistry 280】 and 108. The compound of claim 107, wherein * indicates a bond to the N atom and # indicates a bond to a C atom on the triazole or pyrazole moiety.

109. Ring A is a cyclopentyl having the structure: 【Chemistry 281】 and 108. The compound of claim 107, wherein * indicates a bond to the N atom and # indicates a bond to a C atom on the triazole or pyrazole moiety.

110. Ring A is a cyclopentyl having the structure: 【Chemical 282】 and 108. The compound of claim 107, wherein * indicates a bond to the N atom and # indicates a bond to a C atom on the triazole or pyrazole moiety.

111. Ring A is a cyclopentyl having the structure: 【Chemical 283】 and 108. The compound of claim 107, wherein * indicates a bond to the N atom and # indicates a bond to a C atom on the triazole or pyrazole moiety.

112. The compound of any one of claims 97 to 111, wherein n is 0.

113. 2. The compound of claim 1 selected from Table 1 or a pharmaceutically acceptable salt thereof.

114. A pharmaceutical composition comprising the compound according to any one of claims 1 to 113 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

115. 115. A method of treating a disorder in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 113 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 114.

116. 115. A compound according to any one of claims 1 to 113 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 114, for use in treating a disorder in a subject in need thereof.

117. 116. Use of a compound according to any one of claims 1 to 113 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 114, in the manufacture of a medicament for treating a disorder in a subject in need thereof.

118. wherein the disorder is a myelin-associated disorder, and optionally the myelin-associated disorder is selected from the group consisting of 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, and Alzheimer's disease. , Parkinson's disease, spinal cord injury, traumatic brain injury, post-radiation injury, neurological complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barré syndrome, Charcot-Marie-Tooth disease, Bell's palsy, or radiation-induced demyelination.

119. 118. The method of claim 115, the compound of claim 116, or the use of claim 117, wherein the disorder is multiple sclerosis.

120. 116. A method of promoting myelination in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 113 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 114.

121. A compound according to any one of claims 1 to 113 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 114, for use in promoting myelination in a subject in need thereof.

122. 116. Use of a compound according to any one of claims 1 to 113 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 114, in the manufacture of a medicament for promoting myelination in a subject in need thereof.

123. 121. The method of claim 115 or 120, wherein the subject has a myelin-related disorder.

124. 122. The compound for use according to claim 116 or 121, wherein the subject has a myelin-related disorder.

125. 123. The use of a compound according to claim 117 or 122, wherein the subject has a myelin-related disorder.

126. 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, Parkinson's disease, spinal cord injury, or trauma.

126. The method of claim 123, the compound for use of claim 124, or the use of a compound of claim 125, wherein the condition is inflammatory brain injury, post-radiation injury, neurological complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barré syndrome, Charcot-Marie-Tooth disease, Bell's palsy, or radiation-induced demyelination.

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