Azole modulators of cholesterol biosynthesis and their use for promoting remyelination

Abstract

The subject matter described herein relates to compounds of formula (I) and pharmaceutically acceptable salts thereof that promote myelin, methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of administering the compounds to treat conditions, such as myelin-related conditions. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 377,821, filed September 30, 2022, which is incorporated herein by reference in its entirety.

[0003] field

[0004] The subject matter described herein relates to myelin-promoting compounds of Formula I, methods of making the compounds, their pharmaceutical compositions, and their use in treating myelin-related disorders.

[0005] background

[0006] Myelin-related disorders are disorders that result in abnormal myelin sheaths (e.g., dysmyelination, demyelination, and hypomyelination) in the nerve cells (e.g., CNS neurons, including their axons) of a subject. In such disorders, the loss or degradation of myelin can lead to slowing or cessation of nerve cell conduction. The resulting myelin-related disorders are characterized by defects in sensation, motor function, cognition, or other physiological functions. Myelin-related disorders include, but are not limited to, multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander disease, Pelitzowiez-Merzbacher disease (PMD), white matter ablative diseases, Waller degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Henry Huntington disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post-radiation injury, neurologic 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.

[0007] MS is the most common myelin-related disorder, affecting millions of people worldwide and causing an estimated 18,000 deaths each year. MS is a complex neurological disease characterized by the deterioration of myelin in the central nervous system (CNS). Myelin, composed primarily of lipids (70% lipid, 30% protein), protects axons and enables saltatory conduction, which accelerates axonal electrical impulses. Axonal demyelination in chronic MS can lead to axonal degeneration and neuronal cell death. In addition, MS also damages oligodendrocytes, highly specialized CNS cells that produce and maintain myelin. A repair process called remyelination occurs in the early stages of the disease, but over time, oligodendrocytes are unable to fully rebuild and restore the myelin sheath. Repeated attacks cause the effectiveness of remyelination to gradually decrease until scar-like plaques form around damaged axons. These scars are the root cause of the symptoms.

[0008] Currently, myelin-related disorders have no cure, and only a few disease-modifying therapies are available. Therefore, new therapeutic approaches are needed to treat myelin-related disorders, including promoting myelin regeneration. The subject matter described herein addresses this unmet need.

[0009] Brief Description

[0010] 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.

[0011] 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.

[0012] 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.

[0013] 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.

[0014] 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 pharmaceutical excipient.

[0015] 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, for the manufacture of a medicament for treating a myelin-related disorder.

[0016] In certain embodiments, the subject matter described herein relates to methods of preparing a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof.

[0017] Other embodiments are also described.

[0018] Detailed description

[0019] Described herein are compounds of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, and Ib2, and 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 myelin-promoting compounds.

[0020] Without wishing to be bound by theory, the accumulation of Δ 8,9-unsaturated sterol intermediates of the cholesterol biosynthetic pathway in enhancing and / or inducing oligodendrocyte progenitor cells (OPC) can induce oligodendrocyte generation. It can be, for example, by regulating and / or inhibiting the enzyme and / or Δ 8,9-unsaturated sterol intermediate accumulation in the OPC cholesterol biosynthetic pathway, and the enzyme for which Δ 8,9-unsaturated sterol intermediates are substrates, and directly and / or indirectly applying Δ 8,9-unsaturated sterol intermediates to OPC to enhance and / or induce the accumulation of Δ 8,9-unsaturated sterol intermediates. Enhancement and / or induction of the accumulation of Δ 8,9-unsaturated sterol intermediates can promote OPC differentiation, survival, proliferation and / or maturation, and it is believed that this can treat a subject's disease and / or illness in which myelination is beneficial to the subject.

[0021] Thus, in some embodiments, agents that can enhance and / or induce the accumulation of Δ8,9-unsaturated sterol intermediates of the cholesterol biosynthetic pathway in OPCs (such as compounds of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2 or Ib2, or pharmaceutically acceptable salts thereof) can be administered to a subject and / or OPC in an amount effective to promote and / or induce OPC differentiation, proliferation and / or maturation, and oligodendrogenesis. In certain embodiments, an agent (e.g., a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2 or Ib2, or pharmaceutically acceptable salts thereof) is a compound that inhibits the enzyme-mediated synthesis of one or more sterol intermediates in the cholesterol biosynthetic pathway of OPCs and / or promotes the accumulation of Δ8,9-unsaturated sterol intermediates.

[0022] In certain embodiments, a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2 or Ib2, or a pharmaceutically acceptable salt thereof, can regulate and / or inhibit one or more enzyme-mediated conversion steps of the cholesterol biosynthetic pathway, such as in the pathway from lanosterol to cholesterol, for example, between lanosterol and / or enecholestanol; regulating and / or inhibiting one or more of these steps in OPC can promote and / or induce oligodendrocyte generation. 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 the synthesis of sterol intermediates in the cholesterol biosynthetic pathway mediated by CYP51, sterol 14-reductase (TM7SF2 and / or LBR), SC4MOL, NSDHL and / or emopamil binding protein (EBP) enzymes. In certain embodiments, the compounds of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or pharmaceutically acceptable salts thereof, can inhibit CYP51, sterol 14-reductase, and / or EBP. In certain embodiments, the compounds of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or pharmaceutically acceptable salts thereof, can inhibit EBP.

[0023] For example, in certain embodiments, the compounds of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2 used in the methods described herein, or pharmaceutically acceptable salts thereof, can inhibit the enzyme-mediated conversion of dihydrozymosterol to enocholestanol by inhibiting the enzymatic activity of emopamide binding protein (EBP) isomerase. Alternatively, in certain embodiments, the compounds of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2 used in the methods described herein, or pharmaceutically acceptable salts thereof, can inhibit the enzymatic activity of sterol C14 reductase or CYP51 enzyme activity in the cholesterol biosynthetic pathway.

[0024] Emopamide binding protein (EBP) is an enzyme responsible for one of the final steps in the production of cholesterol. Specifically, EBP converts dihydrozymosterol to enocholestanol, which is then modified by other enzymes to produce cholesterol. EBP is also known as Δ8-Δ7-sterol isomerase, 3-β-hydroxysteroid-Δ(8),Δ(7)-isomerase, CDPX2, CHO2, CPX, or CPXD.

[0025] Without being bound by a particular theory, it is believed that the compounds of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2 or Ib2, or pharmaceutically acceptable salts thereof, can inhibit the EBP-mediated conversion of dihydrozymosterol to enocholestanol in the cholesterol biosynthesis pathway of OPCs, thereby enhancing and / or inducing the accumulation of Δ8,9-unsaturated sterol intermediates. In some embodiments, enhancing and / or inducing the accumulation of Δ8,9-unsaturated sterol intermediates can promote OPC differentiation, survival, proliferation and / or maturation and treat diseases and / or conditions in subjects in which myelination or myelination is beneficial to the subject. This mechanism of promoting myelination is different from the primary effect of immunomodulators commonly used to treat myelin-related disorders.

[0026] The subject matter disclosed in the present invention will now be described more fully hereinafter. However, for those skilled in the art to whom the subject matter disclosed herein is related, in the case of benefiting from the teaching proposed in the description herein, many variations (modification) and other embodiments of the subject matter disclosed herein set forth can be imagined. Therefore, it should be understood that the subject matter disclosed herein is not limited to the specific embodiments disclosed, and variations and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein covers all alternatives, variants and equivalents. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill 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 are different from or contradictory to the present application, including but not limited to defined terms, term usage, described technology, etc., the present application shall prevail.

[0027] I. Definition

[0028] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0029] A dash ("-") that is not between two letters or symbols is used to indicate the 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; a chemical group may be depicted with or without one or more dashes without losing its ordinary meaning. A wavy or dotted line running through or perpendicularly across the end of a line in a structure indicates the designated point of attachment of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply any directionality or stereochemistry.

[0030] The 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.

[0031] Mention herein that " about " value or parameter includes (and describes) embodiment related to the value or parameter itself. In certain embodiments, the term " about " includes indicative amount ± 50%. In certain other embodiments, the term " about " includes indicative amount ± 20%. In certain other embodiments, the term " about " includes indicative amount ± 10%. In other embodiments, the term " about " includes indicative amount ± 5%. In certain other embodiments, the term " about " includes indicative amount ± 1%. In certain other embodiments, the term " about " includes indicative amount ± 0.5%, and in certain other embodiments, includes indicative amount ± 0.1%. Such variations are suitable for carrying out the disclosed method or adopting the disclosed composition. In addition, the term " about x " includes description of " x ". In addition, unless the context clearly provides otherwise, the singular forms " one " and " the / described " include plural referents. Therefore, for example, mentioning " compound " includes a plurality of such compounds, and mentioning " the assay " includes mentioning one or more assays known to those skilled in the art and their equivalents, etc.

[0032] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., C1-C 20 alkyl), 1 to 12 carbon atoms (i.e., C1-C 12The alkyl group may be a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a 2-pentyl group, an isopentyl group, a neopentyl group, a hexyl group, a 2-hexyl group, a 3-hexyl group, and a 3-methylpentyl group. When an alkyl residue having a particular number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons are contemplated; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0033] 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 or "alkylenyl" groups, "arylene" groups or "arylenyl" groups, respectively. In addition, unless otherwise expressly indicated, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl or aralkyl), the last-mentioned group contains the atoms by which the moiety is attached to the rest of the molecule.

[0034] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and, unless otherwise specified, can have from 2 to 20 carbon atoms (i.e., C2-C 20 In some embodiments, the present invention includes alkenyl, 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, vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0035] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and, unless otherwise specified, can have from 2 to 20 carbon atoms (i.e., C2-C 20 The term "alkynyl" also includes groups having one triple bond and one double bond.

[0036] "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, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0037] "Acyl" refers to the group -C(O)R y , where 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 acyl groups include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and benzoyl.

[0038] "Acylamino" refers to the group -C(O)NR y R z The "C-amido" group and the group -NR y C(O)R z "N-amido" groups, wherein 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, or R y and R z Together they form a heterocyclyl; which may be optionally substituted as defined herein.

[0039] "Amino" refers to the group -NR y R z , where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0040] "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, an aryl group has 6 to 20 ring carbon atoms (i.e., C6-C 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 10Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthracenyl. However, aryl does not in any way encompass or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused to a heteroaryl group, the resulting ring system is a heteroaryl group regardless of the point of attachment. If one or more aryl groups are fused to a heterocyclyl group, the resulting ring system is a heterocyclyl group regardless of the point of attachment.

[0041] "Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-", such as (C6-C 10 A non-limiting example of an arylalkyl group is benzyl.

[0042] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, which may include fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and cycloalkenyl groups having at least one sp 3 As used herein, a cycloalkyl group has 3 to 20 ring carbon atoms (i.e., C3-C 20 cycloalkyl), 3 to 12 carbon ring atoms (i.e., C3-C 12 cycloalkyl), 3 to 10 carbon ring atoms (i.e., C3-C 10 In some embodiments, the present invention relates to a cycloalkyl group, wherein the cycloalkyl group comprises a cycloalkyl radical, a cyclopentyl radical, a cyclohexyl radical, a cycloheptyl radical and a cyclooctyl radical. In some embodiments, the cycloalkyl group comprises a cycloalkyl radical, a cyclobutyl radical, a cyclopentyl radical, a cyclohexyl radical, a cycloheptyl radical and a cyclooctyl radical. In some embodiments, the cycloalkyl group comprises a cyclopropyl radical, a cyclobutyl radical, a cyclopentyl radical, a cyclohexyl radical, a cycloheptyl radical and a cyclooctyl radical. In some embodiments, the cycloalkyl group comprises a cyclopropyl radical, a cyclobutyl radical, a cyclopentyl radical, a cyclohexyl radical, a cycloheptyl radical and a cyclooctyl radical. In some embodiments, the cycloalkyl group comprises a cyclopropyl radical, a cyclobutyl radical, a cyclopentyl radical, a cyclohexyl radical, a cycloheptyl radical and a cyclooctyl radical. In some embodiments, the cycloalkyl group comprises a cyclopropyl radical, a cyclobutyl radical, a cyclopentyl radical, a cyclohexyl radical, a cycloheptyl radical and a cyclooctyl radical. In some embodiments, the cycloalkyl group comprises a cyclopropyl radical, a cyclobutyl radical, a cyclopentyl radical, a cyclohexyl radical and a cyclooctyl radical. In some embodiments, the cycloalkyl group comprises a cyclopropyl radical, a cyclobutyl radical, a cyclopentyl radical, a cyclohexyl radical and a cyclooctyl radical. In some embodiments, the cycloalkyl group comprises a cyclopropyl radical, a cyclobutyl radical, a cyclopentyl radical, a cyclohexyl radical and a cyclooctyl radical.

[0043] As used herein, "halocycloalkyl" (such as C3-C7halocycloalkyl) refers to a C3-C7cycloalkylalkyl group substituted with one or more halogens.

[0044] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-", such as (C3-C6cycloalkyl)-C1-C3alkyl.

[0045] "Halogen" or "halo" refers to an atom occupying Group VIIA of the periodic table, such as fluorine (F), chlorine (Cl), bromo (Br), or iodo (I).

[0046] "Haloalkyl" refers to a branched or unbranched alkyl group as defined above, wherein one or more (for example, 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogen. For example, halo-C1-C3 alkyl refers to an alkyl group of 1 to 3 carbons in which at least one hydrogen atom is replaced by halogen. Halo-C1-C6 alkyl refers to an alkyl group of 1 to 6 carbons in which at least one hydrogen atom is replaced by halogen. When the residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties connected. Dihaloalkyl and trihaloalkyl refer to an alkyl group substituted with two (" two ") or three (" three ") halo groups, and the halo group can be, but is not necessarily, the same halogen. The example of haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0047] "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 by halogen. For example, halo-C1-C3 alkoxy refers to an alkoxy group of 1 to 3 carbon atoms in which at least one hydrogen atom is replaced by halogen. Halo-C1-C6 alkoxy refers to an alkoxy group of 1 to 6 carbon atoms in which at least one hydrogen atom is replaced by halogen. Non-limiting examples of haloalkoxy are -OCH2CF3, -OCF2H, and -OCF3.

[0048] "Hydroxyalkyl" refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxy group (e.g., hydroxy-C1-C3-alkyl, hydroxy-C1-C6-alkyl). The term "hydroxy-C1-C3-alkyl" refers to an alkyl chain of one to three carbons when one or more hydrogens on any carbon are replaced by a hydroxy group, particularly a hydrogen on one carbon of the chain is replaced by a hydroxy group. The term "hydroxy-C1-C6-alkyl" refers to an alkyl chain of one to six carbons when one or more hydrogens on any carbon are replaced by a hydroxy group, particularly a hydrogen on one carbon of the chain is replaced by a hydroxy group. Non-limiting examples of hydroxyalkyl include-CH2OH,-CH2CH2OH and-C(CH3)2CH2OH.

[0049] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups, provided that the point of attachment to the rest of the molecule is through a carbon atom. In certain embodiments, 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 heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains with carbon and heteroatoms. For example, 1, 2, or 3 carbon atoms of the alkyl group in "heteroalkyl" can be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc., where 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, -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.), where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. In certain embodiments, the heteroalkyl group may 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.

[0050] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group includes 1 to 20 ring carbon atoms (i.e., C1-C 20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-C 12In some cases, the heteroaryl group includes a 9- to 10-membered ring system (i.e., a 9- to 10-membered heteroaryl), a 5- to 10-membered ring system (i.e., a 5- to 10-membered heteroaryl), a 5- to 7-membered ring system (i.e., a 5- to 7-membered heteroaryl), a 5- to 6-membered ring system (i.e., a 5- to 6-membered heteroaryl), or a 4- to 6-membered ring system (i.e., a 4- to 6-membered heteroaryl), each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl or benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaromatic rings include, but are not limited to, benzo[d]thiazolyl, quinolyl, isoquinolyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl group may be attached via any ring of the fused system. Any aromatic group having single or multiple fused rings and containing at least one heteroatom is considered a heteroaryl group, regardless of its attachment to the rest of the molecule (i.e., through any of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0051] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-" such as (5- to 10-membered monocyclic heteroaryl)-C1-C3alkyl.

[0052] " heterocyclic radical " refers to the saturation or partially unsaturated cyclic alkyl group with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulphur.Term " heterocyclic radical " includes heterocyclenyl group (that is, heterocyclic radical group with at least one double bond), bridged heterocyclic radical group, fused heterocyclic radical group and spiral heterocyclic radical group.Heterocyclic radical can be a single ring or multiple rings, wherein multiple rings can be fused, bridged or spiral.Any non-aromatic ring containing at least one heteroatom is considered to as heterocyclic radical, no matter how connected (that is, can be combined by carbon atom or heteroatom).In addition, the term heterocyclic radical is intended to contain the part comprising any non-aromatic ring containing at least one heteroatom, and the ring can be fused to aryl or heteroaryl ring, no matter how connected with the rest of the molecule.The term heterocyclic radical is also intended to contain the part comprising the cycloalkyl ring fused to heteroaryl ring, no matter how connected with the rest of the molecule.In addition, the term heterocyclic radical is intended to contain the part comprising the cycloalkyl ring fused to heterocyclic ring, no matter how connected with the rest of the molecule. As used herein, a heterocyclyl group has 2 to 20 ring carbon atoms (ie, C2-C 20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-C 12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-C 10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-C8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-C 12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-C8 heterocyclyl) or 3 to 6 ring carbon atoms (i.e., C3-C6 heterocyclyl); having 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 the heterocyclyl ring contains 4 to 6 ring atoms, it is also referred to herein as a 4 to 6-membered heterocyclyl. Also disclosed herein are 5 or 6-membered heterocyclyls having 5 or 6 ring atoms, respectively, and 5 to 10-membered heterocyclyls having 5 to 10 ring atoms. Examples of heterocyclyl groups include, for example, azetidinyl, aza 1,4-Benzodioxolyl, benzo[b][1,4]dioxepanyl, 1,4-Benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyrone, benzofuranyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, furanone, imidazolinyl, imidazolidinyl, indolyl, indolizinyl, isoindolyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydro Isoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. In certain embodiments, when two substitution positions are present on the same carbon atom, the term "heterocyclyl" may include "spiroheterocyclyl" wherein at least one ring of the spiro system contains at least one heteroatom. Examples of spiroheterocyclyl rings include, for example, bicyclic and tricyclic ring systems such as 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, wherein the heterocyclyl group may be attached via either ring of the fused system.

[0053] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-."

[0054] "Oxo" refers to the radical (=O).

[0055] "Cyano" refers to the radical (-CN).

[0056] "Sulfonyl" refers to the group -S(O)2R y , where 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 -SO2(C1-C6 alkyl), which is referred to herein as alkylsulfonyl. Examples of sulfonyl groups are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0057] "Sulfinyl" refers to the group -S(O)R y , where R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of sulfinyl groups are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.

[0058] "Sulfonylamino" refers to the group -SO2NR y R z and -NR y SO2R z , where R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0059] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. In addition, the term "optionally substituted" means that any one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms on a designated atom or group may or may not be replaced with a moiety other than hydrogen.

[0060] As used herein, the term "substituted" refers to 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) of the hydrogen atoms is replaced by a bond to a non-hydrogen moiety. Unless otherwise specified, such non-hydrogen moieties may include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH, =NNH, imino, aminoidene, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)OH, sulfonamido, thiol, thio, N-oxide, or -Si(R) y )3, where each R y is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0061] In certain embodiments, "substituted" includes any of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, wherein one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are independently replaced by deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR g R h 、-NR g C(=O)R h 、-NR g C(=O)NR g R h 、-NR g C(=O)OR h 、-NR g S(=O) 1-2 R h 、-C(=O)R g 、-C(=O)OR g 、-OC(=O)OR g 、-OC(=O)R g 、-C(=O)NR g R h 、-OC(=O)NR g R h 、-OR g 、-SR g 、-S(=O)R g 、-S(=O)2R g 、-OS(=O) 1-2 R g 、-S(=O) 1-2 OR g 、-NR g S(=O) 1-2 NR g R h , =NSO2R g 、=NOR g 、-S(=O) 1- 2NR g R h In certain embodiments, "substituted" also means any of the above groups, wherein one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced by -C(=O)R g 、-C(=O)OR g 、-C(=O)NR g R h 、-CH2SO2R g or -CH2SO2NR g R hIn the above, R g and R h are 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 means any of the above groups wherein one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced by bonds to amino, cyano, hydroxy, imino, nitro, oxo, thio, 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 The two of the alkyl groups, taken together with the atoms to which they are attached, form a heterocyclyl ring which is optionally substituted with oxo, halo, or alkyl which is optionally substituted with oxo, halo, amino, hydroxy, or alkoxy.

[0062] Polymers or similar infinite structures obtained by defining substitution with unlimited additional substituents (e.g., a substituted aryl group with a substituted alkyl group, 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, a substituted aryl group with two other substituted aryl groups is limited to a ((substituted aryl) substituted aryl) substituted aryl group. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., a methyl group substituted with 5 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 describe other chemical groups defined herein.

[0063] In certain embodiments, as used herein, the phrase "one or more" refers to one to five. In certain embodiments, as used herein, the phrase "one or more" refers to one to four. In certain embodiments, as used herein, the phrase "one or more" refers to one to three.

[0064] Any compound or structure given herein is intended to represent unlabeled forms as well as isotopically labeled forms (isotopologues) of the compound. These forms of the compound may also be referred to as and include "isotopically enriched analogs." An isotopically labeled compound has a structure 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 can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 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, compounds into which a radioactive isotope (such as 3 H. 13 C and 14 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 radiotherapy of patients.

[0065] The term "isotopically enriched analogs" includes "deuterated analogs" of the compounds described herein, wherein one or more hydrogens are replaced by deuterium, such as hydrogens on carbon atoms. Such compounds exhibit increased metabolic resistance 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 hydrogens have been replaced by deuterium.

[0066] Deuterium-labeled or substituted therapeutic compounds of the present disclosure can have improved DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages due to its higher metabolic stability (e.g., increasing half-life in vivo, reducing dosage requirements and / or improving therapeutic index). 18 F. 3 H. 11C-labeled compounds can be used for PET or SPECT or other imaging studies. The isotopically labeled compounds of the present disclosure can generally be prepared by following the procedures disclosed in the following schemes or examples and preparations by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents. It should be understood that in this context, deuterium is considered a substituent in the compounds described herein.

[0067] The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotope enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," that position should be understood to have hydrogen in its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium. In addition, in some embodiments, corresponding deuterated analogs are provided.

[0068] 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.

[0069] Also provided are pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, isomers (such as stereoisomers), and isomer mixtures (such as mixtures of stereoisomers) of the compounds described herein.

[0070] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use. Generally, such materials are not biologically or otherwise undesirable; for example, the material can be incorporated into a pharmaceutical composition administered to a patient without causing any significant adverse biological effect or interacting in a deleterious manner with any other ingredients contained in the composition.

[0071] The term "pharmaceutically acceptable salt" of a given compound includes salts that are generally safe and neither biologically nor otherwise unacceptable, and includes those that are acceptable for veterinary as well as human pharmaceutical use. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts formed with inorganic acids as well as salts formed with organic acids. Additionally, if the compounds described herein are obtained as acid addition salts, 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 conventional methods for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize various synthetic methods 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. By way of example only, salts derived from inorganic bases include sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, 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)), dienylamines (i.e., HN(alkenyl)2), trialnylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkyl) , HN(cycloalkyl) , N(cycloalkyl) , mono-, di- or tri-arylamines (i.e., NH(aryl), HN(aryl), N(aryl), or mixed amines, and the like. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0072] The term "hydrate" refers to a complex formed by the combination of 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 presented herein is intended to encompass hydrates and / or solvates of that compound.

[0073] The compounds described herein, or pharmaceutically acceptable salts thereof, may include asymmetric centers and thus may produce enantiomers, diastereomers, and other stereoisomeric forms, which may be defined as (R)- or (S)- in terms of absolute stereochemistry, or as (D)- or (L)- for amino acids. The present disclosure is intended to include all such possible isomers, as well as their racemates and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or separated using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise indicated, it is intended that the compounds contain both E and Z geometric isomers. In some embodiments, the planar structures shown herein include all possible stereochemistries. In certain embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, such as compounds of Formula Ia, Ia', Ia1, or Ia2, or pharmaceutically acceptable salts of any of the foregoing compounds, wherein Ring A is and ring C is The combination of Ring A and Ring C may include any of the following stereoisomers: In certain embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, such as compounds of Formula Ib, Ib', Ib1, or Ib2, or pharmaceutically acceptable salts of any of the foregoing compounds, wherein Ring A is and ring C is The combination of Ring A and Ring C may include any of the following stereoisomers:

[0074] The compounds described herein can contain any combination of stereocenters and any combination of stereochemistry at each stereocenter.

[0075] "Stereoisomers" refer to compounds made up of the same atoms joined by the same bonds but having 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 each other.

[0076] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0077] Relative centers of compounds depicted herein are indicated graphically using a "thick bond" style (bold or parallel lines), and absolute stereochemistry is depicted using wedge-shaped bonds (bold or parallel lines).

[0078] "Treatment" or "treating" is a method of obtaining a beneficial or desired result (including but not limited to a clinical result). Beneficial or desired results may include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the extent of the disease or condition); b) slowing or preventing the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or c) alleviating the disease or condition, i.e., causing clinical symptoms to resolve (e.g., improving the disease state, providing partial or complete relief of the disease or condition, enhancing the effect of another drug, delaying the progression of the disease, improving the quality of life, and / or prolonging survival). "Treatment" or "treating" also encompasses mitigating the pathological consequences of demyelination.

[0079] "Prevention" or "preventing" means any treatment of a disease or condition that prevents clinical symptoms of the disease or condition from occurring. In some embodiments, the compound can be administered to a subject (including a human) who is at risk for the disease or condition or has a family history of the disease or condition.

[0080] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experiment. The methods described herein can be used for human treatment and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0081] The term "therapeutically effective amount" or "effective amount" of a compound as described herein, or a pharmaceutically acceptable salt thereof, refers to an amount sufficient to achieve treatment when administered to a subject, thereby providing a therapeutic benefit (such as improving symptoms or slowing the progression of a disease). A therapeutically effective amount can 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 mode of administration, which can be readily determined by one of ordinary skill in the art. In such treatment methods, the effective amount of a compound of the present disclosure is, for example, from about 0.01 mg / kg / day to about 1000 mg / kg / day.

[0082] As used herein, the term "excipient" refers to an inert or inactive substance that can be used to produce a medicament or pharmaceutical composition, such as a tablet containing a compound described herein (or a pharmaceutically acceptable salt) as an active ingredient. The term excipient can encompass a variety of substances, including but not limited to any substance used as a diluent, filler or extender, binder, disintegrant, wetting agent, coating, emulsifier or dispersant, compression / encapsulation aid, cream or lotion, lubricant, parenteral solution, material for chewable tablets, sweetener or flavoring agent, suspending agent / gelling agent or wet granulation agent. Binders may include, for example, carbomer, povidone, xanthan gum, etc.; coatings may include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include, for example, calcium carbonate, dextran, fructose DC (DC - "directly compressible"), honey DC, lactose (anhydrous or monohydrate; optionally used in combination with aspartame, cellulose or microcrystalline cellulose), starch DC, sucrose, etc.; disintegrants include, for example, cross-linked sodium carboxymethyl cellulose, gellan gum, sodium starch glycolate, etc.; lactose Creams or lotions include maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, for example, dextran, fructose dc, lactose (monohydrate, optionally combined with aspartame or cellulose), etc.; suspending agents / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, aspartame, dextran, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc. In some cases, the term "excipient" encompasses a pharmaceutical carrier.

[0083] Additional definitions may be provided below, as appropriate.

[0084] II.Compounds

[0085] In certain embodiments, the subject matter described herein relates to compounds of Formula I:

[0086]

[0087] or a pharmaceutically acceptable salt thereof,

[0088] in:

[0089] n is 0 or 1;

[0090] p is 1 or 2;

[0091] Ring A is a saturated 5-membered or 6-membered monocyclic or bicyclic carbocyclic group;

[0092] Ring B is phenyl, 6-membered heteroaryl, or 6-membered saturated or partially saturated cycloalkyl, wherein the heteroaryl contains one or two heteroatoms;

[0093] R3 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, halo and cyano;

[0094] G is N or CR G , where R G selected from the group consisting of: hydrogen, C1-C6 alkyl and halo-C1-C6 alkyl;

[0095] R N1 selected from the group consisting of hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, and C3-C5 cycloalkyl;

[0096] R 2 Selected from the group consisting of: C1-C6 alkyl, halo and halo-C1-C6 alkyl;

[0097] y is 1 or 2;

[0098] m is 0, 1, 2, or 3;

[0099] X is O or NR H ;

[0100] R H 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;

[0101] and,

[0102] R 1 in each case selected from the group consisting of: 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

[0103] R E and R F Each is 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.

[0104] The ring system depicted in Formula I has the following structure and the various subgenera as described herein:

[0105]

[0106] It may also be referred to herein as "Ring C".

[0107] The ring system depicted in Formula I has the following structure and the various subgenera as described herein:

[0108]

[0109] It may also be referred to herein as "Ring D".

[0110] In certain embodiments, the compound includes 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.

[0111] In certain embodiments, the compound includes 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.

[0112] In certain embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, includes a compound of Formula Ia or Formula 1a', or a pharmaceutically acceptable salt thereof:

[0113]

[0114] in,

[0115] Y 1 、Y 2 、Y 3 、Y 4 and Y 5 are each independently N, C or CH, provided that Y 1 、Y 2 、Y 3 、Y 4 and Y 5 Only one or both of may be N; or,

[0116]

[0117] In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof includes a compound of Formula Ib or a pharmaceutically acceptable salt thereof:

[0118]

[0119] or a pharmaceutically acceptable salt thereof,

[0120] in:

[0121] Y 1 、Y 2 、Y 3 、Y 4 and Y 5 are each independently N, C or CH, provided that Y1 、Y 2 、Y 3 、Y 4 and Y 5 Only one or both of may be N; and

[0122] u is 1 or 2.

[0123] In certain embodiments, the compound includes a compound of Formula Ib, or a pharmaceutically acceptable salt thereof, wherein u is 1. In certain embodiments, the compound includes a compound of Formula Ib, or a pharmaceutically acceptable salt thereof, wherein u is 2.

[0124] In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 CH, Y 2 CR 3 , Y 3 CH, Y 4 is N, and Y 5 In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 CH, Y 2 N, Y 3 CR 3 , Y 4 is CH, and Y 5 In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 N, Y 2 CR 3 , Y 3 CH, Y 4 is CH, and Y 5 In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 CH, Y 2 CR 3 , Y 3 CH, Y 4 is CH, and Y 5 In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 CH, Y 2 CR 3 , Y 3 CH, Y 4 is CH, and Y 5 is N. In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 CH, Y 2 N, Y 3 CR 3, Y 4 is N, and Y 5 In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 N, Y 2 CR 3 , Y 3 N, Y 4 is CH, and Y 5 In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 CH, Y 2 CR 3 , Y 3 N, Y 4 is CH, and Y 5 is N. In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 N, Y 2 CR 3 , Y 3 CH, Y 4 is N, and Y 5 In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 CH, Y 2 CR 3 , Y 3 CR 3 , Y 4 is CH, and Y 5 In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 CH, Y 2 N, Y 3 CR 3 , Y 4 CR 3 , and Y 5 In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 CH, Y 2 CR 3 , Y 3 N, Y 4 is CH, and Y 5 In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 CH, Y 2 CR 3 , Y 3 N, Y 4 is CH, and Y 5In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 CH, Y 2 CH, Y 3 CR 3 , Y 4 is CH, and Y 5 In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 N, Y 2 CH, Y 3 CR 3 , Y 4 is CH, and Y 5 In certain embodiments, the compound includes a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein Y 1 CR 3 , Y 2 CH, Y 3 CH, Y 4 is CH, and Y 5 For CH.

[0125] In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof includes a compound of Formula Ib':

[0126]

[0127] or a pharmaceutically acceptable salt thereof.

[0128] In certain embodiments, the compound includes a compound of Formula Ib′, or a pharmaceutically acceptable salt thereof, wherein u is 1. In certain embodiments, the compound includes a compound of Formula Ib, or a pharmaceutically acceptable salt thereof, wherein u is 2.

[0129] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, or Ib', or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of: halo-C1-C6 alkyl, halo, cyano, C1-C6 alkyl, and halo-C1-C6 alkoxy. In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, or Ib', or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of: -CF3, -CHF2, methyl, fluoro, chloro, cyano, -OCF3 and -OCHF2. In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ib or 1b' or a pharmaceutically acceptable salt thereof, wherein R 3 It is -CF3.

[0130] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, or Ib', or a pharmaceutically acceptable salt thereof, wherein at least one R 3In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ib or 1b' or a pharmaceutically acceptable salt thereof, wherein R 3 At least one of is fluorine.

[0131] In certain embodiments, compounds include compounds of Formula I, Ia, Ia', Ib, or Ib', or pharmaceutically acceptable salts thereof, wherein G is N. In certain embodiments, compounds include those having Formula I, Ia, Ia', Ib, or Ib', or pharmaceutically acceptable salts thereof, wherein G is CH.

[0132] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, or Ib', or a pharmaceutically acceptable salt thereof, wherein R N1 is selected from the group consisting of: C1-C6 alkyl and C3-C5 cycloalkyl. In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ib or 1b' or a pharmaceutically acceptable salt thereof, wherein R N1 is selected from the group consisting of methyl, ethyl, propyl, butyl, and cyclopropyl. In certain embodiments, the compound includes a compound of Formula Ia, Ib, or Ic, or a pharmaceutically acceptable salt thereof, wherein R N1 In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ib or 1b' or a pharmaceutically acceptable salt thereof, wherein R N1 It is isopropyl.

[0133] In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0134] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, or Ib', or a pharmaceutically acceptable salt thereof, wherein X is O. In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, or Ib', or a pharmaceutically acceptable salt thereof, wherein y is 1. In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, or Ib', or a pharmaceutically acceptable salt thereof, wherein y is 2. In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, or Ib', or a pharmaceutically acceptable salt thereof, wherein R 1 In each case, the compound is selected from the group consisting of: C1-C6 alkyl and halo-C1-C6 alkyl. In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib or Ib', or a pharmaceutically acceptable salt thereof, wherein R 1 In each case, the compound is selected from the group consisting of: methyl, ethyl, and -CH2F. In certain embodiments, the compound comprises a compound of Formula I, Ia, Ia', Ib, or Ib', or a pharmaceutically acceptable salt thereof, wherein R 1In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib or Ib' or a pharmaceutically acceptable salt thereof, wherein both R 1 In certain embodiments, the compounds include compounds of Formula I, Ia, Ia', Ib, or Ib', or pharmaceutically acceptable salts thereof, wherein m is 0. In certain embodiments, the compounds include compounds of Formula I, Ia, Ia', Ib, or Ib', or pharmaceutically acceptable salts thereof, wherein m is 1. In certain embodiments, the compounds include compounds of Formula I, Ia, Ia', Ib, or Ib', or pharmaceutically acceptable salts thereof, wherein m is 2. In certain embodiments, the compounds include compounds of Formula I, Ia, Ia', Ib, or Ib', or pharmaceutically acceptable salts thereof, wherein Ring C is any one of the following:

[0135]

[0136] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, or Ib', or a pharmaceutically acceptable salt thereof, wherein X is NR H In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, or Ib', or a pharmaceutically acceptable salt thereof, wherein R H is selected from the group consisting of: C3-C5 cycloalkyl, hydroxy-C1-C6 alkyl, and C1-C6 alkoxy-C1-C6 alkyl. In certain embodiments, the compound includes a compound of Formula I, Ia, 1a', Ib, or 1b', or a pharmaceutically acceptable salt thereof, wherein R H is selected from the group consisting of: -CH2CH2OCH3, cyclobutyl, and -CH2CH2OH. In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, or Ib', or a pharmaceutically acceptable salt thereof, wherein m is 0. In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, or Ib', or a pharmaceutically acceptable salt thereof, wherein Ring C is any one of the following:

[0137]

[0138] In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof includes a compound of Formula Ia1 or Formula 1b1 or a pharmaceutically acceptable salt thereof:

[0139]

[0140] in:

[0141] u is 1 or 2;

[0142] m is 0, 1, or 2;

[0143] Y 1 、Y 2 、Y 3、Y 4 and Y 5 Each independently is CH, CR 3 or N, condition is Y 1 、Y 2 、Y 3 、Y 4 and Y 5 Only one or both of may be N;

[0144] G is N or CH; and

[0145] R 1 If present, each occurrence is independently selected from the group consisting of: C1-C6 alkyl and halo-C1-C6 alkyl; or wherein two R 1 The groups together form a -CH2- or -CH2CH2- bridge.

[0146] In certain embodiments, the compound includes a compound of Formula Ib, Ib', or Ib1, or a pharmaceutically acceptable salt thereof, wherein u is 1. In certain embodiments, the compound includes a compound of Formula Ib, Ib', or Ib1, or a pharmaceutically acceptable salt thereof, wherein u is 2.

[0147] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein R N1 is selected from the group consisting of: C1-C6 alkyl and C3-C5 cycloalkyl. In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, Ib', Ia1 or Ib1, or a pharmaceutically acceptable salt thereof, wherein R N1 is selected from the group consisting of methyl, ethyl, propyl, butyl and cyclopropyl. In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, Ib', Ia1 or Ib1, or a pharmaceutically acceptable salt thereof, wherein R N1 In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, Ib', Ia1 or Ib1, or a pharmaceutically acceptable salt thereof, wherein R N1 It is isopropyl.

[0148] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein y is 1. In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein y is 2.

[0149] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein R 1is in each case selected from the group consisting of methyl, ethyl and -CH2F.

[0150] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein m is 0. In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0151] In certain embodiments, the compound comprises a compound of Formula I, Ia, Ib, Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein Y 1 CH, Y 2 CR 3 , Y 3 CH, Y 4 is N, and Y 5 CH; Y 1 CH, Y 2 N, Y 3 CR 3 , Y 4 is CH, and Y 5 CH; Y 1 N, Y 2 CR 3 , Y 3 CH, Y 4 is CH, and Y 5 CH; Y 1 CH, Y 2 CR 3 , Y 3 CH, Y 4 is CH, and Y 5 CH; Y 1 CH, Y 2 CR 3 , Y 3 CH, Y 4 is CH, and Y 5 N; Y 1 CH, Y 2 N, Y 3 CR 3 , Y 4 is N, and Y 5 CH; Y 1 N, Y 2 CR 3 , Y 3 N, Y 4 is CH, and Y 5 CH; Y 1 CH, Y 2 CR3 , Y 3 N, Y 4 is CH, and Y 5 N; Y 1 N, Y 2 CR 3 , Y 3 CH, Y 4 is N, and Y 5 CH; Y 1 CH, Y 2 CR 3 , Y 3 CR 3 , Y 4 is CH, and Y 5 CH; Y 1 CH, Y 2 N, Y 3 CR 3 , Y 4 CR 3 , and Y 5 CH; Y 1 CH, Y 2 CR 3 , Y 3 N, Y 4 is CH, and Y 5 CH; Y 1 CH, Y 2 CH, Y 3 CR 3 , Y 4 is CH, and Y 5 CH; Y 1 N, Y 2 CH, Y 3 CR 3 , Y 4 is CH, and Y 5 CH; or Y 1 CR 3 , Y 2 CH, Y 3 CH, Y 4 is CH, and Y 5 For CH.

[0152] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein R 3is selected from the group consisting of: halo-C1-C6 alkyl, halo, cyano, C1-C6 alkyl, and halo-C1-C6 alkoxy. In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of: -CF3, -CHF2, methyl, fluoro, chloro, cyano, -OCF3 and -OCHF2. 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 3 It is -CF3.

[0153] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, Ib', Ia1, or Ib1, or a pharmaceutically acceptable salt thereof, wherein at least one R 3 In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ib, Ib', Ia1 or Ib1, or a pharmaceutically acceptable salt thereof, wherein R 3 At least one of is fluorine.

[0154] In certain embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, includes a compound of Formula Ia2 or Formula Ib2, or a pharmaceutically acceptable salt thereof:

[0155]

[0156]

[0157] in:

[0158] u is 1 or 2;

[0159] Y 1 、Y 2 、Y 3 、Y 4 and Y 5 Each independently is CH, CR 3 or N, condition is Y 1 、Y 2 、Y 3 、Y 4 and Y 5 Only one or both of may be N; and

[0160] G is N or CH.

[0161] In certain embodiments, the compound includes a compound of Formula Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein u is 1.

[0162] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ia1, Ia2, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein y is 1.

[0163] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ia1, Ia2, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein R H is selected from the group consisting of: C3-C5 cycloalkyl, hydroxy-C1-C6 alkyl, and C1-C6 alkoxy-C1-C6 alkyl. In certain embodiments, the compound includes a compound of Formula I, Ia, Ia2, Ib, or Ib2, or a pharmaceutically acceptable salt thereof, wherein R H Selected from the group consisting of: -CH2CH2OCH3, cyclobutyl, and -CH2CH2OH.

[0164] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ia1, Ia2, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein R N1 In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ia1, Ia2, Ib, Ib', Ib1 or Ib2, or a pharmaceutically acceptable salt thereof, wherein R N1 is selected from the group consisting of methyl, ethyl, propyl, and butyl. In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ia1, Ia2, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein R N1 In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ia1, Ia2, Ib, Ib', Ib1 or Ib2, or a pharmaceutically acceptable salt thereof, wherein R N1 It is isopropyl.

[0165] In certain embodiments, the compound comprises a compound of Formula I, Ia, Ia1, Ia2, Ib, Ib1, or Ib2, or a pharmaceutical use thereof, wherein Y 1 CH, Y 2 N, Y 3 CR 3 , Y 4 is CH, and Y 5 CH; or Y 1 N, Y 2 CR 3 , Y 3 CH, 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 pharmaceutical use thereof, wherein R 3In certain embodiments, the compound includes a compound of Formula I, Ia, Ia1, Ia2, Ib, Ib1 or Ib2, or a pharmaceutical use thereof, wherein R 3 It is -CF3.

[0166] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ia1, or Ia2, or a pharmaceutically acceptable salt thereof, wherein Ring A is a bicyclo[3.1.0]hexane having the structure:

[0167]

[0168] Where # is the point of attachment to C on ring D, and * is the point of attachment to N on ring C.

[0169] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ia1, or Ia2, or a pharmaceutically acceptable salt thereof, wherein Ring A is a bicyclo[3.1.0]hexane having the structure:

[0170]

[0171] Where # is the point of attachment to C on ring D, and * is the point of attachment to N on ring C.

[0172] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ia1, or Ia2, or a pharmaceutically acceptable salt thereof, wherein Ring A is a bicyclo[3.1.0]hexane having the structure:

[0173]

[0174] Where # is the point of attachment to C on ring D, and * is the point of attachment to N on ring C.

[0175] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ia1, or Ia2, or a pharmaceutically acceptable salt thereof, wherein Ring A is a bicyclo[3.1.0]hexane having the structure:

[0176]

[0177] Where # is the point of attachment to C on ring D, and * is the point of attachment to N on ring C.

[0178] In certain embodiments, the compound includes a compound of Formula I, Ia, Ia', Ia1, or Ia2, or a pharmaceutically acceptable salt thereof, wherein Ring A is a bicyclo[3.1.0]hexane having the structure:

[0179]

[0180] Where # is the point of attachment to C on ring D, and * is the point of attachment to N on ring C.

[0181] In certain embodiments, the compound includes a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is a cyclohexyl group having the structure:

[0182]

[0183] Where # is the point of attachment to C on ring D, and * is the point of attachment to N on ring C.

[0184] In certain embodiments, the compound includes a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is a cyclohexyl group having the structure:

[0185]

[0186] Where # is the point of attachment to C on ring D, and * is the point of attachment to N on ring C.

[0187] In certain embodiments, the compound includes a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is a cyclohexyl group having the structure:

[0188]

[0189] Where # is the point of attachment to C on ring D, and * is the point of attachment to N on ring C.

[0190] In certain embodiments, the compound includes a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is a cyclohexyl group having the structure:

[0191]

[0192] Where # is the point of attachment to C on ring D, and * is the point of attachment to N on ring C.

[0193] In certain embodiments, the compound includes a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is a cyclohexyl group having the structure:

[0194]

[0195] Where # is the point of attachment to C on ring D, and * is the point of attachment to N on ring C.

[0196] In certain embodiments, the compound includes a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is a cyclopentyl group having the structure:

[0197]

[0198] Where # is the point of attachment to C on ring D, and * is the point of attachment to N on ring C.

[0199] In certain embodiments, the compound includes a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is a cyclopentyl group having the structure:

[0200]

[0201] Where # is the point of attachment to C on ring D, and * is the point of attachment to N on ring C.

[0202] In certain embodiments, the compound includes a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is a cyclopentyl group having the structure:

[0203]

[0204] Where # is the point of attachment to C on ring D, and * is the point of attachment to N on ring C.

[0205] In certain embodiments, the compound includes a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is a cyclopentyl group having the structure:

[0206]

[0207] Where # is the point of attachment to C on ring D, and * is the point of attachment to N on ring C.

[0208] In certain embodiments, the compound includes a compound of Formula I, Ib, Ib', Ib1, or Ib2, or a pharmaceutically acceptable salt thereof, wherein Ring A is a cyclopentyl group having the structure:

[0209]

[0210] Where # is the point of attachment to C on ring D, and * is the point of attachment to N on ring C.

[0211] In certain embodiments, the compound includes a compound of the formula:

[0212]

[0213]

[0214] The variables are as described in this article.

[0215] 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 isolated isomer group, but stereochemistry has been arbitrarily specified. Each enantiomer and diastereomer is included in the table below by compound name, and its corresponding structure can be easily determined thereby. In some cases, the enantiomer or enantiomers of the present disclosure can be identified by their respective properties, such as retention time, NMR peaks and / or biological activity (e.g., as further described in the examples) obtained by chiral HPLC, and the absolute stereoconfiguration of one or more chiral centers is arbitrarily specified (e.g., the stereochemistry of all chiral centers is arbitrarily specified, or the stereochemical configuration of one chiral center is known and the stereochemistry of the remaining chiral centers is arbitrarily specified, etc.).

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244] III. Pharmaceutical Compositions and Modes of Administration

[0245] The compounds provided herein are generally administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions are also provided herein, comprising: one or more of the compounds described herein or their pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers; and one or more pharmaceutical excipients. Suitable pharmaceutical excipients may include, for example, inert solid diluents and fillers, liquid diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition (GS Banker & C.T. Rhodes, Eds.).

[0246] 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.

[0247] The pharmaceutical composition can be administered in a single dose or multiple doses. The pharmaceutical composition can be administered by a variety of methods, including, for example, rectal, oral, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition can be administered by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.

[0248] One mode of administration is parenteral administration, such as by injection. The pharmaceutical compositions described herein can be incorporated into forms for administration by injection, including, for example, aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0249] Oral administration can be another route of administration of the compounds described herein. Administration can be via, for example, capsules or tablets, such as enteric-coated tablets. When preparing a pharmaceutical composition comprising at least one compound as described herein or a pharmaceutically acceptable salt thereof, a stereoisomer or a mixture of stereoisomers, the active ingredient is typically diluted and / or encapsulated in such a carrier in the form of a capsule, a pouch, paper or other container by an excipient. When an excipient is used as a diluent, it can be in the form of a solid, semisolid or liquid material, which serves as a vehicle, carrier or medium for the active ingredient. Therefore, the composition can be in the form of a tablet, pill, powder, lozenge, pouch, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), an ointment containing, for example, up to 10% by weight of an active compound, soft gelatin capsules and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[0250] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulation may also include lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

[0251] Compositions comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, a stereoisomer, or a mixture of stereoisomers can be formulated so as to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject 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 used in the methods disclosed herein employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide a continuous or discontinuous infusion of a controlled amount of a compound described herein. The construction and use of transdermal patches for delivering medicaments are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches can be constructed for continuous, pulsed, or on-demand delivery of medicaments.

[0252] To prepare solid compositions such as tablets, the principal active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. When these preformulation compositions are referred to as homogeneous, the active ingredient is evenly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0253] The tablet or pill of compound described herein can be coated or otherwise compounded to provide the dosage form with the advantage of prolonged effect, or protect from the influence of the acidic conditions of the stomach.For example, tablet or pill can include internal dose and external dose component, the latter being in the form of the envelope on the former.These two components can be separated by enteric layer, and enteric layer is used to resist the disintegration in the stomach and allows internal component to enter the duodenum or delay release intactly.Multiple materials can be used for such enteric layer or coating, and such material includes a mixture of multiple polymeric acid and polymeric acid with materials such as shellac, cetyl alcohol and cellulose acetate.

[0254] 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 pharmaceutical excipients as described herein. In some embodiments, the composition is administered by oral or nasal respiratory route to obtain a local or systemic effect. In other embodiments, the composition in a pharmaceutically acceptable solvent may be atomized using an inert gas. The atomized solution may be inhaled directly from the atomizing device, or the atomizing device may be attached to a mask tent or intermittent positive pressure breathing machine. The solution, suspension or powder composition may be administered from a device that delivers the formulation in an appropriate manner, preferably orally or nasally.

[0255] For any particular subject, the specific dosage level of the compound of the present application will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, route of administration and excretion rate, drug combination, and the severity of the specific disease of the subject undergoing therapy. For example, the dosage can be expressed as milligrams of the compound described herein per kilogram of subject body weight (mg / kg). A dosage between about 0.1 and 150 mg / kg may be suitable. In some embodiments, about 0.1 and 100 mg / kg may be suitable. In other embodiments, a dosage between 0.5 and 60 mg / kg may be suitable. When adjusting the dosage between subjects with very different body sizes, such as when using drugs in children and adults or converting the effective dose of non-human subjects (such as dogs) to a dosage suitable for human subjects, it is particularly useful to normalize according to the subject's weight. A certain dosage can be administered once a day (QID), twice a day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including the absorption, distribution, metabolism, and excretion of the specific compound. In addition, toxic factors may affect the dosage and administration regimen. When administered orally, the pill, capsule, or tablet may be taken daily or less frequently for a specified period of time. This regimen may be repeated for multiple treatment cycles.

[0256] IV. Treatment Methods

[0257] Described herein are methods for promoting myelination of central nervous system neurons in subjects with myelin-related disorders, the methods 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 use in promoting myelination of central nervous system neurons in subjects with myelin-related disorders. 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, in the manufacture of a medicament for promoting myelination of central nervous system neurons in subjects with myelin-related disorders.

[0258] 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 the same, inhibits the enzyme-mediated synthesis of one or more sterol intermediates in the cholesterol biosynthetic pathway.

[0259] 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 the same, promotes the accumulation of a Δ8,9-unsaturated sterol intermediate in the cholesterol biosynthetic pathway.

[0260] 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 the same, inhibits one or more of the CYP51-, sterol-14-reductase-, or EBPase-mediated synthesis of sterol intermediates in the cholesterol biosynthetic pathway.

[0261] In certain embodiments, in a method for promoting myelination of central nervous system neurons in a subject with 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 the same, induces, promotes and / or regulates oligodendrocyte precursor cell (OPC) differentiation, proliferation and / or maturation. In certain embodiments, the induction of OPC differentiation is characterized by an increase in myelin basic protein (MBP) expression.

[0262] In certain embodiments, the subject matter described herein relates to 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 of Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2, or Ib2, or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject suffers from 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 some 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 some embodiments, the compound of Formula I is a compound of Formula Ia1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ib1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ia2, or a pharmaceutically acceptable salt thereof. In some 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.

[0263] 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 condition in a subject in need thereof. In certain embodiments, the subject suffers from a myelin-related condition. 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 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 Ib', or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ia1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ib1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ia2, or a pharmaceutically acceptable salt thereof. In some 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.

[0264] 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 condition in a subject in need thereof. In certain embodiments, the subject suffers from a myelin-related condition. 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 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 Ib', or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ia1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ib1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ia2, or a pharmaceutically acceptable salt thereof. In some 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.

[0265] In certain embodiments, the subject matter disclosed 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. In certain embodiments, the subject suffers from 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 Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ia1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ib1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ia2, or a pharmaceutically acceptable salt thereof. In some 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.

[0266] 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 suffers from 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 Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ia1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ib1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ia2, or a pharmaceutically acceptable salt thereof. In some 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.

[0267] 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 the compound, in the manufacture of a medicament for promoting myelination in a subject in need thereof. In certain embodiments, the subject suffers from 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 Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ia1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ib1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ia2, or a pharmaceutically acceptable salt thereof. In some 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.

[0268] In certain embodiments, the subject matter disclosed herein 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 suffers from a myelin-related disorder. In certain embodiments, the myelin-related disorder is multiple sclerosis.

[0269] Such myelin-related disorders include, but are not limited to, multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander disease, Pelitzaus-Merzbacher disease (PMD), white matter ablative diseases, Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post-radiation injury, neurologic 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.

[0270] Formula I, Ia, Ia', Ib, Ib', Ia1, Ib1, Ia2 or Ib2 compounds or pharmaceutically acceptable salts 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 may include any disease, condition (e.g., those caused by traumatic spinal cord injury and cerebral infarction) or illness that causes myelin abnormalities. Abnormalities may be caused by myelin loss (referred to as demyelination), myelin dysfunction (referred to as myelin dysplasia) or failure to form enough myelin (referred to as poor myelination). Myelin-related disorders described herein may be caused by one or more of a genetic disorder or a variety of neurotoxic injuries. 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 Ib or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ia1 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ib1 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ia2 or a pharmaceutically acceptable salt thereof. In some 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.

[0271] As used herein, "demyelination" refers to the act of demyelination, or damage or loss of part or all of the myelin sheath that isolates a nerve, and is a hallmark of a myelin-related disorder. In certain embodiments, demyelination refers to damage or loss of part or all of the myelin sheath that isolates a subset of nerves in an individual, such as, for example, one or more nerves located in a specific area of ​​the body (e.g., neurons in the brain or spinal cord, or neurons in both the brain and spinal cord; or the optic nerve).

[0272] Oligodendrocytes are required for the myelination of neurons. As used herein, the term "myelination" refers to the generation of nerve myelin by replacing myelin-producing cells or restoring their function. The neurons undergoing remyelination may be located 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 rate of myelin production in cells (or multiple cells) with a level below average production. Such an increase may encompass increasing the myelin production rate to as high as or above the average production level; but may also encompass increasing the myelin production rate to a level still below average but higher than the previous level.

[0273] As used herein, " promoting myelination " refers to increasing myelin production rate rather than just the net increase of myelin amount compared with the baseline level of myelin production rate in the subject. The increase of myelin production rate can be determined using imaging techniques or functional measurements. In certain embodiments, myelination is promoted by increasing OPC differentiation, increasing the accumulation of 8,9-unsaturated sterol intermediates in the biosynthetic pathway, increasing the formation of OPC or its any combination. Such activity can, for example, be assessed using one or more in vitro assays (such as those described herein or well known to those skilled in the art).

[0274] As used herein, "baseline level of myelin production rate" refers to the myelin production rate in a subject receiving treatment prior to the start of treatment.

[0275] V. Methods for preparing compounds of formula I and pharmaceutically acceptable salts thereof

[0276] The compounds can be synthesized by the following synthetic routes, which include processes similar to those well known in the chemical art, particularly in view of the description contained herein, and those for other heterocycles described in Comprehensive Heterocyclic Chemistry II, edited by Katritzky and Rees, Elsevier, 1997, e.g., Volume 3; Liebigs Annalen der Chemie, (9): 1910-16, (1985); Helvetica Chimica Acta, 41: 1052-60, (1958); Arzneimittel-Forschung, 40(12): 1328-31, (1990), each of which is expressly incorporated herein by reference. Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared by methods well known to those skilled in the art (e.g., by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, NY (eds. 1967-2006), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available through the Beilstein online database)).

[0277] Synthetic chemistry transformations and protecting group methods (protection and deprotection), as well as the necessary reagents and intermediates, that can be used to synthesize the compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

[0278] Compounds can be prepared individually or as a library of compounds comprising at least two, for example, 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 combinatorial 'split and mix' methods or multiple parallel synthesis methods using solution phase or solid phase chemistry, by methods known to those skilled in the art. Thus, according to a further aspect, a library of compounds comprising at least two compounds or pharmaceutically acceptable salts thereof is provided.

[0279] Examples

[0280] Examples provide exemplary methods for preparing compounds. Those skilled in the art will recognize that other synthetic routes can be used to synthesize compounds. Although specific starting materials and reagents are described and discussed in the schemes, general procedures, and examples, other starting materials and reagents can be easily substituted to provide various derivatives and / or reaction conditions. In addition, according to this disclosure, conventional chemical methods well known to those skilled in the art can be used to further modify many exemplary compounds prepared by the methods described. Asterisks (*) indicate isolated isomers or isolated isomer groups, but stereochemistry is not yet specified.

[0281] 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*)

[0282]

[0283] Step 1: 3-Bromo-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1-isopropyl-pyrazole

[0284]

[0285] 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-ene-8-yl)-1,3,2-dioxaborolane (575 mg, 2.05 mmol), bis(triphenylphosphine)palladium(II) chloride (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 under N2 for 18 hours. The reaction mixture was cooled to room temperature, diluted with DCM, washed with brine, dried over anhydrous Mg2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (heptane / isopropyl acetate) to give the title compound (380 mg, 62% yield). LCMS (ESI) [M+2H] + =328.1.

[0286] Step 2: 3-[5-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)-1-isopropyl-pyrazol-3-yl]-5-(trifluoromethyl)pyridine

[0287]

[0288] 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) chloride (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 under N2 for 18 hours. The reaction mixture was cooled to room temperature, diluted with DCM, washed with brine, dried over anhydrous Mg2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (heptane / isopropyl acetate) to give the title compound (80 mg, 18% yield). LCMS(ESI)[M+H] + =394.2.

[0289] Step 3: 3-[5-(1,4-dioxaspiro[4.5]decan-8-yl)-1-isopropyl-pyrazol-3-yl]-5-(trifluoromethyl)pyridine

[0290]

[0291] 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 at room temperature overnight, filtered through a celite pad, rinsed three times with ethanol and dried to give the title compound as a crude intermediate, which was used in the next step without further purification. LCMS (ESI) [M+H] + =396.2.

[0292] Step 4: 4-[2-Isopropyl-5-[5-(trifluoromethyl)-3-pyridyl]pyrazol-3-yl]cyclohexanone

[0293]

[0294] To a solution of 3-[5-(1,4-dioxaspiro[4.5]decane-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 Mg2SO4 and concentrated under reduced pressure to give the title compound (62 mg, quantitative yield) as a crude intermediate, which was used in the next step without purification. LCMS (ESI) [M+H] + =352.2.

[0295] 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*)

[0296]

[0297] 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 hours, 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 x 21.2 mm, 5 μm); 15% isocratic, 0.1% NH4OH in MeOH at 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. The relative stereochemistry was assigned arbitrarily.

[0298] Compound 1*: 1 H NMR: (400MHz, DMSO-d6)δ9.31(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,4 H),2.95–2.85(m,1H),2.43–2.39(m,3H),2.21–2.15(m,1H),2.02–1.9 3(m,2H),1.86–1.74(m,2H),1.65–1.51(m,4H),1.44(d,J=6.5Hz,6H).

[0299] Compound 2*: 1 H NMR: (400MHz, DMSO-d6)δ9.27(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).

[0300] 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)

[0301]

[0302] Step 1: (R)-3-(1-Isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentanone

[0303]

[0304] To a solution of (1R)-3-oxocyclopentanecarboxylic acid (500.0 mg, 3.9 mmol) and 6-(trifluoromethyl)pyridine-3-amidine HCl (1300.0 mg, 5.76 mmol) in N,N-dimethylformamide (4 mL) was added N,N-diisopropylethylamine (2.65 mL, 15.61 mmol) and HATU (1632 mg, 4.29 mmol) and stirred at 20 ° C for 1 hour. 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 the consumption of the acyl amidine intermediate. After 2 hours, the reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate (20 mL), adjusted to pH = 8 with NaHCO3 (aqueous solution), and extracted with ethyl acetate (100 mL×3). The combined organic matter is washed with brine (100mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in dioxane (10mL) and HCl (12M, 5mL) and stirred at 20 ° C for 2 hours. The mixture is adjusted to pH=8 with NaHCO (aqueous solution) and extracted with ethyl acetate (100mL). The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue is purified by silica gel flash column chromatography (eluted with 0% to 50% ethyl acetate in petroleum ether) to provide the title compound (600mg, 45% yield). LCMS (ESI), [M+H] + =339.1.

[0305] Step 2: 4-((3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane

[0306]

[0307] 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 To a solution of molecular sieves in anhydrous 1,2-dichloroethane (3mL) was added acetic acid (213.0mg, 3.55mmol). The reaction mixture was stirred at 25°C for 1 hour. Sodium triacetoxyborohydride (1127mg, 5.32mmol) was then added and stirred at 25°C for 16 hours. The reaction was quenched with saturated sodium bicarbonate (10mL) and extracted with DCM (50mL x 3). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0% to 10% MeOH in DCM) to provide the title compound (550mg, 1.2858mmol, 72.5% yield). LCMS (ESI), [M+H] + =424.2.

[0308] 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)

[0309]

[0310] 4-[exo-(3R)-3-[2-isopropyl-5-[6-(trifluoromethyl)-3-pyridinyl]-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*30 mm, 10 μm); 0.1% NH in H2O; MeOH 30 / 30; 70 mL / min] to provide the title compounds 3 (the first peak on SFC, 26.8 mg, 4.7% yield) and 4 (the second peak on SFC, 454.2 mg, 81.8% yield). The relative stereochemistry was determined based on 2D-NMR analysis.

[0311] Compound 3: 1H NMR(400MHz, DMSO-d6)δ9.27(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).

[0312] Compound 4: 1 H NMR (400MHz, DMSO-d6) δ9.27(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),3.16-3.07(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).

[0313] 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)

[0314]

[0315] Step 1: (S)-3-(1-Isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentanone

[0316]

[0317] To a solution of (1S)-3-oxocyclopentanecarboxylic acid (500.0 mg, 3.9 mmol) and 6-(trifluoromethyl)pyridine-3-amidine HCl (1300.0 mg, 5.76 mmol) in N,N-dimethylformamide (4 mL) was added N,N-diisopropylethylamine (2.65 mL, 15.61 mmol) and HATU (1632 mg, 4.29 mmol) and stirred at 20 ° C for 1 hour. Acetic acid (2.20 mL, 39 mmol) and isopropylhydrazine HCl (647.0 mg, 5.85 mmol) were then added. The reaction mixture was heated to 80 ° C and the consumption of the acyl amidine intermediate was monitored by LCMS. After 2 hours, the reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate (20 mL), adjusted to pH = 8 with NaHCO3 (aqueous solution), and extracted with ethyl acetate (100 mL×3). The combined organic matter is washed with brine (100mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in dioxane (10mL) and HCl (12M, 5mL) and stirred at 20 ° C for 2 hours. The mixture is adjusted to pH=8 with NaHCO (aqueous solution) and extracted with ethyl acetate (100mL). The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by silica gel flash column chromatography (eluted with 0% to 50% ethyl acetate in petroleum ether) to provide the title compound (600mg, 45% yield). LCMS (ESI), [M+H] + =339.1.

[0318] Step 2: 4-((3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)-1,4-oxazepane

[0319]

[0320] 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 methanol (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 x 3). The combined organic matter was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0% to 10% methanol in dichloromethane) to provide the title compound (100 mg, 79.9% yield). LCMS (ESI), [M+H] + =424.2.

[0321] 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)

[0322]

[0323] 4-[exo-(3S)-3-[2-isopropyl-5-[6-(trifluoromethyl)-3-pyridinyl]-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*30 mm, 10 μm); 0.1% NH 3 H 2 O; MeOH; 25 / 25; 70 mL / min] to provide the title compounds 5 (1st peak on SFC, 25.68 mg, 16.9% yield) and 6 (2nd peak on SFC, 87.3 mg, 57.6% yield). The relative stereochemistry was determined by 2D-NMR.

[0324] Compound 5: 1H NMR(400MHz, DMSO-d6)δ9.26(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),2.82-2.61(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).

[0325] Compound 6: 1 H NMR (400MHz, DMSO-d6) δ9.26 (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).

[0326] 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*)

[0327]

[0328] The title compound was synthesized according to a procedure similar to that of Example E and F compounds 5 and 6, except that 4-oxocyclohexane-1-carboxylic acid, ethylhydrazine HCl, and 6-(trifluoromethyl)nicotinamide HCl were used in step 1. The cis / trans mixture was separated by reverse phase HPLC to provide the title compounds 7* (the first peak obtained by LCMS, 26 mg, 13% yield) and 8* (the second peak obtained by LCMS, 39 mg, 20% yield). LCMS (ESI) [M+H] + = 424.20. The relative stereochemistry was assigned arbitrarily.

[0329] Compound 7*: 1 H NMR(400MHz, DMSO-d6)δ9.26(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).

[0330] Compound 8*: 1 H NMR(400MHz, DMSO-d6)δ9.35(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).

[0331] 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*)

[0332]

[0333] The title compound was synthesized by a procedure similar to that of Example E and F compounds 5 and 6, except that cyclopropylhydrazine HCl and 6-(trifluoromethyl)pyridinecarboximidamide HCl were used in step 1. The cis / trans mixture was separated by chiral SFC [Chiralpak ID (150 x 21.2 mm, 5 μm); 30% isocratic, 0.1% NH4OH in methanol; 40°C; 70 mL / min] to provide the title compound 9* (1st peak on SFC, 10 mg, 9% yield) and compound 10* (2nd peak on SFC, 47 mg, 42% yield). LCMS (ESI) [M+H] + = 422.10. The relative stereochemistry is arbitrarily assigned.

[0334] Compound 9*: 1 H NMR(400MHz, DMSO-d6)δ8.27(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).

[0335] Compound 10*: 1 H NMR(400MHz, DMSO-d6)δ8.28(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).

[0336] 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*)

[0337]

[0338] The title compound was synthesized by a procedure similar to that of Example C and D compounds 3 and 4, except that cyclopropylhydrazine HCl and 6-(trifluoromethyl)pyridinecarboximidamide HCl were used in step 1. The cis / trans mixture was separated by chiral SFC [Chiralpak IB-N (150 x 21.2 mm, 5 μm); 30% isocratic, 0.1% NH4OH in methanol; 30°C; 70 mL / min] to provide the title compounds 11* (1st peak on SFC, 6 mg, 5% yield) and 12* (2nd peak on SFC, 41 mg, 33% yield). LCMS (ESI) [M+H] += 422.10. The relative stereochemistry is arbitrarily assigned.

[0339] Compound 11*: 1 H NMR(400MHz, DMSO-d6)δ8.27(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).

[0340] Compound 12*: 1 H NMR(400MHz,DMSO-d6)δ8.28(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).

[0341] 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)

[0342]

[0343] 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

[0344]

[0345] Following the general procedure in J. Org. Chem. 2011, 76, 1177, using (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 gel flash column chromatography (1pROAc / heptane). LCMS (ESI) [M+H] + =590.3.

[0346] 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

[0347]

[0348] To a mixture of 5-((1R,5S)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-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 hours. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO 200 mL), and then extracted with 1 pROAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO, filtered, concentrated and purified by flash chromatography on silica gel (0% to 100% heptane / 1 pROAc) to provide the title compound (750 mg, 96% yield). LCMS (ESI) [M+H] + =352.2.

[0349] 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

[0350]

[0351] 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]hexane-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 hours. Saturated aqueous NaHCO3 solution (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 hours. The organic layer was separated and the aqueous layer was extracted with DCM (100 mL×2). The combined organic layers were washed with brine, filtered over anhydrous Mg2SO4, concentrated and purified by flash chromatography on silica gel (1pR0Ac / heptane) to give the title compound (710 mg, 2 mmol). LCMS(ESI)[M+H] + =350.1.

[0352] 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)

[0353]

[0354] 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]hexane-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 hours, cooled, then diluted with DCM, washed with saturated aqueous NaHCO 3 solution, dried over anhydrous Mg 2 SO 4, 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% to 80% B over 10 min, 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.

[0355] Compound 13: 1 H NMR(400MHz,DMSO-d6)δ8.23–8.16(m,1H),8.16–8.11(m,1H),7.78–7.71(m,1H),7.7 1–7.63(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).

[0356] Compound 14: 1H NMR (400MHz, DMSO-d6) δ8.23–8.17(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).

[0357] 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)

[0358]

[0359] The title compound was synthesized according to a procedure similar to that of Example K and L compounds 13 and 14, except that 6-(trifluoromethyl)picolinamidine HCl was used in step 1. The cis / trans mixture was purified by reverse phase HPLC (Interchim HPLC, 0.1% aqueous ammonium hydroxide, solvent B: acetonitrile, column: XSelect CSH Prep C18, column size: 50 x 30 mm (5 μm), column temperature: 25° C., method: 30% to 70% B over 10 minutes, 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.

[0360] Compound 15: 1H NMR(400MHz,DMSO-d6)δ9.24–9.18(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).

[0361] Compound 16: 1 H NMR (400MHz, DMSO-d6) δ9.24–9.19(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).

[0362] 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)

[0363]

[0364] The title compound was synthesized by a procedure similar to that of Example K and L compounds 13 and 14, except that 3-(trifluoromethoxy)benzimidamide was used 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% to 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.

[0365] Compound 17: 1 H NMR(400MHz,DMSO-d6)δ7.97–7.89(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).

[0366] Compound 18: 1 H NMR(400MHz,DMSO-d6)δ7.97–7.90(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).

[0367] 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*)

[0368]

[0369] The title compound was synthesized by a procedure similar to that of Example K and L compounds 13 and 14, except that morpholine was used 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, 50x30mm x5μm), 25°C, 40% to 80% over 10 min, 60 mL / min) 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. The relative stereochemistry was assigned arbitrarily.

[0370] Compound 19*: 1 H NMR (400MHz, DMSO-d6) δ8.23–8.17(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).

[0371] Compound 20*: 1H NMR(400MHz, DMSO-d6)δ8.24–8.17(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).

[0372] 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*)

[0373]

[0374] The title compound was synthesized following a procedure similar to that of Example C and D compounds 3 and 4, except that 3-(trifluoromethyl)benzimidamide HCl was used in step 1 and morpholine was used in step 2. The cis / trans mixture was separated by chiral SFC [PIC 200; Cellulose-2 (250 x 21.2 mm, 5 μm); 15% isocratic, 0.1% NH4OH in MeOH, 40°C; 70 mL / min] to provide the title compounds 21* (1st peak on SFC, 27.6 mg, 13% yield) and 22* (2nd peak on SFC, 75.4 mg, 36% yield). LCMS (ESI) [M+H] + = 409.2. The relative stereochemistry was assigned arbitrarily.

[0375] Compound 21*: 1H NMR(400MHz,DMSO-d6)δ8.26(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,1 H),3.60(s,5H),3.19–3.13(m,1H),2.79(s,1H),2.45–2.39(m,2H),2.30–2.2 4(m,2H),2.14(s,1H),2.05–1.99(m,1H),1.91–1.82(m,1H),1.49–1.41(m,6H)

[0376] Compound 22*: 1 H NMR(400MHz,DMSO-d6)δ8.30–8.22(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).

[0377] Example L: 4-((1S,3S)-3-(1-Isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine and 4-((1R,3S)-3-(1-Isopropyl-3-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine (Compounds 23* and 24*)

[0378]

[0379] The title compounds were synthesized following a procedure similar to that of Example E and F compounds 5 and 6, except that 3-(trifluoromethyl)benzimidamide HCl was used in step 1 and morpholine was used in step 2. The cis / trans mixture was separated by chiral SFC [Cellulose-2 (250 x 21.2 mm x 5 μm); 15% isocratic, 0.1% NH4OH in MeOH, 40°C; 70 mL / min] to provide the title compounds 23* (1st peak on SFC, 22.9 mg, 11% yield) and 24* (2nd peak on SFC, 68.9 mg, 32.4% yield). LCMS (ESI) [M+H] + = 409.2. The relative stereochemistry was assigned arbitrarily.

[0380] Compound 23*: 1 H NMR (400MHz, DMSO-d6) δ8.30–8.22(m,1H),8.22–8.16(m,1H),7.82–7.74(m,1H ),7.74–7.65(m,1H),4.72(h,J=6.5Hz,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,1 H),2.05–1.93(m,2H),1.93–1.77(m,1H),1.61–1.47(m,1H),1.47–1.40(m,6H).

[0381] Compound 24*: 1 H NMR(400MHz,DMSO-d6)δ8.30–8.22(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).

[0382] 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*)

[0383]

[0384] The title compounds were synthesized following a procedure similar to that of compounds 3 and 4 of Examples C and D, except that 6-(trifluoromethyl)pyridinecarboximidamide HCl was used in step 1 and morpholine was used in step 2. The cis / trans mixture was separated by chiral SFC [chiralcelOX (150 x 21.2 mm, 5 μm); 20% isocratic; 0.1% NH4OH in MeOH, 40°C; 70 mL / min] to provide the title compounds 24* (1st peak on SFC, 28.2 mg, 13.3% yield) and 26* (2nd peak on SFC, 115.7 mg, 55% yield). LCMS (ESI) [M+H] + = 410.2. The relative stereochemistry is arbitrarily assigned.

[0385] Compound 25*: 1 H NMR (400MHz, DMSO-d6) δ8.30(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).

[0386] Compound 26*: 1H NMR(400MHz,DMSO-d6)δ8.31(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).

[0387] 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*)

[0388]

[0389] The title compounds were synthesized following a procedure similar to that of Example C and D compounds 3 and 4, except that 4-(trifluoromethyl)pyridinecarboximidamide HCl was used in step 1 and morpholine was used in step 2. The cis / trans mixture was separated by chiral SFC [Chiralpak IC (150 x 21.2 mm x 5 μm); 20% isocratic, 0.1% NH4OH in MeOH; 40°C; 70 mL / min] to provide the title compounds 27* (1st peak on SFC, 1 mg, 3% yield) and 28* (2nd peak on SFC, 4.1 mg, 19% yield). LCMS (ESI) [M+H] + = 410.2. The relative stereochemistry is arbitrarily assigned.

[0390] Compound 27: Not measured.

[0391] Compound 28: 1H NMR(400MHz,DMSO-d6)δ8.96–8.89(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),2.7 4–2.61(m,1H),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).

[0392] 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)

[0393]

[0394] 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

[0395]

[0396] To (1R, 5S, 6r) -6- (3- iodo -1- isopropyl -1H- pyrazole -5- bases) bicyclo [3.1.0] hexane -3- ketone (2.0g, 6.1mmol) and 3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -5- (trifluoromethyl) pyridine (2.5g, 9.2mmol) in 1,4- dioxane (32mL) and water (8mL) solution CsCO (6g, 18.4mmol) and bis (di- tert-butyl (4- dimethylaminophenyl) phosphine) dichloropalladium (II) (460mg, 0.65mmol). Then the reaction mixture is placed under a nitrogen atmosphere and stirred at 100 ° C for 4 hours. The reaction is quenched with water (30mL) and extracted with ethyl acetate (100mL x2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0% to 30% ethyl acetate in petroleum ether) to provide the title compound (2.1 g, 5.8 mmol, 96% yield). LCMS (ESI) [M+H] + =350.2.

[0397] 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*)

[0398]

[0399] To a solution of (1R, 5S, 6r) -6- (1- isopropyl -3- (5- (trifluoromethyl) pyridin-3-yl) -1H- pyrazol-5-yl) bicyclo [3.1.0] hexane -3- ketone (100 mg, 0.28 mmol) and 1,4- oxazacycloheptane hydrochloride (60 mg, 0.44 mmol) in anhydrous methanol (4 mL) was added NaBH CN (90 mg, 1.44 mmol) at 20 ° C. The reaction mixture was then heated to 70 ° C and stirred for 2 hours. The reaction was quenched by saturated NaHCO solution (5 mL) and extracted with dichloromethane (30 mL x2). The combined organic phases were washed with salt water, dried over anhydrous Na SO dried, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (6% methanol in dichloromethane) to provide a mixture of diastereomeric compounds (90 mg, 72% yield), which were separated by chiral SFC (Daicel Chiralcecl OJ-H (250 mm*30 mm, 5 μm); supercritical CO 2 / EtOH + NH 3 · H 2 O = 90 / 10; 60 mL / min) to provide compound 29 (first peak on SFC, 14.8 mg, 16.3% yield) and compound 30 (second peak on SFC, 23.5 mg, 26% yield). LCMS (ESI) [M+H] + =435.4. 1 H NMR assigned relative stereochemistry.

[0400] Compound 29: 1 H NMR (400MHz, CDCl3) δ9.11(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).

[0401] Compound 30: 1H NMR (400MHz, CDCl3) δ9.11(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,2H),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).

[0402] 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)

[0403]

[0404] The title compound was synthesized using 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine in step 1 according to a procedure similar to compound 29*. The crude mixture was purified by silica gel flash chromatography (0% to 100% ethyl acetate in petroleum ether) to provide compound 31 (second peak on HPLC (basic), 19.2 mg, 23% yield) and compound 32 (first peak on HPLC (basic), 18.7 mg, 22% yield). LCMS (ESI) [M+H] + = 421.1. The relative stereochemistry was determined by 2D-NMR analysis.

[0405] Compound 31: 1 H NMR (400MHz, CD3OD) δ8.15(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).

[0406] Compound 32: 1 H NMR (400MHz, DMSO-d6) δ8.17–8.11(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,4 H),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).

[0407] 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)

[0408]

[0409] The title compound was synthesized using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine in step 1 according to a procedure similar to compound 29*. The crude mixture was purified by reverse phase chromatography (column: Phenomenex Gemini C18 250*50mm*10um; mobile phase: [water (0.05% ammonium hydroxide); acetonitrile; 60% to 80%, 10 min) to provide compound 33 (first peak on HPLC (basic), 24.4 mg, 23.5% yield) and compound 34 (second peak on HPLC (basic), 13.5 mg, 13% yield). LCMS (ESI) [M+H] + = 449.3. The relative stereochemistry was determined by 2D-NMR.

[0410] Compound 33: 1H NMR(400MHz,CD3OD)δ9.15(s,1H),8.73(s,1H),8.41(s,1H),6.43(s,1H),4.82–4.75(m,1H),3.75–3.6 5(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).

[0411] Compound 34: 1 H NMR (400MHz, CD3OD) δ9.15(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).

[0412] 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,3s,5S,6R)-6-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl) -((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*)

[0413]

[0414] The title compound was synthesized using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine in step 1 following a procedure similar to compound 29*. The crude mixture was purified by reverse phase chromatography (acetonitrile 70% to 100% / (0.05% NH3H2O+10 mM NH4HCO3 in water)) to provide a mixture of cis diastereomers (first peak on HPLC (basic), 70 mg, 32.2% yield) and a mixture of trans diastereomers (second peak on HPLC (basic), 100 mg, 49% yield). LCMS (ESI) [M+H] + =433.4.

[0415] The cis mixture (peak 1) was confirmed by 2D NMR (first peak on HPLC (basic), 70 mg), and separated by chiral SFC (Daicel Chiralcel OJ-H (250 mm*30 mm, 5 μm); supercritical CO2 / EtOH+NH3·H2O=85 / 15; 60 mL / min) to provide the cis title compound 35* (first peak on SFC, 13.9 mg, 18.9% yield) and the cis title compound 36* (second peak on SFC, 12.1 mg, 16.4% yield). LCMS (ESI) [M+H] + = 433.4. The absolute stereochemistry was assigned arbitrarily.

[0416] Compound 35*: 1 H NMR (400MHz, CDCl3) δ9.12(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,1H),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).

[0417] Compound 36*: 1H NMR (400MHz, CDCl3) δ9.12(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).

[0418] The trans stereochemistry was confirmed by 2D NMR (second peak on 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 provide the trans title compound 37* (first peak on SFC, 33.9% yield) and the trans title compound 38* (second peak on SFC, 49.4 mg, 48.4% yield). The absolute stereochemistry was arbitrarily assigned. LCMS (ESI) [M+H] + =433.4.

[0419] Compound 37*: 1 H NMR(400MHz, CDCl3)δ9.11(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),3.65–3.5 6(m,2H),3.35–3.31(m,1H),2.93–2.88(m,1H),2.52–2.40(m,2H),2.1 6–1.93(m,3H),1.69–1.63(m,4H),1.56(d,J=6.8Hz,6H),1.26(s,1H).

[0420] Compound 38*: 1H NMR (400MHz, CDCl3) δ9.11 (d, J = 1.6Hz, 1H), 8.74 (s, 1H), 8.29 (s, 1H), 6.12 (s, 1H), 4.7 2–4.68(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).

[0421] 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*)

[0422]

[0423] The title compound was synthesized using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine in step 1 according to a procedure similar to compound 29*. The crude residue was purified by reverse phase chromatography (acetonitrile 70% to 100% / (0.05% NH3H2O+10mM NH4HCO3 in water)) to provide a mixture of cis diastereomers (first peak on HPLC (basic), 80 mg, 39.6% yield) and a mixture of trans diastereomers (second peak on HPLC (basic), 73 mg, 36.1% yield). LCMS (ESI) [M+H] +=435.4.

[0424] The cis diastereoisomer stereochemistry was confirmed by 2D NMR (first peak on HPLC (basic), 80 mg) and separated by chiral SFC (SFC-17; DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 um); supercritical CO2 / EtOH+NH3·H2O=90 / 10; 60 mL / min) to provide the title compound 39* (first peak on SFC, 21.9 mg, 27.4% yield) and the title compound 40* (second peak on SFC, 14.7 mg, 18.4% yield). LCMS (ESI) [M+H] + = 435.4. The absolute stereochemistry was assigned arbitrarily.

[0425] Compound 39*: 1 H NMR(400MHz, CDCl3)δ9.11(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).

[0426] Compound 40*: 1 H NMR(400MHz, CDCl3)δ9.11(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).

[0427] The anti-stereochemistry was confirmed by 2D NMR (second peak on HPLC (basic), 73 mg), and separated by chiral SFC (Daicel Chiralcel OJ-H (250 mm*30 mm, 5 μm); supercritical CO2 / EtOH+NH3·H2O=90 / 10; 60 mL / min) to provide the title compound 41* (first peak on SFC, 21.6 mg, 29.6% yield) and the title compound 42* (second peak on SFC, 18.5 mg, 25.3% yield). LCMS (ESI) [M+H] + = 435.4. The absolute stereochemistry was assigned arbitrarily.

[0428] Compound 41*: 1 H NMR(400MHz, CDCl3)δ9.11(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).

[0429] Compound 42*: 1 H NMR(400MHz, CDCl3)δ9.10(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).

[0430] 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*)

[0431]

[0432] The title compound was synthesized using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine in step 1 according to a procedure similar to compound 29*. The crude residue was purified by reverse phase chromatography (acetonitrile 70% to 100% / (0.05% NH3H2O+10mM NH4HCO3 in water)) to provide a cis mixture (first peak on HPLC (basic), 75 mg, 36.8% yield) and a trans mixture (second peak on HPLC (basic), 100 mg, 49.5% yield). LCMS (ESI) [M+H] + =435.4.

[0433] The cis stereochemistry was confirmed by 2D NMR analysis, and the mixture (first peak on HPLC (basic), 75 mg) was separated by chiral SFC (Daicel Chiralcel OJ-H (250 mm*30 mm, 5 μm); supercritical CO 2 / EtOH + NH 3 · H 2 O = 90 / 10; 60 mL / min) to provide the title compound 43 * (first peak on SFC, 12.1 mg, 16.1% yield) and the title compound 44 * (second peak on SFC, 14.4 mg, 19.2% yield). LCMS (ESI) [M+H] + = 435.4. The absolute stereochemistry was assigned arbitrarily.

[0434] Compound 43*: 1H NMR (400MHz, CDCl3) δ9.11(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).

[0435] Compound 44*: 1 H NMR (400MHz, CDCl3) δ9.11(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,3 H),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).

[0436] The anti stereochemistry was confirmed by 2D NMR, and the mixture (second peak on HPLC (basic), 100 mg) was separated by chiral SFC (Daicel Chiralcel OJ-H (250 mm*30 mm, 5 μm); supercritical CO 2 / EtOH + NH 3 · H 2 O = 90 / 10; 60 mL / min) to provide the title compound 45 * (first peak on SFC, 27.7 mg, 27.4% yield) and the title compound 46 * (second peak on SFC, 26.6 mg, 26.3% yield). LCMS (ESI) [M+H] + = 435.4. The absolute stereochemistry was assigned arbitrarily.

[0437] Compound 45*: 1H NMR(400MHz, CDCl3)δ9.11(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),2.64–2.61(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).

[0438] Compound 46*: 1 H NMR (400MHz, CDCl3) δ9.11 (d, J = 1.2Hz, 1H), 8.74 (s, 1H), 8.29 (s, 1H), 6.1 3(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).

[0439] 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)

[0440]

[0441] The title compound was synthesized using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine in step 1 according to a procedure similar to compound 29*. The crude residue was purified by reverse phase chromatography (water (0.05% NH3H2O ​​+ 10mM NH4HCO3)-ACN, 70% to 100%) to provide the title compound 47 (second peak on SFC, 57.9 mg, 31% yield) and the title compound 48 (first peak on SFC, 46.1 mg, 25% yield). LCMS (ESI) [M+H] + = 435.3. The relative stereochemistry was determined by 2D-NMR.

[0442] Compound 47: 1 H NMR(400MHz, CDCl3)δ9.04(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),2.8 8–2.65(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).

[0443] Compound 48: 1 H NMR(400MHz, CDCl3)δ9.02(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),3.84–3.7 3(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).

[0444] 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)

[0445]

[0446] The title compound was synthesized using 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine in step 1 following a procedure similar to compound 29*. The crude mixture was purified by reverse phase chromatography (acetonitrile 30% to 60% / 0.1% NH4OH in water) to provide compound 49 (first peak on HPLC (basic), 20.1 mg, 16% yield) and compound 50 (second peak on HPLC (basic), 16.1 mg, 12.3% yield). LCMS (ESI) [M+H] + = 435.3. The relative stereochemistry was determined by 2D-NMR.

[0447] Compound 49: 1 H NMR (400MHz, CD3OD) δ8.15(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).

[0448] Compound 50: 1 H NMR (400MHz, CD3OD) δ8.15(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).

[0449] 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)

[0450]

[0451] Step 1: Benzyl (E)-(amino(methylthio)methylene)carbamate

[0452]

[0453] To the ice-cold mixture of 2-methylisothiourea sulfurous acid (10.g, 58.06mmol) and sodium hydroxide (34.8mL, 69.6mmol, 2N) in dichloromethane (100mL), benzyl chloroformate (7.0mL, 52.26mmol) is added. The mixture is stirred at 25 DEG C for 1 hour. The mixture is extracted with ethyl acetate (500mL x 2), and washed with salt water (100mL). The organic layer is through Na2SO4, is dried, filtered and concentrated. Residue is passed through into flash chromatography on silica gel (0% to 50% ethyl acetate in petroleum ether) and purified, to provide title compound (10g, 77% yield).

[0454] Step 2: Benzyl (Z)-((3-((tert-Butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxamido)(methylthio)methylene)carbamate

[0455]

[0456] 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)-(amino(methylthio)methylene)benzylcarbamate (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 Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0% to 20% ethyl acetate in petroleum ether) to provide the title compound (22 g, 84% yield).

[0457] Step 3: 5-[3-[tert-Butyl(diphenyl)silyl]oxy-6-bicyclo[3.1.0]hexaneyl]-1-isopropyl-1,2,4-triazol-3-amine

[0458]

[0459] To a stirred solution of (Z)-((3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-formamido)(methylthio)methylene)benzylcarbamate (20.0 g, 34.08 mmol) in DMF (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 (100 mL x 3) in ethyl acetate. The combined organic layers were washed with brine (100 mL x 3), dried over Na SO , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0% to 50% ethyl acetate in petroleum ether) to provide the title compound (10 g, 64% yield). LCMS (ESI) [M+H] + =461.3.

[0460] Step 4: 5-(3-((tert-Butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-3-iodo-1-isopropyl-1H-1,2,4-triazole

[0461]

[0462] To an ice-cooled solution of 5-[3-[tert-butyl(diphenyl)silyl]oxy-6-bicyclo[3.1.0]hexyl]-1-isopropyl-1,2,4-triazole-3-amine (5000.0mg, 10.85mmol) in acetonitrile (50mL) and water (10mL) is added 4-methylbenzenesulfonic acid (9331mg, 54.3mmol) and sodium nitrite (1498mg, 21.71mmol) in water (5mL), and stirred at 0°C for 30 minutes. Then sodium iodide (4067.0mg, 27.13mmol) is quickly added to the solution and stirred at 0°C for 3 hours. The reaction is poured into water (50mL) and extracted with ethyl acetate (200mL x 3). The combined organic layer is washed with salt water (50mLx 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography (0% to 20% ethyl acetate in petroleum ether) to provide the title compound (3800 mg, 61% yield). LCMS (ESI) [M+H] + =572.0.

[0463] Step 5: 6-(3-iodo-1-isopropyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-ol

[0464]

[0465] To a stirred solution of tert-butyl-[[6-(5-iodo-2-isopropyl-1,2,4-triazol-3-yl)-3-bicyclo[3.1.0]hexyl]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 NaHCO (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 gel column chromatography (0% to 25% ethyl acetate in petroleum ether) to provide the title compound (2000 mg, 83% yield). LCMS (ESI) [M+H] + =334.0.

[0466] Step 6: 6-(5-iodo-2-isopropyl-1,2,4-triazol-3-yl)bicyclo[3.1.0]hexan-3-one

[0467]

[0468] To a stirred solution of 6-(5-iodo-2-isopropyl-1,2,4-triazole-3-yl)bicyclo[3.1.0]hexane-3-ol (2000mg, 6mmol) in dichloromethane (20mL) was added Dess-Martin periodinane (3055mg, 7.2mmol) and stirred at 25°C for 16 hours. The reaction was quenched with saturated NaHCO3 aqueous solution (80mL) and extracted with ethyl acetate (200mL×3). The combined organic layers were washed with brine (50mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0% to 50% ethyl acetate in petroleum ether) to provide the title compound (1200mg, 59% yield). LCMS(ESI)[M+H] + =332.0.

[0469] Step 7: 6-[2-Isopropyl-5-[5-(trifluoromethyl)-3-pyridinyl]-1,2,4-triazol-3-yl]bicyclo[3.1.0]hexan-3-one

[0470]

[0471] A suspension of KCO (626 mg, 4.53 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (107 mg, 0.15 mmol), 6-(5-iodo-2-isopropyl-1,2,4-triazol-3-yl)bicyclo[3.1.0]hexane-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. under N atmosphere for 2 hours. 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 flash chromatography on silica gel (0% to 50% ethyl acetate in petroleum ether) to provide the title compound (200 mg, 27% yield). LCMS (ESI) [M+H] + =351.1.

[0472] Step 8: 4-[(1R,5S)-6-[2-isopropyl-5-[5-(trifluoromethyl)-3-pyridinyl]-1,2,4-triazol-3-yl]-3-bicyclo[3.1.0]hexyl]-1,4-oxazepane

[0473]

[0474] To a solution of 6-[2-isopropyl-5-[5-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]bicyclo[3.1.0]hexane-3-one (80 mg, 0.23 mmol) and homomorpholine hydrochloride (94 mg, 0.69 mmol) in methanol (3 mL) was added NaBH3CN (72 mg, 1.14 mmol) at 25 ° C. 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 provide the title compound (60 mg, 60% yield) as a mixture of diastereomers.

[0475] 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)

[0476]

[0477] The diastereomeric mixture was purified by reverse phase chromatography (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN; 65% to 95%) to provide compound 51 (first peak on HPLC, 22.2 mg, 19% yield) and compound 52 (second peak on HPLC, 32.6 mg, 27% yield). LCMS (ESI) [M+H] + = 423.3. The relative stereochemistry was determined by 2D-NMR.

[0478] Compound 51: 1H NMR (400 MHz, CD3OD) δ9.37 (d, J = 1.6 Hz, 1H), 8.87 (d, J = 1.2 Hz, 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 = 3.2 Hz, 1H), 2.05–2.01 (m, 2H), 1.90–1.87 (m, 2H), 1.75–1.65 (m, 2H), 1.58 (d, J = 6.8 Hz, 6H).

[0479] Compound 52:1 H NMR (400MHz, CD3OD) δ9.37(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),3.43–3.3 1(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).

[0480] 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)

[0481]

[0482] 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

[0483]

[0484] To a mixture of 5-((1R, 5S, 6r)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-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)palladium(II) chloride (0.28 g, 0.40 mmol). The reaction mixture was then placed under a nitrogen atmosphere and stirred at 75 ° C for 5 hours. 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 flash chromatography on silica gel (0% to 30% ethyl acetate in petroleum ether) to provide the title compound (2.0 g, 88% yield). LCMS (ESI) [M+H] + =548.1.

[0485] 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

[0486]

[0487] To 3-(5-((1R, 5S, 6r)-3-((tert-butyldiphenylsilyl) oxygen base) bicyclo [3.1.0] hexane-6-yl)-1H-pyrazole-3-yl)-5-(trifluoromethyl) pyridine (1.2g, 2.19mmol) and CsCO(1.4g, 4.3mmol) in the stirred mixture in DMF (8mL) is added iodoethane (0.9mL, 11.25mmol), and then stirred at 25 DEG C for 3 hours.The reaction is quenched with water (30mL), and extracted with ethyl acetate (100mL x 3).The combined organic layer is washed with salt water (30mL), through NaSODry, filter, and concentrate.The residue is purified by flash chromatography on silica gel (0% to 15% ethyl acetate in petroleum ether), to provide title compound (890mg, 71% yield). LCMS (ESI) [M+H] + =576.2.

[0488] 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

[0489]

[0490] To 3-(5-((1R,5S,6r)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-yl)-1-ethyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyridine (870 mg, 1.51 mmol) in tetrahydrofuran was added tetrabutylammonium fluoride (12.0 mL, 12 mmol, 1 M) and the mixture was stirred at 25 ° C for 5 hours. The reaction was then quenched by 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 flash chromatography on silica gel (0% to 50% ethyl acetate in petroleum ether) to provide the title compound (500 mg, 98% yield). LCMS(ESI)[M+H] + =338.1.

[0491] 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

[0492]

[0493] To a solution of (1R, 5S, 6r) -6- (1- ethyl -3- (5- (trifluoromethyl) pyridin-3-yl) -1H- pyrazol-5-yl) bicyclo [3.1.0] hexane -3- alcohol (500 mg, 1.48 mmol) in anhydrous dichloromethane (12 mL) was added Dess-Martin periodinane (1000 mg, 2.36 mmol) and stirred at 25 ° C for 4 hours. The mixture was then quenched with Na2SO3 solution (20 mL), followed by quenching with saturated NaHCO3 solution (10 mL), and extracted with dichloromethane (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 flash chromatography on silica gel (0% to 40% ethyl acetate in petroleum ether) to provide the title compound (410 mg, 83% yield). LCMS (ESI) [M+H] + =336.3.

[0494] 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)

[0495]

[0496] To (1R, 5S, 6r) -6- (1- ethyl -3- (5- (trifluoromethyl) pyridin-3-yl) -1H- pyrazole -5- bases) bicyclo [3.1.0] hexane -3- ketone (130mg, 0.38mmol) and 1,4- oxazacycloheptane hydrochloride (135mg, 0.97mmol) in anhydrous methanol (6mL) was added dropwise NaBH at 20 DEG C CN (120mg, 1.92mmol) and acetic acid (0.02mL, 0.35mmol). Then the reaction mixture was heated to 70 DEG C and stirred for 4 hours. The reaction was quenched by saturated NaHCO solution (5mL) and extracted with dichloromethane (30mL x 2). The organic matter merged was washed with salt water, through Na SO dried, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography (acetonitrile 70% to 100% / (0.05% NH3H2O+10 mM NH4HCO3 in water)) to provide the title compound 53 (second peak on SFC, 32.4 mg, 24% yield) and compound 54 (first peak on SFC, 40.3 mg, 30% yield). LCMS (ESI) [M+H] + = 421.4. The relative stereochemistry was determined by 2D-NMR.

[0497] Compound 53: 1 H NMR(400MHz, CDCl3)δ9.10(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,4 H),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).

[0498] Compound 54: 1H NMR (400MHz, CDCl3) δ9.11(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),2.79–2.70(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).

[0499] Instance 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*)

[0500]

[0501] Step 1: 3-Bromocyclopent-2-enone

[0502]

[0503] To a suspension of Ph3PBr2 (4.73 g, 11.2 mmol) in dichloromethane (10 mL) at 25 ° C, cyclopent-4-ene-1,3-dione (1.0 g, 10.2 mmol) and triethylamine (1.56 mL, 11.2 mmol) were added. The reaction mixture was then stirred at 25 ° C for 18 hours. A yellow suspension was formed. The reaction mixture was concentrated under vacuum, and 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 flash chromatography on silica gel (10% to 20% ethyl acetate in petroleum ether) to provide the title compound (1.10 g, 67% yield). 1 HNMR(400MHz, DMSO-d6)δ6.66–6.62(m,1H),3.01–2.94(m,2H),2.50–2.47(m,2H).

[0504] Step 2: 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-enone

[0505]

[0506] By 4- bromocyclopent-2-enone (1.10g, 6.83mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.91g, 7.52mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium dichloride (II) (500mg, 0.68mmol) and KOAc (2.01g, 20.5mmol) in 1,4-dioxane (10mL) mixture degassed and purged three times with N2.Then the reaction mixture was stirred at 100°C under N2 for 12 hours.A brown suspension was formed.The reaction mixture was quenched by water (30mL) and extracted with ethyl acetate (50mL x 3).The combined organic layer was washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography (2% to 3% methanol in dichloromethane) to provide the title compound (1.30 g, 91% yield). 1 H NMR (400MHz, DMSO-d6) δ6.45–6.40(m,1H),2.68–2.63(m,2H),2.28–2.23(m,2H),1.27(s,12H).

[0507] Step 3: 3-(3-Bromo-1-isopropyl-1H-pyrazol-5-yl)cyclopent-2-enone

[0508]

[0509] By 3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- bases) cyclopent-2- enone (1.30g, 6.25mmol), 3,5- dibromo -1- isopropyl -1H- pyrazole (1.67g, 6.25mmol), Cs2CO3 (6.11g, 18.7mmol) and bis (di- tert-butyl (4- dimethylaminophenyl) phosphine) dichloropalladium (II) (457mg, 0.62mmol) in 1,4- dioxane (30mL) and water (6mL) suspension degassed and purged three times with N2, then the reaction mixture was stirred at 100 DEG C under N2 for 1.5 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (40% to 50% ethyl acetate in petroleum ether), to provide the title compound (1.0g, 59% yield). 1H NMR (400MHz, CDCl3) δ6.85 (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.

[0510] Step 4: 3-(1-Isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopent-2-enone

[0511]

[0512] 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)palladium(II) dichloride (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 three times with N, and the reaction mixture was stirred at 100° C. under N for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (30% to 50% ethyl acetate in petroleum ether) to provide the title compound (1000 mg, 80% yield). LCMS (ESI) [M+H] + =336.1.

[0513] Step 5: 3-(1-Isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone

[0514]

[0515] To a solution of 3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopent-2-enone (1.0g, 2.98mmol) in methanol (20mL) was added 10% carbon-supported palladium (0.32g, 0.30mmol) at 25°C, and the reaction mixture was then stirred for 20 hours at 25°C under H2(15psi). The reaction mixture was filtered and the filter cake was washed with methanol (10mLx 2). The combined organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (30% to 50% ethyl acetate in petroleum ether), to provide the title compound (700mg, 70% yield). 1 H NMR(400MHz, CDCl3)δ9.47(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.

[0516] Step 6: 4-(3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine

[0517]

[0518] 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 NaBH3CN (130 mg, 2.08 mmol) in methanol (5 mL) was added acetic acid (0.03 mL), and the reaction mixture was stirred at 50 ° C for 2 hours. The reaction mixture was concentrated. The residue was then purified by flash chromatography on silica gel (5% to 10% methanol in dichloromethane) to provide the title compound (320 mg, 76% yield) as a mixture of enantiomers. LCMS (ESI) [M+H] + =409.2.

[0519] 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*)

[0520]

[0521] 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 separated by SFC (column: ChiralPak AD-3 150×4.6 mm ID, 3 μm, mobile phase: A: CO 2 B:IPA (0.05% DEA) gradient: 5% to 40% B in 5.5 min, then 5% B The 5-mercapto-4-nitropropene was purified by HPLC (HPLC: 500 nm, HPLC: HPLC: 500 nm, HPLC: HPLC: 400 nm, 1.5 min, flow rate: 2.5 mL / min, column temperature: 40° C.; back pressure: 100 bar) to provide the title compound 58* (first peak on SFC, 20.1 mg, 6.2% yield), compound 59* (second peak on SFC, 27.3 mg, 8.4% yield), compound 60* (third peak on SFC, 41.7 mg, 12.2% yield) and compound 61* (fourth peak on SFC, 56.3 mg, 17.4% yield). LCMS (ESI) [M+H] + = 409.2. The relative stereochemistry was assigned arbitrarily.

[0522] 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).

[0523] 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).

[0524] 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).

[0525] Compound 61*: 1H NMR (400MHz, CDCl3) δ9.14(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).

[0526] 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 )-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*)

[0527]

[0528] 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

[0529]

[0530] 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 ID, 3 μm, mobile phase: A: CO2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5.5 minutes, then 5% B 1.5 minutes; flow rate: 2.5 mL / min, column temperature: 40° C., back pressure: 100 bar) to provide (R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone (first peak on SFC, 350 mg, 43.7% yield) and (S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone (second peak on SFC, 370 mg, 46.2% yield). Both were obtained as single unknown stereoisomers. Relative stereochemistry is arbitrarily assigned.

[0531] 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*)

[0532]

[0533] To a solution of (S)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone (second peak on SFC, 100 mg, 0.3 mmol), 1,4-oxaazepine (60 mg, 0.59 mmol) and NaBH3CN (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 was formed. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel (5% to 10% methanol in dichloromethane) to provide a diastereoisomer mixture compound (120 mg, 90% yield). It was purified by chiral SFC (column: Chiral Pak AD-3 150×4.6 mm ID, 3 μm, mobile phase: A: CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5.5 minutes, then 5% B for 1.5 minutes; flow rate: 2.5 mL / min, column temperature: 40° C.; back pressure: 100 bar) to provide compound 63* (first peak on SFC, 22.2 mg, 19% yield) and compound 64* (second peak on SFC, 32.6 mg, 27% yield). LCMS (ESI) [M+H] + = 423.3. The relative stereochemistry is arbitrarily assigned.

[0534] Compound 63*: 1 H NMR (400MHz, CDCl3) δ9.14(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).

[0535] Compound 64*: 1H NMR (400MHz, CDCl3) δ9.15(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),2.89–2.76(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).

[0536] 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*)

[0537]

[0538] To a solution of (R)-3-(1-isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone (first peak on 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 was formed. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel (5% to 10% methanol in dichloromethane) to give the compound (120 mg, 90% yield) as a racemic mixture. The excitatory mixture was purified by chiral SFC (column: Chiral Pak AD-3 150×4.6 mm ID, 3 μm, mobile phase: A: CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5.5 minutes, then 5% B for 1.5 minutes; flow rate: 2.5 mL / min, column temperature: 40° C.; back pressure: 100 bar) to provide compound 65* (first peak on SFC, 16.7 mg, 13.1% yield) and compound 62* (second peak on SFC, 37.8 mg, 31.2% yield). LCMS (ESI) [M+H] + = 423.3. The relative stereochemistry is arbitrarily assigned.

[0539] Compound 65*: 1 H NMR (400MHz, CDCl3) δ9.15(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,2 H),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).

[0540] Compound 62*: 1 H NMR(400MHz, CDCl3)δ9.16(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,4H) ,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).

[0541] 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)

[0542]

[0543] The title compound was synthesized in step 1 using 3-(trifluoromethyl)benzimidamide hydrochloride and (1R,5S)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxylic acid according to a procedure similar to compound 68. The crude mixture was purified by preparative TLC (10% methanol in dichloromethane) to provide compound 66 (first peak on SFC, 36.41 mg, 28.7% yield) and compound 67 (second peak on SFC, 30.31 mg, 24% yield). LCMS (ESI) [M+H] + = 435.2. The relative stereochemistry was determined by 2D-NMR.

[0544] Compound 66: 1 H NMR (400MHz, CD3OD) δ8.30(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).

[0545] Compound 67: 1 H NMR (400MHz, CD3OD) δ8.31(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).

[0546] 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)

[0547]

[0548] 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

[0549]

[0550] To a solution of (1R,5S,6r)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxylic acid (2 g, 5.26 mmol) and 5-bromonicotinomidamide 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. Isopropylhydrazine hydrochloride (872 mg, 7.88 mmol) and acetic acid (3 mL, 52.56 mmol) were added to the above mixture and stirred at 80 ° C for another 1.5 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (30 mL x 3) and concentrated. The residue was purified by flash chromatography on silica gel (0% to 10% ethyl acetate in petroleum ether) to give the title compound (2.5 g, 79% yield). LCMS (ESI), [M+H] + =602.2.

[0551] 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-pyridinyl]-1H-1,2,4-triazol-5-yl]bicyclo[3.1.0]hexan-3-ol

[0552]

[0553] A solution of [(1S,5R)-6-[5-(5-bromo-3-pyridyl)-2-isopropyl-1,2,4-triazol-3-yl]-3-bicyclo[3.1.0]hexyl]oxy-tert-butyl-diphenyl-silane (900 mg, 1.5 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (51 mg, 0.12 mmol), Pd2(dba)3 (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 N2 for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (6 mL). The product is then added into the mixture of 4-[4-(2-fluoro-3-oxo-1-yl)-1-oxo-2-propane-2-yl)-2-nitro-4-oxo-2-propane-2-yl]-4-nitro-2-propane-2-yl]-4-nitro-2-propane-2-yl]-4-nitro-2-propane-2-yl]-4-nitro-2-propane-2-yl]-4-nitro-2-propane-2-yl]-4-nitro-2-propane-2-yl]-4-nitro-2-propane-2-yl]-4-nitro-2-propane-2-yl]-4-nitro-2-propane-2-yl]-4-nitro-2-propane-2-yl) ...]-4-nitro-2-propane-2-yl]-4-nitro-2-propane-2-yl]-4-nitro-2-propane-2 + =589.3 and the deprotected title compound (200 mg, 38% yield). LCMS (ESI), [M+H] + =351.1.

[0554] 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

[0555]

[0556] 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]hexyl]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 hours. The reaction mixture was quenched by saturated NaHCO 3 . The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x2), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0% to 80% ethyl acetate in petroleum ether) to provide the title compound (300 mg, 84% yield). LCMS (ESI), [M+H] + =351.1.

[0557] 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

[0558]

[0559] To a solution of (1R, 5S, 6r) -6- (3- (5- (difluoromethoxy) pyridin-3-yl) -1- isopropyl -1H-1, 2, 4- triazole -5- yl) bicyclo [3.1.0] hexane -3- alcohol (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 hours. The reaction mixture was diluted with water (15 mL) and the resulting solution was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with Na2SO3 (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0% to 80% ethyl acetate in petroleum ether) to provide the title compound (270 mg, 54% yield).

[0560] 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)

[0561]

[0562] 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] hexane -3- one (130 mg, 0.37 mmol), homomorpholine hydrochloride (62 mg, 0.45 mmol) and acetic acid (22 mg, 0.37 mmol) in methanol (5 mL) was added sodium cyanoborohydride (117 mg, 1.87 mmol) and stirred at 50 ° C for 16 hours. The reaction mixture was diluted with water (10 mL) and the pH was adjusted to 9 with NaHCO . 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 under vacuum. The residue was purified by reverse phase chromatography (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, 50% to 80%, 25 mL / min) to provide compound 68 (second peak on SFC, 44.55 mg, 26% yield) and compound 69 (first peak on SFC, 35.38 mg, 22% yield). LCMS (ESI), [M+H] + = 434.3. The relative stereochemistry was determined by 2D-NMR.

[0563] Compound 68: 1H NMR(400MHz,CD3OD)δ9.01(d,J=1.6Hz,1H),8.43(d,J=2.8Hz,1H),8.14(s,1 H),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).

[0564] Compound 69: 1 H NMR(400MHz,CD3OD)δ9.00(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),3.4 8–3.37(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).

[0565] 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*)

[0566]

[0567] The title compound was synthesized in step 1 using 3-(trifluoromethyl)benzimidamide hydrochloride and (1R,5S)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxylic acid according to a procedure similar to compound 68. The crude mixture was purified by preparative TLC (10% methanol in dichloromethane) to provide compound 70* (first peak on SFC, 41.35 mg, 33% yield) and compound 71* (second peak on SFC, 43.68 mg, 35% yield). LCMS (ESI) [M+H] + = 435.3. The relative stereochemistry was assigned arbitrarily.

[0568] Compound 70*: 1 H NMR (400MHz, CDCl3) δ8.30 (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).

[0569] Compound 71*: 1 H NMR (400MHz, CDCl3) δ8.31 (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).

[0570] 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)

[0571]

[0572] The title compound was synthesized using (R)-3-methylmorpholine in the last step according to a procedure similar to compound 51. The crude mixture was purified by reverse phase chromatography (water (0.05% NH3H2O+10mM NH4HCO3)-ACN, 55% to 85%) to provide compound 72 (first peak on HPLC, 32.76 mg, 17.4% yield) and compound 73 (second peak on HPLC, 69.52 mg, 36.9% yield). LCMS (ESI), [M+H] + = 436.2. The relative stereochemistry was determined by 2D-NMR.

[0573] Compound 72: 1 H NMR (400MHz, CD3OD) δ8.25(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).

[0574] Compound 73: 1 H NMR (400MHz, CD3OD) δ8.25(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,1 H),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,3 H), 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).

[0575] 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)

[0576]

[0577] The title compound was synthesized using 3-bromobenzimidamide hydrochloride in step 1 according to a procedure similar to compound 68. The crude mixture was purified by reverse phase chromatography (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, 60% to 90%) to provide compound 74 (first peak on SFC, 35.84 mg, 28.2% yield) and compound 75 (second peak on SFC, 35.65 mg, 27% yield). LCMS (ESI), [M+H] + = 433.2. The relative stereochemistry was determined by 2D-NMR.

[0578] Compound 74: 1 H NMR (400MHz, CD3OD) δ7.83(d,J=7.6Hz,1H),7.72(s,1H),7.44(t,J=8.0Hz,1H),7.1 5(dd,J=2.4,8.0Hz,1H),7.06–6.66(m,1H),4.86–4.81(m,1H),3.79(t,J=6.0Hz,2H) ,3.77–3.73(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).

[0579] Compound 75: 1H NMR (400MHz, CD3OD) δ7.82(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).

[0580] Examples A-F: (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)

[0581]

[0582] The title compound was synthesized using (3R)-3-methylmorpholine in the last step according to a procedure similar to compound 74. The crude mixture was purified by preparative TLC (ethyl acetate / methanol 1=10 / 1) to provide 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.

[0583] Compound 76: 11H NMR (400 MHz, CD3OD) δ 7.83 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.15 (dd, J = 2.4, 8.0 Hz, 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 = 6.4 Hz, 6H), 1.09 (d, J = 6.4 Hz, 3H).

[0584] Compound 77: 1 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J = 7.2 Hz, 1H), 7.72 (s, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.15 (dd, J = 2.4, 8.0 Hz, 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, 6.4 Hz, 6H), 1.13 (d, J = 6.4 Hz, 3H).

[0585] 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 79*) , (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*)

[0586]

[0587] Step 1: 2-(1-Isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-1,2,4-triazol-3-yl)-6-(trifluoromethyl)pyridine

[0588]

[0589] To a solution of 6-(trifluoromethyl)pyridine-2-formamidine hydrochloride (300.0mg, 1.33mmol) and 1,4-dioxaspiro [4.5] decane-8-formic acid (371.43mg, 1.99mmol) in DMF (12mL) was added HATU (556mg, 1.46mmol) and N,N-diisopropylethylamine (0.68mL, 3.99mmol) and stirred at 20°C for 1 hour. Isopropylhydrazine hydrochloride (221mg, 1.99mmol) and acetic acid (0.76mL, 13.3mmol) were then added and stirred at 80°C for 1.5 hours. The mixture was diluted with ethyl acetate (500mL) and washed with water and brine (50mL x 3). The organic layer was dried over sodium sulfate, filtered and concentrated to provide the title compound (520mg, 98.6% yield). LCMS (ESI) [M+H]+ = 397.2.

[0590] Step 2: 4-(1-Isopropyl-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)cyclohexanone

[0591]

[0592] To a solution of 2-[5-(1,4-dioxaspiro[4.5]decane-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 for 16 hours at 25 ° C. 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 x 2). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0% to 30% ethyl acetate in petroleum ether) to provide the title compound (270 mg, 58.4% yield). LCMS (ESI) [M+H] + = 353.2

[0593] 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*)

[0594]

[0595] 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 methanol (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 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 x 3) and the combined organic layers were concentrated under vacuum. The residue was purified by reverse phase chromatography (30% to 60% acetonitrile / 0.05% aqueous ammonium hydroxide) to provide compound 78* (second peak on SFC, 37.54 mg, 29% yield) and compound 79* (first peak on SFC, 14.25 mg, 11% yield). Relative stereochemistry was arbitrarily assigned.

[0596] Compound 78*: 1H NMR (400MHz, CD3OD) δ8.33(d,J=7.6Hz,1H),8.12(t,J=8.0Hz,1H),7.82(d,J=7.6Hz,1H),4.8 6–4.76(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).

[0597] Compound 79*: 1 H NMR (400MHz, CD3OD) δ8.36(d,J=8.0Hz,1H),8.12(t,J=8.0Hz,1H),7.81(d,J=7.6Hz,1H),4.8 2–4.71(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).

[0598] 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*)

[0599]

[0600] 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) was added (R)-3-methylmorpholine (373 mg, 3.69 mmol), acetic acid (22 mg, 0.37 mmol) and sodium cyanoborohydride (70 mg, 1.11 mmol) 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 x 3) and the combined organic layers were concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (30% to 60% acetonitrile / 0.05% aqueous ammonium hydroxide) to provide compound 80* (second peak on SFC, 7.79 mg, 5% yield) and compound 81* (first peak on SFC, 32.82 mg, 20% yield). LCMS (ESI) [M+H] + = 438.1. The relative stereochemistry was assigned arbitrarily.

[0601] Compound 80*: 1 H NMR (400MHz, CD3OD) δ8.33(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=11.2 Hz,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).

[0602] Compound 81*: 1H NMR (400MHz, CD3OD) δ8.36(d,J=8.0Hz,1H),8.12(t,J=7.6Hz,1H),7.82(d,J=7.6Hz,1H),4.7 7–4.71(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).

[0603] 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)

[0604]

[0605] The title compound was synthesized using 6-(trifluoromethyl)nicotinamide hydrochloride and (R)-3-oxocyclopentanecarboxylic acid in step 1 according to a procedure similar to compound 68. The crude mixture was purified by flash chromatography on silica gel (0% to 10% methanol in dichloromethane) to provide the title compound (50 mg, 68.2% yield) as a mixture of diastereoisomers. The diastereoisomer mixture was separated using chiral SFC (Daicel Chiralpak SFC-21; DAICEL CHIRALCEL OD-H (250 mm * 30 mm, 5 um); 0.1% NH in ETOH; 15 / 15; 60 mL / min) to provide compound 82 (the first peak on SFC, 3.65 mg, 6.9% yield) and compound 83 (the second peak on SFC, 30.03 mg, 59.5% yield). LCMS (ESI), [M+H] + = 467.3. The relative stereochemistry was determined by 2D-NMR.

[0606] Compound 82: 1H NMR (400MHz, CD3OD) δ9.32(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).

[0607] Compound 83: 1 H NMR(400MHz,CD3OD)δ9.32(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 –2.03(m,2H),2.01–1.92(m,1H),1.87–1.80(m,1H),1.53(dd,J=2.8,6.8Hz,6H).

[0608] 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)

[0609]

[0610] The title compound was synthesized 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 according to a procedure similar to compound 29*. The crude mixture was purified by reverse phase chromatography (Phenomenex Gemini-NX C18 75*30mm*3um water (0.05% NH3H2O+10mM NH4HCO3)-CAN; 57% to 87%) to provide compound 84 (second peak on SFC, 33.71 mg, 25% yield) and compound 85 (first peak on SFC, 35.5 mg, 26% yield). LCMS (ESI) [M+H] + = 474.3. The relative stereochemistry was determined by 2D-NMR.

[0611] Compound 84: 1 H NMR (400MHz, CD3OD) δ8.15(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),2.8 0–2.76(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).

[0612] Compound 85: 1 H NMR (400MHz, CD3OD) δ8.15(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=8.4 Hz,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).

[0613] 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*),

[0614]

[0615] 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

[0616]

[0617] According to the procedure of compound 58*, 2400 mg of 3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone was prepared and purified by SFC (SFC-11, Phenomenex-Cellulose-2 (250 mm*50 mm, 10 um, 0.1% NH 3 H 2 O ETOH, 25 / 25, 200 ml / min) to provide the title compound-1 (first peak on SFC, 1 g, 42% yield) and the title compound-2 (second peak on SFC, 1 g, 42% yield). LCMS (ESI), [M+H] + = 338. 1. Relative stereochemistry is arbitrarily assigned.

[0618] Step 2: 2-(4-((3R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)piperazin-1-yl)ethanol

[0619]

[0620] A solution of (R)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentanone (100 mg, 0.30 mmol), 2-(piperazine-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 a NaHCO aqueous solution. The resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash chromatography (0% to 5% methanol in dichloromethane) to give the title compound (100 mg, 75% yield) as a mixture of diastereomers. LCMS (ESI), [M+H]+ = 452.2.

[0621] 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*)

[0622]

[0623] The diastereomeric mixture (120 mg, 0.27 mmol) was separated using chiral SFC (SFC-17, DAICELCHIRALPAK IG (250 mm * 30 mm, 10 um), 0.1% NH 3 H 2 O ETOH, 40 / 40, 70 ml / min) to provide compound 86 * (trans isomer, first peak on SFC, 17.76 mg, 15% yield) and compound 87 * (cis isomer, second peak on SFC, 75.74 mg, 63% yield). Relative stereochemistry is arbitrarily assigned.

[0624] Compound 86*: 1H NMR(400MHz,CD3OD)δ9.10(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).

[0625] Compound 87*: 1 H NMR (400MHz, CD3OD) δ9.10(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).

[0626] 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*)

[0627]

[0628] Step 1: 2-(4-((3S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)cyclopentyl)piperazin-1-yl)ethanol

[0629]

[0630] 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-(piperazine-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 a NaHCO aqueous solution. The resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel flash chromatography (0% to 5% methanol in dichloromethane) to give the title compound as a mixture of diastereomers (120 mg, 74% yield). LCMS (ESI), [M+H] + = 452.2.

[0631] 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

[0632]

[0633] The diastereomeric mixture (120 mg, 0.27 mmol) was separated using chiral SFC (SFC-13, Phenomenex-Cellulose-2 (250 mm*50 mm, 10 μm), 0.1% NH 3 H 2 O ETOH, 35 / 35, 60 ml / min) to give compound 88* (trans isomer, first peak on SFC, 13.53 mg, 11% yield) and compound 89* (cis isomer, second peak on SFC, 75.77 mg, 63% yield). Relative stereochemistry was arbitrarily assigned.

[0634] Compound 88*: 1H NMR (400MHz, CD3OD) δ9.10 (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).

[0635] Compound 89*: 1 H NMR (400MHz, CD3OD) δ9.10(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=6.0 Hz,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).

[0636] 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*)

[0637]

[0638] The title compound was synthesized following a procedure analogous to compound 86* using 1-(2-methoxyethyl)piperazine and 3-[2-isopropyl-5-[6-(trifluoromethyl)-3-pyridyl]pyrazol-3-yl]cyclopentanone (first peak on SFC) in the reductive amination step. The crude mixture was purified by preparative TLC (10% methanol in dichloromethane) to afford the title compound as a mixture of diastereomers (100 mg, 95% yield). The diastereomeric mixture (100 mg, 0.21 mmol) was separated using chiral SFC (SFC-11; Daicel Chiralpak AD (250 mm*30 mm, 10 um); 0.1% NH 3 H 2 O; ETOH; 20 / 20; 60 mL / min) to provide compound 90* (first peak on SFC, 12.48 mg, 12% yield) and compound 91* (second peak on SFC, 53.25 mg, 52% yield). LCMS (ESI) [M+H] + = 466.3. The relative stereochemistry was assigned arbitrarily.

[0639] Compound 90*: 1 H NMR (400MHz, CD3OD) δ9.06(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=5.6H z,2H),3.36(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).

[0640] Compound 91*: 1 H NMR (400MHz, CD3OD) δ9.07(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),2.1 7–2.14(m,1H),2.03–2.01(m,1H),1.87–1.64(m,4H),1.54(d,J=6.8Hz,6H).

[0641] 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*)

[0642]

[0643] The title compound was synthesized following a procedure analogous to compound 86* using 1-(2-methoxyethyl)piperazine and 3-[2-isopropyl-5-[6-(trifluoromethyl)-3-pyridyl]pyrazol-3-yl]cyclopentanone (second peak on SFC) in the final reductive amination step. The crude mixture was purified by preparative TLC (10% methanol in dichloromethane) to afford the title compound as a mixture of diastereomers (90 mg, 90% yield). The diastereomeric mixture (90 mg, 0.19 mmol) was separated using chiral SFC (Daicel Chiralpak AD (250 mm*30 mm, 10 um); 0.1% NH 3 H 2 O; IPA; 15 / 15; 60 mL / min) to provide compound 92* (first peak on SFC, 7.54 mg, 7% yield) and compound 93* (second peak on SFC, 53.51 mg, 52% yield). LCMS (ESI) [M+H] + = 466.3. The relative stereochemistry was assigned arbitrarily.

[0644] Compound 92*: 1 H NMR (400MHz, CD3OD) δ9.06(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).

[0645] Compound 93*: 1H NMR (400MHz, CD3OD) δ9.06(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).

[0646] 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)

[0647]

[0648] The title compound was synthesized in step 1 using 2-(trifluoromethyl)pyrimidine-5-carboxamidine hydrochloride and (S)-3-oxocyclopentanecarboxylic acid according to a procedure similar to compound 68. The crude mixture was purified by flash chromatography on silica gel (0% to 10% methanol in dichloromethane) to provide the title compound (150 mg, 73% yield) as a diastereomeric mixture. The diastereomeric mixture (150 mg, 0.37 mmol) was separated using chiral SFC (DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); 0.1% NH H O+MEOH, 20 / 20; 60 mL / min) to provide compound 94 (the first peak on SFC, 33.31 mg, 20.4% yield) and compound 95 (the second peak on SFC, 73.33 mg, 46% yield) as a colorless oil. LCMS (ESI) [M+H] + = 411.2. Relative stereochemistry was determined by 2D-NMR.

[0649] Compound 94: 1H NMR (400MHz, CD3OD) δ9.51 (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).

[0650] Compound 95: 1 H NMR(400MHz,CD3OD)δ9.51(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,1H),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).

[0651] 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)

[0652]

[0653] The title compound was synthesized in step 1 using (1R,5S,6r)-6-(3-iodo-1-isopropyl-1H-pyrazol-5-yl)bicyclo[3.1.0]hexane-3-one and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine according to a procedure similar to compound 29*. The crude mixture was purified by reverse phase chromatography (Boston Prime C18 150*30mm*5um; water (0.05% NH3H2O+10mM NH4HCO3)-ACN; 65% to 95%) to provide compound 96 (first peak on SFC, 28.44 mg, 22% yield) and compound 97 (second peak on SFC, 56.2 mg, 45% yield). LCMS (ESI), [M+H] + = 436.2. The relative stereochemistry was determined by 2D-NMR.

[0654] Compound 96: 1 H NMR (400MHz, CD3OD) δ9.27(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),2.88–2.68(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).

[0655] Compound 97: 1 H NMR (400MHz, CD3OD) δ9.26(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).

[0656] 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)

[0657]

[0658] Step 1: 1-(3-((tert-Butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-3-(2-(trifluoromethyl)pyrimidin-4-yl)propane-1,3-dione

[0659]

[0660] To a solution of 1-[3-[tert-butyl(diphenyl)silyl]oxy-6-bicyclo[3.1.0]hexyl]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 N2 and stirred for 0.5 hours. 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 N2. The reaction mixture was then stirred at 20°C for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL) and diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0% to 20% ethyl acetate in petroleum ether) to provide the title compound (2 g, 74% yield). LCMS (ESI) [M+H] + =553.0.

[0661] 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

[0662]

[0663] To a solution of 1-[3-[tert-butyl(diphenyl)silyl]oxy-6-bicyclo[3.1.0]hexyl]-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 hours. The mixture was concentrated in vacuo, and the residue was purified by silica gel flash chromatography (0% to 5% ethyl acetate in petroleum ether) to provide the title compound (1.5 g, 70% yield). LCMS (ESI) [M+H] + =591.6.

[0664] 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

[0665]

[0666] 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]hexyl]oxy]-diphenyl-silane (1.5 g, 2.54 mmol) in tetrahydrofuran (10 mL) was added TABF (5 mL, 30.4 mmol, 1 M in THF) 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 x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0% to 50% ethyl acetate in petroleum ether) to provide the title compound (680 mg, 74% yield). LCMS (ESI) [M+H] + =352.9.

[0667] 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

[0668]

[0669] To a solution of (1R, 5S)-6-[2-isopropyl-5-[2-(trifluoromethyl)pyrimidin-4-yl]pyrazol-3-yl]bicyclo[3.1.0]hexane-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 hours. The mixture was then diluted with H2O (5 mL) and subsequently diluted with aqueous Na2SO3 solution (10 mL) and aqueous NaHCO3 solution (10 mL). The resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0% to 40% ethyl acetate in petroleum ether) to provide the title compound (430 mg, 62% yield). LCMS (ESI) [M+H] + =351.2.

[0670] 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)

[0671]

[0672] To a mixture of (1R, 5S)-6-[2-isopropyl-5-[2-(trifluoromethyl)pyrimidin-4-yl]pyrazol-3-yl]bicyclo[3.1.0]hexane-3-one (80 mg, 0.23 mmol) in methanol (8 mL) was added morpholine (0.1 mL, 1.14 mmol) and acetic acid (0.06 mL, 0.69 mmol), NaBH3CN (43 mg, 0.69 mmol) and stirred at 60°C for 16 hours. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organics were washed with brine (50 mL x 2), dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase chromatography (Boston Prime C18 150*30mm*5um; water (0.05% NH3H2O+10mM NH4HCO3)-ACN; 60% to 90%) to provide compound 98 (first peak on SFC, 43.49 mg, 45% yield) and compound 99 (second peak on SFC, 26.71 mg, 27% yield). LCMS (ESI) [M+H]+=422.1. Relative stereochemistry was determined by 2D-NMR.

[0673] Compound 98: 1 H NMR (400MHz, CD3OD) δ8.83(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).

[0674] Compound 99: 1 H NMR (400MHz, CD3OD) δ8.84(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).

[0675] 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)

[0676]

[0677] The title compound was synthesized using a procedure similar to that of 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*30mm*5um; water (0.05% NH3H2O+10mM NH4HCO3)-ACN; 65% to 95%) to provide compound 100 (second peak on SFC, 33.93 mg, 27% yield) and compound 101 (first peak on SFC, 34.36 mg, 28% yield). LCMS (ESI) [M+H] + = 436.3. The relative stereochemistry was determined by 2D-NMR.

[0678] Compound 100: 1 H NMR(400MHz,CD3OD)δ8.84(d,J=5.2Hz,1H),8.12(d,J=5.6Hz,1H),6.64(s,1H),4.86–4 .83(m,1H),3.72–3.68(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).

[0679] Compound 101: 1 H NMR(400MHz,CD3OD)δ8.84(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).

[0680] 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)

[0681]

[0682] The title compound was synthesized using a procedure similar to that of 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*30mm*5um; water (0.05% NH3H2O+10mM NH4HCO3)-ACN; 65% to 95%) to provide compound 102 (second peak on SFC, 27.8 mg, 18% yield) and compound 103 (first peak on SFC, 34.53 mg, 22% yield). LCMS (ESI) [M+H] + =436.3

[0683] Relative stereochemistry was determined by 2D-NMR.

[0684] Compound 102: 1 H NMR (400MHz, CD3OD) δ8.83(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),3.1 0–3.00(m,1H),2.88–2.75(m,1H),2.74–2.68(m,1H),2.50–2.41(m,1H),2.3 3–2.16(m,2H),1.94–1.76(m,5H),1.54(d,J=6.8Hz,6H),1.13–1.09(m,3H).

[0685] Compound 103: 1H NMR (400MHz, CD3OD) δ8.84(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=3.2Hz,1H),1.77–1.69(m,4H),1.56(d,J=6.8Hz,6H),1.09(d,J=6.4Hz,3H).

[0686] 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)

[0687]

[0688] The title compound was synthesized in step 1 using 6-(trifluoromethyl)nicotinamidine hydrochloride and (S)-3-oxocyclopentanecarboxylic acid according to a procedure similar to compound 68. The crude mixture was purified by flash chromatography on silica gel (0% to 65% ethyl acetate in petroleum ether) to provide the title compound (90 mg, 73.6% yield) as a diastereomeric mixture. A chiral SFC (DAICEL CHIRALPAK OD (250 mm * 30 mm, 10 um) was used for the separation of diastereomeric mixtures (90.0 mg, 0.22 mmol); 0.1% NH H O ETOH 15 / 15; 60 mL / min) to provide compound 104 (the first peak on SFC, 14.39 mg, 15.3% yield) and compound 105 (the second peak on SFC, 41.4 mg, 45.5% yield). LCMS (ESI) [M+H] + = 410.2. Relative stereochemistry was determined by 2D-NMR.

[0689] Compound 104: 1H NMR (400MHz, CD3OD) δ9.32(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) ,3.01–2.93(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).

[0690] Compound 105: 1 H NMR (400MHz, CD3OD) δ9.32 (s, 1H), 8.60 (d, J = 8.4Hz, 1H), 7.90 (d, J = 8.4Hz, 1 H),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),2.61(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).

[0691] 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)

[0692]

[0693] Step 1: 1-(3-((tert-Butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-3-(6-(trifluoromethyl)pyrimidin-4-yl)propane-1,3-dione

[0694]

[0695] To a solution of 1-[3-[tert-butyl(diphenyl)silyl]oxy-6-bicyclo[3.1.0]hexyl]ethanone (1.0 g, 2.64 mmol) in tetrahydrofuran (10 mL) was added NaH (0.16 g, 3.96 mmol, 60% in mineral oil) at 0 ° C under N2 atmosphere and stirred at 0 ° C for 1 hour. Then 6-(trifluoromethyl)pyrimidine-4-carboxylic acid methyl ester (0.82 g, 3.96 mmol) was added to the above reaction mixture and stirred at 20 ° C for 2 hours. The reaction was quenched with NH4Cl aqueous solution (20 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0% to 5% ethyl acetate in petroleum ether) to provide the title compound (1200 mg, 95.7% yield). LCMS (ESI), [M+H]+=553.2.

[0696] 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

[0697]

[0698] To a solution of 1-[3-[tert-butyl(diphenyl)silyl]oxy-6-bicyclo[3.1.0]hexyl]-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 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (0% to 25% ethyl acetate in petroleum ether) to provide the title compound (1000 mg, 78% yield). LCMS (ESI), [M+H] + = 591.2.

[0699] 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

[0700]

[0701] To a stirred solution of tert-butyl-diphenyl-[[external rotation-(1R, 5S)-6-[2-isopropyl-5-[6-(trifluoromethyl) pyrimidin-4-yl] pyrazol-3-yl]-3-bicyclo[3.1.0]hexyl]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 hours. The reaction mixture was adjusted to pH=9 with an aqueous NaOH solution (4 M). The resulting solution was extracted with dichloromethane (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0% to 50% ethyl acetate in petroleum ether) to provide the title compound (550 mg, 91.3% yield). LCMS (ESI), [M+H]+=353.2.

[0702] Step 4: (1R,5S,6r)-6-(1-isopropyl-3-(6-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one

[0703]

[0704] To a solution of (1R,5S)-6-[2-isopropyl-5-[6-(trifluoromethyl)pyrimidin-4-yl]pyrazol-3-yl]bicyclo[3.1.0]hexane-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 N2. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with an aqueous Na2S2O3 solution (10 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with an aqueous NaHCO3 solution (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0% to 25% ethyl acetate in petroleum ether) to provide the title compound (350 mg, 63.4% yield). LCMS (ESI), [M+H]+=351.3. 1 H NMR(400MHz,CD3OD)δ9.24(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).

[0705] 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)

[0706]

[0707] To a solution of rac-(1R,5S)-6-[2-isopropyl-5-[6-(trifluoromethyl)pyrimidin-4-yl]pyrazol-3-yl]bicyclo[3.1.0]hexane-3-one (100 mg, 0.29 mmol) in methanol (4 mL) was added (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) 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 x 2). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered and concentrated under vacuum. The residue was purified by reverse phase chromatography (water (0.05% NH 3 H 2 O + 10 mM NH 4 HCO 3 )-ACN, 65% to 95%) to provide compound 202 (first peak on HPLC, 21.28 mg, 15.7% yield) and compound 106 (second peak on HPLC, 27.83 mg, 28.3% yield). LCMS (ESI) [M+H] + = 436.2. Relative stereochemistry was determined by 2D-NMR.

[0708] Compound 202: 1 H NMR(400MHz,CD3OD)δ9.22(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),1.8 3(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).

[0709] Compound 106: 1H NMR (400MHz, CD3OD) δ9.22(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=2.8 Hz,1H),1.76–1.65(m,4H),1.57(d,J=6.8Hz,6H),1.11(d,J=6.4Hz,3H).

[0710] 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)

[0711]

[0712] The title compound was synthesized in step 1 using methyl 6-(trifluoromethyl)pyrazine-2-carboxylate and 1-[3-[tert-butyl(diphenyl)silyl]oxy-6-bicyclo[3.1.0]hexyl]ethanone according to a procedure similar to compound 202. The crude mixture was purified by reverse phase chromatography (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, 55% to 80%) to provide the title compound 107 (first peak on HPLC, 8.8 mg, 6.9% yield) and the title compound 108 (second peak on HPLC, 11 mg, 8.8% yield). LCMS (ESI) [M+H] + = 422.3. The relative stereochemistry was determined by 2D-NMR.

[0713] Compound 107: 1 H NMR(400MHz,CD3OD)δ9.38(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).

[0714] Compound 108: 1 H NMR(400MHz,CD3OD)δ9.38(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).

[0715] 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*)

[0716]

[0717] The title compound was synthesized following a procedure analogous to compound 68 using 2-(trifluoromethyl)pyrimidine-5-carboximidamide hydrochloride and (S)-3-oxocyclopentanecarboxylic acid in step 1. The crude mixture was purified by silica gel flash chromatography (0% to 10% methanol in dichloromethane) to provide the title compound as a mixture of diastereomers (300 mg, 56.3% yield).

[0718] The diastereomeric mixture (300 mg, 0.68 mmol) was separated using chiral SFC (DAICEL CHIRALPAK IE (250 mm*30 mm, 10 um); hexane-IPA (0.1% NH4OH), 10 / 10; 25 mL / min) to provide compound 109* (first peak on SFC, 50.08 mg, 16% yield) and compound 110* (second peak on SFC, 45.7 mg, 14% yield). LCMS (ESI), [M+H] + = 439.3. The relative stereochemistry was assigned arbitrarily.

[0719] Compound 109*: 1H NMR (400MHz, CD3OD) δ9.51 (s, 2H), 4.81–4.74 (m, 1H), 3.88 (dd, J = 2.0, 11.6H z,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),2.28–2.14(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).

[0720] Compound 110*: 1 H NMR (400MHz, CD3OD) δ9.51 (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).

[0721] 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*)

[0722]

[0723] The title compound was synthesized using 3-fluoro-4-(trifluoromethyl)benzimidamide and (S)-3-oxocyclopentanecarboxylic acid in step 1 according to a procedure similar to compound 68. The crude mixture was purified by reverse phase chromatography (Boston Prime C18 150*30mm*5um / water (NH3H2O+NH4HCO3)-ACN), 35% to 65%) to provide compound 111* (second peak on SFC, 18.1 mg, 12.4% yield) and compound 112* (first peak on SFC, 11.91 mg, 8.2% yield). LCMS (ESI), [M+H] + = 427.1. The relative stereochemistry was assigned arbitrarily.

[0724] Compound 111*: 1 H NMR (400MHz, CDCl3) δ7.97–7.91(m,2H),7.62(t,J=8.0Hz,1H),4.56–4.49(m,1H),3.85–3.75(m,4H) ,3.29–3.24(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).

[0725] Compound 112*: 1 H 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).

[0726] 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*)

[0727]

[0728] The title compound was synthesized in step 1 using 3-fluoro-4-(trifluoromethyl)benzimidamide and (R)-3-oxocyclopentanecarboxylic acid according to a procedure similar to compound 68. The crude mixture was purified by reverse phase chromatography (Boston Prime C18 150*30mm*5um / water (0.5% NH3H2O+NH4HCO3)-CAN, 35% to 65%) to provide the title compound 113* (second peak on SFC, 11.65 mg, 16% yield) and compound 114* (first peak on SFC, 6.71 mg, 8.9% yield). LCMS (ESI), [M+H] + = 427.2. The relative stereochemistry was assigned arbitrarily.

[0729] Compound 113*: 1 H NMR (400MHz, CDCl3) δ7.97–7.91(m,2H),7.62(t,J=7.6Hz,1H),4.58–4.49(m,1H),3.80(s,4H) ,3.30–3.21(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).

[0730] Compound 114*: 1 H NMR (400MHz, CDCl3) δ7.97–7.91(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).

[0731] 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*)

[0732]

[0733] Step 1: 3-(5-Bromo-1-isopropyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)pyridine.

[0734]

[0735] 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)Cl2 (544.0 mg, 0.74 mmol) and K2CO3 (3.08 g, 22.31 mmol). The reaction mixture was degassed and purged with N2 three times and stirred at 90 ° C under N2 for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 10% ethyl acetate in petroleum ether) to provide the title compound (600 mg, 24.1% yield). LCMS (ESI), [M+H] + =335.0.

[0736] Step 2: 3-(1-Isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopent-2-enone.

[0737]

[0738] To a solution of 3-(5-bromo-1-isopropyl-1H-1,2,4-triazole-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)Cl2 (131.0 mg, 0.18 mmol) and K2CO3 (742 mg, 5.37 mmol). The reaction mixture was degassed and purged with N2 three times and stirred at 100 ° C under N2 for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 20% ethyl acetate in petroleum ether) to provide the title compound (350 mg, 58.1% yield). LCMS (ESI), [M+H] + =337.2.

[0739] Step 3: 3-(1-Isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentanone.

[0740]

[0741] 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 and purged with H2 three times and stirred at 25 ° C under H2 (15 psi) for 1 hour. 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.

[0742] Step 4: 4-(3-(1-Isopropyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazol-5-yl)cyclopentyl)morpholine.

[0743]

[0744] 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 methanol (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 hour. The mixture was then adjusted to pH 7-8 with NaHCO (aqueous solution) and extracted with dichloromethane (20 mL x 3). The combined organics were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0% to 10% methanol in dichloromethane) to provide the title compound (200 mg, 64% yield). LCMS (ESI), [M+H] + =410.1.

[0745] 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 )-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*)

[0746]

[0747] The diastereomeric mixture (200.0 mg, 0.49 mmol) was separated using chiral SFC (Daicel Chiralcel OD-H (250 mm*30 mm, 5 um) / 0.1% NH 3 H 2 O IPA, 15 / 15) to provide compound 115* (first peak on SFC, 10.22 mg, 5.1% yield), compound 116* (second peak on SFC, 9.39 mg, 4.7% yield), compound 117* (third peak on SFC, 19.62 mg, 9.8% yield) and compound 118* (fourth peak on SFC, 31.73 mg, 15.9% yield). LCMS (ESI), [M+H] + = 410.1. The relative stereochemistry is arbitrarily assigned.

[0748] Compound 115*: 1 H NMR (400MHz, CD3OD) δ9.43(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),3.01–2.93(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).

[0749] Compound 116*: 11H NMR (400 MHz, CD3OD) δ 9.43 (s, 1H), 8.90 (s, 1H), 8.65 (s, 1H), 4.81–4.74 (m, 1H), 3.73 (t, J = 4.4 Hz, 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, 6.8 Hz, 6H).

[0750] Compound 117*: 1 1H NMR (400 MHz, CD3OD) δ 9.43 (d, J = 1.6 Hz, 1H), 8.90 (s, 1H), 8.65 (s, 1H), 4.80–4.73 (m, 1H), 3.73 (t, J = 4.8 Hz, 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, 6.4 Hz, 6H).

[0751] Compound 118*: 1 1H NMR (400 MHz, CD3OD) δ 9.43 (d, J = 1.6 Hz, 1H), 8.89 (s, 1H), 8.65 (s, 1H), 4.80–4.73 (m, 1H), 3.73 (t, J = 4.8 Hz, 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, 6.4 Hz, 6H).

[0752] Examples A-Z:(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)

[0753]

[0754] The title compound was synthesized in step 1 using 5-(trifluoromethyl)nicotinamide hydrochloride and (1R,5S)-3-[tert-butyl(diphenyl)silyl]oxybicyclo[3.1.0]hexane-6-carboxylic acid according to a procedure similar to compound 68. The crude mixture was purified by reverse phase chromatography (water (NH3H2O ​​+ NH4HCO3)-ACN, 55% to 85%, 25 ml / min) to provide compound 119 (first peak on HPLC, 15.3 mg, 20.3% yield) and compound 120 (second peak on HPLC, 23.5 mg, 31.2% yield). LCMS (ESI), [M+H] + = 436.2. The relative stereochemistry was determined by 2D-NMR.

[0755] Compound 119: 1 H NMR(400MHz,CD3OD)δ9.38(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).

[0756] Compound 120: 1H NMR (400MHz, CD3OD) δ9.38(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).

[0757] 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)

[0758]

[0759] The title compound was synthesized in step 1 using 5-(trifluoromethyl)nicotinamide hydrochloride and (1R,5S)-3-[tert-butyl(diphenyl)silyl]oxybicyclo[3.1.0]hexane-6-carboxylic acid according to a procedure similar to compound 68. The crude mixture was purified by reverse phase chromatography (water (NH3H2O ​​+ NH4HCO3)-ACN, 50% to 80%, 25 ml / min) to provide compound 121 (first peak on HPLC, 22.04 mg, 27.8% yield) and compound 122 (second peak on HPLC, 26 mg, 34.5% yield). LCMS (ESI), [M+H] + = 436.2. The relative stereochemistry was determined by 2D-NMR.

[0760] Compound 121: 1H NMR (400MHz, CD3OD) δ9.38(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).

[0761] Compound 122: 1 H NMR (400MHz, CD3OD) δ9.37(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),2.53–2.49(m,1H),2.33–2.20(m,2H),2.16–2.15(m,1H),2.04(b rs,2H),1.85–1.72(m,2H),1.58(d,J=6.4Hz,6H),1.09(d,J=6.4Hz,3H).

[0762] 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)

[0763]

[0764] The title compound was synthesized using 5-fluoronicotinamide and (S)-3-oxocyclopentanecarboxylic acid in step 1 according to a procedure similar to compound 68. The crude mixture was purified by silica gel flash chromatography (0% to 10% methanol in dichloromethane) to give the title compound (80 mg) as a mixture of diastereomers, which was purified using chiral SFC (SFC-16; DAICELCHIRALPAK IG (250 mm*30 mm, 10 um); 0.1% NH3H2O ​​MEOH, 35 / 35; 70 mL / min) to provide compound 123 (59.61 mg, 75% yield). LCMS (ESI) [M+H] + = 388.3. The relative stereochemistry was determined by 2D-NMR.

[0765] Compound 123: 1H NMR (400MHz, CDCl3) δ9.11(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),2.92–2.89(m,2H),2.88–2.85(m,1H),2.36–2.22(m,2H),2.15–2.10(m,2H),2.08–2.0 5(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).

[0766] 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)

[0767]

[0768] The title compound was synthesized using 5-fluoronicotinamidine and (S)-3-oxocyclopentanecarboxylic acid in step 1 according to a procedure similar to compound 68. The crude mixture was purified by silica gel flash chromatography (0% to 10% methanol in dichloromethane) to give the title compound (80 mg) as a mixture of diastereomers, which was purified using chiral SFC (SFC-16; DAICELCHIRALPAK IG (250 mm*30 mm, 10 um); 0.1% NH3H2O ​​MEOH, 35 / 35; 70 mL / min) to provide compound 124 (48.82 mg, 61% yield). LCMS (ESI) [M+H] + = 388.3. The relative stereochemistry was determined by 2D-NMR.

[0769] Compound 124: 1H NMR (400MHz, CDCl3) δ9.11(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).

[0770] 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)

[0771]

[0772] The title compound was synthesized using 5-chloronicotinamidine and (S)-3-oxocyclopentanecarboxylic acid in step 1 according to a procedure similar to compound 68. The crude mixture was purified by flash chromatography on silica gel (0% to 10% methanol in dichloromethane) to provide 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 * 30 mm, 10 um); 0.1% NH H O MEOH, 35 / 35; 70 mL / min) to provide compound 125 (the first peak on SFC, 6.7 mg, 6% yield) and compound 126 (the second peak on SFC, 62.8 mg, 57% yield). LCMS (ESI) [M+H] + = 390.2. Relative stereochemistry was determined by 2D-NMR.

[0773] Compound 125: 1H NMR (400MHz, CD3OD) δ9.09(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),2.62–2.59(m,1H),2.24–2.20(m,2H),2.10–2.04(m,2H),2.00–1.8 9(m,1H),1.80–1.67(m,1H),1.53(d,J=6.8Hz,6H),1.15(d,J=6.4Hz,3H).

[0774] Compound 126: 1 H NMR (400MHz, CD3OD) δ9.10(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,3 H), 1.94–1.85 (m, 1H), 1.54 (dd, J = 3.2, 6.4Hz, 6H), 1.13 (d, J = 6.4Hz, 3H).

[0775] 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)

[0776]

[0777] The title compound was synthesized in step 1 using 6-(trifluoromethyl)nicotinamide hydrochloride and (S)-3-oxocyclopentanecarboxylic acid according to a procedure similar to compound 68. The crude mixture was purified by flash chromatography on silica gel (0% to 10% methanol in dichloromethane) to provide the title compound (100 mg) as a mixture of diastereomers. The diastereomers were separated using chiral SFC (DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); 0.1% NH4OH; IPA, 15 / 15, 70 mL / min) to provide compound 127 (76.74 mg, 77% yield). LCMS (ESI), [M+H] += 438.2. The relative stereochemistry was determined by 2D-NMR.

[0778] Compound 127: 1 H NMR (400MHz, CD3OD) δ9.32(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,2 H),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).

[0779] 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)

[0780]

[0781] The title compound was synthesized in step 1 using 6-(trifluoromethyl)nicotinamide hydrochloride and (S)-3-oxocyclopentanecarboxylic acid according to a procedure similar to compound 68. The crude mixture was purified by flash chromatography on silica gel (0% to 10% methanol in dichloromethane) to provide the title compound (100 mg) as a mixture of diastereoisomers. The diastereoisomer mixture was separated using chiral SFC (DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); 0.1% NH4OH; EtOH, 10 / 10, 70 mL / min) to provide compound 128 (76.8 mg, 77% yield). LCMS (ESI), [M+H] + = 438.2. The relative stereochemistry was determined by 2D-NMR.

[0782] Compound 128: 1H NMR (400MHz, CD3OD) δ9.32(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).

[0783] Instance 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)

[0784]

[0785] The title compound was synthesized using 5-chloronicotinamidine and (S)-3-oxocyclopentanecarboxylic acid in step 1 according to a procedure similar to compound 68. The crude mixture was purified by flash chromatography on silica gel (0% to 10% methanol in dichloromethane) to provide 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 um); 0.1% NH H OETOH, 40 / 40, 80 mL / min) to provide compound 129 (62.9 mg, 63% yield). LCMS (ESI), [M+H] + = 404.2. The relative stereochemistry was determined by 2D-NMR.

[0786] Compound 129: 1H NMR (400MHz, CD3OD) δ9.10(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) ,3.57–3.36(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).

[0787] 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*)

[0788]

[0789] Step 1: (S)-3-(1-Isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentanone

[0790]

[0791] A mixture of (S)-3-(3-bromo-1-isopropyl-1H-pyrazol-5-yl)cyclopentanone (500 mg, 1.84 mmol, second peak on 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)palladium(II) chloride (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 hours. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography on silica gel (0% to 20% ethyl acetate in petroleum ether) to provide the title compound (600 mg, 93% yield). LCMS (ESI), [M+H] + = 338.9.

[0792] Step 2: ((2R)-4-((3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholin-2-yl)methanol

[0793]

[0794] To a mixture of (S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazole-5-yl)cyclopentanone (300mg, 0.89mmol) in dichloromethane (3mL), (R)-morpholine-2-ylmethanol hydrochloride (272mg, 1.77mmol) and N,N-diisopropylethylamine (344mg, 2.66mmol) was added and stirred at 25°C for 16 hours. NaBH(OAc) was then added (564mg, 2.66mmol) and stirred at 25°C for 16 hours. The mixture was diluted with water (10mL) and the NaHCO aqueous solution was used to adjust the pH to 9. The resulting mixture was extracted with ethyl acetate (50mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel flash chromatography (0% to 2% methanol in dichloromethane) to provide the title compound as a mixture of diastereomers (300 mg, 77% yield). LCMS (ESI), [M+H] + = 440.2.

[0795] Step 3: (2R)-2-(Fluoromethyl)-4-((3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine

[0796]

[0797] 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 a NaHCO3 aqueous solution. The resulting mixture was extracted with ethyl acetate (50 mL x 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 provide the title compound (100 mg, 66% yield) as a mixture of diastereomers. LCMS (ESI), [M+H]+=442.3.

[0798] 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*)

[0799]

[0800] The diastereomers (100 mg, 0.23 mmol) were separated using chiral SFC (SFC-22, DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm), 0.1% NH H O ETOH, 15 / 15, 80 ml / min) to provide compound 130* (trans isomer, first peak on SFC, 8.34 mg, 8% yield) and compound 131* (cis isomer, second peak on SFC, 28.78 mg, 28% yield). LCMS (ESI), [M+H] + = 442.3. Relative stereochemistry is arbitrarily assigned.

[0801] Compound 130*: 1 H NMR (400MHz, CD3OD) δ9.31(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).

[0802] Compound 131*: 1H NMR(400MHz,CD3OD)δ9.31(s,2H),6.78(s,1H),4.70–4.63(m,1H),4.47(d,J=4.0Hz,1 H),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).

[0803] 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*)

[0804]

[0805] Step 1: ((2S)-4-((3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholin-2-yl)methanol

[0806]

[0807] To a mixture of (S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazole-5-yl)cyclopentanone (300mg, 0.89mmol) in dichloromethane (3mL), (S)-morpholine-2-ylmethanol hydrochloride (272mg, 1.77mmol) and N,N-diisopropylethylamine (344mg, 2.66mmol) was added and stirred at 25°C for 16 hours. NaBH(OAc) was then added (564mg, 2.66mmol) and stirred at 25°C for 16 hours. The mixture was diluted with water (25mL) and the NaHCO aqueous solution was used to adjust the pH to 9. The resulting mixture was extracted with ethyl acetate (50mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel flash chromatography (0% to 2% methanol in dichloromethane) to provide the title compound as a mixture of diastereomers (350 mg, 90% yield). LCMS (ESI), [M+H] + = 440.3

[0808] Step 2: (2S)-2-(Fluoromethyl)-4-((3S)-3-(1-isopropyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)cyclopentyl)morpholine

[0809]

[0810] 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 a NaHCO3 aqueous solution. The resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether / ethyl acetate / ethanol=4 / 3 / 1) to provide the title compound (100 mg, 66% yield) as a mixture of diastereomers. LCMS (ESI), [M+H]+=442.3

[0811] 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*)

[0812]

[0813] The diastereomers (100 mg, 0.23 mmol) were separated using chiral SFC (SFC-11, DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um), 0.1% NH 3 H 2 O MEOH, 20 / 20, 70 ml / min) to provide compound 132* (trans isomer, first peak on SFC, 11.93 mg, 12% yield) and compound 133* (cis isomer, second peak on SFC, 37.02 mg, 37% yield). LCMS (ESI), [M+H] + = 442.3.

[0814] Compound 132*: 1 H NMR(400MHz,CD3OD)δ9.31(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).

[0815] Compound 133*: 1H NMR (400MHz, CD3OD) δ9.31(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),3.8 3–3.66(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).

[0816] 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)

[0817]

[0818] The title compound was synthesized in step 1 using 2-(trifluoromethyl)pyrimidine-5-carboximidamide and (S)-3-oxocyclopentanecarboxylic acid according to a procedure similar to compound 68. The crude mixture was purified by flash chromatography on silica gel (0% to 5% methanol in dichloromethane) to provide 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% NH4OH; EtOH, 25 / 25, 70 ml / min) to provide compound 134 (the second peak on SFC, 43.96 mg, 44% yield) and compound 135 (the first peak on SFC, 4.53 mg, 4.5% yield). LCMS (ESI), [M+H] + = 425.2. Relative stereochemistry was determined by 2D-NMR.

[0819] Compound 134: 1H NMR(400MHz,CD3OD)δ9.51(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) ,2.42–2.36(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).

[0820] Compound 135: 1 H NMR(400MHz,CD3OD)δ9.51(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) ,2.26–2.17(m,4H),2.12–2.04(m,1H),1.99–1.93(m,1H),1.91–1.85(m,1 H), 1.71–1.60 (m, 1H), 1.54 (dd, J = 2.4, 6.8Hz, 6H), 1.16 (d, J = 6.4Hz, 3H).

[0821] 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)

[0822]

[0823] The title compound was synthesized using 5-fluoro-6-(trifluoromethyl)nicotinamide and (S)-3-oxocyclopentanecarboxylic acid in step 1 according to a procedure similar to compound 68. The crude mixture was purified by silica gel flash chromatography (0% to 50% ethyl acetate in petroleum ether) to provide the title compound 146 (25.0 mg, 45% yield). LCMS (ESI), [M+H] = 456.2. Relative stereochemistry was determined by 2D-NMR.

[0824] Compound 146: 1H NMR (400MHz, CD3OD) δ9.14 (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),1.8 8–1.82(m,1H),1.53(dd,J=3.6,6.4Hz,6H),1.50–1.44(m,2H),0.95(t,J=7.6Hz,3H).

[0825] 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)

[0826]

[0827] The title compound was synthesized using 5-fluoro-6-(trifluoromethyl)nicotinamide and (S)-3-oxocyclopentanecarboxylic acid in step 1 according to a procedure similar to compound 68. The crude mixture was purified by silica gel flash chromatography (0% to 50% ethyl acetate in petroleum ether) to provide the title compound 147 (23.9 mg, 13.5% yield). LCMS (ESI), [M+H] = 456.2. Relative stereochemistry was determined by 2D-NMR.

[0828] Compound 147: 1 H NMR (400MHz, CD3OD) δ9.14 (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,1 H), 1.53 (dd, J = 2.4, 6.4Hz, 6H), 1.51–1.45 (m, 2H), 0.96 (t, J = 7.2Hz, 3H).

[0829] 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)

[0830]

[0831] The title compound was synthesized using 2-(trifluoromethyl)pyrimidine-5-carboximidamide and (R)-3-oxocyclopentanecarboxylic acid in step 1 according to a procedure similar to compound 68. The crude mixture was purified by reverse phase chromatography (Boston Prime C18 150*30mm*5um / water (NH3H2O+NH4HCO3)-CAN, 35% to 65%) to provide compound 148 (second peak on SFC, 54.48 mg, 43.1% yield) and compound 149 (first peak on SFC, 7.18 mg, 4.7% yield). LCMS (ESI), [M+H] + = 425.2. The relative stereochemistry was determined by 2D-NMR.

[0832] Compound 148: 1 H NMR (400MHz, CD3OD) δ9.51(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).

[0833] Compound 149: 1H NMR (400MHz, CD3OD) δ9.51(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)

[0834] 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)

[0835]

[0836] The title compound was synthesized using 2-(trifluoromethyl)pyrimidine-5-carboximidamide and (R)-3-oxocyclopentanecarboxylic acid in step 1 according to a procedure similar to compound 68. The crude mixture was purified by reverse phase chromatography (Boston Prime C18 150*30mm*5um / water (NH3H2O+NH4HCO3)-CAN, 35% to 65%) to provide compound 150 (second peak on SFC, 68.53 mg, 44.7% yield) and compound 151 (first peak on SFC, 16.03 mg, 10.4% yield). LCMS (ESI), [M+H] + = 425.1. The relative stereochemistry was determined by 2D-NMR.

[0837] Compound 150: 1H NMR(400MHz,CD3OD)δ9.51(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) ,2.43–2.36(m,1H),2.25–2.14(m,2H),2.10–2.02(m,2H),1.99–1.90(m,2 H), 1.88–1.82 (m, 1H), 1.54 (dd, J = 3.2, 6.8Hz, 6H), 1.14 (d, J = 6.4Hz, 3H).

[0838] Compound 151: 1 H NMR(400MHz,CD3OD)δ9.51(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).

[0839] 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)

[0840]

[0841] The title compound was synthesized using 2-(trifluoromethyl)pyrimidine-5-carboximidamide and (R)-3-oxocyclopentanecarboxylic acid in step 1 according to a procedure similar to compound 68. The crude mixture was purified by reverse phase chromatography (Boston Prime C18 150*30mm*5um / water (NH3H2O+NH4HCO3)-CAN, 30% to 70%) to provide compound 152 (second peak on SFC, 48.92 mg, 37.5% yield) and compound 153 (first peak on SFC, 5.59 mg, 3.2% yield). LCMS (ESI), [M+H] + = 439.2. The relative stereochemistry was determined by 2D-NMR.

[0842] Compound 152: 1 H NMR(400MHz,CD3OD)δ9.51(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) ,2.42–2.36(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,1 H),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).

[0843] Compound 153: 1 H NMR(400MHz,CD3OD)δ9.51(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).

[0844] 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)

[0845]

[0846] The title compound was synthesized using 2-(trifluoromethyl)pyrimidine-5-carboximidamide and (R)-3-oxocyclopentanecarboxylic acid in step 1 according to a procedure similar to compound 68. The crude mixture was purified by reverse phase chromatography (Boston Prime C18 150*30mm*5um / water (NH3H2O+NH4HCO3)-CAN, 30% to 70%) to provide compound 154 (second peak on SFC, 43.92 mg, 33.6% yield) and compound 155 (first peak on SFC, 4.71 mg, 2.9% yield). LCMS (ESI), [M+H] + = 439.2. The relative stereochemistry was determined by 2D-NMR.

[0847] Compound 154: 1 H NMR(400MHz,CD3OD)δ9.51(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,1H),1.54(dd,J=3.2,6.4Hz,6H),1.50–1.44(m,2H),0.95(t,J=7.6Hz,3H).

[0848] Compound 155: 1H NMR(400MHz,CD3OD)δ9.51(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) ,2.26–2.17(m,4H),2.09–2.04(m,1H),1.96–1.87(m,2H),1.71–1.64(m,1 H), 1.54 (dd, J = 2.4, 6.8 Hz, 6H), 1.52–1.47 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H).

[0849] 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)

[0850]

[0851] The title compound was synthesized in step 1 using 6-(difluoromethyl)nicotinamide and (S)-3-oxocyclopentanecarboxylic acid according to a procedure similar to compound 68. The crude mixture was purified by flash chromatography on silica gel (0% to 10% methanol in dichloromethane) to provide the title compound (60 mg, 0.13 mmol, 70% yield) as a diastereomeric mixture. The diastereomeric mixture (60 mg, 0.13 mmol) was separated using chiral SFC (Daicel Chiralpak AD (250 mm * 30 mm, 10 um); 0.1% NH 3 H 2 O; IPA; 60 / 60, 60 mL / min) to provide compound 156 (first peak on SFC, 25.39 mg, 41% yield). LCMS (ESI) [M+H] + = 420.3. The relative stereochemistry was determined by 2D-NMR.

[0852] Compound 156: 1H NMR (400MHz, CD3OD) δ9.25 (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).

[0853] 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*)

[0854]

[0855] Step 1: 5-(5-Bromo-1-isopropyl-1H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine

[0856]

[0857] 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)pyridine-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 N2 three times, and then the reaction mixture was stirred at 90 ° C under N2 for 1 hour. A black suspension was formed. The reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0% to 30% ethyl acetate in petroleum ether) to provide the title compound (850 mg, 32.6% yield). LCMS (ESI) [M+H] + =350.2.

[0858] Step 2: 3-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopent-2-enone

[0859]

[0860] A suspension of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (177mg, 0.24mmol), potassium carbonate (1g, 7.27mmol), 5-(5-bromo-1-isopropyl-1,2,4-triazole-3-yl)-3-(trifluoromethyl)pyridine-2-amine (850mg, 2.43mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-ene-1-one (757mg, 3.64mmol) in 1,4-dioxane (10mL) and water (2mL) was degassed and purged three times with N2, and the reaction mixture was then stirred at 90°C under N2 for 4 hours. The reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0% to 30% ethyl acetate in petroleum ether) to provide the title compound (500mg, 58.6% yield). LCMS (ESI) [M+H] + =352.1.

[0861] Step 3: 3-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-1,2,4-triazol-5-yl)cyclopentanone

[0862]

[0863] To a solution of 3-[5-[6-amino-5-(trifluoromethyl)-3-pyridyl]-2-isopropyl-1,2,4-triazol-3-yl]cyclopent-2-ene-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 at 20 ° C under H2 (15 psi) for 12 hours. The reaction mixture was filtered and the filter cake was washed with methanol (10 mL x 2). The combined organic layers were concentrated under vacuum to provide the title compound (200 mg, 99.4% yield). LCMS (ESI) [M+H] + =354.1.

[0864] Step 4: 5-(1-Isopropyl-5-(3-morpholinocyclopentyl)-1H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine

[0865]

[0866] 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)3 (1607 mg, 7.58 mmol). The mixture was stirred at 60 ° C for 2 hours. The reaction mixture was diluted with ethyl acetate (60 mL) and the resulting mixture was washed with brine (30 mL x 3). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0% to 10% methanol in dichloromethane) to provide the title compound (570 mg, 70.8% yield). LCMS (ESI) [M+H] + =425.2.

[0867] 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

[0868]

[0869] 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 um)); 0.1% NH3H2O+ETOH, 30 / 30; 60 mL / min) to provide the title compound-1 (first peak on SFC (diastereoisomer mixture, 175 mg, 30.7% yield) and the title compound-2 (second peak on SFC, 170 mg, 29.8% yield).

[0870] 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*)

[0871]

[0872] To a mixture of 5-[1-isopropyl-5-[racemized-(1R, 5S)-3-morpholino-6-bicyclo[3.1.0]hexyl]pyrazol-3-yl]-3-(trifluoromethyl)pyridine-2-amine (140mg, 0.33mmol) in pyridine (1mL) at 0°C, hydrogen fluoride-pyridine (2ml, 0.52mmol) was added, followed by the addition of sodium nitrite (14mg, 0.21mmol). 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 (10mL) and extracted with dichloromethane (20mLx 3). The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase chromatography (water (NH3H2O+NH4HCO3)-CAN, 25% to 55%). The diastereomeric mixture (70 mg) was separated using chiral SFC (Daicel Chiralpak AD (250 mm*30 mm, 10 um); 0.1% NH4OH+MeOH; 40 / 40; 60 mL / min) to provide compound 157* (first peak on SFC, 11.5 mg, 16% yield) and compound 158* (second peak on SFC, 49 mg, 70% yield). LCMS (ESI) [M+H] + = 428.3. The relative stereochemistry was assigned arbitrarily.

[0873] Compound 157*:1 H NMR (400MHz, CD3OD) δ8.79(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).

[0874] Compound 158*: 1 H NMR (400MHz, CD3OD) δ9.06 (s, 1H), 8.84–8.65 (m, 1H), 4.78–4.72 (m, 1H), 3.74 (t, J = 4.4Hz, 4H), 3.5 4–3.44(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).

[0875] 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*)

[0876]

[0877] 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 x 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% to 55%) to provide compound 159* (20 mg, 38.1% yield). LCMS (ESI) [M+H] + = 428.2. The relative stereochemistry was assigned arbitrarily.

[0878] Compound 159*: 1H NMR (400MHz, CD3OD) δ9.06 (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).

[0879] 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)

[0880]

[0881] The title compound was synthesized using 3-fluoro-4-(trifluoromethyl)benzimidamide and (S)-3-oxocyclopentanecarboxylic acid in step 1 following a procedure similar to compound 130*. The crude mixture was purified by preparative TLC (10% methanol in dichloromethane) to provide compound 160 (23.67 mg, 25.9% yield). LCMS (ESI), [M+H] + = 459.1. The relative stereochemistry was determined by 2D-NMR.

[0882] Compound 160: 1 H NMR (400MHz, CD3OD) δ8.01(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),3.5 1–3.43(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).

[0883] 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)

[0884]

[0885] The title compound was synthesized using 2-(trifluoromethyl)pyrimidine-5-carboximidamide and (S)-3-oxocyclopentanecarboxylic acid in step 1 according to a procedure similar to compound 130*. The crude mixture was purified by preparative TLC [(petroleum ether / (ethyl acetate / ethanol=3 / 1)]=1 / 1) to provide the title compound 161 (25.23 mg, 58.4% yield). LCMS (ESI), [M+H] + = 443.2. The relative stereochemistry was determined by 2D-NMR.

[0886] Compound 161: 1 H NMR (400MHz, CD3OD) δ9.51 (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),2.99–2.89(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).

[0887] 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)

[0888]

[0889] The title compound was synthesized using (1R, 5S, 6r) -6- (1-isopropyl -3- (5- (trifluoromethyl) pyridin-3-yl) -1H-1, 2, 4-triazol-5-yl) bicyclo [3.1.0] hexane-3-one and (2R) -2-methylmorpholine in the final step according to a procedure similar to compound 51. The crude mixture was purified by reverse phase chromatography (water (NH3H2O ​​+ NH4HCO3) -CAN, 20% to 50%) to provide the title compound 162 (first peak on HPLC (basic), 20.1 mg, 22.9% yield) and the title compound 163 (second peak on HPLC (basic), 27.1 mg, 30.8% yield). LCMS (ESI) [M + H] + = 436.1. The relative stereochemistry was determined by 2D-NMR.

[0890] Compound 162: 1 H NMR(400MHz,CD3OD)δ9.37(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)

[0891] Compound 163: 1 H NMR (400MHz, CD3OD) δ9.37(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),3.0 2–2.81(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).

[0892] 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, (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 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 164* and 165* and 166* and 167*)

[0893]

[0894] 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

[0895]

[0896] A suspension of tert-butyl-diphenyl-[[exo-(1R,5S)-6-(5-iodo-2-isopropyl-1,2,4-triazol-3-yl)-3-bicyclo[3.1.0]hexyl]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)Cl2 (92 mg, 0.13 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was degassed and purged with N2 three times and stirred at 90° C. under N2 for 4 hours. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel flash chromatography (0% to 10% ethyl acetate in petroleum ether) to provide the title compound (700 mg, 93.6% yield). LCMS (ESI) [M+H] + =594.4.

[0897] Step 2: Benzyl (Z)-(((1R,5S)-3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxamido)(methylthio)methylene)carbamate

[0898]

[0899] To a solution of tert-butyl-[[(1S, 5R)-6-[2-isopropyl-5-[4-(trifluoromethyl) cyclohexene-1-yl]-1,2,4-triazole-3-yl]-3-bicyclo[3.1.0]hexyl]oxy]-diphenyl-silane (700mg, 1.18mmol) in ethanol (10mL) was added 10% carbon-supported palladium (250mg, 0.24mmol) at 25°C, and the reaction mixture was then stirred at 25°C under H2 (15psi) for 12 hours. The reaction mixture was filtered and the filter cake was washed with methanol (10mL x 2). The combined organic layers were concentrated under vacuum to provide the title compound (700mg, 99.4% yield).

[0900] 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

[0901]

[0902] To a stirred solution of tert-butyl-diphenyl-[[exo-(1R, 5S)-6-[2-isopropyl-5-[4-(trifluoromethyl)cyclohexyl]-1,2,4-triazol-3-yl]-3-bicyclo[3.1.0]hexyl]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 hours. The reaction mixture was adjusted to pH = 9 with aqueous NaOH solution (4 M). The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0% to 50% ethyl acetate in petroleum ether) to provide the title compound (280 mg, 66.7% yield). LCMS (ESI) [M+H] + =358.3.

[0903] 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

[0904]

[0905] To a solution of (1R, 5S)-6-[2-isopropyl-5-[4-(trifluoromethyl)cyclohexyl]-1,2,4-triazol-3-yl]bicyclo[3.1.0]hexane-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 hours. 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 flash chromatography on silica gel (0% to 50% ethyl acetate in petroleum ether) to provide the title compound (220 mg, 76% yield). LCMS (ESI) [M+H] + =356.2.

[0906] 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

[0907]

[0908] 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 um)); 0.1% NH 3 H 2 O / IPA=30 / 30; 60 mL / min) to provide the title compound-1 (first peak on SFC, 50 mg, 22.7% yield) and the title compound-2 (second peak on SFC, 95 mg, 43% yield). LCMS (ESI) [M+H] + = 356.2. The relative stereochemistry was assigned arbitrarily.

[0909] 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*)

[0910]

[0911] To a solution of (3R)-3-methylmorpholine hydrochloride (155mg, 1.13mmol) and (1R, 5S, 6r)-6-(1-isopropyl-3-((1R, 4R)-4-(trifluoromethyl) cyclohexyl)-1H-1,2,4-triazol-5-yl) bicyclo[3.1.0]hexane-3-one (50mg, 0.14mmol) in anhydrous 1,2-dichloroethane (2mL) was added molecular sieves and N,N-diisopropylethylamine (0.12mL, 0.7mmol) at 25°C and stirred for 16 hours at 25°C. NaBH(OAc) was then added (149mg, 0.7mmol) and stirred at 65°C for 16 hours. Ethyl acetate (40mL) was added and the resulting mixture was washed with brine (30mL x 3). The organic matter was concentrated in vacuo. The residue was purified by reverse phase chromatography (water (NH3H2O ​​+ NH4HCO3)-CAN, 20% to 50%) to provide compound 164* (first peak on HPLC (basic), 5.98 mg, 9.6% yield) and compound 165* (second peak on HPLC (basic), 4.9 mg, 7.9% yield). LCMS (ESI) [M+H] + = 441.2. The relative stereochemistry is arbitrarily assigned.

[0912] Compound 164*: 1 H NMR (400MHz, CD3OD) δ4.79–4.72(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)

[0913] Compound 165*: 1 H NMR (400MHz, CD3OD) δ4.77–4.70(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),2.54–2.4 4(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).

[0914] 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*)

[0915]

[0916] To a solution of (3R)-3-methylmorpholine hydrochloride (310mg, 2.25mmol) and (1R, 5S, 6r)-6-(1-isopropyl-3-((1s, 4S)-4-(trifluoromethyl) cyclohexyl)-1H-1,2,4-triazol-5-yl) bicyclo[3.1.0]hexane-3-one (95mg, 0.28mmol) in anhydrous 1,2-dichloroethane (4mL) was added molecular sieves and N,N-diisopropylethylamine (0.25mL, 1.41mmol) at 25°C and stirred for 16 hours at 25°C. NaBH(OAc) was then added (149mg, 0.7mmol) and stirred at 65°C for 16 hours. Ethyl acetate (40mL) was added and the resulting mixture was washed with brine (30mL x 3). The organic matter was concentrated in vacuo. The residue was purified by reverse phase chromatography (water (NH3H2O ​​+ NH4HCO3)-CAN, 20% to 50%) to provide compound 166* (first peak on HPLC (basic), 14.1 mg, 11.4% yield) and compound 167* (second peak on HPLC (basic), 10.9 mg, 8.8% yield). LCMS (ESI) [M+H] + = 441.2. The relative stereochemistry is arbitrarily assigned.

[0917] Compound 166*: 1 H NMR (400MHz, CD3OD) δ4.78–4.71(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),2.83–2.6 6(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).

[0918] Compound 167*: 1 H NMR (400MHz, CD3OD) δ4.75–4.69(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).

[0919] 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*):

[0920]

[0921] 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

[0922]

[0923] To a solution of (S)-3-(1-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,4-triazole-5-yl)cyclopentanone (120.0 mg, 0.35 mmol) in dichloromethane (3 mL) was added [(2S)-morpholine-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) 3 (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 x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0% to 10% methanol in dichloromethane) to provide the title compound as a mixture of diastereomers (150 mg, 96% yield). LCMS (ESI), [M+H] + =440.3.

[0924] 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)

[0925]

[0926] 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 hours. The mixture was adjusted to pH 7-8 with NaHCO (aq.) and extracted with dichloromethane (20 mL x 3). The combined organics were washed with brine (20 mL x 2), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography (0% to 10% methanol in dichloromethane) to give the title compound (70 mg, 0.16 mmol, 49%), which was provided as a mixture of diastereomers. LCMS (ESI) [M+H] + =442.2. The diastereomeric mixture (70 mg, 0.16 mmol) was separated using chiral SFC (Daicel Chiralcel OD-H (250 mm*30 mm, 5 μm); 0.1% NH in H2O; ETOH; 15 / 15; 60 mL / min) to provide compound 168* (first peak on SFC, 11.07 mg, 15.3% yield) and compound 169* (second peak on SFC, 54.16 mg, 76.6% yield). Relative stereochemistry is arbitrarily assigned.

[0927] Compound 168*: 1H NMR(400MHz,CD3OD)δ9.32(s,1H),8.61(dd,J=1.6,8.0Hz,1H),7.90(d,J=8.0Hz,1 H),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,1 H),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),

[0928] Compound 169*: 1 H NMR(400MHz,CD3OD)δ9.32(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...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, in: n is 0 or 1; p is 1 or 2; Ring A is a saturated 5-membered or 6-membered monocyclic or bicyclic carbocyclic group; Ring B is phenyl, 6-membered heteroaryl or 6-membered saturated or partially saturated cycloalkyl, wherein the heteroaryl contains one or two heteroatoms; R 3 is independently selected in each case from the group consisting of C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, halo and cyano; G is N or CR G , where 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 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 ; R H 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 In each case selected from the group consisting of: 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's 1 The groups together form a -CH2- or -CH2CH2- bridge; R E and R F Each is 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.

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

3. The compound according to claim 1, wherein ring A is cyclopentyl or bicyclo[3.1.0]hexyl.

4. The compound according to claim 3, wherein Ring A is cyclopentyl and has the following formula:

5. The compound according to claim 3, wherein Ring A is bicyclo[3.1.0]hexane and has the following formula:

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

7. A compound according to any one of claims 1 to 5, wherein n is 1 and R 2 is selected from the group consisting of C1-C3 alkyl, halo and halo-C1-C3 alkyl, or wherein n is 1 and R 2 Selected from the group consisting of methyl, fluorine, -CF3, -CHF2.

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

11. The compound according to claim 10, which is a compound of the following formula:

12. The compound according to any one of claims 1 to 7, wherein ring B is pyridyl, pyrimidinyl or pyrazinyl. The compound according to claim 12 , wherein Ring B is pyridyl or pyrimidinyl.

14. The compound according to claim 1, wherein the compound is a compound of formula Ia or Ia': or a pharmaceutically acceptable salt thereof, in, Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently N, C or CH, provided that Y 1 , Y 2 , Y 3 , Y 4 and Y 5 Only one or both of can be N; or, or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1, wherein the compound is a compound of formula Ib: or a pharmaceutically acceptable salt thereof, in: Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently N, C or CH, provided that Y 1 , Y 2 , Y 3 , Y 4 and Y 5 Only one or both of can be N; and u is 1 or 2.

16. A compound according to claim 14 or claim 15, wherein Y 1 CH, Y 2 CR 3 , Y 3 CH, Y 4 is N, and Y 5 For CH.

17. A compound according to claim 14 or claim 15, wherein Y 1 CH, Y 2 N, Y 3 CR 3 , Y 4 is CH, and Y 5 For CH.

18. A compound according to claim 14 or claim 15, wherein Y 1 N, Y 2 CR 3 , Y 3 CH, Y 4 is CH, and Y 5 For CH.

19. A compound according to claim 14 or claim 15, wherein Y 1 CH, Y 2 CR 3 , Y 3 CH, Y 4 is CH, and Y 5 For CH.

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

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

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

23. A compound according to claim 14 or claim 15, wherein Y 1 CH, Y 2 CR 3 , Y 3 N, Y 4 is CH, and Y 5 is N.

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

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

26. A compound according to claim 14 or claim 15, wherein Y 1 CH, Y 2 N, Y 3 CR 3 , Y 4 CR 3 , and Y 5 For CH.

27. A compound according to claim 14 or claim 15, wherein Y 1 CH, Y 2 CR 3 , Y 3 N, Y 4 is CH, and Y 5 For CH.

28. A compound according to claim 14 or claim 15, wherein Y 1 CH, Y 2 CH, Y 3 CR 3 , Y 4 is CH, and Y 5 For CH.

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

30. A compound according to claim 14 or claim 15, wherein Y 1 CR 3 , Y 2 CH, Y 3 CH, Y 4 is CH, and Y 5 For CH.

31. The compound according to claim 1, wherein the compound is a compound of formula Ib': or a pharmaceutically acceptable salt thereof.

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

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

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

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

36. A compound according to any one of claims 1 to 35, wherein R 3 At least one of is selected from the group consisting of halo-C1-C6 alkyl, halo, cyano, C1-C6 alkyl and halo-C1-C6 alkoxy.

37. The compound according to claim 36, wherein R 3 At least one of is selected from the group consisting of -CF3, -CHF2, methyl, fluorine, chlorine, cyano, -OCF3 and -OCHF2.

38. The compound according to claim 37, wherein R 3 At least one of them is -CF3.

39. A compound according to any one of claims 1 to 36, wherein at least one R 3 It is halogenated.

40. The compound according to claim 39, wherein R 3 At least one of them is fluorine.

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

42. The compound of claim 41 having the formula:

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

44. A compound according to any one of claims 1 to 40, wherein G is CH.

45. The compound of claim 44, having the formula:

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

47. A compound according to any one of claims 1 to 46, wherein R N1 Selected from the group consisting of C1-C6 alkyl and C3-C5 cycloalkyl.

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

49. The compound according to claim 48, wherein R N1 It is propyl.

50. The compound according to claim 48, wherein R N1 It is isopropyl.

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

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

53. A compound according to any one of claims 1 to 51, wherein y is 2.

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

55. A compound according to any one of claims 1 to 53, wherein m is 2.

56. A compound according to any one of claims 1 to 55, wherein R 1 is independently selected at each occurrence from the group consisting of C1-C6 alkyl and halo-C1-C6 alkyl.

57. The compound according to claim 56, wherein R 1 and in each case selected from the group consisting of methyl, ethyl and -CH2F.

58. The compound according to claim 57, wherein R 1 In each case it is methyl.

59. The compound according to claim 55, wherein two R 1 The groups together form a -CH2- or -CH2CH2- bridge.

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

61. A compound according to any one of claims 1 to 60, wherein X, R in the ring 1 , m and y form:

62. according to the compound described in any one of claims 1 to 50, wherein X is NR H .

63. The compound according to claim 62, wherein R H Selected from the group consisting of C3-C5 cycloalkyl, hydroxy-C1-C6 alkyl and C1-C6 alkoxy-C1-C6 alkyl.

64. The compound according to claim 62, wherein R H Selected from the group consisting of: -CH2CH2OCH3, cyclobutyl and -CH2CH2OH.

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

66. A compound according to any one of claims 62 to 65, wherein X, R in the ring 1 , m and y form:

67. The compound according to claim 1, wherein the compound is a compound of formula Ia1 or Ib1: or a pharmaceutically acceptable salt thereof, in: u is 1 or 2; m is 0, 1 or 2; Y 1 , Y 2 , Y 3 , Y 4 and Y 5 Each independently is CH, CR 3 or N, if Y 1 , Y 2 , Y 3 , Y 4 and Y 5 Only one or both of can be N; G is N or CH; and R 1 If present, each occurrence is independently selected from the group consisting of: C1-C6 alkyl and halo-C1-C6 alkyl; or wherein two R 1 The groups together form a -CH2- or -CH2CH2- bridge.

68. The compound according to claim 67, wherein R N1 Selected from the group consisting of C1-C6 alkyl and C3-C5 cycloalkyl.

69. The compound according to claim 67, wherein R N1 Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and cyclopropyl.

70. The compound according to claim 69, wherein R N1 It is propyl.

71. The compound according to claim 69, wherein R N1 It is isopropyl.

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

73. A compound according to any one of claims 67 to 71, wherein y is 2.

74. according to the compound described in any one of claims 67 to 73, wherein R 1 and in each case selected from the group consisting of methyl, ethyl and -CH2F.

75. A compound according to any one of claims 67 to 73, wherein m is 0.

76. A compound according to any one of claims 67 to 74, wherein m is 1.

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

78. A compound according to any one of claims 67 to 76, wherein u is 2.

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

80. A compound according to any one of claims 67 to 79, wherein R 3 is independently selected at each occurrence from the group consisting of halo-C1-C6 alkyl, halo, cyano, C1-C6 alkyl and halo-C1-C6 alkoxy.

81. The compound according to claim 80, wherein R 3 is independently selected at each occurrence from the group consisting of: -CF3, -CHF2, methyl, fluoro, chloro, cyano, -OCF3 and -OCHF2.

82. The compound according to claim 81, wherein at least one R 3 It is -CF3.

83. according to the compound described in any one of claims 67 to 80, wherein at least one R 3 It is halogenated.

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

85. The compound of claim 1, wherein the compound is a compound of formula Ia2 or 1b2: or a pharmaceutically acceptable salt thereof, in: u is 1 or 2; Y 1 , Y 2 , Y 3 , Y 4 and Y 5 Each independently is CH, CR 3 or N, if Y 1 , Y 2 , Y 3 , Y 4 and Y 5 Only one or both of can be N; and G is N or CH.

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

87. A compound according to claim 85 or 86, wherein y is 1.

88. according to the compound described in any one of claims 85 to 87, wherein R H Selected from the group consisting of C3-C5 cycloalkyl, hydroxy-C1-C6 alkyl and C1-C6 alkoxy-C1-C6 alkyl.

89. The compound according to claim 88, wherein R H Selected from the group consisting of: -CH2CH2OCH3, cyclobutyl and -CH2CH2OH.

90. according to the compound described in any one of claims 85 to 89, wherein R N1 It is a C1-C6 alkyl group.

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

92. The compound according to claim 91, wherein R N1 It is propyl.

93. The compound according to claim 92, wherein R N1 It is isopropyl.

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

95. The compound according to claim 94, wherein R 3 It is a halogenated-C1-C6 alkyl group.

96. The compound according to claim 95, wherein R 3 It is -CF3.

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

98. The compound of claim 97, wherein Ring A is a bicyclo[3.1.0]hexane having the structure: wherein * indicates connection to the N-atom and # indicates connection to a C-atom on the triazole or pyrazole moiety.

99. The compound of claim 97, wherein Ring A is a bicyclo[3.1.0]hexane having the structure: wherein * indicates connection to the N-atom and # indicates connection to a C-atom on the triazole or pyrazole moiety.

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

101. The compound of claim 97, wherein Ring A is a bicyclo[3.1.0]hexane having the structure: wherein * indicates connection to the N-atom and # indicates connection to a C-atom on the triazole or pyrazole moiety.

102. The compound of any one of claims 1, 15, 31, 67 or 85, wherein Ring A is a cyclohexyl group having the structure: wherein * indicates connection to the N-atom and # indicates connection to a C-atom on the triazole or pyrazole moiety.

103. The compound according to claim 102, wherein Ring A is a cyclohexyl group having the following structure: wherein * indicates connection to the N-atom and # indicates connection to a C-atom on the triazole or pyrazole moiety.

104. The compound according to claim 102, wherein Ring A is a cyclohexyl group having the structure: wherein * indicates connection to the N-atom and # indicates connection to a C-atom on the triazole or pyrazole moiety.

105. The compound of claim 102, wherein Ring A is a cyclohexyl group having the structure: wherein * indicates connection to the N-atom and # indicates connection to a C-atom on the triazole or pyrazole moiety.

106. The compound of claim 102, wherein Ring A is a cyclohexyl group having the structure: wherein * indicates connection to the N-atom and # indicates connection to a C-atom on the triazole or pyrazole moiety.

107. A compound according to any one of claims 1, 4, 11, 15, 31, 42, 45, 67 or 85, wherein Ring A is a cyclopentyl group having the structure:

108. The compound of claim 107, wherein Ring A is a cyclopentyl group having the structure: wherein * indicates connection to the N-atom and # indicates connection to a C-atom on the triazole or pyrazole moiety.

109. The compound of claim 107, wherein Ring A is a cyclopentyl group having the structure: wherein * indicates connection to the N-atom and # indicates connection to a C-atom on the triazole or pyrazole moiety.

110. The compound according to claim 107, wherein Ring A is a cyclopentyl group having the following structure: wherein * indicates connection to the N-atom and # indicates connection to a C-atom on the triazole or pyrazole moiety.

111. The compound according to claim 107, wherein Ring A is a cyclopentyl group having the following structure: wherein * indicates connection to the N-atom and # indicates connection to a C-atom on the triazole or pyrazole moiety.

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

113. A compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from Table 1.

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

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

116. 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 disease in a subject in need thereof.

117. 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 disease in a subject in need thereof.

118. The method of claim 115, the compound of claim 116, or the use of claim 117, wherein the disorder is a myelin-related disorder, optionally wherein the myelin-related disorder is multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, infantile leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander disease, Pelitzow-Merzbacher disease (PMD), white ablative disease, Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington disease, Alzheimer disease, Parkinson disease, spinal cord injury, traumatic brain injury, post-radiation injury, neurologic 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. The method of claim 115, the compound of claim 116, or the use of claim 117, wherein the disorder is multiple sclerosis.

120. A method of promoting myelination in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 113 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. 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. The method of claim 115 or 120, wherein the subject has a myelin-related disorder.

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

125. Use of a compound according to claim 117 or 122, wherein the subject suffers from a myelin-related disorder.

126. The method according to claim 123, the compound for use according to claim 124, or the use of the compound according to claim 125, wherein the myelin-related disorder is multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophy, neonatal white matter damage, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander disease, Pelitzow-Merzbacher disease (PMD), white matter ablative disease , Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington disease, Alzheimer disease, Parkinson disease, spinal cord injury, traumatic brain injury, post-radiation injury, neurologic 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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