Tertiary pyridylamine modulators of cholesterol biosynthesis and their use for promoting remyelination

Abstract

The subject matter described herein relates to compounds of Formula A and pharmaceutically acceptable salts thereof that promote myelination, methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of administering the compounds to treat conditions, such as myelination-related conditions.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 579,221, filed August 28, 2023, the contents of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0003] The subject matter described herein relates to myelin-promoting compounds of formula I, methods for preparing said compounds, pharmaceutical compositions thereof, and their use in the treatment of myelin-related disorders. Background Technology

[0004] Myelin-related disorders are diseases that cause abnormalities in the myelin sheath of nerve cells, such as CNS neurons (including their axons), including impaired myelination, demyelination, and reduced myelination. In these disorders, the loss or degradation of myelin leads to slowed or stopped nerve conduction. The resulting myelin-related disorders are characterized by deficits in sensory, motor, cognitive, 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, Pelizaeus Merzbacher disease (PMD), white matter ablation disorders, Waller's degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, radiation injury, neurological complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, and Marchiafava-Bignami syndrome. Syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillian-Barre syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination.

[0005] MS is the most common myelin-related disorder, affecting millions worldwide and causing an estimated 18,000 deaths annually. MS is a complex neurological disease characterized by the deterioration of the myelin sheath in the central nervous system (CNS). Myelin, primarily composed of lipids (70% lipid, 30% protein), protects axons and enables skip conduction, thus accelerating axonal electrical impulses. Axonal demyelination in chronic MS can lead to axonal degeneration and neuronal cell death. Furthermore, MS damages oligodendrocytes, highly specialized CNS cells that generate and maintain myelin. A repair process called myelin regeneration occurs in the early stages of the disease, but over time, oligodendrocytes become unable to fully rebuild and restore myelin. Repeated attacks cause a gradual decrease in the effectiveness of myelin regeneration until scar-like plaques form around the damaged axons.

[0006] Currently, myelin-related disorders are incurable, and there are no therapies to prevent the progression of MS. Therefore, new treatment methods are needed to treat myelin-related disorders, including those that promote myelin regeneration. The topic described in this article addresses this unmet need. Summary of the Invention

[0007] In some embodiments, the subject matter described herein relates to compounds of formula A:

[0008]

[0009] in,

[0010] A is selected from the group consisting of: C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclic, each of which is optionally R A1 R A2 and R A3 One or more of them can replace each other.

[0011] Where R A1 R A2 and R A3 Each is independently selected from the group consisting of: C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, oxo, -C(O)-R A4 -S(O)-R A4 and -S(O)2-R A4 ,

[0012] Where R A4 It is a C1-C6 alkyl or C3-C8 cyclic hydrocarbon group, and

[0013] Oxygenation, if present, is determined by R. A1 RA2 and R A3 Both of them, together with the carbon atoms they are attached to, form the structure.

[0014] G can be -CH, C-OH, or N;

[0015] E, if present, is -C(O)- or -O-;

[0016] Y is either -CH or N;

[0017] p is 1, 2, or 3;

[0018] q is either 1 or 0;

[0019] r is 1 or 0;

[0020] When r is 0, A is not a C1-C6 alkyl group;

[0021] R 1 Choose from the group consisting of: C1-C6 alkyl, C3-C8 cycloalkyl, and halogenated-C1-C6 alkyl; or R 1 It is halogenated, and q is 0;

[0022] R 1a Choose from the group consisting of: hydrogen, halogenated, C1-C6 alkyl;

[0023] R 2 Choose from the group consisting of: halogenated, halogenated-C1-C6 alkyl, halogenated-C1-C6 alkoxy, and -S(O)2-(C1-C6 alkyl);

[0024] R 2a Choose from the group composed of hydrogen and halogen;

[0025] and,

[0026] R 3 It is hydrogenated, halogenated, or C1-C6 alkyl.

[0027] Or its pharmaceutically acceptable salts or solvates.

[0028] In some embodiments, the subject matter described herein relates to compounds of formula I:

[0029]

[0030] in,

[0031] A is selected from the group consisting of: C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclic, each of which is optionally R A1 R A2 and R A3 One or more of them can replace each other.

[0032] Where R A1 R A2 and R A3 Each is independently selected from the group consisting of: C1-C6 alkyl, halo-C1-C6 alkyl, halogen, cyano, oxo, -C(O)-R A4 -S(O)-R A4 and -S(O)2-R A4 ,

[0033] Where R A4 It is a C1-C6 alkyl or C3-C8 cyclic hydrocarbon group, and

[0034] Oxygenation, if present, is determined by R. A1 R A2 and R A3 Both of them, together with the carbon atoms they are attached to, form the structure.

[0035] G is either -CH or N;

[0036] Y is either -CH or N;

[0037] p is 1, 2, or 3;

[0038] q is either 1 or 0;

[0039] r is 1 or 0;

[0040] When r is 0, A is not a C1-C6 alkyl group;

[0041] R 1 Choose from the group consisting of: C1-C6 alkyl, C3-C8 cyclic hydrocarbon and halo-C1-C6 alkyl;

[0042] R 1a Choose from the group consisting of: hydrogen, halogenated and C1-C6 alkyl;

[0043] R 2 Choose from the group consisting of: halogenated, halogenated-C1-C6 alkyl, halogenated-C1-C6 alkoxy, and -S(O)2-(C1-C6 alkyl);

[0044] R2a Choose from the group composed of hydrogen and halogen;

[0045] and,

[0046] R 3 It is hydrogenated, halogenated, or C1-C6 alkyl.

[0047] Or its pharmaceutically acceptable salts or solvates.

[0048] In some embodiments, the subject matter described herein relates to a pharmaceutical composition comprising a compound of formula A or formula I or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0049] In some embodiments, the subject matter described herein relates to a method for promoting myelination in a subject with this need, the method comprising administering to the subject an effective amount of a compound of formula A or I or a pharmaceutically acceptable salt or solvation thereof, or a pharmaceutical composition comprising a compound of formula A or I or a pharmaceutically acceptable salt or solvation thereof and a pharmaceutically acceptable excipient. In some embodiments, the subject suffers from a myelin-related disorder.

[0050] In some embodiments, the subject matter described herein relates to a compound of formula A or formula I or a pharmaceutically acceptable salt or solvation thereof, or a pharmaceutical composition comprising a compound of formula A or formula I or a pharmaceutically acceptable salt or solvation thereof and a pharmaceutically acceptable excipient, for use in the treatment of myelin-related disorders.

[0051] In some embodiments, the subject matter described herein relates to the use of a compound of formula A or formula I or a pharmaceutically acceptable salt or solvation thereof, or a pharmaceutical composition comprising a compound of formula A or formula I or a pharmaceutically acceptable salt or solvation thereof and a pharmaceutically acceptable excipient in the manufacture of a medicament for treating myelin-related disorders.

[0052] In some embodiments, the subject matter described herein relates to methods for preparing compounds of formula A or I, or pharmaceutically acceptable salts or solvates thereof.

[0053] In some embodiments, the subject matter described herein relates to a method of inhibiting CYP51 (lanosterol demethylase), the method comprising contacting CYP51 with a compound of formula A or I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of formula A or I or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

[0054] Other embodiments are also described. Detailed Implementation

[0055] This article describes myelin-promoting compounds of formula A and formula I, methods for preparing these compounds, their pharmaceutical compositions, and their use in the treatment of myelin-related disorders.

[0056] Enhancing and / or inducing the accumulation of Δ8,9-unsaturated sterol intermediates in the cholesterol biosynthesis pathway in oligodendrocyte progenitor cells (OPCs) can induce oligodendrocyte production. The accumulation of Δ8,9-unsaturated sterol intermediates can be enhanced and / or induced by regulating and / or inhibiting enzymes within the cholesterol biosynthesis pathway in OPCs, and by directly and / or indirectly administering Δ8,9-unsaturated sterol intermediates to OPCs, where the enzyme enhances and / or induces the accumulation of Δ8,9-unsaturated sterol intermediates, and / or for the enzyme, the Δ8,9-unsaturated sterol intermediates serve as a substrate. 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 disorders in subjects, where myelination is beneficial.

[0057] Therefore, in some embodiments, agents (such as compounds of formula A or I or pharmaceutically acceptable salts or solvates thereof) that can enhance and / or induce the accumulation of Δ8,9-unsaturated sterol intermediates in the cholesterol biosynthesis pathway of OPCs can be administered to the subject and / or OPCs in amounts that effectively promote and / or induce OPC differentiation, proliferation, and / or maturation, as well as oligodendrocyte formation. In some embodiments, the agent (e.g., compounds of formula A or I or pharmaceutically acceptable salts or solvates thereof) is a compound that inhibits the synthesis of one or more enzyme-mediated sterol intermediates in the cholesterol biosynthesis pathway of OPCs and / or promotes the accumulation of Δ8,9-unsaturated sterol intermediates.

[0058] In some embodiments, a compound of formula A or I, or a pharmaceutically acceptable salt or solvate thereof, can modulate and / or inhibit one or more enzyme-mediated conversion steps in the cholesterol biosynthesis pathway, such as in the pathway from lanosterol to cholesterol, for example, between lanosterol and / or 7-enylcholine; modulation and / or inhibition of one or more of these steps in OPC can promote and / or induce oligodendrocyte formation. For example, a compound of formula A or I can inhibit the enzyme-mediated synthesis of sterol intermediates in the cholesterol biosynthesis pathway by CYP51, sterol 14-reductase (TM7SF2 and / or LBR), SC4MOL, NSDHL, and / or EBP. In some embodiments, a compound of formula A or I can inhibit CYP51, sterol 14-reductase, and / or EBP. In some embodiments, a compound of formula A or I can inhibit CYP51.

[0059] For example, in some embodiments, the compound of formula A or formula I used in the methods described herein can inhibit CYP51 enzyme activity in the cholesterol biosynthesis pathway. Alternatively, in some embodiments, the compound of formula I used in the methods described herein can inhibit sterol C14 reductase activity in the cholesterol biosynthesis pathway, or can inhibit enzyme-mediated conversion of zymostenol to 7-encholanol by inhibiting emopamiprobinin-binding protein (EBP) isomerase activity.

[0060] CYP51 belongs to the cytochrome P450 (CYP) monooxygenase superfamily and mediates a crucial step in the sterol biosynthesis pathway. The CYP51 protein is the most conserved protein in the CYP superfamily. Unlike other CYP enzymes, CYP51 exhibits strong substrate specificity. It catalyzes the demethylation of a narrow range of substrates, including lanosterol and 24,25-dihydrolanosterol. The CYP51 protein is also known as a sterol 14α-demethylase and is the only constant P450 present in all sterol biosynthesis pathways.

[0061] Unbound by any particular theory, compounds of formulas A and I, or pharmaceutically acceptable salts or solvates thereof, are believed to inhibit the CYP51-mediated conversion of lanosterol to 14-demethyl-14-dehydrolanosterol (FF-MAS) and 24,25-dihydrolanosterol to MAS-412 in the cholesterol biosynthesis pathway of OPC, thereby leading to enhanced and / or induced accumulation of Δ8,9-unsaturated sterol intermediates. In some embodiments, enhanced and / or induced accumulation of Δ8,9-unsaturated sterol intermediates may promote OPC differentiation, survival, proliferation, and / or maturation and treat diseases and / or disorders in subjects where myelination or myelination is beneficial to the subject. This mechanism of promoting myelination differs from the primary action of immunomodulators commonly used to treat myelin-related disorders.

[0062] The subject matter disclosed herein will now be described more fully below. However, many modifications and other embodiments of the subject matter described herein will conceive by those skilled in the art, benefiting from the teachings set forth in the foregoing description. Therefore, it should be understood that the subject matter disclosed herein is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein encompasses all alternatives, modifications, and equivalents. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. If one or more of the incorporated documents, patents, and similar materials differ from or contradict this application, including but not limited to defined terminology, usage of terms, described techniques, etc., this application shall prevail.

[0063] I. Definition

[0064] 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.

[0065] A dash ("-") not between two letters or symbols is used to indicate the connection point of a substituent. For example, -C(O)NH2 is connected by a carbon atom. A dash before or at the end of a chemical group is for convenience; a chemical group may or may not be depicted with one or more dashes without losing its ordinary meaning. A wavy or dashed line passing through or perpendicular to the end of a structural line indicates the designated connection point of the 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.

[0066] prefix "C" u -C v "" indicates that the following groups have u to v carbon atoms. For example, "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0067] References to the value or parameter “about” herein include (and describe) embodiments relating to that value or parameter itself. In some embodiments, the term “about” includes an indicated amount ± 50%. In some other embodiments, the term “about” includes an indicated amount ± 20%. In some other embodiments, the term “about” includes an indicated amount ± 10%. In other embodiments, the term “about” includes an indicated amount ± 5%. In some other embodiments, the term “about” includes an indicated amount ± 1%. In some other embodiments, the term “about” includes an indicated amount ± 0.5%, and in some other embodiments, it includes an indicated amount ± 0.1%. Such variations are suitable for performing the disclosed methods or employing the disclosed compositions. Additionally, the term “about x” includes a description of “x”. Furthermore, unless the context clearly specifies otherwise, the singular forms “a” and “the / described” include a plural referent. Thus, for example, references to “compound” include a plurality of such compounds, and references to “the assay” include references to one or more assays known to those skilled in the art and their equivalents, etc.

[0068] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C1-C2). 20 Alkyl groups, 1 to 12 carbon atoms (i.e., C1-C1). 12 Alkyl groups are alkyl groups with 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), 1 to 4 carbon atoms (i.e., C1-C4 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue with a specific number of carbons is named by its chemical name or identified by its molecular formula, it can encompass all positional isomers with that number of carbons; 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).

[0069] 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. Furthermore, unless otherwise explicitly stated, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl or aralkyl), the last mentioned group contains the atoms of that moiety that are connected to the remainder of the molecule.

[0070] "Alkenyl" refers to a group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C2-C2). 20 Alkyl groups consisting of 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, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0071] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having the following characteristics: 2 to 20 carbon atoms (i.e., C2-C2). 20 The term "alkynyl" can refer to groups with 2 to 8 carbon atoms (i.e., C2-C8 alkynyl), 2 to 6 carbon atoms (i.e., C2-C6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). The term "alkynyl" also includes groups having one triple bond and one double bond.

[0072] "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-hexyloxy, and 1,2-dimethylbutoxy.

[0073] "Alkylthio" refers to the "alkyl-S-" group.

[0074] "Acyl" refers to the group -C(O)R y , where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted as defined herein. Examples of acyl groups include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0075] "Acylamino" refers to the substituent group -C(O)NR yR z The "C-amide" group and the substituent group -NR y C(O)R z The "N-acylamino" group of both, of which R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted, as defined herein, or R y and R z Together they form a heterocyclic group; which may optionally be substituted, as defined herein.

[0076] "Amino" refers to the -NR group. y R z , where R y and R z Independently, they are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted, as defined herein.

[0077] "Amino group" refers to -C(NR) y (NR) z 2), where R y and R z Independently, they are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted, as defined herein.

[0078] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) (including fused systems). As used herein, aryl groups have 6 to 20 ring carbon atoms (i.e., C6-C). 20 aryl group), 6 to 12 carbon ring atoms (i.e., C6-C) 12 Aryl group or 6 to 10 carbon ring atoms (i.e., C6-C) 10 Aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthracene. However, aryl does not in any way encompass or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is heteroaryl regardless of the connection point. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is heterocyclic regardless of the connection point.

[0079] "Arylalkyl" or "arylalkyl" refers to the group "aryl-alkyl-", such as (C6- ... 10 Aryl)-C1-C3 alkyl. A non-limiting example of an arylalkyl group is benzyl.

[0080] "Carbamoyl" refers to the substituent group -OC(O)NR y R z The "O-carbamoyl" group and the substituent group -NR y C(O)OR z The "N-carbamoyl" group of both, of which R y and R z Independently, they are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted, as defined herein.

[0081] "Carboxylic ester" or "ester" refers to -OC(O)R x and -C(O)OR x Of the two, R x It is an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl group; each of them may optionally be substituted as defined herein.

[0082] "Cyclic hydrocarbon group" refers to a saturated or partially unsaturated cyclic hydrocarbon group having a single ring or multiple rings (including fused ring systems, bridged ring systems, and spiro ring systems). The term "cyclic hydrocarbon group" includes cyclic alkenyl groups (i.e., cyclic groups having at least one double bond) and cyclic groups having at least one sp... 3 A carbocyclic fused ring system with carbon atoms (i.e., at least one non-aromatic ring). As used herein, the cyclic hydrocarbon group has 3 to 20 cyclic carbon atoms (i.e., C3-C4). 20 Cyclic hydrocarbon group), 3 to 12 carbon ring atoms (i.e., C3-C) 12 Cyclic hydrocarbon group), 3 to 10 carbon ring atoms (i.e., C3-C) 10Cycloalkyl groups (C3-C8, C3-C7, or C3-C6) consist of 3 to 8 carbon ring atoms. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclic [2.2.1]heptyl, bicyclic [2.2.2]octyl, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclic [2.2.1]heptyl, etc. Furthermore, the term cycloalkyl is intended to cover any portion comprising a non-aromatic alkyl ring that can fused to an aryl ring, regardless of its connection to the rest of the molecule. Furthermore, when two substitution positions are present on the same carbon atom, cycloalkyl groups also include "spirocycloalkyl groups," such as spiro[2.5]octyl, spiro[4.5]decyl, or spiro[5.5]undecyl. As used herein, "halogenated cycloalkyl group" (such as C3-C7 halogenated cycloalkyl groups) refers to a C3-C7 cycloalkyl group substituted with one or more halogens.

[0083] "Cycloalkyl" refers to the group "cycloalkyl-", such as (C3-C6 cycloalkyl)-C1-C3 alkyl.

[0084] "Guidinyl" refers to -NR y C(=NR z (NR) y R z ), where each R y and R z Independently, they are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted, as defined herein.

[0085] "Hydrazine" refers to -NHNH2.

[0086] "Imine" refers to the group -C(NR) y )R z , where R y and R z Each of them is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of them may optionally be substituted as defined herein.

[0087] "Imidin group" refers to the group -C(O)NR y C(O)R z , where R y and R z Each of them is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of them may optionally be substituted as defined herein.

[0088] "Halogen" or "halogenated" refers to an atom that occupies Group VIIA of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0089] "Haloalkyl" refers to a branched or unbranched alkyl group as defined above, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a halogen. For example, a halo-C1-C3 alkyl group refers to an alkyl group with 1 to 3 carbons in which at least one hydrogen atom is replaced by a halogen. A halo-C1-C6 alkyl group refers to an alkyl group with 1 to 6 carbons in which at least one hydrogen atom is replaced by a halogen. When a residue is substituted with more than one halogen, it can be designated by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halogen groups, which can be, but are not necessarily, the same halogen. Examples of haloalkyl groups include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0090] "Haloalkoxy" refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, a halo-C1-C3 alkoxy group is an alkoxy group with 1 to 3 carbons in which at least one hydrogen atom is replaced by a halogen. A halo-C1-C6 alkoxy group is an alkoxy group with 1 to 6 carbons in which at least one hydrogen atom is replaced by a halogen. Non-limiting examples of haloalkoxy groups are -OCH2CF3, -OCF2H, and -OCF3.

[0091] "Hydroxyalkyl" means 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 hydroxyl group (e.g., hydroxy-C1-C3-alkyl, hydroxy-C1-C6-alkyl). The term "hydroxy-C1-C3 alkyl" refers to a one- to three-carbon alkyl chain in which one or more hydrogen atoms on any carbon are replaced by a hydroxyl group, particularly when one hydrogen atom on one carbon of the chain is replaced by a hydroxyl group. The term "hydroxy-C1-C6 alkyl" refers to a one- to six-carbon alkyl chain in which one or more hydrogen atoms on any carbon are replaced by a hydroxyl group, particularly when one hydrogen atom on one carbon of the chain is replaced by a hydroxyl group. Non-limiting examples of hydroxyalkyl include -CH2OH, -CH2CH2OH, and -C(CH3)2CH2OH.

[0092] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatom groups, provided that the connection point with the rest of the molecule is through a carbon atom. In some embodiments, a heteroalkyl group may 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 having carbon and heteroatoms. For example, 1, 2, or 3 carbon atoms of the alkyl group in a "heteroalkyl" may 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., among which R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2SCH3, etc.), sulfoxides (e.g., -CH2S(O)CH3, -CH(CH3)S(O)CH3, -CH2CH2S(O)CH3, -CH2CH2S(O)CH2CH2OCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2OCH3, etc.), and amines (e.g., -CH2NR). y CH3、-CH(CH3)NR y CH3、-CH2CH2NR y CH3、-CH2CH2NR y CH2CH2NR y CH3, etc., of which R y The hydrocarbon group can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of these may optionally be substituted as defined herein. In some 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.

[0093] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, having one or more cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl groups comprise 1 to 20 cyclic carbon atoms (i.e., C1-C2). 20 Heteroaryl groups), 3 to 12 cyclic carbon atoms (i.e., C3-C) 12 The heteroaryl group comprises 3 to 8 carbon ring atoms (i.e., C3-C8 heteroaryl), and 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some cases, the heteroaryl group includes 9 to 10-membered ring systems (i.e., 9 to 10-membered heteroaryl), 5 to 10-membered ring systems (i.e., 5 to 10-membered heteroaryl), 5 to 7-membered ring systems (i.e., 5 to 7-membered heteroaryl), 5 to 6-membered ring systems (i.e., 5 to 6-membered heteroaryl), or 4 to 6-membered ring systems (i.e., 4 to 6-membered heteroaryl), each independently having 1 to 4, 1 to 3, 1 to 2, or 1 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinel, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzooxazolyl, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenolinyl, dibenzofuranyl, dibenzophenylthio, furanyl, isothiazolyl, Imidazolyl, indazole, indolyl, indazole, isoindolyl, isoquinolinyl, isoxazolyl, naphridinyl, oxadiazolyl, oxazolyl, 1-oxopyridinyl, 1-oxopyrimidine, 1-oxopyrazinyl, 1-oxopyridazinyl, phenazinyl, phthalazinyl, pteridineyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidineyl, pyridazinyl, quinazolinyl, quinoxolinyl, quinolinyl, quininecycloyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophene, indazole, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridyl, and imidazo[1,5-a]pyridyl, wherein the heteroaryl group can be linked via any ring of the fused system. Any aromatic group having one or more fused rings and containing at least one heteroatom is considered a heteroaryl, regardless of its connection to the rest of the molecule (i.e., via any of the fused rings). Heteroaryl does not encompass or overlap with aryl groups as defined above.

[0094] "Heteroarylene alkyl" refers to the group "heteroarylene-alkyl-", such as (5- to 10-membered monocyclic heteroarylene)-C1-C3 alkyl.

[0095] "Heterocyclic group" refers to a saturated or partially unsaturated cyclic alkyl group having one or more cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups. A heterocyclic group can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclic group, regardless of its connection (i.e., it can be bonded by carbon atoms or heteroatoms). Furthermore, the term heterocyclic group is intended to cover a portion containing any non-aromatic ring containing at least one heteroatom, which may be fused to an aryl or heteroaryl ring, regardless of its connection to the rest of the molecule. The term heterocyclic group is also intended to cover a portion containing a cyclic hydrocarbon ring fused to a heteroaryl ring, regardless of its connection to the rest of the molecule. Additionally, the term heterocyclic group is intended to cover a portion containing a cyclic hydrocarbon ring fused to a heterocyclic ring, regardless of its connection to the rest of the molecule. As used in this article, heterocyclic groups have 2 to 20 cyclic carbon atoms (i.e., C2-C). 20 Heterocyclic group), 2 to 12 cyclic carbon atoms (i.e., C2-C) 12 Heterocyclic group), 2 to 10 cyclic carbon atoms (i.e., C2-C) 10 Heterocyclic groups), 2 to 8 ring carbon atoms (i.e., C2-C8 heterocyclic groups), 3 to 12 ring carbon atoms (i.e., C3-C8 heterocyclic groups). 12Heterocyclic groups (3 to 8 ring carbon atoms, i.e., C3-C8 heterocyclic groups) or 3 to 6 ring carbon atoms (i.e., C3-C6 heterocyclic groups); having 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 ring heteroatoms independently selected from nitrogen, sulfur, or oxygen. When the heterocyclic group contains 4 to 6 ring atoms, it is also referred to herein as a 4- to 6-membered heterocyclic group. 5- or 6-membered heterocyclic groups having 5 or 6 ring atoms, respectively, and 5- to 10-membered heterocyclic groups having 5 to 10 ring atoms are also disclosed herein. Examples of heterocyclic groups include, for example, aziridine, benzo[b][1,4]dioxane, 1,4-benzodioxane, benzopyranyl, benzodioxane-hexenyl, benzopyranone, benzofuranone, dioxane-pentyl, dihydropyranyl, hydrogenpyranyl, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, furanone, imidazolinyl, imidazoalkyl, dihydroindolyl, indazinyl, isodihydroindolyl, isothiazolyl, isoxazolyl, and morpholinyl. Octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidylyl, oxazolylyl, ethylene oxide, oxacyclobutyl, phenthiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylyl, pyrazolylyl, quininecycloyl, thiazolyl, tetrahydrofuranyl, tetrahydropyranyl, trithiaalkyl, tetrahydroquinolinyl, phenylthio (i.e., thiophenyl), tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In some embodiments, when two substitution positions are present on the same carbon atom, the term "heterocyclic group" may include "spiroheterocyclic group," wherein at least one ring of the spirosystem contains at least one heteroatom. Examples of spiroheterocyclic rings include, for example, bicyclic and tricyclic systems, such as 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, indololinyl, and isoindololinyl, wherein the heterocyclic group can be linked via any ring of the fused system.

[0096] "Heterocyclic alkyl" refers to the group "heterocyclic-alkyl-".

[0097] "Oxime" refers to the group -CR y (=NOH), where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted as defined herein.

[0098] "O" refers to a radical (=O).

[0099] "Cyano" refers to the group (-CN).

[0100] "N-oxide" refers to the group (-NO).

[0101] "Thiol" refers to the group (-SH).

[0102] "Sulfonyl" refers to the group -S(O)2R y , where R y The sulfonyl group is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of these may optionally be substituted as defined herein. A non-limiting example of a sulfonyl group is -SO2 (C1-C6 alkyl), referred herein as alkylsulfonyl. Examples of sulfonyl groups are methanesulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0103] "Sulinate group" refers to the group -S(O)R y , where R y It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted as defined herein. Examples of sulfinyl groups are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0104] "Sulfonamide" refers to the group -SO2NR. y R z and -NR y SO2R z , where R y and R z Each of them is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of them may optionally be substituted as defined herein.

[0105] The terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and that the description includes both the scenario in which the event or situation occurs and the scenario in which the event or situation does not occur. Furthermore, 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 specified atom or group may or may not be substituted with any of the hydrogen atoms other than hydrogen atoms.

[0106] As used herein, the term "substituted" means any of the above-mentioned groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, and / or heteroalkyl), wherein at least one (e.g., 1 to 5, 1 to 4, or 1 to 3) The hydrogen atom is replaced by a bond attached to a non-hydrogen atom, which is such as, but not limited to, alkyl, alkenyl, alkoxy, alkylthio, acyl, amide, amino, amidyl, aryl, aralkyl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidinyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, -NHNH2, =NNH2, imino, imide, hydroxyl, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamide, thiol, thio, N-oxide, or -Si(R y )3, where each R y Each is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic.

[0107] In some embodiments, "substituted" includes any of the above-described alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are independently substituted with deuterium, halogen, cyano, nitro, azide, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, 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)Rg -S(=O)2R g -OS(=O) 1-2 R g -S(=O) 1-2 OR g -NR g S(=O) 1-2 NR g R h =NSO2R g =NOR g -S(=O) 1-2 NR g R h -SF5, -SCF3, or -OCF3 are substituted. In some embodiments, "substituted" also means any of the above groups in which 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 h Alternative. In the above text, R g and R h The same or different, and independently of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylyl, haloalkyl, heterocyclic, heteroalkylyl, heteroaryl, and / or heteroarylalkyl. In some embodiments, "substituted" also means any of the above groups in which one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced by a bond of amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylyl, haloalkyl, heterocyclic, N-heterocyclic, heteroalkylyl, heteroaryl, and / or heteroarylalkyl, or R g and R h and R i The two atoms in the ring, together with the atoms to which they are attached, form an alkyl-substituted heterocyclic ring that is optionally oxidized, halogenated, or optionally oxidized, halogenated, amino, hydroxyl, or alkoxy-substituted.

[0108] Polymers or similar infinite structures obtained by definition through unlimited addition of further substituents (e.g., a substituted aryl group having a substituted alkyl group, the alkyl group itself being substituted with a substituted aryl group, the aryl group being further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, a substituted aryl group having two other substituted aryl groups is limited to a ((substituted aryl)-substituted aryl)-substituted aryl group. Similarly, the above definitions are not intended to include prohibited substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such prohibited substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein.

[0109] In some embodiments, as used herein, the phrase "one or more" refers to one through five. In some embodiments, as used herein, the phrase "one or more" refers to one through four. In some embodiments, as used herein, the phrase "one or more" refers to one through three.

[0110] Any compound or structure described herein is intended to represent both unlabeled and isotopically labeled forms (isotopes) of the compound. These forms of the compound may also be referred to as and include “isotopically enriched analogs.” Isotopically labeled compounds have the structures described herein, differing in that one or more atoms are replaced by atoms having selected atomic masses or mass numbers. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively, 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 isotope-labeled compounds or their pharmaceutical salts disclosed herein, for example, those doped with radioactive isotopes (such as...) 3 H, 13 C and 14Those compounds of type C) or their pharmaceutical salts. Such isotopically labeled compounds can be used in metabolic 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 for the radiotherapy of patients.

[0111] The term “isotope-enriched analogues” includes “deuterated analogues” of the compounds described herein, wherein one or more hydrogen atoms are replaced by deuterium, such as hydrogen on a carbon atom. Such compounds exhibit increased metabolic resistance and are therefore used to increase the half-life of any compound when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0112] The deuterium-labeled or substituted therapeutic compounds of this disclosure may possess improved DMPK (drug metabolism and pharmacokinetics) properties related to adsorption, distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages due to their greater metabolic stability (e.g., increased in vivo half-life, reduced dose requirements, and / or improved therapeutic index). 18 F, 3 H, 11 C-labeled compounds can be used in PET, SPECT, or other imaging studies. The isotope-labeled compounds disclosed herein can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents by performing the procedures disclosed in the schemes or examples and preparations described below. It should be understood that, in this context, deuterium is considered a substituent in the compounds described herein.

[0113] The concentration of such heavier isotopes, particularly deuterium, can be defined by the isotope condensation factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen,” that position should be understood to have hydrogen in its natural abundance isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium. Furthermore, in some embodiments, corresponding deuterated analogs are provided.

[0114] In many cases, the compounds disclosed herein are capable of forming acidic and / or basic salts in the presence of amino and / or carboxyl groups or similar groups.

[0115] Pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, isomers (such as stereoisomers), and mixtures of isomers (such as mixtures of stereoisomers) of the compounds described herein are also provided.

[0116] "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0117] The term "pharmaceutically acceptable salt" for a given compound refers to a salt that retains the biological effects and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts formed with inorganic acids and salts formed with organic acids. Additionally, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, can be produced according to 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 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, etc. 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, and salicylic acid. 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), trienylamines (i.e., N(alkenyl)3), and substituted alkenylamines (i.e., NH2(substituted alkyl)). Suitable amines include, by way of example only, isopropylamine, trimethylamine, di(substituted alkenyl)amine (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amine (i.e., N(substituted alkenyl)3), mono-, di-, or tricyclic alkylamines (i.e., NH2(cyclic alkyl), HN(cyclic alkyl)2, N(cyclic alkyl)3), mono-, di-, or triarylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. 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, etc.

[0118] The term "hydrate" refers to a complex formed by the combination of the compounds described herein with water.

[0119] "Solvate" refers to an association or complex of one or more solvent molecules with the compounds disclosed herein. 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.

[0120] Some of the compounds described herein may exist as tautomers. These tautomers are in equilibrium with each other. For example, amide-containing compounds may exist in equilibrium with their imine tautomers. Regardless of which tautomer is exhibited and regardless of the nature of the equilibrium between the tautomers, those skilled in the art will understand that the compound comprises both the amide and the imine tautomer. Therefore, amide-containing compounds are understood to include their imine tautomers. Similarly, imine-containing compounds are understood to include their amide tautomers.

[0121] The compounds described herein, or their pharmaceutically acceptable salts, may include asymmetric centers and thus can produce enantiomers, diastereomers, and other stereoisomers, which can be defined as (R)- or (S)- according to absolute stereochemistry, or (D)- or (L)- for amino acids. This disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or separated using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise stated, it is intended to indicate that these compounds simultaneously contain both E and Z geometric isomers.

[0122] "Stereoisomers" are compounds composed of identical atoms linked by the same bonds but with different three-dimensional structures and are not interchangeable. This disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are mirror images of each other and are not superimposed.

[0123] A “diastereomer” is a stereoisomer that has at least two asymmetric atoms that are not mirror images of each other.

[0124] The relative centers of the compounds described in this article are indicated graphically using a “thick bond” style (bold or parallel lines), and absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).

[0125] "Treatment / treating" is a method used to obtain a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes may include one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the severity of the disease or condition); b) slowing or halting 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 the clinical symptoms to subside (e.g., improving the disease state, causing partial or complete remission of the disease or condition, enhancing the effect of another medication, delaying disease progression, improving quality of life, and / or prolonging survival).

[0126] "Prevention" or "preventing" means any treatment of a disease or condition that prevents the occurrence of clinical symptoms of that disease or condition. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of a disease or condition or who have a family history of a disease or condition.

[0127] "Subject" refers to an animal, such as a mammal (including humans), that has been or will be used as the subject of treatment, observation, or experimentation. 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.

[0128] The term "therapeutic effective amount" or "effective amount" as used herein refers to an amount sufficient to provide therapeutic benefit, such as improvement of symptoms or slowing of disease progression, when administered to a subject. Therapeutic effective amounts 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 method of administration, and can be readily determined by those skilled in the art. In such treatments, the effective amount of the compounds disclosed herein is, for example, from about 0.01 mg / kg / day to about 1000 mg / kg / day, or from about 0.1 mg / kg / day to about 100 mg / kg / day.

[0129] As used herein, the term "excipient" refers to an inert or inactive substance that can be used in the manufacture of pharmaceuticals or pharmaceutical compositions, such as tablets containing a compound (or a pharmaceutically acceptable salt) described herein as an active ingredient. The term "excipient" can cover a wide range of substances, including but not limited to any substance used as a diluent, filler or spreader, binder, disintegrant, humectant, coating, emulsifier or dispersant, compression / encapsulation aid, cream or lotion, lubricant, parenteral solution, material for chewable tablets, sweetener or flavoring agent, suspending / 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 coating, etc.; compression / encapsulation aids may 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 may include, for example, croscarmellose cellulose. Sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions including maltodextrin, carrageenan, etc.; lubricants including, for example, magnesium stearate, stearic acid, sodium stearoyl fumarate, etc.; materials for chewable tablets including, for example, dextran, fructose DC, lactose (monohydrate, optionally combined with aspartame or cellulose), etc.; suspending / gelling agents including, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners including, for example, aspartame, dextran, fructose DC, sorbitol, sucrose DC, etc.; and wet granulation agents including, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc. In some cases, the term "excipient" encompasses pharmaceutically acceptable carriers.

[0130] Additional definitions may be provided below as appropriate.

[0131] II.Compounds

[0132] In some embodiments, the subject matter described herein relates to compounds of formula A:

[0133]

[0134] in,

[0135] A is selected from the group consisting of: C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclic, each of which is optionally R A1 R A2 and R A3 One or more of them can replace each other.

[0136] Where R A1 R A2 and R A3Each is independently selected from the group consisting of: C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, oxo, -C(O)-R A4 -S(O)-R A4 and -S(O)2-R A4 ,

[0137] Where R A4 It is a C1-C6 alkyl or C3-C8 cyclic hydrocarbon group, and

[0138] Oxygenation, if present, is determined by R. A1 R A2 and R A3 Both of them, together with the carbon atoms they are attached to, form the structure.

[0139] G can be -CH, C-OH, or N;

[0140] E, if present, is -C(O)- or -O-;

[0141] Y is either -CH or N;

[0142] p is 1, 2, or 3;

[0143] q is either 1 or 0;

[0144] r is 1 or 0;

[0145] When r is 0, A is not a C1-C6 alkyl group;

[0146] R 1 Choose from the group consisting of: C1-C6 alkyl, C3-C8 cycloalkyl, and halogenated-C1-C6 alkyl; or R 1 It is halogenated, and q is 0;

[0147] R 1a Choose from the group consisting of: hydrogen, halogenated, C1-C6 alkyl;

[0148] R 2 Choose from the group consisting of: halogenated, halogenated-C1-C6 alkyl, halogenated-C1-C6 alkoxy, and -S(O)2-(C1-C6 alkyl);

[0149] R 2a Choose from the group composed of hydrogen and halogen;

[0150] and,

[0151] R 3 It is hydrogenated, halogenated, or C1-C6 alkyl.

[0152] Or its pharmaceutically acceptable salts or solvates.

[0153] In some embodiments, the compound comprises those of formula A, or a pharmaceutically acceptable salt or solvate thereof, wherein G is CH, r is 1, and E is -O-, and the compound has the structure of formula Ai:

[0154]

[0155] In some embodiments, the compounds include those of formula Ai, or pharmaceutically acceptable salts or solvates thereof, wherein p is 2; R 1a R 2a and R 3 Each component is hydrogen, and the compound has the structure of formula Ai':

[0156]

[0157] In some embodiments, the compound comprises those of formula A, or pharmaceutically acceptable salts or solvates thereof, wherein G is C-OH and r is 0, and the compound has the structure of formula A-ii:

[0158]

[0159] In some embodiments, the compounds include those of formula A, or pharmaceutically acceptable salts or solvates thereof, wherein p is 2 and R 1a R 2a and R 3 Each component is hydrogen, and the compound has the structure of formula A-ii':

[0160]

[0161] In some embodiments, the compound comprises those of formula Ai, A-i', A-ii, or A-ii', or pharmaceutically acceptable salts or solvates thereof, wherein q is 1 and R 1 CH3. In some embodiments, the compound comprises those of formula Ai, A-i', A-ii, or A-ii', or pharmaceutically acceptable salts or solvates thereof, wherein R 2 It is CF3 or OCHF2. In some embodiments, the compound includes those of formula Ai, A-i', A-ii or A-ii', or pharmaceutically acceptable salts or solvates thereof, wherein Y is CH.

[0162] In some embodiments, the compound comprises those of formula A, or pharmaceutically acceptable salts or solvates thereof, wherein E is -C(O)-, and the compound has the structure of formula I.

[0163] In some embodiments, the subject matter described herein relates to compounds of formula I:

[0164]

[0165] in,

[0166] A is selected from the group consisting of: C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclic, each of which is optionally R A1 R A2 and R A3 One or more of them can replace each other.

[0167] Where R A1 R A2 and R A3 Each is independently selected from the group consisting of: C1-C6 alkyl, halo-C1-C6 alkyl, halogen, cyano, oxo, -C(O)-R A4 -S(O)-R A4 and -S(O)2-R A4 ,

[0168] Where R A4 It is a C1-C6 alkyl or C3-C8 cyclic hydrocarbon group, and

[0169] Oxygenation, if present, is determined by R. A1 R A2 and R A3 Both of them, together with the carbon atoms they are attached to, form the structure.

[0170] G is either -CH or N;

[0171] Y is either -CH or N;

[0172] p is 1, 2, or 3;

[0173] q is either 1 or 0;

[0174] r is 1 or 0;

[0175] When r is 0, A is not a C1-C6 alkyl group;

[0176] R 1Choose from the group consisting of: C1-C6 alkyl, C3-C8 cyclic hydrocarbon and halo-C1-C6 alkyl;

[0177] R 1a Choose from the group consisting of: hydrogen, halogenated and C1-C6 alkyl;

[0178] R 2 Choose from the group consisting of: halogenated, halogenated-C1-C6 alkyl, halogenated-C1-C6 alkoxy, and -S(O)2-(C1-C6 alkyl);

[0179] R 2a Choose from the group composed of hydrogen and halogen;

[0180] and,

[0181] R 3 It is hydrogenated, halogenated, or C1-C6 alkyl.

[0182] Or its pharmaceutically acceptable salts or solvates.

[0183] In some embodiments, the compounds include those of formulas A and I, or pharmaceutically acceptable salts or solvates thereof, wherein G is CH.

[0184] In some embodiments, the compounds include those of formula I, or pharmaceutically acceptable salts or solvates thereof, wherein G is N and includes compounds having the structure of formula I':

[0185]

[0186] In some embodiments, the compound comprises those of formula I or I', or pharmaceutically acceptable salts or solvates thereof, wherein q is 1. In some embodiments, the compound comprises those of formula I or I', or pharmaceutically acceptable salts or solvates thereof, wherein q is 0.

[0187] In some embodiments, the compound comprises those of formula I or I', or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is a C1-C6 alkyl or C3-C8 cyclic hydrocarbon group. In some embodiments, the compound includes those of formula I or I', or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It can be methyl, ethyl, or cyclopropyl.

[0188] In some embodiments, compounds of formula I or I', or pharmaceutically acceptable salts or solvates thereof, include compounds having the structure of formula Ia, Ib, or Ic, or pharmaceutically acceptable salts or solvates thereof:

[0189]

[0190] In some embodiments, the compounds include those of formula A, or pharmaceutically acceptable salts or solvates thereof, wherein q is 0 and R 1 The compound is a halogen. In some embodiments, the compound comprises those of formula A, or pharmaceutically acceptable salts or solvates thereof, wherein q is 0 and R 1 -Cl. In some embodiments, the compound comprises those of formula A, or pharmaceutically acceptable salts or solvates thereof, wherein r and q are each 0, and R 1a and R 1b Each is hydrogen, and R 1 As a halogen, the compound has the structure of formula Id:

[0191]

[0192] In some embodiments, the compounds include those of formula Id, wherein R 1 -Cl. In some embodiments, the compound includes those of formula Id, wherein R 2 For CF3. In some embodiments, the compound includes those of formula Id, wherein R 3 Y is hydrogen. In some embodiments, the compound includes those of formula Id, where Y is N. In some embodiments, the compound includes those of formula Id, where G is N and p is 2.

[0193] In some embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', I, I', Ia, Ib, Ic, or Id, wherein one or more hydrogen atoms are replaced by deuterium.

[0194] In some embodiments, the compounds include those of formula A, having the structure of formula A-iii:

[0195]

[0196] In some embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein R 1 It is -CD3.

[0197] In some embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein Y is N. In some embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein Y is -CH.

[0198] In some embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein R 2 It is a halo-C1-C6 alkyl or halo-C1-C6 alkoxy. In some embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein R 2 It is a halo-C1-C6 alkyl group. In some embodiments, the compound includes those of formula I, I', Ia, Ib, or Ic, wherein R 2 -CF3. In some embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein R 2 It is a halo-C1-C6 alkoxy group. In some embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein R 2 It is -O-CHF2.

[0199] In some embodiments, the compound comprises those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein p is 1 or 2. In some embodiments, the compound comprises those of formula A, Ai, A-ii, A-iii, I, I', Ia, Ib, Ic, or Id, wherein p is 1. In some embodiments, the compound comprises those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein p is 2.

[0200] In some embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein R 3It is a C1-C6 alkyl group. In some embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein R 3 The compound is methyl. In some embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein R 3 It is hydrogen.

[0201] In some embodiments, the compound comprises those of formula A, Ai, A-i', A-iii, I, I', Ia, Ib, or Ic, wherein r is 1. In some embodiments, the compound comprises those of formula A, Ai, A-i', A-iii, I, I', Ia, Ib, or Ic, wherein r is 1 and A is a C1-C6 alkyl group. In some embodiments, the compound comprises those of formula A, Ai, A-i', A-iii, I, I', Ia, Ib, or Ic, wherein r is 1 and A is -CH3 or -CH2CH3. In some embodiments, the compound comprises those of formula A, A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein r is 0. In some embodiments, the compound includes those of formula A, A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein r is 0, and A is a C3-C8 cyclic hydrocarbon group, optionally via R A1 R A2 and R A3 One or more of them can be replaced.

[0202] In some embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein r is 0 or 1, and A is a C3-C5 cyclic hydrocarbon group, optionally via R A1 R A2 and R A3 One or more of them may be substituted. In some embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein A is , or In the examples of the above embodiments, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein R A1 It is a cyano or halo-C1-C6 alkyl group. In the examples of the above embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, or Ic, wherein R A1 The value is -CF3. In the examples of the above embodiments, the compound includes those of formula A, Ai, A-i', A-iii, I, I', Ia, Ib or Ic, where r is 1.

[0203] In some embodiments, the compound includes those of formula A, A-ii, A-ii', I, I', Ia, Ib, Ic, or Id, wherein r is 0 and A is a phenyl group, optionally via R A1 R A2 and R A3 One or more of the compounds may be substituted. In some embodiments, the compound comprises those of formula A, A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein r is 0 and A is a phenyl group, optionally substituted with R A1 and R A2 One or more of them may be substituted. In some embodiments, the compound includes those of formula A, A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein r is 0, and A has the following structure: In the examples of the above embodiments, the compounds include those of formula A, A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein R A1 -S(O)2-R A4 And R A2 Halogenated. In some embodiments, the compound includes those of formula A, A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where r is 0, and A has the following structure: In the examples of the above embodiments, the compounds include those of formula A, A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein R A1 Choose from the group consisting of: halogenated, cyano, -S(O)2-R A4 and -C(O)-R A4 .

[0204] In some embodiments, the compound comprises those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein r is 0 or 1, and A is a 5- to 6-membered heterocyclic group, optionally via R A1 R A2 and R A3 One or more of the above-described embodiments may be substituted. In examples of the above embodiments, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein A is a heterocyclic group comprising one or two heteroatoms selected from the group consisting of N, S, and O. In examples of the above-described embodiments, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein A is a 5- to 6-membered heterocyclic group. In examples of the above-described embodiments, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein A is a 5- to 6-membered heterocyclic group comprising one or two heteroatoms selected from the group consisting of N, S, and O. In the examples of the above embodiments, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein A is or .

[0205] In some embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where r is 0 or 1, and A is a derivative of R. A1 R A2 and R A3 Substituted 5- to 6-membered heterocyclic groups. In the examples of the above embodiments, the compounds include those of formula A, Ai, A-i', A-ii, A-iii, A-ii', I, I', Ia, Ib, Ic, or Id, wherein R A2 and R A3 Together with the carbon atoms they are attached to, they form an oxo group, where A is... or And R A1It is a C1-C6 alkyl group. In the examples of the above embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein R A2 It is an ethyl group.

[0206] In some embodiments, the compound comprises those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, or Ic, wherein r is 0 or 1, and A is a 5- to 6-membered heteroaryl group, optionally via R A1 R A2 and R A3 One or more of them may be substituted. In the examples of the above embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein A is selected from the group consisting of pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, oxadiazolyl, pyrroleyl, imidazoleyl, pyrazolyl, and thiazolyl, optionally via R A1 R A2 and R A3 One or more of them may be substituted. In the examples of the above embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein A is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, and pyrroleyl, which may optionally be substituted by R A1 R A2 and R A3 One or more of them may be substituted. In the examples of the above embodiments, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein A is a pyridyl group, which optionally is substituted with R A1 R A2 and R A3 One or more of them may be substituted. In the examples of the above embodiments, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein A is a pyridyl group, which optionally is substituted with R A1 Substitution. In the examples of the above embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein A is , or In the examples of the above embodiments, the compounds include those of formula I, I', Ia, Ib, or Ic, wherein R A1 Choose from the group consisting of: C1-C6 alkyl, halo-C1-C6 alkyl, halogen, cyano, and -S(O)2-R A4 In the examples of the above embodiments, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein A is In the examples of the above embodiments, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein A is a pyrimidinyl or pyrazinyl group, optionally via R A1 R A2 and R A3 One or more of them may be substituted. In the examples of the above embodiments, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein A is a pyrimidinyl or pyrazinyl group, which optionally is substituted with R A1 Substitution. In the examples of the above embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein A is , , , , or In the examples of the above embodiments, the compounds include those of formula I, I', Ia, Ib, Ic, or Id, wherein R A1 Choose from the group consisting of: C1-C6 alkyl, halo-C1-C6 alkyl, halogen, cyano, and -S(O)2-R A4 In the examples of the above embodiments, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein R A1 The compound is CH2OCH3. In the examples of the above embodiments, the compound includes those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein A is CH2OCH3. .

[0207] In the examples of the above embodiments, the compounds include those of formula I, I', Ia, Ib, or Ic, wherein A is an oxadiazolyl and a pyrroleyl group, optionally via R A1 R A2 and R A3 One or more of them may be substituted. In the examples of the above embodiments, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein the oxadiazolyl and pyrrolyl groups are optionally substituted via R A1 Substitution. In the examples of the above embodiments, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, Id, wherein A is or .

[0208] The subjects described herein include the following compounds or their pharmaceutically acceptable salts listed in Table 1. The individual enantiomers and diastereomers are listed in the table below by compound name, and their respective structures can be readily determined therefrom. In some cases, the enantiomers or diastereomers of this disclosure can be identified by their respective properties, such as chiral HPLC retention time, NMR peaks, and / or biological activity (e.g., as further described in the examples), without specifying the absolute stereoconfiguration of one or more chiral centers.

[0209] Table 1. Compounds

[0210]

[0211] The topics described herein include the following compounds in Table A or their pharmaceutically acceptable salts.

[0212] Table A. Compounds

[0213]

[0214] In some embodiments, the subject matter described herein relates to compounds selected from Table 1. In some embodiments, the subject matter described herein relates to compounds selected from Table A. In some embodiments, the subject matter described herein relates to compounds selected from both Table 1 and Table A.

[0215] III. Pharmaceutical Composition and Administration

[0216] The compounds described herein are typically administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions comprising: one or more of the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, or mixtures thereof; and one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable 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 industry. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (GSBanker & CT Rhodes, editors).

[0217] In some embodiments, the pharmaceutical composition comprises a compound of formula A or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of formula Ai or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of formula Ai' or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of formula A-ii or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of formula A-ii' or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of formula A-iii or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of formula I' or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of formula Ia or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of formula Ib or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of formula Ic or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of formula Id or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Table 1 or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Table A or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of both Table 1 and Table A or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient.

[0218] The pharmaceutical composition can be administered in single or multiple doses. The pharmaceutical composition can be administered by a variety of methods, including, for example, rectal, oral, intranasal, and percutaneous routes. In some embodiments, the pharmaceutical composition can be administered via intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhaler.

[0219] One method of administration is parenteral administration, such as by injection. The pharmaceutical compositions described herein may be incorporated into forms for injection, including, for example, aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical carriers.

[0220] Oral administration may be another route of administration for the compounds described herein. Administration may be via, for example, capsules or tablets, such as enteric-coated tablets. In preparing pharmaceutical compositions comprising at least one of the compounds described herein or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, the active ingredient is typically diluted with an excipient and / or encapsulated in such a carrier, which may be in the form of capsules, sachets, paper, or other containers. When the excipient is used as a diluent, it may be in the form of a solid, semi-solid, or liquid material that acts as a medium, carrier, or mediator of the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft gelatin capsules and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0221] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, 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 methylparaben and propylparaben; sweeteners; and flavoring agents.

[0222] Compositions comprising at least one of the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, or mixtures thereof, can be formulated to provide a rapid, sustained, or delayed release of the active ingredient upon 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 for 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 controlled amount of the compound described herein for continuous or discontinuous infusion. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. These patches can be constructed for continuous, pulsed, or on-demand drug delivery.

[0223] To prepare solid compositions such as tablets, a major active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compound described herein or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. When these preformulation compositions are referred to as homogeneous, the active ingredient can be uniformly dispersed throughout the composition, making it easy to subdivide the composition into equally effective unit dosage forms such as tablets, pills, and capsules.

[0224] The tablets or pills containing the compounds described herein may be coated or otherwise compounded to provide a dosage form with the advantage of prolonged action, or to protect against the acidic conditions of the stomach. For example, a tablet or pill may comprise an internal dose component and an external dose component, the latter in the form of a coating over the former. These two components may be separated by an enteric coating layer, which resists disintegration in the stomach and allows the internal component to enter the duodenum intact or delay release. A variety of materials may be used for such enteric coatings or coatings, including various polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0225] Compositions for inhalation or inhalation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the composition is administered via the oral or nasal inhalation route to achieve local or systemic effects. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be attached to a face mask tent or intermittent positive pressure ventilation machine. Solution, suspension, or powder compositions may be administered from a device that delivers the formulation in a suitable manner, preferably orally or nasally.

[0226] For any given subject, the specific dose level of the compounds described herein will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, time of administration, route of administration and excretion rate, drug combination, and the severity of the subject's specific disease undergoing therapy. For example, the dose may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of the subject's body weight. A dose between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments, a dose between 0.5 and 60 mg / kg may be appropriate. Normalization based on the subject's weight is particularly useful when adjusting the dose among subjects with significant differences in body size, such as when the drug is used in both children and adults, or when converting an effective dose for a non-human subject (such as a dog) to a dose suitable for a human subject. A particular dose may be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic characteristics, including the absorption, distribution, metabolism, and excretion of the specific compound. In addition, toxicity factors may affect dosage and administration regimen. When administered orally, pills, capsules, or tablets can be taken daily within a specified time period or at a lower frequency. This regimen can be repeated for multiple treatment cycles.

[0227] IV. Treatment Methods

[0228] This document describes a method for promoting myelination of central nervous system neurons in subjects suffering from myelin-related disorders, the method comprising administering to the subject a therapeutically effective amount of a compound of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or a pharmaceutical composition comprising thereus. In some embodiments, the subject matter disclosed herein relates to a compound of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or a pharmaceutically acceptable salt or solvate thereof, for promoting myelination of central nervous system neurons in subjects suffering from myelin-related disorders. In another embodiment, the subject matter described herein relates to the use of compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or pharmaceutically acceptable salts or solvates thereof, in the manufacture of a medicament for promoting myelination of neurons in the central nervous system of a subject suffering from myelin-related disorders.

[0229] In some embodiments, in a method for promoting myelination of neurons in the central nervous system of a subject suffering from myelin-related disorders, compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions comprising them, inhibit the enzyme-mediated synthesis of one or more sterol intermediates in the cholesterol biosynthesis pathway.

[0230] In some embodiments, in a method for promoting myelination of neurons in the central nervous system of a subject suffering from myelin-related disorders, compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions comprising them, promote the accumulation of Δ8,9-unsaturated sterol intermediates in the cholesterol biosynthesis pathway.

[0231] In some embodiments, in a method for promoting myelination of neurons in the central nervous system of a subject suffering from myelin-related disorders, compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions comprising thereof, inhibit one or more of the CYP51, sterol-14-reductase, or EBP enzyme-mediated synthesis of sterol intermediates in the cholesterol biosynthesis pathway. In some embodiments, compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions comprising thereof, inhibit CYP51.

[0232] In some embodiments, in a method for promoting myelination of neurons in the central nervous system of a subject suffering from myelin-related disorders, compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions comprising them, induce, promote, and / or regulate oligodendrocyte precursor cell (OPC) differentiation, proliferation, and / or maturation. In some embodiments, the induction of OPC differentiation is characterized by an increase in myelin basic protein (MBP) expression.

[0233] In some embodiments, the subject matter described herein relates to a method of treating a disease in a subject with such a need, the method comprising administering to the subject with a therapeutically effective amount of a compound of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, the subject suffers from a myelin-related disease. In some embodiments, compound A is a compound of formula I, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula Ai, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula Ai', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula A-ii, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula A-ii', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula A-iii, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is compound Id, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is compound I', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is compound Ia, or a pharmaceutically acceptable salt or solvation thereof. In other embodiments, compound I is compound Ib, or a pharmaceutically acceptable salt or solvation thereof. In other embodiments, compound I is compound Ic, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is a compound of Table 1, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of Table A, or a pharmaceutically acceptable salt or solvation thereof.

[0234] In some embodiments, the subject matter disclosed herein relates to compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or pharmaceutically acceptable salts or solvates thereof, used to treat a condition in a subject requiring such treatment. In some embodiments, the subject suffers from a myelin-related disorder. In some embodiments, compound A is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, compound A is a compound of formula Ai, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, compound A is a compound of formula Ai', or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, compound A is a compound of formula A-ii, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, compound A is a compound of formula A-ii', or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, compound A is a compound of formula A-iii, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, compound A is compound Id, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is compound I', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is compound Ia, or a pharmaceutically acceptable salt or solvation thereof. In other embodiments, compound I is compound Ib, or a pharmaceutically acceptable salt or solvation thereof. In other embodiments, compound I is compound Ic, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is a compound of Table 1, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of Table A, or a pharmaceutically acceptable salt or solvation thereof.

[0235] In some embodiments, the subject matter disclosed herein relates to the use of compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or pharmaceutically acceptable salts or solvates thereof, in the manufacture of a medicament for treating a disorder in a subject with such a need. In some embodiments, the subject suffers from a myelin-related disorder. In some embodiments, compound A is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, compound A is a compound of formula Ai, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, compound A is a compound of formula Ai', or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, compound A is a compound of formula A-ii, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, compound A is a compound of formula A-ii', or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, compound A is a compound of formula A-iii, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, compound A is compound Id, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is compound I', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is compound Ia, or a pharmaceutically acceptable salt or solvation thereof. In other embodiments, compound I is compound Ib, or a pharmaceutically acceptable salt or solvation thereof. In other embodiments, compound I is compound Ic, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is a compound of Table 1, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of Table A, or a pharmaceutically acceptable salt or solvation thereof.

[0236] In some embodiments, the subject matter disclosed herein relates to a method for promoting myelination in a subject with this need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, the subject suffers from a myelin-related disorder. In some embodiments, compound A is a compound of formula I, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula Ai, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula Ai', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula A-ii, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula A-ii', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula A-iii, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is compound Id, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is compound I', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, the subject has a myelin-related disorder. In some embodiments, compound I is compound Ia, or a pharmaceutically acceptable salt or solvation thereof. In other embodiments, compound I is compound Ib, or a pharmaceutically acceptable salt or solvation thereof. In other embodiments, compound I is compound Ic, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is a compound of Table 1, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of Table A, or a pharmaceutically acceptable salt or solvation thereof.

[0237] In some embodiments, the subject matter disclosed herein relates to compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or pharmaceutical compositions comprising such compounds for use in promoting myelination in a subject with a need for it. In some embodiments, the subject has a myelin-related disorder. In some embodiments, compound A is a compound of formula I, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula Ai, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula Ai', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula A-ii, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula A-ii', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula A-iii, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is compound Id or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is compound I' or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is compound Ia or a pharmaceutically acceptable salt or solvation thereof. In other embodiments, compound I is compound Ib or a pharmaceutically acceptable salt or solvation thereof. In other embodiments, compound I is compound Ic or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is a compound of Table 1 or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is a compound of Table A or a pharmaceutically acceptable salt or solvation thereof.

[0238] In some embodiments, the subject matter disclosed herein relates to the use of compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or pharmaceutical compositions comprising such compounds, in the manufacture of a medicament for promoting myelination in a subject with such need. In some embodiments, the subject suffers from a myelin-related disorder. In some embodiments, compound A is a compound of formula I, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula Ai, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula Ai', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula A-ii, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula A-ii', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula A-iii, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is compound Id, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is compound I', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is compound Ia, or a pharmaceutically acceptable salt or solvation thereof. In other embodiments, compound I is compound Ib, or a pharmaceutically acceptable salt or solvation thereof. In other embodiments, compound I is compound Ic, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is a compound of Table 1, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of Table A, or a pharmaceutically acceptable salt or solvation thereof.

[0239] In some embodiments, the subject matter disclosed herein relates to a method for inducing differentiation of endogenous oligodendrocyte precursor cells (OPCs) in a subject with such need, the method comprising administering to the subject a therapeutically effective amount of a compound of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or a pharmaceutically acceptable salt or solvation thereof, or a pharmaceutical composition comprising thereof. In some embodiments, the subject suffers from a myelin-related disorder. In some embodiments, the myelin-related disorder is multiple sclerosis.

[0240] These 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, Perizoise-Metzbach disease (PMD), white matter ablation disorders, Waller's degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, radiation injury, neurological complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, and Marchiafava-Bignami syndrome. Syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barré syndrome, Charcot-Marie-Tuss disease, Bell's palsy, and radiation-induced demyelination.

[0241] Compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or pharmaceutically acceptable salts or solvates thereof, may be administered alone or in combination with another agent to subjects suffering from myelin-related disorders 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 disorder that causes myelin abnormalities. Abnormalities may be caused by loss of myelin (called demyelination), dysfunction of myelin (called myelin dysplasia), or failure to form sufficient myelin (called myelin dysplasia). The 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, compound A is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, compound A is a compound of formula Ai, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, compound A is a compound of formula Ai', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula A-ii, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula A-ii', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula A-iii, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound A is a compound of formula Id, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is a compound of formula I', or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, compound I is a compound of formula Ia, or a pharmaceutically acceptable salt or solvation thereof. In other embodiments, compound I is a compound of formula Ib, or a pharmaceutically acceptable salt or solvation thereof. In other embodiments, compound I is a compound of formula Ic, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a compound of formula I is a compound of Table 1, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a compound of formula A is a compound of Table A, or a pharmaceutically acceptable salt or solvation thereof.

[0242] As used herein, “demyelinating” refers to the act of demyelination, or the partial or complete damage or loss of the myelin sheath that isolates a nerve, and is a marker of myelin-related disorders. In some embodiments, demyelination refers to the partial or complete damage or loss of the myelin sheath that isolates a subset of nerves in an individual, such as one or more nerves located, for example, in a specific region 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).

[0243] Neuronal myelination requires oligodendrocytes. As used herein, the term "myelination" refers to the generation of a neural myelin sheath by replacing or restoring the function of myelin-producing cells. Neurons undergoing myelination may be located in the brain, spinal cord, or both. Restoring the function of myelin-producing cells can include, for example, increasing the rate of myelination in cells (or cells) with below-average production levels. Such an increase may encompass raising the rate of myelination to up to or above the average production level; but it may also encompass raising the rate of myelination to a level that is still below average but higher than the previous level.

[0244] As used herein, “promoting myelination” means an increase in the rate of myelination compared to baseline levels of myelination rate in subjects, and not merely a net increase in the amount of myelin. An increase in the rate of myelination can be determined using imaging techniques or functional measurements. In some embodiments, myelination is promoted by increasing OPC differentiation, increasing the accumulation of 8,9-unsaturated sterol intermediates in biosynthetic pathways, increasing OPC formation, or any combination thereof. Such activities can be assessed, for example, using one or more in vitro assays, such as those described herein or known to those skilled in the art.

[0245] As used in this article, “baseline level of myelination rate” refers to the myelination rate in subjects who received treatment prior to the start of treatment.

[0246] V. Methods for preparing compounds of formula A and I and their pharmaceutically acceptable salts.

[0247] The compounds can be synthesized via synthetic routes that include processes similar to those well-known in the field of chemistry, especially given the descriptions contained herein and those used for other heterocycles described in the following literature: Comprehensive Heterocyclic Chemistry II, edited by Katritsky 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 can be prepared using methods well known to those skilled in the art (e.g., by methods commonly described below: 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)).

[0248] Synthetic chemical transformations and protecting group methods (protection and deprotection) that can be used to synthesize compounds, as well as the necessary reagents and intermediates, are known in the art, and include, for example, R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, Vol. 1989. 3rd edition, John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and those described in subsequent editions.

[0249] The compounds can be prepared individually or as a compound library comprising at least two, for example, five to 1,000 compounds or 10 to 100 compounds. Libraries of compounds of formula A and formula I, or pharmaceutically acceptable salts thereof, can be prepared by a combined "split and mix" method or by multiple parallel syntheses using solution-phase or solid-phase chemistry, through procedures known to those skilled in the art. Therefore, according to a further aspect, a compound library comprising at least two compounds, or pharmaceutically acceptable salts thereof, is provided.

[0250] VI. Further Examples

[0251] The topics described herein include the following examples:

[0252] 1. A compound of formula I:

[0253]

[0254] in,

[0255] A is selected from the group consisting of: C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclic, each of which is optionally R A1 R A2 and R A3 One or more of them can replace each other.

[0256] Where R A1 R A2 and R A3 Each is independently selected from the group consisting of: C1-C6 alkyl, halo-C1-C6 alkyl, halogen, cyano, oxo, -C(O)-R A4 -S(O)-R A4 and -S(O)2-R A4 ,

[0257] Where R A4 It is a C1-C6 alkyl or C3-C8 cyclic hydrocarbon group, and

[0258] Oxygenation, if present, is determined by R. A1 R A2 and R A3 Both of them, together with the carbon atoms they are attached to, form the structure.

[0259] G is either -CH or N;

[0260] Y is either -CH or N;

[0261] p is 1, 2, or 3;

[0262] q is either 1 or 0;

[0263] r is 1 or 0;

[0264] When r is 0, A is not a C1-C6 alkyl group;

[0265] R 1 Choose from the group consisting of: C1-C6 alkyl, C3-C8 cyclic hydrocarbon and halo-C1-C6 alkyl;

[0266] R 1a Choose from the group consisting of: hydrogen, halogenated and C1-C6 alkyl;

[0267] R 2 Choose from the group consisting of: halogenated, halogenated-C1-C6 alkyl, halogenated-C1-C6 alkoxy, and -S(O)2-(C1-C6 alkyl);

[0268] R 2a Choose from the group composed of hydrogen and halogen;

[0269] and,

[0270] R 3 It is hydrogenated, halogenated, or C1-C6 alkyl.

[0271] Or its pharmaceutically acceptable salts or solvates.

[0272] 2. The compound according to Example 1, or a pharmaceutically acceptable salt or solvate thereof, wherein G is N and the compound has the structure of formula I':

[0273]

[0274] 3. The compound according to Example 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1.

[0275] 4. The compound according to Example 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.

[0276] 5. The compound according to any one of Examples 1 to 4, or a pharmaceutically acceptable salt or solvation thereof, wherein R 1 It is a C1-C6 alkyl or C3-C8 cyclic hydrocarbon group.

[0277] 6. The compound according to Example 5, or a pharmaceutically acceptable salt or solvation thereof, wherein R 1 It can be methyl, ethyl, or cyclopropyl.

[0278] 7. The compound according to any one of Examples 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, having a structure of formula Ia, Ib or Ic:

[0279]

[0280] 8. The compound according to any one of Examples 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is N.

[0281] 9. The compound according to any one of Examples 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -CH.

[0282] 10. The compound according to any one of Examples 1 to 9, or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is a halo-C1-C6 alkyl or halo-C1-C6 alkoxy.

[0283] 11. The compound according to Example 10, or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is a halogenated -C1-C6 alkyl group.

[0284] 12. The compound according to Example 11, or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is -CF3.

[0285] 13. The compound according to Example 10, or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is a halogenated -C1-C6 alkoxy group.

[0286] 14. The compound according to Example 11, or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is -O-CHF2.

[0287] 15. The compound according to any one of Examples 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1 or 2.

[0288] 16. The compound according to any one of Examples 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

[0289] 17. The compound according to any one of Examples 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0290] 18. The compound according to any one of Examples 1 to 17, or a pharmaceutically acceptable salt or solvation thereof, wherein R 3 It is a C1-C6 alkyl group.

[0291] 19. The compound according to Example 18, or a pharmaceutically acceptable salt or solvation thereof, wherein R 3 It is a methyl group.

[0292] 20. The compound according to any one of Examples 1 to 17, or a pharmaceutically acceptable salt or solvation thereof, wherein R 3 It is hydrogen.

[0293] 21. The compound according to any one of Examples 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein r is 1.

[0294] 22. The compound according to Example 21, or a pharmaceutically acceptable salt or solvation thereof, wherein A is a C1-C6 alkyl group.

[0295] 23. The compound according to Example 22, or a pharmaceutically acceptable salt or solvate thereof, wherein A is -CH3 or -CH2CH3.

[0296] 24. The compound according to any one of Examples 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein r is 0.

[0297] 25. The compound according to Example 21 or 24, or a pharmaceutically acceptable salt or solvation thereof, wherein A is a C3-C8 cyclic hydrocarbon group, optionally via R A1 R A2 and R A3 One or more of them can be replaced.

[0298] 26. The compound according to Example 25, or a pharmaceutically acceptable salt or solvation thereof, wherein A is a C3-C5 cyclic hydrocarbon group, optionally via R A1 R A2 and R A3 One or more of them can be replaced.

[0299] 27. The compound according to Example 26, or a pharmaceutically acceptable salt or solvation thereof, wherein A is...

[0300] , or .

[0301] 28. The compound according to Example 27, or a pharmaceutically acceptable salt or solvate thereof, wherein R A1 It is cyano or halo-C1-C6 alkyl.

[0302] 29. The compound according to Example 28, or a pharmaceutically acceptable salt or solvation thereof, wherein R A1 It is -CF3.

[0303] 30. The compound according to Example 21 or 24, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a phenyl group, optionally via R... A1 R A2 and R A3 One or more of them can be replaced.

[0304] 31. The compound according to Example 30, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a phenyl group, optionally via R... A1 and R A2 One or more of them can be replaced.

[0305] 32. The compound according to Example 31, or a pharmaceutically acceptable salt or solvation thereof, wherein A is...

[0306] .

[0307] 33. The compound according to Example 32, or a pharmaceutically acceptable salt or solvation thereof, wherein R A1 -S(O)2-R A4 And R A2 Halogenated.

[0308] 34. The compound according to Example 31, or a pharmaceutically acceptable salt or solvation thereof, wherein A is...

[0309] .

[0310] 35. The compound according to Example 34, or a pharmaceutically acceptable salt or solvation thereof, wherein R A1 Choose from the group consisting of: halogenated, cyano, -S(O)2-R A4 and -C(O)-R A4 .

[0311] 36. The compound according to Example 21 or 24, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a 5- to 6-membered heterocyclic group, optionally via R A1R A2 and R A3 One or more of them can be replaced.

[0312] 37. The compound according to Example 36, or a pharmaceutically acceptable salt or solvate thereof, wherein the heterocyclic group comprises one or two heteroatoms selected from the group consisting of N, S and O.

[0313] 38. The compound according to Example 36, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a 5- or 6-membered heterocyclic group.

[0314] 39. The compound according to Example 38, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a 5- to 6-membered heterocyclic group comprising one or two heteroatoms selected from the group consisting of N, S, and O.

[0315] 40. The compound according to Example 39, or a pharmaceutically acceptable salt or solvation thereof, wherein A is...

[0316] or .

[0317] 41. The compound according to Example 21 or 24, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a 5- to 6-membered heteroaryl group, optionally via R A1 R A2 and R A3 One or more of them can be replaced.

[0318] 42. The compound according to Example 41, or a pharmaceutically acceptable salt or solvation thereof, wherein A is selected from the group consisting of: pyridinyl, pyrazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxadiazolyl, pyrroleyl, imidazoleyl, pyrazolyl, and thiazolyl, optionally via R A1 R A2 and R A3 One or more of them can be replaced.

[0319] 43. The compound according to Example 42, or a pharmaceutically acceptable salt or solvation thereof, wherein A is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, and pyrroleyl, optionally via R A1 R A2 and R A3 One or more of them can be replaced.

[0320] 44. The compound according to Example 43, or a pharmaceutically acceptable salt or solvation thereof, wherein A is a pyridyl group, optionally via R A1 R A2 and R A3 One or more of them can be replaced.

[0321] 45. The compound according to Example 44, or a pharmaceutically acceptable salt or solvation thereof, wherein A is derived from R A1 Substituted pyridinyl group.

[0322] 46. ​​The compound according to Example 45, or a pharmaceutically acceptable salt or solvation thereof, wherein A is...

[0323] , , or .

[0324] 47. The compound according to Example 46, or a pharmaceutically acceptable salt or solvation thereof, wherein R A1 Choose from the group consisting of: C1-C6 alkyl, halo-C1-C6 alkyl, halogen, cyano, and -S(O)2-R A4 .

[0325] 48. The compound according to Example 43, or a pharmaceutically acceptable salt or solvation thereof, wherein A is pyrimidinyl or pyrazinyl, optionally via R A1 R A2 and R A3 One or more of them can be replaced.

[0326] 49. The compound according to Example 48, or a pharmaceutically acceptable salt or solvation thereof, wherein A is pyrimidinyl or pyrazinyl, optionally via R A1 replace.

[0327] 50. The compound according to Example 49, or a pharmaceutically acceptable salt or solvation thereof, wherein A is...

[0328] , , , , or .

[0329] 51. The compound according to Example 50, or a pharmaceutically acceptable salt or solvation thereof, wherein R A1Choose from the group consisting of: C1-C6 alkyl, halo-C1-C6 alkyl, halogen, cyano, and -S(O)2-R A4 .

[0330] 52. The compound according to Example 43, or a pharmaceutically acceptable salt or solvation thereof, wherein A is an oxadiazolyl and a pyrroleyl group, optionally via R A1 R A2 and R A3 One or more of them can be replaced.

[0331] 53. The compound according to Example 52 or a pharmaceutically acceptable salt or solvate thereof, wherein A is an oxadiazolyl and a pyrroleyl group, optionally via R A1 replace.

[0332] 54. The compound according to Example 53, or a pharmaceutically acceptable salt or solvation thereof, wherein A is...

[0333] or .

[0334] 55. The compound according to Example 54, or a pharmaceutically acceptable salt or solvation thereof, wherein R A1 It is a C1-C6 alkyl group.

[0335] 56. The compound according to Example 1, or a pharmaceutically acceptable salt or solvation thereof, selected from Table 1.

[0336] 57. A pharmaceutical composition comprising a compound according to any one of Examples 1 to 56 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0337] 58. A method for promoting myelination in a subject with such need, the method comprising administering to the subject with such need a therapeutically effective amount of a compound according to any one of Examples 1 to 56 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to Example 57.

[0338] 59. The compound of any one of Examples 1 to 56 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of Example 57, used to treat a disease in a subject who requires such treatment.

[0339] 60. The compound of any one of Examples 1 to 56 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of Example 57, used to promote myelination in a subject with such need.

[0340] 61. Use of the compound of any one of Examples 1 to 56 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of Example 57, in the manufacture of a medicament for treating a disease in a subject with such need.

[0341] 62. Use of the compound of any one of Examples 1 to 56 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of Example 57, in the manufacture of a medicament for promoting myelin formation in a subject with such need.

[0342] 63. The method according to Example 58, wherein the subject suffers from myelin-related disorders.

[0343] 64. The compound used according to Example 59 or 60, wherein the subject suffers from myelin-related disorders.

[0344] 65. The use as described in Example 61 or 62, wherein the subject suffers from myelin-related disorders.

[0345] 66. The method according to Example 63, the compound used according to Example 64, or the use according to Example 65, wherein the myelin-related disorder is 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, Perizoise-Metzbach disease (PMD), white matter ablation disorders, Waller's degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post-radiation injury, neurological complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E. Deficiency syndrome, Basen-Cotsweig syndrome, Marshall-Biehl syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barré syndrome, Charcot-Marie-Tuss disease, Bell's palsy, or radiation-induced demyelination.

[0346] 67. The method according to Example 63, the compound according to Example 64, or the use according to Example 65, wherein the disease is multiple sclerosis.

[0347] 68. A method for inhibiting CYP51 (lanosterol demethylase), comprising contacting CYP51 with a compound according to any one of Examples 1 to 56 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to Example 57.

[0348] Example

[0349] The examples provide exemplary methods for preparing compounds. Those skilled in the art will recognize that other synthetic routes can be used to synthesize the 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 readily substituted to provide a variety of derivatives and / or reaction conditions. Furthermore, many of the exemplary compounds prepared by said methods can be further modified using conventional chemical methods well known to those skilled in the art, according to this disclosure.

[0350] Example A: S)-4-cyclopropyl-N-(4-(trifluoromethyl)phenyl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-yl)pyridin-3-amine (Compound 1):

[0351]

[0352] Step 1: (S)-3-((4-chloropyridin-3-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0353]

[0354] To a mixture of (3S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (1.16 g, 6.24 mmol, 1.06 mL), 3-bromo-4-chloropyridine (1 g, 5.20 mmol), and t-BuONa (1.50 g, 15.59 mmol) in toluene (15 mL), Pd(OAc)2 (233.33 mg, 1.04 mmol) and t-Bu3P (2.08 mmol, 487.85 μL, 10 wt% toluene solution) were added, the mixture was degassed and purged three times with N2, and then stirred at 100 °C under N2 atmosphere for 12 h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0% to 25% ethyl acetate eluent in petroleum ether) to give the title compound (633 mg, 2.13 mmol, 41% yield). LCMS [M+H]+ =298.2.

[0355] Step 2: (S)-3-((4-chloropyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0356]

[0357] To a mixture of (3S)-3-[(4-chloro-3-pyridinyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 1.34 mmol), 1-bromo-4-(trifluoromethyl)benzene (604 mg, 2.69 mmol), and tBuONa (516 mg, 5.37 mmol) in toluene (5 mL), Pd(OAc)2 (60.32 mg, 268.65 μmol) and t-Bu3P (537.31 μmol, 1.26 mL, 10 wt% toluene solution) were added, the mixture was degassed and purged three times with N2, and then stirred at 120 °C under N2 atmosphere for 16 h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0% to 25% ethyl acetate eluent in petroleum ether) to provide the title compound (409 mg, 925.60 μmol, 69% yield). LCMS (ESI) [M+H]+ = 386.1

[0358] Step 3: (S)-3-((4-cyclopropylpyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0359]

[0360] A mixture of (3S)-3-[N-(4-chloro-3-pyridinyl)-4-(trifluoromethyl)aniline]pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.452 mmol), cyclopropylboronic acid (117 mg, 1.36 mmol), Pd(OAc)₂ (10.16 mg, 0.0452 mmol), Cs₂CO₃ (442.4 mg, 1.36 mmol), and bis(1-adamantyl)-butylphosphine (32 mg, 0.091 mmol) in toluene (1 mL) and H₂O (0.1 mL) was degassed and purged three times with N₂. The mixture was then stirred in a microwave reactor at 120 °C under N₂ atmosphere for 1 hour. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether solution of 50% ethyl acetate) to provide the title compound (100.4 mg, 224 μmol, 50% yield). LCMS (ESI) [M+H]+ = 448.3.

[0361] Step 4: (S)-4-cyclopropyl-N-(pyrrolidone-3-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride

[0362]

[0363] At 25 °C, a mixture of (3S)-3-[N-(4-cyclopropyl-3-pyridyl)-4-(trifluoromethyl)aniline]pyrrolidine-1-carboxylic acid tert-butyl ester (180 mg, 402.24 μmol) was added in a single addition of HCl / dioxane (4 M, 3.00 mL) and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (130 mg, 374.23 μmol, 93.04% yield), which was used in the next step without further purification. LCMS (ESI) [M+H]+ = 348.2

[0364] Step 5: (S)-4-cyclopropyl-N-(4-(trifluoromethyl)phenyl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-yl)pyridin-3-amine (Compound 1)

[0365]

[0366] DIEA (131.31 mg, 1.02 mmol) was added in a single step to a mixture of 4-cyclopropyl-N-[(3S)-pyrrolidine-3-yl]-N-[4-(trifluoromethyl)phenyl]pyridine-3-amine (130 mg, 338.68 μmol, HCl) and 2-fluoro-5-(trifluoromethyl)pyridine (83.87 mg, 508.03 μmol) in DMF (1 mL). The mixture was stirred at 80 °C for 4 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic matter was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (10% to 50% ethyl acetate in petroleum ether solution) to provide the title compound (140 mg, 284.29 μmol, 83.94% yield) as a yellow solid (SFC: 30:70). A mixture of enantiomers (130 mg, 263.98 μmol) was purified by SFC (SFC-12; DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 μm), 0.1% NH3H2O ​​ETOH; 30% to 30%, 60 mL / min) to give title compound-1 (first peak on SFC, compound 1, 50.7 mg, 101.92 μmol, 38.61% yield). LCMS (ESI) [M+H] + = 493.1. Only the above enantiomers of compound 1 showed activity.

[0367] Compound 1: 1 HNMR: (400 MHz, CDCl3) δ 8.50 - 8.20 (m, 3H), 7.63 - 7.57 (m,1H), 7.49 - 7.41 (m, 2H), 6.82 - 6.72 (m, 1H), 6.65 - 6.58 (m, 2H), 6.35 -6.27 (m, 1H), 4.85-4.81 (m, 1H), 4.07 - 4.03 (m, 1H), 3.66 - 3.63 (m, 1H), 3.48 - 3.45 (m, 2H), 2.44 - 2.42 (m, 1H), 2.15 - 2.03 (m, 1H), 1.90 - 1.80(m, 1H), 1.10 - 0.95 (m, 2H), 0.86 - 0.76 (m, 2H).

[0368] Example B: 2-(4-((4-cyclopropylpyridin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 2):

[0369]

[0370] Step 1: 4-((4-chloropyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0371]

[0372] The mixture of tert-butyl 4-amino-1-piperidincarnate (3747 mg, 18.71 mmol), tBuONa (4494 mg, 46.77 mmol), 3-bromo-4-chloropyridine (3000.0 mg, 15.59 mmol), tBu3P (7.33 mL, 3.12 mmol, 10 wt% toluene solution) and Pd(OAc)2 (350 mg, 1.56 mmol) in toluene (50 mL) was degassed and purged three times with N2, and then the mixture was stirred at 80 °C under N2 for 19 hours.

[0373] The mixture was concentrated to dryness under reduced pressure, and the residue was purified by rapid silica gel chromatography (silica gel, 100 to 200 mesh, petroleum ether solution of 50% ethyl acetate) to give the title compound (2200 mg, 7.056 mmol, 45% yield). LCMS (ESI) [M+H]+ = 312.1. 1 H NMR (400 MHz, CDCl3) δ ppm 8.07 (s, 1H),7.89 (s, 1H), 7.23 (d, J = 5.2 Hz, 1H), 4.15 (d, J = 6.8 Hz, 1H), 4.00 - 4.12(m, 2H), 3.51 - 3.65 (m, 1H), 2.98 (t, J = 11.6 Hz, 2H), 2.05 - 2.10 (m, 2H), 1.50 (d, J = 1.6 Hz, 2H), 1.48 (s, 9H).

[0374] Step 2: 4-((4-chloropyridin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0375]

[0376] A mixture of 5-bromo-2-(trifluoromethyl)pyridine (870 mg, 3.85 mmol), tBuONa (555 mg, 5.77 mmol), tert-butyl 4-[(4-chloro-3-pyridyl)amino]piperidin-1-carboxylate (600.0 mg, 1.92 mmol), tBu3P (1.81 mL, 0.77 mmol, 10 wt% toluene solution), and Pd(OAc)2 (86.4 mg, 0.38 mmol) in toluene (10 mL) was stirred at 120 °C under N2 for 12 h. The mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel rapid chromatography (0% to 50% ethyl acetate in petroleum ether solution) to give the title compound (600 mg, 1.31 mmol, 68% yield). LCMS (ESI) [M+H]+ = 401.2.

[0377] Step 3: 4-((4-cyclopropylpyridin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0378]

[0379] A mixture of cyclopropylboronic acid (594 mg, 2.5 mmol), 4-((4-chloropyridin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (1000.0 mg, 2.28 mmol), Cs₂CO₃ (2.224 g, 6.83 mmol), di(adamantane-1-yl)(butyl)phosphonane (331 mg, 0.46 mmol), and Pd(OAc)₂ (51.1 mg, 0.23 mmol) in water (1 mL) and toluene (10 mL) was purged with nitrogen (N₂) for 3 min. The mixture was heated to 120 °C under nitrogen in a microwave reactor for 1 h. Water (20 mL) was added to the mixture and it was extracted with ethyl acetate (50 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0% to 50% ethyl acetate in petroleum ether solution) to give the title compound (600 mg, 1.30 mmol, 57% yield). LCMS (ESI) [M+H]+ = 463.2.

[0380] Step 4: 4-Cyclopropyl-N-(piperidin-4-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-3-amine hydrochloride

[0381]

[0382] To a solution of tert-butyl piperidine-1-carboxylate (600.0 mg, 1.3 mmol) in dioxane (5 mL), HCl / dioxane (5.0 mL, 20.0 mmol, 4 M) was added, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under vacuum to give the title compound (517 mg, 1.3 mmol, 100% yield) as a white solid. LCMS (ESI) [M+H]+ = 363.2.

[0383] Step 5: 2-(4-((4-cyclopropylpyridin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 2):

[0384]

[0385] N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) was added to a solution of N-(4-cyclopropyl-3-pyridinyl)-N-(4-piperidinyl)-6-(trifluoromethyl)pyridine-3-amine (50.0 mg, 0.14 mmol) and 2-chloropyrimidin-5-carboxynitrile (23.1 mg, 0.17 mmol) in N,N-dimethylformamide (1 mL) and stirred for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organics were washed with brine (10 mL x 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether solution) to provide the title compound (10.5 mg, 0.0205 mmol, 15% yield). LCMS(ESI) [M+H]+ = 466.3.

[0386] Compound 2: 1H NMR (400 MHz, CDCl3) δ ppm 8.49 (s, 3H), 8.28 (s, 1H), 8.11 (s, 1H), 7.50 (d, J = 9.2 Hz, 1H), 6.83 (d, J = 6.4 Hz, 2H), 5.06 (d, J= 14.0 Hz, 2H), 4.35 (s, 1H), 3.09 (t, J = 12.8 Hz, 2H), 2.23 (d, J = 12.0Hz, 2H), 1.91 (s, 1H), 1.48 (d, J = 13.6 Hz, 2H), 1.15 (d, J = 6.4 Hz, 2H),0.89 (d, J = 6.4 Hz, 2H).

[0387] Example C: 4-Cyclopropyl-N-(1-(4-(methanesulfonyl)phenyl)piperidin-4-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-3-amine (Compound 3):

[0388]

[0389] Step 1: 4-Cyclopropyl-N-(piperidin-4-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-3-amine

[0390]

[0391] A basic resin (1.0 g) was added to a solution of N-(4-cyclopropyl-3-pyridinyl)-N-(4-piperidinyl)-6-(trifluoromethyl)pyridine-3-amine hydrochloride (500.0 mg, 1.25 mmol) in methanol (10 mL), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered, and the methanol was concentrated under vacuum to give the title compound (420 mg, 1.16 mmol, 93% yield).

[0392] Step 2: 4-Cyclopropyl-N-(1-(4-(methanesulfonyl)phenyl)piperidin-4-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-3-amine (Compound 3):

[0393]

[0394] A solution of N-(4-cyclopropyl-3-pyridinyl)-N-(4-piperidinyl)-6-(trifluoromethyl)pyridine-3-amine (50.0 mg, 0.14 mmol), RuPhos Pd G3 (12 mg, 0.01 mmol), 1-bromo-4-(methanesulfonyl)benzene (39 mg, 0.17 mmol), and tBuONa (40 mg, 0.41 mmol) in 1,4-dioxane (3 mL) was purged three times with N2. The reaction mixture was stirred at 110 °C for 16 h. The resulting residue was concentrated under reduced pressure and purified by preparative TLC (50% ethyl acetate in petroleum ether solution) to give the title compound (53 mg, 0.0995 mmol, 72% yield). LCMS (ESI) [M+H]+ = 517.3.

[0395] Compound 3: 1 H NMR (400 MHz, CDCl3) δ ppm 8.53 (d, J = 5.6 Hz, 1H), 8.30 (s, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8Hz, 1H), 7.28 (s, 1H), 6.93 (d, J = 9.2 Hz, 2H), 6.78 - 6.86 (m, 1H), 4.24 (t, J = 11.6 Hz, 1H), 4.00 (d, J = 12.8 Hz, 2H), 3.04 -3.13 (m, 2H), 3.03 (s,3H), 2.25 - 2.21 (m, 2H), 1.86 - 1.92 (m, 1H), 1.66 - 1.63 (m, 2H), 1.12 (d,J = 6.4 Hz, 2H), 0.88 (d, J = 6.0 Hz, 2H).

[0396] Example D: 2-(4-((4-ethylpyridin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 4):

[0397]

[0398] Step 1: 4-((6-(trifluoromethyl)pyridin-3-yl)(4-vinylpyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0399]

[0400] A mixture of tert-butyl 4-[(4-chloro-3-pyridyl)-[6-(trifluoromethyl)-3-pyridyl]amino]piperidine-1-carboxylate (300.0 mg, 0.66 mmol), Cs₂CO₃ (642 mg, 1.97 mmol), Pd(OAc)₂ (7.4 mg, 0.033 mmol), bis(1-adamantyl)-butylphosphine (23.5 mg, 0.066 mmol), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxacyclopentaborane (303.0 mg, 1.97 mmol) in water (1 mL) and toluene (9 mL) was purged three times with nitrogen. The mixture was heated to 120 °C for 1 hour in a microwave reactor.

[0401] The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic matter was washed with brine (20 mL x 2), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel rapid chromatography (petroleum ether solution of 0% to 50% ethyl acetate) to provide the title compound (200 mg, 0.646 mmol, 68%). LCMS (ESI) [M+H]+ = 449.2.

[0402] Step 2: 4-((4-ethylpyridin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0403]

[0404] A mixture of Pd / C (40 mg, 10 wt% on carbon) and tert-butyl 4-[[6-(trifluoromethyl)-3-pyridyl]-(4-vinyl-3-pyridyl)amino]piperidine-1-carboxylate (200.0 mg, 0.45 mmol) in ethanol (10 mL) was stirred at 25 °C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (180 mg, 0.40 mmol, 90% yield). LCMS (ESI) [M-56+H]+ = 395.1.

[0405] Step 3: 4-Ethyl-N-(piperidin-4-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-3-amine hydrochloride

[0406]

[0407] 4-[(4-ethyl-3-pyridyl)-[6-(trifluoromethyl)-3-pyridyl]amino]piperidine-1-carboxylic acid tert-butyl ester (180.0 mg, 0.40 mmol) was dissolved in HCl / dioxane (4 mL, 4 M) and stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give the title compound (200 mg, 0.0034 mmol, 0.90% yield). LCMS(ESI) [M+H]+ = 350.2.

[0408] Step 4: 2-(4-((4-ethylpyridin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (compound 4):

[0409]

[0410] N,N-diisopropylethylamine (0.12 mL, 0.68 mol) was added to a solution of N-(4-ethyl-3-pyridinyl)-N-(4-piperidinyl)-6-(trifluoromethyl)pyridine-3-amine (80.0 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL) at 0 °C, and the mixture was stirred at 0 °C for 5 min, followed by the addition of 2-chloropyrimidin-5-carboxynitrile (32 mg, 0.23 mmol). The reaction mixture was then stirred at 25 °C for 1 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel rapid chromatography (0% to 30% ethyl acetate in petroleum ether solution) to give the title compound (11.6 mg, 0.0026 mmol, 12% yield). LCMS (ESI) [M+H]+ = 454.2.

[0411] Compound 4: 1 H NMR (400 MHz, CD3OD) δ 8.57 - 8.52 (m, 3H), 8.32 - 8.28(m, 1H), 7.88 - 7.84 (m, 1H), 7.63 - 7.57 (m, 2H), 7.16 - 7.11 (m, 1H), 1.18 (t, J = 7.6 Hz, 3H).

[0412] Example E: 2-(4-((4-methoxypyridin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 5):

[0413]

[0414] Step 1: 4-[(4-methoxy-3-pyridyl)amino]piperidine-1-carboxylic acid tert-butyl ester

[0415]

[0416] NaBH(OAc)3 (20.49 g, 96.66 mmol) was added to a solution of 4-methoxypyridine-3-amine (10 g, 80.55 mmol) and tert-butyl 4-oxopiperidinium-1-carboxylate (19.26 g, 96.66 mmol) in isopropyl acetate (100 mL), and the mixture was stirred at 0 °C for 0.1 h. Then, 2,2,2-trifluoroacetic acid (27.56 g, 241.66 mmol, 17.89 mL) was added to the mixture, and the mixture was stirred in an ice bath for 2 h, and then at 30 °C for 24 h. The reaction mixture was adjusted with saturated NaHCO3 aqueous solution (200 mL) and stirred for 30 min. The resulting mixture was extracted with ethyl acetate (150 mL x 3), and the combined organic layers were washed with brine (50 mL x 3). The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1, then converted to a DCM solution using 3% to 10% methanol) to give the title compound (21 g, 68.32 mmol, 85% yield, 100% purity). LCMS (ESI) [M+H]⁺ = 308.2. 1 HNMR (400MHz, DMSO-d6): 8.10 (d, J = 6.0 Hz, 1H), 8.05 (s, 1H), 7.32 (d, J = 6.0 Hz,1H), 5.84 (d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 3.96-3.93 (m, 2H), 3.57-3.54 (m,2H), 2.84 (brs, 2H), 1.86-1.82 (m, 2H), 1.40 (s, 9H).

[0417] Step 2: 4-((4-methoxypyridin-3-yl)(5-(trifluoromethyl)pyridin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0418]

[0419] A mixture of tert-butyl 4-[(4-methoxy-3-pyridyl)amino]piperidine-1-carboxylate (3 g, 9.76 mmol), 5-bromo-2-(trifluoromethyl)pyridine (4.41 g, 19.52 mmol), tBu3P Pd G2 (1.00 g, 1.95 mmol), and tBuONa (2.81 g, 29.28 mmol) in toluene (20 mL) was degassed and purged three times with N2, and then stirred at 120 °C under N2 atmosphere for 12 h. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by silica gel rapid chromatography (petroleum ether solution of 0% to 60% ethyl acetate) to provide the title compound (2.78 g, 6.14 mmol, 63% yield). LCMS (ESI) [M+H]+ = 453.3

[0420] Step 3: 4-Methoxy-N-(piperidin-4-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-3-amine

[0421]

[0422] To a solution of tert-butyl piperidine-1-carboxylate (600 mg, 1.33 mmol) in dioxane (2 mL), HCl / dioxane (4 M, 3 mL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to provide the title compound (510 mg, 1.31 mmol, 99% yield). LCMS (ESI) [M+H]+ = 353.2.

[0423] Step 4: 2-(4-((4-methoxypyridin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 5):

[0424]

[0425] 2-Chloroprene-5-carboxynitrile (22 mg, 0.15 mmol) was added to a solution of N-(4-methoxy-3-pyridinyl)-N-(4-piperidinyl)-6-(trifluoromethyl)pyridine-3-amine (50.0 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.39 mmol) in N,N-dimethylformamide (1 mL) and stirred for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic compounds were washed with brine (10 mL x 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether solution) to provide the title compound (27.8 mg, 0.0574 mmol, 45% yield). LCMS (ESI)[M+H]+ = 456.2

[0426] Compound 5: 1 H NMR (400 MHz, CDCl3) δ ppm 8.58 (d, J = 5.2 Hz, 1H), 8.47(s, 2H), 8.28 (s, 1H), 8.01 (s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.00 (d, J =5.2Hz, 1H), 6.84 (d, J = 7.2 Hz, 1H), 5.01 (d, J = 13.2 Hz, 2H), 4.23 (t, J =11.6 Hz, 1H), 3.82 (s, 3H), 3.01 - 3.10 (m, 1H), 2.15 (d, J = 13.2 Hz, 2H),1.40 (d, J = 9.2 Hz, 2H).

[0427] Example F: 1-(4-((4-cyclopropylpyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)acetoone (compound 6):

[0428]

[0429] Step 1: 4-[N-(4-chloro-3-pyridyl)-4-(trifluoromethyl)anilino]piperidine-1-carboxylic acid tert-butyl ester

[0430]

[0431] A mixture of tert-butyl 4-[(4-chloro-3-pyridyl)amino]piperidine-1-carboxylate (600 mg, 1.92 mmol), 1-bromo-4-(trifluoromethyl)benzene (866 mg, 3.85 mmol), Pd(OAc)2 (87 mg, 384.85 μmol), t-Bu3P (1.56 g, 769.71 μmol, 1.81 mL, 10% purity) and tBuONa (740 mg, 7.70 mmol) in toluene (20 mL) was degassed and purged three times with N2, and then the mixture was stirred at 120 °C under N2 atmosphere for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0% to 40% ethyl acetate in petroleum ether solution) to provide the title compound (420 mg, 921.25 μmol, 47.88% yield). LCMS(ESI) [M-56+H]+ = 400.2

[0432] Step 2: 4-((4-cyclopropylpyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0433]

[0434] A mixture of tert-butyl 4-[N-(4-chloro-3-pyridyl)-4-(trifluoromethyl)anilino]piperidine-1-carboxylate (250 mg, 548 μmol), cyclopropylboronic acid (94.21 mg, 1.10 mmol), Pd(OAc)₂ (12.31 mg, 55 μmol), bis(1-adamantyl)-butylphosphine (39 mg, 110 μmol), and Cs₂CO₃ (536.00 mg, 1.65 mmol) in H₂O (0.4 mL) and toluene (4 mL) was degassed and purged three times with N₂, and then the mixture was stirred at 120 °C in a microwave reactor for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (petroleum ether eluent for 0% to 45% ethyl acetate) to provide the title compound (240 mg). LCMS (ESI) [M+H] + =462.3.

[0435] Step 3: 4-Cyclopropyl-N-(piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine

[0436]

[0437] To a solution of tert-butyl piperidine-1-carboxylate (240 mg, 520.02 μmol) in dioxane (2 mL), HCl / dioxane (4 M, 1.30 mL) was added and the mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to provide the title compound (200 mg, crude), which is an HCl salt. LCMS (ESI) : [M+H]+ = 362.2.

[0438] Step 4: 1-(4-((4-cyclopropylpyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)acetoone (compound 6):

[0439]

[0440] Triethylamine (84 mg, 830 μmol) was added to a solution of 4-cyclopropyl-N-(4-piperidinyl)-N-[4-(trifluoromethyl)phenyl]pyridine-3-amine (100 mg, 277 μmol) and acetyl chloride (43.44 mg, 553.40 μmol) in dichloromethane (2 mL) at 0 °C, and the mixture was stirred for 1 h. The reaction mixture was concentrated under vacuum, and the residue was purified by reversed-phase HPLC (Welch Xtimate C18 150*30 mm*5 μm; mobile phase: [water(FA)-ACN]; B%: 29% to 59%, 7 min) to provide the title compound (33.3 mg, 82.54 μmol, 30% yield). LCMS (ESI) [M+H]+ = 403.9.

[0441] Compound 6: 1H NMR (400 MHz, CDCl3) δ 8.57 - 8.41 (m, 1H), 8.29 - 8.14(m, 1H), 7.46 - 7.39 (m, 2H), 6.80 - 6.68 (m, 1H), 6.54 (d, J = 8.8 Hz, 2H),4.79 -4.75 (m, 1H), 4.26 - 4.16 (m, 1H), 3.96 - 3.88 (m, 1H), 3.28 - 3.17 (m,1H), 2.71 - 2.61 (m, 1H), 2.19 - 2.09 (m, 2H), 2.08 (s, 3H), 1.92 - 1.84 (m, 1H), 1.48 - 1.35 (m, 2H), 1.08 - 1.01 (m, 2H), 0.82 - 0.81 (m, 2H).

[0442] Example G: 1-(4-((4-cyclopropylpyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)prop-1-one (Compound 7)

[0443]

[0444] Triethylamine (38 mg, 377.01 μmol) was added to a solution of 4-cyclopropyl-N-(4-piperidinyl)-N-[4-(trifluoromethyl)phenyl]pyridine-3-amine (50 mg, 125.67 μmol) and propionyl chloride (23.26 mg, 251.34 μmol) in dichloromethane (2 mL), and the mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was passed by reversed-phase HPLC (Welch Xtimate C18 150 * 30 mm * 5 μm; mobile phase: [water(FA)-ACN]; B%: 29% to 59%, 7 min) to provide the title compound (compound 7, 33.3 mg, 79.77 μmol, 63% yield). LCMS (ESI) [M+H]+ = 418.0

[0445] Compound 7: 1H NMR (400 MHz, CDCl3) δ 8.54 - 8.41 (m, 1H), 8.27 - 8.17(m, 1H), 7.45 - 7.39 (m, 2H), 6.80 - 6.72 (m, 1H), 6.57 - 6.51 (m, 2H), 4.80- 4.77 (m, 1H), 4.29 - 4.14 (m, 1H), 4.04 - 3.91 (m, 1H), 3.26 - 3.10 (m,1H), 2.67 - 2.65 (m, 1H), 2.32 (q, J = 7.2 Hz, 2H), 2.16 - 2.08 (m, 2H), 1.92- 1.85 (m, 1H), 1.41 - 1.30 (m, 2H), 1.12 (t, J = 7.6 Hz, 3H), 1.08 - 1.03(m, 2H), 0.82 - 0.81 (m, 2H).

[0446] Example H: 2-(4-((4-cyclopropoxypyridin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 8):

[0447]

[0448] Step 1: 4-Cyclopropoxy-3-nitropyridine

[0449]

[0450] 4-Chloro-3-nitropyridine (2.2 g, 13.88 mmol) was added to a solution of cyclopropanol (1.21 g, 20.81 mmol) and NaH (832.51 mg, 20.81 mmol, 60% purity) in DMF (20 mL) at 0 °C, and the mixture was stirred at this temperature under a N2 atmosphere for 2 h. The reaction mixture was quenched with NH4Cl (70 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (petroleum ether eluent of 0% to 30% ethyl acetate) to provide the title compound (1.93 g, 10.50 mmol, 76% yield). LCMS (ESI) [M+H]+ = 181.0.

[0451] Step 2: 4-Cyclopropoxypyridine-3-amine

[0452]

[0453] A mixture of 4-(cyclopropoxy)-3-nitropyridine (2.13 g, 11.82 mmol) and Pd / C (0.5 g, 10% purity) in EtOH (20 mL) was degassed and purged three times with H2, and then stirred at 25 °C under H2 (15 psi) atmosphere for 1 h. The reaction mixture was filtered and concentrated under vacuum to provide the title compound (1.73 g, 11.52 mmol, 97% yield). LCMS (ESI) [M+H]+ = 151.2.

[0454] Step 3: 4-((4-cyclopropoxypyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0455]

[0456] NaBH(OAc)3 (2.93 g, 13.82 mmol) was added to a solution of 4-(cyclopropoxy)pyridine-3-amine (1.73 g, 11.52 mmol) and tert-butyl 4-oxopiperidinium-1-carboxylate (3.44 g, 17.28 mmol) in isopropyl acetate (30 mL) at 0 °C. o Add TFA (3.94 g, 34.56 mmol, 2.56 mL) dropwise to the above mixture. Stir the mixture at 25 °C for 12 hours. Adjust the reaction mixture with saturated NaOH aqueous solution (50 mL) and stir for 10 minutes. Extract the resulting mixture with ethyl acetate (100 mL x 3). Wash the combined organic layers with brine (50 mL), dry to Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by rapid silica gel chromatography (0% to 3% methanol eluent in dichloromethane) to provide the title compound (1.65 g, 4.95 mmol, 43% yield). LCMS (ESI) [M+H]+ = 334.3.

[0457] Step 4: 4-((4-cyclopropoxypyridin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0458]

[0459] A mixture of tert-butyl 4-[[4-(cyclopropoxy)-3-pyridyl]amino]piperidine-1-carboxylate (500 mg, 1.50 mmol), 5-bromo-2-(trifluoromethyl)pyridine (677.80 mg, 3.00 mmol), tBuONa (576.46 mg, 6.00 mmol), Pd(OAc)2 (67.33 mg, 299.92 μmol), and t-Bu3P (599.84 μmol, 1.41 mL, 10% purity) in toluene (15 mL) was degassed and purged three times with N2, and then the mixture was stirred at 120 °C under N2 atmosphere for 24 h. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by rapid silica gel chromatography (petroleum ether eluent for 0% to 60% ethyl acetate) to provide the title compound (319 mg, 667 μmol, 44% yield). LCMS (ESI) [M+H] + = 479.3.

[0460] Step 5: 4-Cyclopropoxy-N-(piperidin-4-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-3-amine.

[0461]

[0462] To a solution of tert-butyl piperidine-1-carboxylate (100 mg, 208.98 μmol) in dioxane (2 mL), HCl / dioxane (4 M, 5 mL) was added and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to provide the title compound (78 mg, 206.14 μmol, crude), which is a yellow solid. LCMS (ESI) [M+H]+ = 379.2.

[0463] Step 6: 2-(4-((4-cyclopropoxypyridin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 8):

[0464]

[0465] 2-Chloroprene-5-carboxynitrile (28.76 mg, 206.14 μmol) was added to a solution of N-[4-(cyclopropoxy)-3-pyridinyl]-N-(4-piperidinyl)-6-(trifluoromethyl)pyridine-3-amine (78 mg, 206.14 μmol) and DIEA (79.92 mg, 618.41 μmol, 107.72 μL) in DMF (2 mL), and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue. The residue was purified by reversed-phase HPLC (Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 39% to 69%, 7 min) to provide the title compound (55.1 mg, 114.44 μmol, 56% yield). LCMS (ESI) [M+H]+ = 482.4

[0466] Compound 8: 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 5.6 Hz, 1H), 8.47 (s,2H), 8.24 (s, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.46 - 7.41 (m, 1H), 7.31 (d, J= 5.6 Hz, 1H), 6.80 (dd, J = 2.8, 8.8 Hz, 1H), 5.04 - 4.96 (m, 2H), 4.25 -4.16 (m, 1H), 3.80 - 3.74 (m, 1H), 3.09 - 3.00 (m, 2H), 2.15 -2.10 (m, 2H),1.44 - 1.36 (m, 2H), 0.85 - 0.77 (m, 2H), 0.60 - 0.53 (m, 2H).

[0467] Example I: 4-(4-((4-methoxypyridin-3-yl)(4-(methanesulfonyl)phenyl)amino)piperidin-1-yl)benzylnitrile: (Compound 9)

[0468]

[0469] Step 1: 4-((4-methoxypyridin-3-yl)(4-(methanesulfonyl)phenyl)amino)piperidine-1-carboxylic acid tert-butyl ester:

[0470]

[0471] A mixture of tert-butyl 4-[(4-methoxy-3-pyridyl)amino]piperidine-1-carboxylate (1 g, 3.25 mmol), 1-bromo-4-methanesulfonylbenzene (1.53 g, 6.51 mmol), tBu3P Pd G2 (333.39 mg, 650.65 μmol), and tBuONa (1.25 g, 13.01 mmol) in toluene (20 mL) was stirred at 125 °C under a nitrogen atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel chromatography (0% to 5% MeOH in DCM solution) to provide the title compound (430 mg, 931.60 μmol, 29% yield). LCMS (ESI), [M+H]+ = 462.3.

[0472] Step 2: 4-Methoxy-N-(4-(methanesulfonyl)phenyl)-N-(piperidin-4-yl)pyridine-3-amine:

[0473]

[0474] 4-(N-(4-methoxy-3-pyridinyl)-4-methanesulfonyl-anilino)piperidine-1-carboxylic acid tert-butyl ester (430 mg, 931.60 μmol) was dissolved in HCl / dioxane (4 M, 4 mL) and the mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (336 mg, 929.57 μmol, 99.78% yield).

[0475] Step 3: 4-(4-((4-methoxypyridin-3-yl)(4-(methanesulfonyl)phenyl)amino)piperidin-1-yl)benzylnitrile (compound 9):

[0476]

[0477] A mixture of 4-methoxy-N-(4-methanesulfonylphenyl)-N-(4-piperidinyl)pyridine-3-amine (50 mg, 138.33 μmol), 4-fluorobenzyl nitrile (25.13 mg, 207.49 μmol), and K₂CO₃ (95.59 mg, 691.64 μmol) in DMSO (3 mL) was stirred at 120 °C for 12 h. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 22% to 52%, 7 min) to provide the title compound (25 mg, 54.05 μmol, 39% yield). LCMS (ESI), [M+H]⁺ = 463.3.

[0478] Compound 9: 1 H NMR (400 MHz, CD3OD) 8.51 (s, 1H), 8.19 (s, 1H), 7.68 (d,J = 8.8 Hz, 3H), 7.48 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 5.6 Hz, 1H), 6.97 (d,J = 8.4 Hz, 2H), 6.70 (d, J = 8.0 Hz, 2H), 4.35 - 4.33 (m, 1H), 4.02 - 3.99(m, 2H), 3.85 (s, 3H), 3.04 (s, 3H), 2.14 - 2.11 (m, 2H), 1.46 - 1.43 (m,2H), 1.31 - 1.29 (m, 2H).

[0479] Example J: 4-Cyclopropyl-N-(1-(4-(Cyclopropylsulfonyl)phenyl)piperidin-4-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-3-amine (Compound 10):

[0480]

[0481] The title compound was synthesized using a method similar to that used in Example C (Compound 3).

[0482] The compound was purified by reversed-phase HPLC (Welch Xtimate C18 150 * 30 mm * 5 μm; mobile phase: [water(FA)-ACN]; B%: 37% to 67%, 7 min) to provide the title compound (1 mg, 1.84 μmol, 2.23% yield). LCMS (ESI), [M+H]+ = 543.0.

[0483] Compound 10: 1 H NMR (400 MHz, CDCl3) δ 8.54 - 8.48 (m, 1H), 8.30 - 8.25(m, 1H), 8.09 - 8.07 (m, 1H), 7.74 - 7.70 (m, 2H), 7.49 - 7.45 (m, 1H), 6.91(d, J = 9.2 Hz, 2H), 6.82 - 6.76 (m, 2H), 4.27 - 4.17 (m, 1H), 4.02 - 3.95(m, 2H), 3.09 - 2.99 (m, 2H), 2.46 (s, 1H), 2.26 - 2.18 (m, 2H), 1.90 - 1.84(m, 1H), 1.26 (s, 2H), 1.10 - 1.06 (m, 2H), 1.01 - 0.97 (m, 2H), 0.89 - 0.80 (m, 4H).

[0484] Example K: 6-(4-((4-methoxypyridin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)amino)piperidin-1-yl)nicotinonitrile (Compound 11):

[0485]

[0486] The title compound was synthesized using a method similar to that used in Example E (Compound 5).

[0487] The title compound was purified by rapid silica gel chromatography (petroleum ether eluent for 0% to 30% ethyl acetate) to provide the title compound (30 mg, 66.01 μmol, 32% yield). LCMS (ESI), [M+H]+ = 455.3.

[0488] Compound 11: 1H NMR (400 MHz, CDCl3) δ 8.58 - 8.54 (m, 1H), 8.39 - 8.36(m, 1H), 8.26 - 8.24 (m, 1H), 8.01 (d, J = 2.8 Hz, 1H), 7.62 - 7.57 (m, 1H),7.47 - 7.43 (m, 1H), 6.98 - 6.95 (m, 1H), 6.85 - 6.80 (m, 1H), 6.61 - 6.58(m, 1H), 4.60 - 4.53 (m, 2H), 4.25 - 4.16 (m, 1H), 3.81 (s, 3H), 3.09 - 3.01 (m, 2H), 2.18 - 2.11 (m, 2H), 1.47 - 1.37 (m, 2H).

[0489] Example L: 4-Methoxy-N-(1-(5-(methanesulfonyl)pyrimidin-2-yl)piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 12):

[0490]

[0491] Step 1: 4-[N-(4-methoxy-3-pyridyl)-4-(trifluoromethyl)aniline]piperidine-1-carboxylic acid tert-butyl ester

[0492]

[0493] Under N2 atmosphere, tBu3P Pd G2 (333.39 mg, 650.65 μmol) and tBuONa (1.88 g, 19.52 mmol) were added in a single step to a mixture of 4-[(4-methoxy-3-pyridyl)amino]piperidine-1-carboxylic acid tert-butyl ester (2 g, 6.51 mmol) and 1-bromo-4-(trifluoromethyl)benzene (2.93 g, 13.01 mmol) in toluene (20 mL), and the reaction mixture was stirred at 120 °C for 24 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel rapid chromatography (0% to 40% ethyl acetate in petroleum ether solution) to provide the title compound (2.9 g, 6.42 mmol, 99% yield). LCMS (ESI), [M+H]+ = 452.2.

[0494] Step 2: 4-Methoxy-N-(piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride

[0495]

[0496] 4-[N-(4-methoxy-3-pyridinyl)-4-(trifluoromethyl)anilino]piperidine-1-carboxylic acid tert-butyl ester (2.9 g, 6.42 mmol) was dissolved in dioxane (3.0 mL), HCl / dioxane (4 M, 10 mL) was added, and the mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to provide the title compound (2.4 g, 6.19 mmol, 96% yield) as a yellow solid. LCMS (ESI), [M+H]+ = 352.1.

[0497] Step 3: 4-Methoxy-N-(1-(5-(methanesulfonyl)pyrimidin-2-yl)piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 12):

[0498]

[0499] DIEA (49.99 mg, 386.77 μmol) was added in a single step to a solution of 4-methoxy-N-(4-piperidinyl)-N-[4-(trifluoromethyl)phenyl]pyridine-3-amine (50 mg, 128.92 μmol) and 2-chloro-5-methanesulfonyl-pyrimidine (24.83 mg, 128.92 μmol) in DMF (1 mL), and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (water (NH3H2O+NH4HCO3)-ACN]; B%: 45% to 75%, 7 min) to provide the title compound (36.2 mg, 71.33 μmol, 55.32% yield). LCMS (ESI), [M+H]+ = 508.1.

[0500] Compound 12: 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 2H), 8.53 (d, J = 5.6 Hz,1H), 8.22 (s, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.00 - 6.98 (m, 1H), 7.00 - 6.93(m, 1H), 6.55 (d, J = 8.8 Hz, 2H), 5.04 (d, J = 13.6 Hz, 2H), 4.32 - 4.19 (m,1H), 3.81 (s, 3H), 3.17 - 3.07 (m, 2H), 3.06 (s, 3H), 2.18 - 2.15 (m, 2H),1.46 - 1.24 (m, 2H).

[0501] Example M: ​​4-Methoxy-N-(4-(trifluoromethyl)phenyl)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)pyridin-3-amine (Compound 13):

[0502]

[0503] The title compound was synthesized using a method similar to that used in Example L (Compound 12).

[0504] The title compound was purified by preparative HPLC (acetonitrile 50% / 0.2% formic acid aqueous solution) to provide the title compound (120 mg, 241.72 μmol, 42.58% yield). LCMS (ESI), [M+H]+ = 497.2.

[0505] Compound 13: 1 H NMR (400 MHz, CD3OD) 8.46 (d, J = 5.6 Hz, 1H), 8.28 (s,1H), 8.16 (s, 1H), 7.69-7.60 (m, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.23 (d, J =5.6 Hz, 1H), 6.85 (d, J = 9.2 Hz, 1H), 6.65 (d, J = 8.8 Hz, 2H), 4.55 - 4.52(m, 2H), 4.39 - 4.28 (m, 1H), 3.83 (s, 3H), 3.11 - 3.08 (m, 2H), 2.14 - 2.11(m, 2H), , 1.47 - 1.28 (m, 2H).

[0506] Example N: 6-(4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)nicotinonitrile (Compound 14):

[0507]

[0508] The title compound was synthesized using a method similar to that used in Example L (Compound 12).

[0509] The title compound was purified by preparative HPLC (50% acetonitrile / 0.2% formic acid aqueous solution) to provide the title compound (120 mg, 264.63 μmol, 46.49% yield). LCMS (ESI), [M+H]+ = 454.2.

[0510] Compound 14: 1 H NMR (400 MHz, CD3OD) 8.46 (d, J = 5.6 Hz, 1H), 8.34 (d, J= 1.6 Hz, 1H), 8.16 (s, 1H), 7.69 - 7.6 (m, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 5.6 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.65 (d, J = 8.8 Hz, 2H), 4.59 - 4.56 (m, 2H), 4.44 - 4.34 (m, 1H), 3.83 (s, 3H), 3.18 - 3.05 (m, 2H),2.14 - 2.12 (m, 2H), 1.36 - 1.28 (m, 2H).

[0511] Example O: 2-(4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 15):

[0512]

[0513] The title compound was synthesized using a method similar to that used in Example L (Compound 12).

[0514] The title compound was purified by preparative HPLC (acetonitrile 35% to 50% / 0.2% formic acid aqueous solution) to provide the title compound (120 mg, 264.06 μmol, 46.39% yield). LCMS (ESI), [M+H]+ = 455.2.

[0515] Compound 15: 1 H NMR (400 MHz, CD3OD) 8.54 (s, 2H), 8.46 (d, J = 6.4 Hz,1H), 8.16 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 2.0 Hz, 1H), 6.65(d, J = 8.4 Hz, 2H), 4.97 - 4.94 (m, 2H), 4.43 - 4.36 (m, 1H), 3.83 (s, 3H), 3.17 - 3.11 (m, 2H), 2.16 -2.13 (m, 2H), 1.33 - 1.26 (m, 1H), 1.40 - 1.21 (m,1H).

[0516] Example P: 4-Methoxy-N-(1-(4-(methanesulfonyl)phenyl)piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 16):

[0517]

[0518] The title compound was synthesized using a method similar to that used in Example C (Compound 3).

[0519] The title compound was subjected to preparative HPLC (Welch Xtimate C18 150*30mm*5um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 50% to 80%, 8 min) to provide the title compound (82.5 mg, 163.19 μmol, 48.53% yield). LCMS (ESI), [M+H]+ = 506.1.

[0520] Compound 16: 1H NMR (400 MHz, CD3OD) 8.47 (d, J = 6.0 Hz, 1H), 8.18 (s,1H), 7.69 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 6.4 Hz,1H), 7.03 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.8 Hz, 2H), 4.34 - 4.22 (m, 1H), 4.07 - 4.03 (m, 2H), 3.83 (s, 3H), 3.10 - 3.07 (m, 2H), 3.02 (s, 3H), 2.16 -2.12 (m, 2H), 1.52 - 1.39 (m, 2H).

[0521] Example Q: 4-Methoxy-N-(1-(5-(methanesulfonyl)pyrimidin-2-yl)piperidin-4-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-3-amine (Compound 17):

[0522]

[0523] The title compound was synthesized using a method similar to that used in Example E (Compound 5).

[0524] The title compound was subjected to preparative HPLC (column: Welch Xtimate C18 150 * 30 mm * 5 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 37% to 67%, 8 min) to provide the title compound (180 mg, 353.97 μmol, 44.40% yield). LCMS (ESI), [M+H]+ = 509.1.

[0525] Compound 17: 1H NMR (400 MHz, CD3OD) 8.65 (s, 2H), 8.51 (d, J = 5.6 Hz,1H), 8.24 (s, 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.27(d, J = 5.6 Hz, 1H), 7.18 (dd, J = 2.8, 8.8 Hz, 1H), 5.04 - 5.01 (m, 2H), 4.48 - 4.39 (m, 1H), 3.86 (s, 3H), 3.21 - 3.16 (m, 2H), 3.11 (s, 3H), 2.17 -2.14 (m, 2H), 1.38 - 1.30 (m, 2H).

[0526] Example R: 2-(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 18):

[0527]

[0528] Step 1: 4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0529]

[0530] A mixture of tert-butyl 4-[(4-methoxy-3-pyridyl)amino]piperidine-1-carboxylate (2.0 g, 6.51 mmol), 1-bromo-4-(difluoromethoxy)benzene (2.32 g, 10.41 mmol), tBu3P Pd G2 (666.78 mg, 1.30 mmol), and tBuONa (1.88 g, 19.52 mmol) in dioxane (50 mL) was degassed and purged three times with N2, and then stirred at 120 °C under N2 atmosphere for 24 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel rapid chromatography (0% to 40% ethyl acetate in petroleum ether solution) to provide the title compound (1600 mg, 3.45 mmol, 52.98% yield). LCMS (ESI), [M+H]+ = 450.1.

[0531] Step 2: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(piperidin-4-yl)pyridine-3-amine hydrochloride

[0532]

[0533] 4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (1.6 g, 3.56 mmol) was dissolved in dioxane (3.0 mL), HCl / dioxane (4 M, 6 mL) was added, and the mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to provide the title compound (1.37 g, 3.56 mmol, 100% yield). LCMS (ESI), [M+H]+ = 350.1.

[0534] Step 3: 2-(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 18):

[0535]

[0536] 2-Chloroprene-5-carboxynitrile (103.85 mg, 744.19 μmol) was added to a mixture of N-[4-(difluoromethoxy)phenyl]-4-methoxy-N-(4-piperidinyl)pyridine-3-amine (260 mg, 744.19 μmol) and triethylamine (301.22 mg, 2.98 mmol) in DMF (5 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was subjected to preparative HPLC (water (NH3H2O+NH4HCO3)-ACN]; B%: 45% to 75%, 7 min) to provide the title compound (153.4 mg, 339.04 μmol, 45.56% yield). LCMS (ESI), [M+H]+ = 453.2.

[0537] Compound 18: 1H NMR (400 MHz, CD3OD) δ 8.53 (s, 2H), 8.41 (d, J = 5.6 Hz,1H), 8.14 (s, 1H), 7.18 (d, J = 5.6 Hz, 1H), 6.94 (d, J = 9.2 Hz, 2H), 6.84 -6.36 (m, 3H), 4.94 - 4.92 (m, 2H), 4.32 - 4.26 (m, 1H), 3.81 (s, 3H), 3.20 -3.04 (m, 2H), 2.13 - 2.10 (m, 2H), 1.32 - 1.23 (m, 2H).

[0538] Example S: 2-(4-((4-(difluoromethoxy)phenyl)(4-methylpyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 19):

[0539]

[0540] Step 1: 4-((4-(difluoromethoxy)phenyl)(4-methylpyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0541]

[0542] A mixture of tert-butyl 4-[(4-methyl-3-pyridyl)amino]piperidine-1-carboxylate (1 g, 3.43 mmol), 1-bromo-4-(difluoromethoxy)benzene (1.53 g, 6.86 mmol), tBu3PPdG2 (351.70 mg, 686.37 μmol), and tBuONa (989.44 mg, 10.30 mmol) in toluene (20 mL) was degassed and purged three times with N2, and then stirred at 120 °C under N2 atmosphere for 12 h. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by rapid silica gel chromatography (petroleum ether eluent for 0% to 35% ethyl acetate) to provide the title compound (0.99 g, 2.28 mmol, 66.55% yield). LCMS (ESI), [M+H]+ = 434.2.

[0543] Step 2: N-(4-(difluoromethoxy)phenyl)-4-methyl-N-(piperidin-4-yl)pyridine-3-amine

[0544]

[0545] To a solution of tert-butyl piperidine-1-carboxylate (0.99 g, 2.28 mmol) in dioxane (5 mL), HCl / dioxane (4 M, 5 mL) was added. The mixture was stirred for 1 h at 25 °C. The reaction mixture was concentrated under reduced pressure to provide the title compound (0.9 g, crude, HCl salt).

[0546] Step 3: 2-(4-((4-(difluoromethoxy)phenyl)(4-methylpyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 19):

[0547]

[0548] DIEA (524.19 mg, 4.06 mmol) was added to a solution of N-[4-(difluoromethoxy)phenyl]-4-methyl-N-(4-piperidinyl)pyridine-3-amine (300 mg, 811.17 μmol) and 2-chloropyrimidin-5-carboxynitrile (135.83 mg, 973.40 μmol) in acetonitrile (5 mL). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by reversed-phase HPLC (Boston Prime C18 150*30 mm*5 μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 60% to 90%, 7 min) to provide the title compound (100.8 mg, 230.95 μmol, 28.47% yield). LCMS (ESI), [M+H] + = 437.1

[0549] Compound 19: 1 H NMR (400 MHz, CD3OD) δ 8.59 - 8.46 (m, 2H), 8.41 - 8.33(m, 1H), 8.27 - 8.20 (m, 1H), 7.46 - 7.36 (m, 1H), 7.03 - 6.93 (m, 2H), 6.84- 6.41 (m, 3H), 5.01 - 4.92 (m, 2H), 4.45 - 4.33 (m, 1H), 3.20 - 3.09 (m,2H), 2.16 (s, 3H), 2.13 - 2.10 (m, 2H), 1.35 - 1.31 (m, 2H).

[0550] Example T: 4-methoxy-N-(1-(1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (compound 20):

[0551]

[0552] The title compound was synthesized using a method similar to that used in Example C (Compound 3).

[0553] The title compound was subjected to preparative HPLC (Welch Xtimate C18 150*30mm*5um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 25% to 40%, 8 min) to provide the title compound (75 mg, 173.83 μmol, 20.36% yield). LCMS (ESI), [M+H]+ = 432.2.

[0554] Compound 20: 1 H NMR (400 MHz, CD3OD) 8.51 (d, J = 6.0 Hz, 1H), 8.23 ​​(s,1H), 7.39 (d, J = 8.8 Hz, 2H), 7.30 - 7.27 (m, 2H), 6.63 (d, J = 8.8 Hz, 2H), 5.90 (d, J = 2.0 Hz, 1H), 4.20 - 4.14 (m, 1H), 3.86 (s, 3H), 3.61 (s, 3H), 3.22 - 3.19 (m, 2H), 2.91 - 2.85 (m, 2H), 2.14 - 2.10 (m, 2H), 1.67 - 1.57(m, 2H).

[0555] Example U: (R)-(4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)(tetrahydrofuran-3-yl)methyl ketone (compound 21):

[0556]

[0557] DIEA (220.70 mg, 1.71 mmol) and HATU (324.65 mg, 853.82 μmol) were added in a single step to a mixture of 4-methoxy-N-(4-piperidinyl)-N-[4-(trifluoromethyl)phenyl]pyridine-3-amine (200 mg, 569.21 μmol) and (3R)-tetrahydrofuran-3-carboxylic acid (66.09 mg, 569.21 μmol) in DMF (3 mL) at 20 °C. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was purified by preparative HPLC (water (NH3H2O+NH4HCO3)-ACN; B%: 45% to 75%, 7 min) to provide the title compound (45.9 mg, 102.12 μmol, 17.94% yield, 100% purity). LCMS (ESI), [M+H] + = 450.2.

[0558] Compound 21: 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, J =5.6 Hz, 1H), 8.22 (s,1H), 7.39 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 5.6 Hz, 1H), 6.52 (d, J = 8.8 Hz,2H), 4.77 - 4.73 (m, 1H), 4.15 - 4.08 (m, 1H), 4.04 - 3.97 (m, 2H), 3.87 -3.83 (m, 3H), 3.81 (s, 3H), 3.26 - 3.15 (m, 2H), 2.69 - 2.64 (m, 1H), 2.18 -2.04 (m, 4H), 1.78 - 1.73 (m, 1H), 1.35 - 1.18 (m, 2H).

[0559] Example V: 1-(4-((4-ethoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-2-methyl-piperidin-1-yl)prop-1-one (compound 22):

[0560]

[0561] Step 1: 4-[N-(4-ethoxy-3-pyridyl)-4-(trifluoromethyl)anilino]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester

[0562]

[0563] tBu3P Pd G2 (76.38 mg, 149.06 μmol) and tBuONa (429.73 mg, 4.47 mmol) were added in a single addition to a mixture of 4-[(4-ethoxy-3-pyridyl)amino]-2-methyl-piperidin-1-carboxylic acid tert-butyl ester (500 mg, 1.49 mmol) and 1-bromo-4-(trifluoromethyl)benzene (670.78 mg, 2.98 mmol) in toluene (20 mL), and the mixture was stirred at 120 °C under N2 for 19 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel rapid chromatography (0% to 30% ethyl acetate in petroleum ether solution) to provide the title compound (600 mg, 1.25 mmol, 83.94% yield). LCMS (ESI), [M+H]+ = 480.2.

[0564] 1 H NMR (400MHz, CD3CN) δ 8.50 - 8.45 (m, 1H), 8.19 (s, 1H), 7.40 (d, J= 8.8 Hz, 2H), 7.10 - 7.04 (m, 1H), 6.60 (d, J = 8.8 Hz, 2H), 4.11 - 4.05 (m,2H), 3.83-3.84 (m, 1H), 3.57- 3.54 (m, 1H), 3.31 - 3.20 (m, 1H), 2.90 - 2.78(m, 2H), 1.43 (s, 9H), 1.23 - 1.16 (m, 6H).

[0565] Step 2: 4-ethoxy-N-(2-methyl-4-piperidinyl)-N-[4-(trifluoromethyl)phenyl]pyridine-3-amine

[0566]

[0567] To a solution of tert-butyl 4-[N-(4-ethoxy-3-pyridinyl)-4-(trifluoromethyl)anilino]-2-methyl-piperidin-1-carboxylate (600 mg, 1.25 mmol) in dioxane (2.0 mL), HCl / dioxane (4 M, 1.61 mL) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to provide the title compound (520 mg, 1.25 mmol, 99.93% yield, HCl salt), as a yellow solid. LCMS (ESI), [M+H]+ = 380.1.

[0568] Step 3: 1-(4-((4-ethoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-2-methylpiperidin-1-yl)prop-1-one (compound 22):

[0569]

[0570] At 0 °C, propionyl chloride (182.89 mg, 1.98 mmol) was added dropwise to a solution of 4-ethoxy-N-(2-methyl-4-piperidinyl)-N-[4-(trifluoromethyl)phenyl]pyridine-3-amine (500 mg, 1.32 mmol) and Et3N (400.05 mg, 3.95 mmol) in dichloromethane (3.0 mL). The mixture was stirred at 0 °C for 1 hour. The mixture was concentrated under vacuum, and the resulting residue was purified by preparative HPLC (water (0.05% FA)-ACN, 35% to 65%) to provide the title compound (280 mg, 623.68 μmol, 47.33% yield). LCMS (ESI), [M+H]+ = 436.2.

[0571] Compound 22: 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 5.6 Hz, 1H), 8.29 (s,1H), 8.15 (s, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 5.6 Hz, 1H), 6.53(d, J = 8.8 Hz, 2H), 4.32 (s, 1H), 4.16 - 4.00 (m, 3H), 3.86 (s, 1H), 3.41 -3.21 (m, 1H), 2.47 - 2.26 (m, 3H), 2.14 - 2.10 (m, 1H), 1.59 - 1.53 (m, 1H),1.51 - 1.39 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H), 1.22 - 1.16 (m, 6H).

[0572] Example W: 1-(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)prop-1-one (compound 23):

[0573]

[0574] The title compound was synthesized using a method similar to that of Example V (Compound 22).

[0575] The title compound was purified by preparative HPLC (column: Welch Xtimate C18 150 * 30 mm * 5 μm; mobile phase: (water (0.05% FA)-ACN, 20% to 50%, 8 min) to provide the title compound (87.1 mg, 214.83 μmol, 41.44% yield, 100% purity). LCMS (ESI), [M+H]+ = 406.1.

[0576] Compound 23: 1 H NMR (400 MHz, CDCl3) 8.50 (d, J = 5.6 Hz, 1H), 8.25 -8.15 (m, 1H), 6.98 - 6.91 (m, 3H), 6.64 - 6.60 (m, 1H), 6.57 (s, 1H), 6.48(d, J = 8.8 Hz, 2H), 6.38 (s, 1H), 4.74 - 4.70 (m, 1H), 4.08 - 4.02 (m, 1H), 3.98 - 3.86 (m, 1H), 3.79 (s, 3H), 3.16 - 3.09 (m, 1H), 2.64 - 2.61 (m, 1H),2.38 - 2.25 (m, 2H), 2.07 - 2.02 (m, 2H), 1.38 - 1.19 (m, 2H), 1.10 (t, J =7.6 Hz, 3H).

[0577] Example X: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(5-(methanesulfonyl)pyridin-imine-2-yl)piperidin-4-yl)pyridin-3-amine (compound 24):

[0578]

[0579] The title compound was synthesized using a method similar to that used in Example L (Compound 12).

[0580] The title compound was purified by preparative HPLC (acetonitrile 26% to 35% / 0.2% formic acid aqueous solution) to provide the title compound (172.4 mg, 334.20 μmol, 42.98% yield, 98% purity). LCMS (ESI), [M+H]+ = 506.0.

[0581] Compound 24: 1 H NMR (400 MHz, CDCl3) 8.66 (s, 2H), 8.49 (d, J = 5.6 Hz,1H), 8.23 ​​(s, 1H), 7.00 - 6.93 (m, 3H), 6.58 (s, 1H), 6.54 - 6.49 (m, 2H), 6.41 - 6.18 (m, 1H), 5.03 - 4.99 (m, 2H), 4.25 - 4.15 (m, 1H), 3.80 (s, 3H), 3.12 - 3.02 (m, 5H), 2.16 - 2.13 (m, 2H), 1.42 - 1.31 (m, 2H).

[0582] Example Y: 2-(4-((6-(difluoromethoxy)pyridin-3-yl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 25):

[0583]

[0584] Step 1: 4-((6-chloropyridin-3-yl)(4-methoxypyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0585]

[0586] A mixture of tert-butyl 4-[(4-methoxy-3-pyridyl)amino]piperidine-1-carboxylate (4.0 g, 13.01 mmol), 5-bromo-2-chloropyridine (5.01 g, 26.02 mmol), (tBu)3P Pd G2 (666.78 mg, 1.30 mmol), and tBuONa (5.00 g, 52.04 mmol in 20 mL toluene solution) was degassed and purged three times with N2, and then stirred at 120 °C under N2 atmosphere for 12 h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (20% to 70% ethyl acetate in petroleum ether solution) to provide the title compound (4.0 g, 9.55 mmol, 73.39% yield). LCMS (ESI) [M+H]+ = 419.2.

[0587] Step 2: 4-((6-hydroxypyridin-3-yl)(4-methoxypyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0588]

[0589] To a solution of tert-butyl piperidine-1-carboxylate (2000 mg, 4.77 mmol) in dioxane (20 mL) and H₂O (4 mL), di-tert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphine (183.45 mg, 381.60 μmol), Pd₂(dba)₃ (174.72 mg, 190.80 μmol), and KOH (1.07 g, 19.08 mmol) were added. The reaction mixture was concentrated under reduced pressure to give the title compound (1.91 g, 3.86 mmol, 80.99% yield, 81% purity), and the crude product was used directly in the next step. LCMS (ESI) [M+H]+ = 401.2.

[0590] Step 3: 4-((6-(difluoromethoxy)pyridin-3-yl)(4-methoxypyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0591]

[0592] A mixture of tert-butyl 4-[(6-hydroxy-3-pyridinyl)-(4-methoxy-3-pyridinyl)amino]piperidine-1-carboxylate (700 mg, 1.29 mmol, 74% purity) was dissolved in CH3CN (6 mL), KOH (6 M, 2.58 mL), and difluoromethyl trifluoromethanesulfonate (776 mg, 3.88 mmol), and the mixture was then stirred at 25 °C for 0.03 h. The reaction mixture was diluted with brine (20 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent of 0% to 60% ethyl acetate / petroleum ether) and then by preparative TLC (petroleum ether / ethyl acetate / ETOH = 4 / 3 / 1) to provide the title compound (240 mg, 41% yield). LCMS (ESI) [M+H]+ = 451.1.

[0593] Step 4: 6-(difluoromethoxy)-N-(4-methoxypyridin-3-yl)-N-(piperidin-4-yl)pyridin-3-amine hydrochloride

[0594]

[0595] HCl / dioxane (4 M, 2 mL) was added to a solution of 4-[[6-(difluoromethoxy)-3-pyridyl]-(4-methoxy-3-pyridyl)amino]piperidine-1-carboxylic acid tert-butyl ester (215.07 mg, 477.42 μmol) in dioxane (2 mL) at 25 °C, and the mixture was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure to provide the title compound (184 mg, 475.67 μmol, 99.63% yield, HCl salt). LCMS (ESI) [M+H]+ = 351.1.

[0596] Step 5: 2-(4-((6-(difluoromethoxy)pyridin-3-yl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 25):

[0597]

[0598] A mixture of 6-(difluoromethoxy)-N-(4-methoxy-3-pyridinyl)-N-(4-piperidinyl)pyridin-3-amine (40 mg, 103.41 μmol, HCl salt), 2-chloropyrimidin-5-carboxynitrile (17.32 mg, 124.09 μmol), and DIEA (40.09 mg, 310.22 μmol) in DMF (2.0 mL) was stirred at 0 °C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue. The residue was purified by rapid silica gel chromatography (0% to 5% methanol eluent in dichloromethane) to provide the title compound (34 mg, 72.73 μmol, 70.34% yield, 97% purity). LCMS (ESI) [M+H]+ = 454.1.

[0599] Compound 25: 1HNMR (400 MHz, DMSO-d6): 8.71 (s, 2H), 8.46 (d, J = 5.6 Hz,1H), 8.20 (s, 1H), 7.54(s, 1H), 7.48 (t, J = 74 Hz, 1H), 7.19(d, J = 5.6 Hz,1H), 7.02 (d, J = 3.2 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.78 - 4.75 (m, 2H),4.34 - 4.28 (m, 1H), 3.76 (s, 3H), 3.19-3.14 (m, 2H), 2.05-2.02 (m, 2H),1.17-1.14 (m, 2H).

[0600] Example Z: 6-(difluoromethoxy)-N-(4-methoxypyridin-3-yl)-N-(1-(5-(methanesulfonyl)pyrimidin-2-yl)piperidin-4-yl)pyridin-3-amine (compound 26):

[0601]

[0602] The title compound was synthesized using a method similar to that used in Example Y (Compound 25).

[0603] The residue was purified by rapid silica gel chromatography (0% to 5% methanol with dichloromethane eluent) to provide the title compound (40 mg, 77.39 μmol, 74.84% yield). LCMS (ESI) [M+H]+ = 507.1.

[0604] Compound 26: 1 H NMR (400 MHz, CDCl3) 8.66 (s, 2H), 8.49 (d, J = 5.2 Hz,1H), 8.25 (s, 1H), 7.58(s, 1H), 7.27 (t, J = 75.2 Hz, 1H), 6.93 - 6.88 (m,2H), 6.74 (d, J = 8.8 Hz, 1H), 5.03 - 4.99 (m, 2H), 4.15 - 4.09 (m, 1H), 3.79 (s, 3H), 3.09 - 3.03 (m, 5H), 2.15 - 2.12 (m, 2H), 1.42 - 1.34 (m, 2H).

[0605] Example AA: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)pyridine-3-amine (compound 27):

[0606]

[0607] The title compound was synthesized using a method similar to that used in Example C (Compound 3).

[0608] The title compound was purified by preparative TLC (ethanol:ethyl acetate:petroleum ether = 1:3:4) to provide the title compound (41 mg, 92.60 μmol, 16.18% yield). LCMS (ESI), [M+H]+ = 430.2.

[0609] Compound 27: 1 H NMR (400 MHz, CDCl3) 8.53 (d, J = 5.6 Hz, 1H), 8.30 (s,1H), 7.36 (d, J = 2.0 Hz, 1H), 7.05 - 6.93 (m, 3H), 6.59 (s, 1H), 6.53 (d, J= 9.2 Hz, 2H), 6.43 - 6.18 (m, 1H), 5.80 (d, J = 2.0 Hz, 1H), 4.01 - 3.92 (m,1H), 3.84 (s, 3H), 3.66 (s, 3H), 3.19 - 3.15 (m, 2H), 2.86 - 2.74 (m, 2H),2.09 - 2.06 (m, 2H), 1.58 - 1.55 (m, 2H).

[0610] Example AB: (4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)(pyridin-4-yl)methyl ketone (compound 28):

[0611]

[0612] The title compound was synthesized using a method similar to that used in Example U (Compound 21).

[0613] The title compound was purified by preparative TLC (10% methanol in dichloromethane solution) to provide the title compound (129.8 mg, 285.61 μmol, 66.52% yield). LCMS (ESI), [M+H]+ = 455.2.

[0614] Compound 28: 1 H NMR (400 MHz, CD3OD) δ 8.69 - 8.59 (m, 2H), 8.46 (d, J =5.6 Hz, 1H), 8.18 (s, 1H), 7.43 - 7.35 (m, 2H), 7.22 (d, J = 5.6 Hz, 1H),7.00 - 6.89 (m, 2H), 6.80 - 6.39 (m, 3H), 4.68 (d, J = 13.6 Hz, 1H), 4.3.-4.20 (m, 1H), 3.83 (s, 3H), 3.63 - 3.60 (m, 1H), 3.39 - 3.34 (m, 1H), 3.05 -3.01 (m, 1H), 2.16 - 2.13 (m, 1H), 2.05 - 1.93 (m, 1H), 1.49 - 1.33 (m, 2H).

[0615] Example AC: (4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)(pyridin-4-yl)methyl ketone (compound 29):

[0616]

[0617] The title compound was synthesized using a method similar to that used in Example U (Compound 21).

[0618] The title compound was purified by preparative TLC (10% methanol in dichloromethane solution) to provide the title compound (135 mg, 295.75 μmol, 69.28% yield). LCMS (ESI), [M+H]+ = 457.2.

[0619] Compound 29: 1H NMR (400 MHz, CD3OD) δ 8.63 (d, J = 6.0 Hz, 2H), 8.51 (d,J = 5.6 Hz, 1H), 8.20 (s, 1H), 7.42 - 7.34 (m, 4H), 7.26 (d, J = 5.6 Hz, 1H),6.64 (d, J = 8.8 Hz, 2H), 4.73 - 4.69 (m, 1H), 4.37 - 4.28 (m, 1H), 3.85 (s,3H), 3.65 - 3.62 (m, 1H), 3.40 - 3.34 (m, 1H), 3.05 - 3.01 (m, 1H), 2.19 -2.16 (m, 1H), 2.05 - 2.02 (m, 1H), 1.42 - 1.31 (m, 2H).

[0620] Example AD: 6-(difluoromethoxy)-N-(4-methoxypyridin-3-yl)-N-(1-(1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)pyridin-3-amine (compound 30):

[0621]

[0622] Step 1: N-(1-(3-bromo-1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)-6-(difluoromethoxy)-N-(4-methoxypyridin-3-yl)pyridine-3-amine

[0623]

[0624] A mixture of 6-(difluoromethoxy)-N-(4-methoxy-3-pyridinyl)-N-(4-piperidinyl)pyridine-3-amine (60 mg, 155.11 μmol, HCl salt), 3,5-dibromo-1-methyl-4-nitropyrazole (53.03 mg, 186.13 μmol), and DIEA (60.14 mg, 465.33 μmol) in CH3CN (2.0 mL) was stirred at 80 °C for 4 hours. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by rapid silica gel chromatography (10% to 45% ethyl acetate in petroleum ether solution) to provide the title compound (56 mg, 101.02 μmol).

[0625] Step 2: N-(1-(4-amino-3-bromo-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)-6-(difluoro-methoxy)-N-(4-methoxypyridin-3-yl)pyridine-3-amine

[0626]

[0627] A solution of N-[1-(5-bromo-2-methyl-4-nitro-pyrazol-3-yl)-4-piperidinyl]-6-(difluoromethoxy)-N-(4-methoxy-3-pyridinyl)pyridine-3-amine (56 mg, 101.02 μmol) in EtOH (5 mL) and H2O (1 mL), NH4Cl (27.02 mg, 505.10 μmol), and Fe (28.21 mg, 505.10 μmol) was added in a single step, and the mixture was then stirred at 80 °C for 1 hour. The reaction mixture was cooled to room temperature and then filtered through a diatomaceous earth stopper, and the filtrate was concentrated. The residue was diluted with ethyl acetate and the suspension was filtered. The filtrate was concentrated to provide the title compound (52 mg, 99.17 μmol, 98.17% yield); it was used in the next step without further purification. LCMS(ESI) [M+H] + = 513.9.

[0628] Step 3: N-(1-(3-bromo-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)-6-(difluoromethoxy)-N-(4-methoxypyridin-3-yl)pyridine-3-amine

[0629]

[0630] Concentrated H₂SO₄ (103.67 mg, 1.06 mmol) was slowly added to a stirred solution of N-[1-(4-amino-5-bromo-2-methylpyrazol-3-yl)-4-piperidinyl]-6-(difluoromethoxy)-N-(4-methoxy-3-pyridinyl)pyridine-3-amine (52 mg, 99.17 μmol) in EtOH (6 mL). The reaction mixture was stirred at 0 °C for 5 min, and then a solution of NaNO₂ (20.53 mg, 297.51 μmol) in H₂O (0.4 mL) was added dropwise. The reaction mixture was stirred in an ice bath for 15 min, and then heated to 100 °C and stirred for 1 h. H₃PO₂ (128.90 mg, 991.68 μmol, 50% purity) was added, and the resulting reaction mixture was stirred at 0 °C to 100 °C for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude residue. The residue was purified by rapid silica gel chromatography (25% to 45% EE (ethanol / ethyl acetate) eluent in petroleum ether) to provide the title compound (38 mg, 74.61 μmol, 75.23% yield), which was given as a white solid. LCMS (ESI) [M+H]⁺ = 511.1.

[0631] Step 4: 6-(difluoromethoxy)-N-(4-methoxypyridin-3-yl)-N-(1-(1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)pyridin-3-amine (compound 30):

[0632]

[0633] A mixture of N-[1-(5-bromo-2-methylpyrazol-3-yl)-4-piperidinyl]-6-(difluoromethoxy)-N-(4-methoxy-3-pyridinyl)pyridine-3-amine (38 mg, 74.61 μmol) and Pd / C (25 mg, 74.61 μmol, 10% purity) in methanol (10 mL) was degassed and purged three times with H2, and then the mixture was stirred at 28 °C under H2 (15 psi) for 4 h. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by silica gel chromatography (eluting with petroleum ether / ethyl acetate / ethanol = 4:3:1, followed by preparative TLC) to provide the title compound (22 mg, 48.04 μmol, 64.40% yield). LCMS (ESI) [M+H]+ = 431.2.

[0634] Compound 30: 1 H NMR (400 MHz, CDCl3) 8.54 (d, J = 5.6 Hz,, 1H), 8.32 (s,1H), 7.55 (d, J = 3.2 Hz, 1H), 7.36 - 7.27 (m, 2H), 6.96 (d, J = 5.6 Hz, 1H), 6.88 (d, J = 3.2 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 5.79 (s, 1H), 3.97 - 3.91(m, 1H), 3.81 (s, 3H), 3.62 (s, 3H), 3.19 - 3.16 (m, 2H), 2.81 - 2.75 (m,12), 2.08 - 2.05 (m, 2H), 1.59 - 1.57 (m, 2H).

[0635] Example AE: (4-chlorophenyl)(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)methyl ketone (compound 31):

[0636]

[0637] The title compound was synthesized using a method similar to that used in Example U (Compound 21).

[0638] The title compound was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 50% to 80%, 10 min) to provide the title compound (125 mg, 255.16 μmol, 44.57% yield). LCMS (ESI), [M+H]+ = 488.0.

[0639] Compound 31: 1 H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.24 (s, 1H), 7.43 -7.34 (m, 2H), 7.33 - 7.28 (m, 2H), 6.95 (d, J = 9.2 Hz, 3H), 6.63 - 6.17 (m,3H), 4.78 (s, 1H), 4.17 - 4.03 (m, 1H), 3.80 (s, 4H), 3.26 - 2.72 (m, 2H), 2.14 - 2.02 (m, 2H), 1.35- 1.30 (m, 2H).

[0640] Example AF: 4-(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidine-1-carbonyl)benzylnitrile (compound 32):

[0641]

[0642] The title compound was synthesized using a method similar to that used in Example U (Compound 21).

[0643] The title compound was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 38% to 50%, 10 min) to provide the title compound (110 mg, 227.59 μmol, 39.76% yield). LCMS (ESI), [M+H]+ = 479.0.

[0644] Compound 32: 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 4.8 Hz, 1H), 8.24 (s,1H), 7.70 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 9.2 Hz,3H), 6.60 - 6.18 (m, 3H), 4.79 - 4.76 (m, 1H), 4.13 - 4.07 (m, 1H), 3.81 (s,3H), 3.75 - 3.67 (m, 1H), 3.20 - 3.16 (m, 1H), 2.95 - 2.89 (m, 1H), 2.22 -1.93 (m, 2H), 1.52 - 1.12 (m, 2H).

[0645] Example AG: (4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)(4-(methanesulfonyl)phenyl)methyl ketone (compound 33):

[0646]

[0647] The title compound was synthesized using a method similar to that used in Example U (Compound 21).

[0648] The title compound was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 44% to 74%, 10 min) to provide the title compound (130 mg, 242.11 μmol, 42.29% yield). LCMS (ESI), [M+H]+ = 532.0.

[0649] Compound 33: 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 5.2 Hz, 1H), 8.25 (s,1H), 7.99 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.8 Hz,3H), 6.61 - 6.19 (m, 3H), 4.81 - 4.76 (m,1H), 4.15 - 4.10 (m, 1H), 3.81 (s,3H), 3.68 - 3.64 (m, 1H), 3.19-3.07 (m, 1H), 3.07 (s, 3H), 2.93 - 2.89 (m,1H), 2.21 - 1.93 (m, 2H), 1.52 - 1.21 (m, 2H).

[0650] Example AH: 6-(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)nicotinonitrile (Compound 34):

[0651]

[0652] The title compound was synthesized using a method similar to that used in Example R (Compound 18).

[0653] The title compound was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 55% to 85%, 10 min) to provide the title compound (104 mg, 223.45 μmol, 39.03% yield). LCMS (ESI), [M+H]+ = 452.0.

[0654] Compound 34: 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 4.8 Hz, 1H), 8.24 (s,1H), 7.70 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 9.2 Hz,3H), 6.60 - 6.18 (m, 3H), 4.81 - 4.76 (s, 1H), 4.14 - 4.09 (m, 1H), 3.81 (s,3H), 3.69 - 3.66 (m, 1H), 3.21 - 3.18 (m, 1H), 2.94 - 2.88 (m, 1H), 2.22 -1.93 (m, 2H), 1.52 - 1.12 (m, 2H).

[0655] Example AI: Cyclobutyl(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)methyl ketone (compound 35):

[0656]

[0657] The title compound was synthesized using a method similar to that used in Example U (Compound 21).

[0658] The title compound was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 50% to 80%, 10 min) to provide the title compound (115.0 mg, 261.20 μmol, 45.63% yield). LCMS (ESI), [M+H]+ = 432.2.

[0659] Compound 35: 1H NMR (400 MHz, CD3OD) δ 8.43 (d, J = 5.6 Hz, 1H), 8.14 (s,1H), 7.19 (d, J = 5.6 Hz, 1H), 6.93 (d, J = 9.2 Hz, 2H), 6.79 - 6.39 (m, 3H),4.57 - 4.46 (m, 1H), 4.22-4.13 (m, 1H), 3.91 - 3.77 (m, 4H), 3.41 - 3.33 (m,1H), 3.22 - 3.08 (m, 1H), 2.78-2.70 (m, 1H), 2.23 - 1.92 (m, 7H), 1.86 - 1.72(m, 1H), 1.28 - 1.08 (m, 2H).

[0660] Example AJ: Cyclobutyl(4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)methyl ketone (compound 36):

[0661]

[0662] The title compound was synthesized using a method similar to that used in Example U (Compound 21).

[0663] The title compound was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 50% to 80%, 10 min) to provide the title compound (131.8 mg, 304.06 μmol, 53.42% yield). LCMS (ESI), [M+H]+ = 434.1.

[0664] Compound 36: 1H NMR (400 MHz, CD3OD) δ 8.56 - 8.44 (m, 1H), 8.25 - 8.12(m, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.30 - 7.21 (m, 1H), 6.70 - 6.57 (m, 2H),4.63 - 4.54 (m, 1H), 4.36 - 4.26 (m, 1H), 3.92 - 3.89 (M, 1H), 3.86 (s, 3H),3.44 - 3.36 (m, 1H), 3.25 - 3.12 (m, 1H), 2.83 - 2.72 (m, 1H), 2.29 - 2.05 (m, 6H), 2.03 - 1.91 (m, 1H), 1.87 - 1.74 (m, 1H), 1.32 - 1.14 (m, 2H).

[0665] Example AK: (4-fluoro-2-(methanesulfonyl)phenyl)(4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)methyl ketone (compound 37):

[0666]

[0667] Step 1: Preparation of tert-butyl 4-((4-methoxypyridin-3-yl)amino)piperidine-1-carboxylate:

[0668]

[0669] At room temperature, 4-methoxypyridine-3-amine (5.0 g, 40.27 mmol, 1.0 eq.), acetic acid (2.53 mL, 44.30 mmol, 1.1 eq.), and sodium triacetoxyborohydride (12.80 g, 60.41 mmol, 1.5 eq.) were sequentially added to a stirred solution of tert-butyl 4-oxopiperidinium-1-carboxylate (12.03 g, 60.41 mmol, 1.0 eq.) in anhydrous dichloromethane (75 mL). The resulting reaction mixture was stirred under reflux for 20 h. The progress of the reaction was monitored by TLC and UPLC-MS, which indicated product formation and complete consumption of the starting materials. The reaction mixture was then cooled to room temperature, and the pH was adjusted to approximately 8 with 2M aqueous sodium hydroxide solution (100 mL) and extracted with dichloromethane (2 × 200 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered to remove the drying agent, and the solution was concentrated under reduced pressure to obtain a crude residue. The crude substance was purified by combined rapid chromatography using silica gel, eluted with EtOAc, and the pure fraction was concentrated under reduced pressure to give tert-butyl 4-((4-methoxypyridin-3-yl)amino)piperidine-1-carboxylate (7.80 g, 63%). MS (ESI): against C 16 H 25 N3O3, calculated mass value 307.39; measured m / z value 308.2 [M+H] + .

[0670] 1 H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.76 (d, J = 5.2 Hz, 1H), 6.83 (d, J = 5.2 Hz, 1H), 4.61 (d, J = 8.4 Hz, 1H), 3.90 (d, J = 12.4 Hz, 2H), 3.82 (s, 3H), 3.50 (br s, 1H), 2.86 (br s, 2H), 1.90 - 1.86 (m, 2H), 1.40 (s,9H), 1.34 - 1.26 (m, 2H).

[0671] Step 2: Preparation of tert-butyl 4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate:

[0672]

[0673] 4-((4-methoxypyridin-3-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (7.80 g, 25.37 mmol, 1.0 eq), 1-bromo-4-(trifluoromethyl)benzene (5.71 g, 25.37 mmol, 1.0 eq), sodium tert-butoxide (4.80 g, 50.74 mmol, 2.0 eq), and toluene (150 mL) were added to a sealed tube under an argon atmosphere at room temperature. The resulting mixture was degassed using an argon balloon for 10 min, and then Ruphos-Pd-G3 (1.06 g, 1.26 mmol, 0.05 eq) was added under argon atmosphere. The tube was then sealed and stirred at 120 °C for 16 h. The reaction was monitored by TLC and UPLC-MS, indicating product formation. The reaction mixture was cooled to room temperature and passed through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure to obtain the crude product. The obtained crude material was purified by elution with 80% EtOAc in hexane solution using a combined rapid chromatography method with silica gel, and the pure fraction was concentrated under reduced pressure to provide tert-butyl 4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-carboxylate (5, 4.40 g, 38%). MS (ESI): against C 23 H 28 F3N3O3, calculated mass value 451.49; measured m / z value 452.2 [M+H] + .

[0674] 1 H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 5.6 Hz, 1H), 8.21 (s, 1H), 7.36 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 6.0 Hz, 1H), 6.47 (d, J = 8.8 Hz, 2H), 4.18(br s, 2H), 4.06 – 3.97 (tt, J = 11.6 Hz, J = 3.6 Hz, 1H), 3.79 (s, 3H), 2.81 (m, 2H), 1.32 – 1.25 (td, J = 12.4 Hz, J = 4.0 Hz, 2H), 1.42 (s, 9H),1.32 - 1.25 (td, J = 12.4 Hz, J = 4.0 Hz, 2H).

[0675] Step 3: Preparation of 4-methoxy-N-(piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride:

[0676]

[0677] Trimethylchlorosilane (6.80 mL) was added dropwise to a solution of 4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-carboxylic acid tert-butyl ester (4.40 g, 9.74 mmol, 1.0 eq) in 2,2,2-trifluoroethanol (25.0 mL) at 0 °C and stirred at room temperature for 1 h. The reaction progress was monitored by TLC, which showed complete consumption of the starting material. The volatiles were removed under reduced pressure to obtain the crude product. The crude product was ground with acetonitrile (10.0 mL) to give 4-methoxy-N-(piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridin-3-amine hydrochloride (3.10 g (crude product)). MS (ESI): against C 18 H 20 F3N3O, calculated mass value 351.16; measured m / z value 352.1 [M+H] + .

[0678] 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J = 8.8 Hz, 1H), 8.92 - 8.90 (m,2H), 8.74 ( s, 1H), 7.79 (d, J = 6.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.78(d, J = 8.4 Hz, 2H), 4.43 (t, J = 11.6 Hz, 1H), 4.00 (s, 3H), 3.25 (d, J =12.0 Hz, 2H), 3.11 - 3.02 (m, 2H), 2.03 (d, J = 12.8 Hz, 2H), 1.68 - 1.59 (m,2H).

[0679] Step 4: Preparation of 4-fluoro-2-(methanesulfonyl)benzoic acid (7)

[0680]

[0681] Sodium methanesulfonate (0.47 g, 3.99 mmol, 3.5 eq), CuI (0.86 g, 4.56 mmol, 4.0 eq), and sodium hydroxide (0.22 mL, 1.14 mmol, 1.0 eq) in dimethyl sulfoxide (15.0 mL) were added to a solution of 2-bromo-4-fluorobenzoic acid (0.25 g, 1.14 mmol, 4.0 eq) at room temperature and stirred at 120 °C for 2 h. The reaction progress was monitored by TLC, which showed complete consumption of the starting materials. The reaction mixture was cooled to room temperature, diluted with water (20.0 mL), and washed with EtOAc (2 × 10 mL). The aqueous layer was acidified with 2N HCl aqueous solution (2.0 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered to remove the desiccant, and the solution was concentrated under reduced pressure to obtain 4-fluoro-2-(methanesulfonyl)benzoic acid (0.15 g, crude). MS (ESI): calculated value for C₈H₇FO₄S 218.00; m / z measured value 216.98 [MH] - .

[0682] 1 H NMR (400 MHz, DMSO-d6) δ 7.93 - 788 (m, 2H), 7.40 - 7.37 (m, 1H), 3.44 (s, 3H).

[0683] Step 5: Preparation of (4-fluoro-2-(methanesulfonyl)phenyl)(4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)methyl ketone (compound 37):

[0684]

[0685] At 0 °C, diisopropylethylamine (0.17 mL, 1.02 mmol, 4.0 eq.) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxyhexafluorophosphate (HATU, 0.11 g, 0.30 mmol, 1.2 eq.) were added to a stirred solution of 4-methoxy-N-(piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)benzoic acid (0.06 g, 0.30 mmol, 1.2 eq.) in N,N-dimethylformamide (2.0 mL). The resulting reaction mixture was then stirred at room temperature for 8 hours. The reaction progress was monitored by TLC and UPLC-MS, which indicated product formation and complete consumption of the starting material. The reaction mixture was poured into ice-cold water (5.0 mL). The resulting solid was collected by filtration, and the solid cake was washed with excess cold water (5.0 mL) and dried under vacuum to give (4-fluoro-2-(methanesulfonyl)phenyl)(4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)methyl ketone (0.14 g, 66% yield). MS (ESI): against C 26 H 25 F4N3O4S, calculated mass value 551.15; measured m / z value 552.3 [M+H] + HPLC purity: 95.77%

[0686] Compound 37: Rotational Isomer 1H NMR (400 MHz, CDCl3) δ 8.53 (dd, J = 18.0Hz, J = 5.6 Hz, 1H), 8.17 (d, J = 38.4 Hz, 1H), 7.74 - 7.60 (m, 2H), 7.59 -7.53 (m, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.25 (dd, J = 16.8 Hz, J = 6.0 Hz,1H), 6.62 - 6.57 (m, 2H), 4.59 - 4.46 (m, 1H), 4.33 - 4.24 (dd, J = 24.0 Hz,J = 11.6 Hz, 1H), 3.76 (d, J = 14.8 Hz, 3H), 3.26 (d, J = 7.6 Hz, 3H), 3.25 -3.09 (m, 2H), 2.99 - 2.86 (m, 1H), 2.06 - 1.94 (m, 2H), 1.85 - 1.68 (d, J =56.0 Hz, J = 12.0 Hz 1H), 1.48- 1.23 (m, 2H).

[0687] Example AL: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(4-(methanesulfonyl)phenyl)piperidin-4-yl)pyridine-3-amine (compound 38):

[0688]

[0689] Step 1: Preparation of tert-butyl 4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidine-1-carboxylate:

[0690]

[0691] 4-((4-methoxypyridin-3-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (1.50 g, 4.88 mmol, 1.0 eq), 1-bromo-4-(difluoromethoxy)benzene (1.30 g, 5.86 mmol, 1.2 eq), sodium tert-butoxide (0.93 g, 9.76 mmol, 2.0 eq), and toluene (30.0 mL) were added to a sealed tube under an argon atmosphere at room temperature. The resulting mixture was degassed by argon purging for 10 min, and then P(t-Bu)3Pd-G2 (0.15 g, 0.29 mmol, 0.05 eq) was added. The tube was then sealed and stirred at 120 °C for 16 h. The reaction was monitored by UPLC, which showed product formation. The reaction mixture was cooled to room temperature and passed through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude material was purified by rapid silica gel chromatography via elution with a hexane solution of 60% EtOAc. The purified fraction was concentrated under reduced pressure to give tert-butyl 4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidine-1-carboxylate (0.40 g, 17% yield). MS (ESI): against C 23 H 29 F₂N₃O₄, calculated mass 449.21; measured m / z 450.2 [M+H] + .

[0692] 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 5.6 Hz, 1H), 8.15 (s, 1H), 7.21 (d, J = 7.2 Hz, 1H), 7.16 - 6.97 (t, J = 75 Hz, 1H), 6.96 - 6.93 (d, J =9.2 Hz, 2H), 6.45 (d, J = 9.2 Hz, 2H), 4.09 - 4.05 (m, 1H), 3.93 (br s, 2H), 3.76 (s, 3H), 2.86 (br s, 2H), 1.88 (d, J = 12.0 Hz, 2H), 1.33 (s, 9H), 1.10- 1.08 (m, 2H).

[0693] Step 2: Preparation of N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(piperidin-4-yl)pyridine-3-amine hydrochloride (11)

[0694]

[0695] Trimethylchlorosilane (0.70 mL) was added dropwise to a solution of tert-butyl 4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-carboxylate (0.40 g, 0.89 mmol, 1.0 eq) in 2,2,2-trifluoroethanol (3.0 mL). The reaction mixture was then stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure to obtain the crude product. The obtained crude product was ground with acetonitrile (10.0 mL) to give N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(piperidin-4-yl)pyridin-3-amine hydrochloride (crude product, 0.25 g). MS (ESI): against C 18 H 21 F₂N₃O₂, calculated mass value 349.16; measured m / z value 350.1 [M+H] +

[0696] 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J = 9.2 Hz, 1H), 8.84 - 8.82 (m,2H), 8.69 (s, 1H), 7.73 (d, J = 6.8 Hz, 1H), 7.25 - 6.88 (t, J = 75 Hz, 1H),7.01 (d, J = 9.2 Hz, 2H), 6.74 (d, J = 12 Hz, 2H), 4.31 - 4.25 (m, 1H), 3.97(s, 3H), 3.25 (d, J = 12 Hz, 2H), 3.08 - 2.99 (m, 2H), 2.01 (d, J = 12.4 Hz,2H), 1.67 - 1.58 (m, 2H).

[0697] Step 3: Preparation of N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(4-(methanesulfonyl)phenyl)piperidin-4-yl)pyridine-3-amine (compound 38)

[0698]

[0699] N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(piperidin-4-yl)pyridine-3-amine hydrochloride (0.21 g, 0.54 mmol, 1.0 eq), 1-bromo-4-(methanesulfonyl)benzene (0.19 g, 0.81 mmol, 1.5 eq), sodium tert-butoxide (0.15 g, 1.62 mmol, 3.0 eq), and dry 1,4-dioxane (10.0 mL) were added to a sealed tube under an argon atmosphere at room temperature. The reaction mixture was degassed with argon for 10 min, and then Ruphos-Pd-G3 (0.02 g, 0.027 mmol, 0.05 eq) was added under argon. The tube was sealed with a cap and stirred at 110 °C for 16 h. The reaction mixture was cooled to room temperature, passed through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude material obtained was purified by rapid chromatography using silica gel by elution with a hexane solution of 60% EtOAc to give N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(4-(methanesulfonyl)phenyl)piperidin-4-yl)pyridine-3-amine (0.08 g, 22% yield). MS (ESI): against C 25 H 27 F₂N₃O₄S, calculated mass 503.56; measured m / z 504.1 [M+H] + HPLC purity: 98.27%.

[0700] Compound 38: 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 5.6 Hz, 1H), 8.16(s, 1H), 7.61 (d, J = 9.2 Hz, 2 H), 7.20 (d, J = 5.6 Hz, 1H), 7.17 (t, J = 75Hz, 1H), 7.02 - 7.00 (d, J = 9.2 Hz, 2H), 6.97 - 6.94 (d, J = 9.2 Hz, 2H), 6.49 (d, J = 9.2 Hz, 2H), 4.20 - 4.14 (m, 1H), 3.97 (d, J = 13.2 Hz, 2H),3.75 (s, 3H), 3.02 - 2.99 (m, 5H), 1.98 (d, J = 11.6 Hz, 2H), 1.29 - 1.21 (m, 2H).

[0701] Example AM: N-(1-(5-(difluoromethyl)pyridin-2-yl)piperidin-4-yl)-4-methoxy-N-(4-(trifluoromethyl)phenyl)pyridin-3-amine (compound 39):

[0702]

[0703] 4-Methoxy-N-(piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrogen chloride (0.60 g, 1.54 mmol, 1.0 eq), 2-chloro-5-(difluoromethyl)pyridine (0.25 g, 1.54 mmol, 1.3 eq), sodium tert-butoxide (0.297 g, 3.09 mmol, 2.0 eq), and toluene (5.0 mL) were added to a microwave-safe tube under an argon atmosphere at room temperature. The resulting mixture was then degassed with argon for 10 min, and Ruphos-Pd-G3 (0.06 g, 0.077 mmol, 0.05 eq) was added under argon atmosphere. The microwave-safe tube was sealed with a cap and stirred at 130 °C for 2 h. The reaction progress was monitored by TLC, and complete consumption of the starting material was observed. The reaction mixture was cooled to room temperature, passed through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to obtain the crude substance. The obtained crude substance was purified by combined rapid chromatography on silica gel by elution with 100% EtOAc hexane solution to give N-(1-(5-(difluoromethyl)pyridin-2-yl)piperidin-4-yl)-4-methoxy-N-(4-(trifluoromethyl)phenyl)pyridin-3-amine (0.23 g, 31% yield). MS (ESI): against C 24 H 23 F5N4O, calculated mass value 478.47; measured m / z value 479.3 [M+H] + HPLC purity: 95.15%.

[0704] Compound 39: 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 5.6 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 7.61 (dd, J = 9.2 Hz, J = 2.4 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 5.6 Hz, 1H), 7.06 - 6.74 (t, J = 50Hz, 1H), 6.89 - 6.87 (m, 1H), 6.61 (d, J = 8.8 Hz, 2H), 4.44 (d, J = 13.6 Hz,2H), 4.36 - 4.31 (m, 1H), 3.76 (s, 3H), 3.07 - 3.01 (m, 2H), 2.10 (d, J =12.0 Hz, 2H), 1.23 - 1.16 (m, 2H).

[0705] Example AN: 6-(4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)-1-methylpyridin-2(1H)-one (compound 40):

[0706]

[0707] Step 1: Preparation of 6-bromo-1-methylpyridin-2(1H)-one

[0708]

[0709] K₂CO₃ (0.99 g, 7.18 mmol, 5.0 eq) and CH₃I (0.44 mL, 7.18 mmol, 5.0 eq) were added to a solution of 6-bromopyridin-2-ol (0.25 g, 1.43 mmol, 1.0 eq) in N,N-dimethylformamide (5.0 mL) at room temperature. The reaction mixture was then stirred at room temperature for 18 hours. The progress of the reaction was monitored by TLC, which showed complete consumption of the starting material. The reaction mixture was quenched with water (5.0 mL) and extracted with EtOAc (2 × 10⁻⁶ mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered off the drying agent, and the solution was concentrated under reduced pressure to obtain the crude substance. The crude material obtained was purified by rapid chromatography with silica gel by elution with a hexane solution of 30% to 35% EtOAc. The pure fraction was concentrated under reduced pressure to give 6-bromo-1-methylpyridin-2(1H)-one (0.23 g, 31% yield).

[0710] 1 H NMR (400 MHz, CDCl3) δ 7.16 - 7.12 (dd, J = 9.2 Hz, J = 7.2 Hz,1H), 6.53 - 6.48 (m, 2H), 6.68 (d, J = 8.0 Hz, 1H), 3.74 (s, 3H).

[0711] Step 2: Preparation of 6-(4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)-1-methylpyridin-2(1H)-one (compound 40):

[0712]

[0713] 4-Methoxy-N-(piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride (0.15 g, 0.38 mmol, 1.0 eq Curia lot number IN-NRM-G-39), 6-bromo-1-methylpyridin-2(1H)-one (0.07 g, 0.42 mmol, 1.1 eq), sodium tert-butoxide (0.11 g, 1.15 mmol, 3.0 eq), and dried toluene (3.0 mL) were added to a microwave tube under an argon atmosphere at room temperature. The resulting mixture was degassed with argon for 10 min, and Ruphos-Pd-G3 (0.016 g, 0.01 mmol, 0.05 eq) was added under argon atmosphere. The microwave tube was sealed and stirred at 120 °C for 2 h. The reaction progress was monitored by TLC and UPLC-MS, which showed product formation. The reaction mixture was cooled to room temperature, passed through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to obtain a crude substance. The obtained crude substance was purified by combined rapid chromatography on silica gel by elution with 4% MeOH in CH2Cl2 solution. The pure fraction was concentrated under reduced pressure to give 6-(4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)-1-methylpyridin-2(1H)-one (0.15 g, 51% yield). MS (ESI): against C 24 H 25 F3N4O2, calculated mass value 458.49; measured m / z value 459.2 [M+H] + HPLC purity: 99.73%.

[0714] Compound 40: 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 5.6 Hz, 1H), 8.26(s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.35 - 7.28 (m, 2H), 6.60 (d, J = 8.8 Hz, 2H), 6.08 (d, J = 8.4 Hz, 1H), 5.83 - 5.81 (m, 1H), 4.22 - 4.16 (m, 1H), 3.80 (s, 3H), 3.27 (s, 3H), 3.16 (d, J = 12.0 Hz, 2H), 2.83 (t, J = 11.6 Hz, 2H),2.03 (d, J = 12.0 Hz, 2H), 1.47 - 1.39 (m, 2H).

[0715] Example AO: Bicyclo[1.1.1]pent-1-yl(4-((4-(difluoromethoxy)phenyl)(4-methoxy-pyridin-3-yl)amino)piperidin-1-yl)methyl ketone (compound 41):

[0716]

[0717] The title compound was synthesized using a method similar to that used in Example U (Compound 21).

[0718] The title compound was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 22% to 52%, 7 min) to provide the title compound (49.4 mg, 109.16 μmol, 84.24% yield). LCMS (ESI), [M+H]+ = 444.1.

[0719] Compound 41: 1 H NMR (400 MHz, CD3OD) δ 8.59 (d, J = 6.4 Hz, 1H), 8.49 (s,1H), 7.58 (d, J = 6.8 Hz, 1H), 7.02 (d, J = 9.2 Hz, 2H), 6.88 - 6.45 (m, 3H),4.52 - 4.48 (m, 1H), 4.35 - 4.31 (m, 1H), 4.27 - 4.16 (m, 1H), 3.99 (s, 3H), 3.26 - 3.23 (m, 1H), 2.84 - 2.71 (m, 1H), 2.45 (s, 1H), 2.16 - 2.11 (m, 6H),2.10 - 1.96 (m, 2H), 1.36 - 1.21 (m, 2H).

[0720] Example AP: (4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)(3-fluorobicyclo[1.1.1]pent-1-yl)methyl ketone (compound 42):

[0721]

[0722] The title compound was synthesized using a method similar to that used in Example U (Compound 21).

[0723] The title compound was purified by preparative HPLC (column: Phenomenex C18 80*40mm*3um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 50% to 80%, 7 min) to provide the title compound (26 mg, 55.05 μmol, 70.79% yield). LCMS (ESI), [M+H]+ = 462.0.

[0724] Compound 42: 1 H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 8.16 (s, 1H), 7.20 (d, J = 4.4 Hz, 1H), 6.93 (d, J = 9.2 Hz, 2H), 6.81 - 6.39 (m, 4H), 4.53 -4.50 (m, 1H), 4.26 - 4.18 (m, 1H), 4.13 - 4.09 (m, 1H), 3.82 (s, 3H), 3.29 -3.22 (m, 1H), 2.88 - 2.74 (m, 1H), 2.36 (s, 6 H), 2.13 - 2.09 (m, 1H), 2.08 -2.06 (m, 1H), 1.33 - 1.09 (m, 3H).

[0725] Example AQ: 3-(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidine-1-carbonyl)bicyclo[1.1.1]pentane-1-carboxynitrile (compound 43):

[0726]

[0727] The title compound was synthesized using a method similar to that used in Example U (Compound 21).

[0728] The title compound was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 20% to 50%, 7 min) to provide the title compound (56.6 mg, 118.40 μmol, 91.36% yield). LCMS (ESI), [M+H]+ = 469.0.

[0729] Compound 43: 1H NMR (400 MHz, CD3OD) δ 8.60 (d, J = 6.4 Hz, 1H), 8.51 (s,1H), 7.61 (d, J = 6.8 Hz, 1H), 7.03 (d, J = 9.2 Hz, 2H), 6.94 - 6.43 (m, 3H),4.49 - 4.46 (m, 1H), 4.31 - 4.09 (m, 2H), 4.00 (s, 3H), 3.29 - 3.21 (m, 1H), 2.81 - 2.78 (m, 1H), 2.56 (s, 6H), 2.15 - 1.97 (m, 2H), 1.42 - 1.22 (m, 2H).

[0730] Example AR: 4-methoxy-N-(1-(pyrazin-2-yl)piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (compound 44):

[0731]

[0732] The title compound was synthesized using a method similar to that used in Example C (Compound 3).

[0733] The title compound was purified by preparative TLC (SiO2, dichloromethane: methanol = 10:1) to provide the title compound (129.2 mg, 288.82 μmol, 50.74% yield). LCMS (ESI), [M+H]+ = 430.1.

[0734] Compound 44: 1 H NMR (400 MHz, CD3OD) δ 8.47 (d, J = 6.0 Hz, 1H), 8.16 (d,J = 4.4 Hz, 2H), 8.04 - 8.03 (m, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.39 (d, J =8.8 Hz, 2H), 7.23 (d, J = 5.6 Hz, 1H), 6.64 (d, J = 8.8 Hz, 2H), 4.47 - 4.44(m, 2H), 4.37 - 4.29 (m, 1H), 3.83 (s, 3H), 3.11 - 3.00 (m, 2H), 2.15 - 2.11(m, 2H), 1.43 - 1.33 (m, 2H).

[0735] Example AS: Bicyclo[1.1.1]pent-1-yl(4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)methyl ketone (compound 45):

[0736]

[0737] The title compound was synthesized using a method similar to that used in Example U (Compound 21).

[0738] The title compound was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 26% to 56%, 7 min) to give the title compound (56 mg, 125.71 μmol, 97.51% yield). LCMS (ESI), [M+H]+ = 446.1.

[0739] Compound 45: 1 H NMR (400 MHz, CD3OD) δ 8.60 (d, J = 6.0 Hz, 1H), 8.35 (s,1H), 7.45 - 7.39 (m, 3H), 6.70 (d, J = 8.8 Hz, 2H), 4.57 - 4.49 (m, 1H), 4.38- 4.31 (m, 2H), 3.93 (s, 3H), 3.28 - 3.21 (m, 1H), 2.79 - 2.76 (m, 1H), 2.45 (s, 1H), 2.14 - 2.02 (m, 8H), 1.31 - 1.23 (m, 2H).

[0740] Example AT: (3-fluorobicyclo[1.1.1]pent-1-yl)(4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)methyl ketone (compound 46):

[0741]

[0742] The title compound was synthesized using a method similar to that used in Example U (Compound 21).

[0743] The title compound was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 26% to 56%, 7 min) to give the title compound (69.9 mg, 150.82 μmol, 97.49% yield). LCMS (ESI), [M+H]+ = 464.1.

[0744] Compound 46: 1 H NMR (400 MHz, CD3OD) δ 8.76 - 8.74 (m, 1H), 8.60 (s, 1H),7.71 (d, J = 7.2 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H),4.61 - 4.55 (m, 1H), 4.42 - 4.33 (m, 1H), 4.17 - 4.13 (m, 1H), 4.05 (s, 3H), 3.29 - 3.23 (m, 1H), 2.83 - 2.82 (m, 1H), 2.38 (s, 6H), 2.18 - 2.05 (m, 2H),1.36 - 1.25 (m, 2H).

[0745] Example AU: 3-(4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-carbonyl)bicyclo[1.1.1]pentane-1-carboxynitrile (compound 47):

[0746]

[0747] The title compound was synthesized using a method similar to that used in Example U (Compound 21).

[0748] The title compound was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 25% to 55%, 7 min) to give the title compound (65 mg, 125.72 μmol, 97.52% yield). LCMS (ESI), [M+H]+ = 471.1.

[0749] Compound 47: 1H NMR (400 MHz, CD3OD) δ 8.75 (dd, J = 0.8, 6.8 Hz, 1H), 8.60 (d, J = 0.8 Hz, 1H), 7.71 (d, J = 6.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 4.61 - 4.55 (m, 1H), 4.42 - 4.33 (m, 1H), 4.17 -4.13 (m, 1H), 4.05 (s, 3H), 3.29 - 3.23 (m, 1H), 2.83 - 2.82 (m, 1H), 2.38(s, 6H), 2.18 - 2.05 (m, 2H), 1.36 - 1.25 (m, 2H).

[0750] Example AV: (4-((4-(trifluoromethyl)phenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl ketone (compound 48):

[0751]

[0752] The title compound was synthesized using a method similar to that used in Example U (Compound 21).

[0753] The title compound was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 33% to 63%, 7 min) to provide the title compound (74.2 mg, 141.62 μmol, 82.93% yield) as a white solid. LCMS (ESI), [M+H]+ = 514.1.

[0754] Compound 48: 1H NMR (400 MHz, CD3OD) δ 8.52 (d, J = 7.6 Hz, 1H), 8.19 (s,1H), 7.39 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 6.0 Hz, 1H), 6.63 (d, J = 8.8 Hz,2H), 4.55 - 4.52 (m, 1H), 4.35 - 4.30 (m, 1H), 4.23 - 4.20 (m, 1H), 3.85 (s,3H), 3.26 - 3.24 (m, 1H), 2.86 - 2.78 (m, 1H), 2.33 (s, 6H), 2.20 - 2.03 (m,2H), 1.30 - 1.22 (m, 2H).

[0755] Example AW: (4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl ketone (compound 49):

[0756]

[0757] The title compound was synthesized using a method similar to that used in Example U (Compound 21).

[0758] The title compound was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 29% to 59%, 7 min) to provide the title compound (56.45 mg, 110.37 μmol, 77.12% yield). LCMS (ESI), [M+H]+ = 512.0.

[0759] Compound 49: 1H NMR (400 MHz, CD3OD) δ 8.59 (d, J = 6.8, 1H), 8.511 (s,1H), 7.61 (d, J = 6.8 Hz, 1H), 7.03 (d, J = 8.8, 2H), 6.87 - 6.50 (m, 3H),4.57 - 4.47 (m, 1H), 4.23 - 4.19 (m, 2H), 3.99 (s, 3H), 3.31 - 3.26 (m, 1H), 2.88 - 2.72 (m, 1H), 2.31 (s, 6H), 2.16 - 2.07 (m, 1H), 2.06 - 1.97 (m, 1H),1.43 - 1.29 (m, 2H).

[0760] Example AX: 4-methoxy-N-(1-(5-methylpyrazin-2-yl)piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (compound 50):

[0761]

[0762] The title compound was synthesized using a method similar to that used in Example C (Compound 3).

[0763] The title compound was purified by reversed-phase HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 32% to 62%, 6 min) to provide the title compound (136.4 mg, 298.35 μmol, 52.42% yield). LCMS (ESI), [M+H]+ = 444.1.

[0764] Compound 50: 1 H NMR (400 MHz, CD3OD) δ 8.47 (d, J = 4.4 Hz, 1H), 8.17 (s,1H), 8.05 (s, 1H), 7.95 (s, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.23 (d, J = 4.0Hz, 1H), 6.64 (d, J = 8.0 Hz, 2H), 4.39 - 4.29 (m, 1H), 3.84 (s, 3H), 3.08 -2.97 (m, 2H), 2.34 (s, 3H), 2.17 - 2.09 (m, 2H), 1.43 - 1.31 (m, 2H).

[0765] Example AY: 4-Methoxy-N-(1-(pyrimidin-5-yl)piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 51):

[0766]

[0767] The title compound was synthesized using a method similar to that used in Example C (Compound 3).

[0768] The title compound was purified by reversed-phase HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 32% to 62%, 6 min) to provide the title compound (156.6 mg, 364.66 μmol, 64.07% yield). LCMS (ESI), [M+H]+ = 430.1.

[0769] Compound 51: 1 H NMR (400 MHz, CD3OD) δ 8.54 - 8.46 (m, 2H), 8.44 (s, 2H), 8.22 (s, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 6.0 Hz, 1H), 6.64 (d, J= 8.8 Hz, 2H), 4.29 - 4.21 (m, 1H), 3.93 - 3.89 (m, 2H), 3.85 (s, 3H), 3.07 -2.98 (m, 2H), 2.18 - 2.15 (m, 2H), 1.54 - 1.48 (m, 2H).

[0770] Example AZ: 4-Methoxy-N-(1-(2-methylpyrimidin-5-yl)piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 52):

[0771]

[0772] The title compound was synthesized using a method similar to that used in Example C (Compound 3).

[0773] The title compound was purified by reversed-phase HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 30% to 60%, 6 min) to provide the title compound (126.6 mg, 279.77 μmol, 49.15% yield). LCMS (ESI), [M+H]+ = 444.1.

[0774] Compound 52: 1 H NMR (400 MHz, CD3OD) δ 8.49 (d, J = 6.0 Hz, 1H), 8.35 (s,2H), 8.22 - 8.20 (m, 1H), 7.41 - 7.38 (m, 2H), 7.26 - 7.25 (m, 1H), 6.65 -6.63 (m, 2H), 4.25 -4.22 (m, 1H), 3.86 (s, 3H), 3.84 - 3.81 (m, 2H), 3.01 -2.94 (m, 2H), 2.56 - 2.55 (m, 3H), 2.17 - 2.14 (m, 2H), 1.58 - 1.50 (m, 2H).

[0775] Example BA: 5-(4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)pyrimidin-2-carboxynitrile (Compound 53):

[0776]

[0777] The title compound was synthesized using a method similar to that used in Example L (Compound 12).

[0778] The title compound was purified by rapid silica gel chromatography (SepaFlash® Silica Flash Column, 0% to 50% ethyl acetate / petroleum ether eluent, 40 mL / min) to provide the title compound (164.2 mg, 328.80 μmol, 63.76% yield). LCMS (ESI), [M+H]+ = 455.1.

[0779] Compound 53: 1H NMR (400 MHz, CD3OD) δ 8.48 (d, J = 5.6 Hz, 1H), 8.44 (s,2H), 8.19 (s, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 5.6 Hz, 1H), 6.65(d, J = 8.8 Hz, 2H), 4.37 - 4.31 (m, 1H), 4.12 - 4.08 (m, 2H), 3.86 (s, 3H), 3.20 - 3.13 (m, 2H), 2.19 - 2.13 (m, 2H), 1.53 - 1.43 (m, 2H).

[0780] Example BB: 4-Methoxy-N-(4-(trifluoromethyl)phenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)piperidin-4-yl)pyridine-3-amine (Compound 54):

[0781]

[0782] The title compound was synthesized using a method similar to that used in Example C (Compound 3).

[0783] The title compound was purified by reversed-phase HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 40% to 70%, 6 min) to provide the title compound (160 mg, 308.78 μmol, 54.25% yield). LCMS (ESI), [M+H]+ = 498.1.

[0784] Compound 54: 1 H NMR (400 MHz, CD3OD) δ 8.49 - 8.48 (m, 3H), 8.20 (s, 1H),7.39 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 6.0 Hz, 1H), 6.65 (d, J = 8.4 Hz, 2H),4.35 - 4.27 (m, 1H), 4.08 - 4.04 (m, 2H), 3.84 (s, 3H), 3.16 - 3.10 (m, 2H), 2.20 - 2.16 (m, 2H), 1.56 - 1.49 (m, 2H).

[0785] Example BC: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(pyrazin-2-yl)piperidin-4-yl)pyridine-3-amine (compound 55):

[0786]

[0787] The title compound was synthesized using a method similar to that used in Example C (Compound 3).

[0788] The title compound was purified by reversed-phase HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 40% to 70%, 6 min) to provide the title compound (0.20 g, 459.77 μmol, 80.32% yield). LCMS (ESI), [M+H]+ = 428.0.

[0789] Compound 55: 1 H NMR (400 MHz, CD3OD) δ 8.41 (d, J = 5.6 Hz, 1H), 8.14 (d,J = 5.6 Hz, 2H), 8.02 (s, 1H), 7.69 (s, 1H), 7.17 (d, J = 5.6 Hz, 1H), 6.93(d, J = 5.6 Hz, 2H), 6.78 (d, J = 5.6 Hz, 2H), 6.59 - 6.41 (m, 3H), 4.43 -4.39 (m, 2H), 4.25 - 4.15 (m, 1H), 3.80 (s, 3H), 3.06 - 2.99 (m, 2H), 2.11 -2.07 (m, 2H), 1.37 - 1.33 (m, 2H).

[0790] Example BD: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(5-methylpyrazin-2-yl)piperidin-4-yl)pyridine-3-amine (compound 56):

[0791]

[0792] The title compound was synthesized using a method similar to that used in Example C (Compound 3).

[0793] The title compound was purified by reversed-phase HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 23% to 53%, 7 min) to provide the title compound (113.62 mg, 257.37 μmol, 44.96% yield). LCMS (ESI), [M+H]+ = 442.3.

[0794] Compound 56: 1 H NMR (400 MHz, CD3OD) δ 8.41 (d, J = 5.6 Hz, 1H), 8.26 (s,1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.24 (d, J = 5.6 Hz, 1H), 6.82 (d, J = 8.8Hz, 2H), 6.65 - 6.35 (m, 3H), 4.44 - 4.32 (m, 2H), 4.19 - 4.09 (m, 1H), 3.81(s, 3H), 3.12 - 2.99 (m, 2H), 2.33 (s, 3H), 2.18 - 2.10 (m, 2H), 1.43 - 1.32(m, 2H).

[0795] Example BE: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(pyrimidin-5-yl)piperidin-4-yl)pyridine-3-amine (compound 57):

[0796]

[0797] The title compound was synthesized using a method similar to that used in Example C (Compound 3).

[0798] The title compound was purified by reversed-phase HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 15% to 45%, 7 min) to provide the title compound (238.4 mg, 557.73 μmol, 97.43% yield). LCMS (ESI), [M+H]+ = 428.0.

[0799] Compound 57: 1H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 8.50 (s, 3H), 8.21(s, 1H), 7.25 (d, J = 6.0 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.72 - 6.45 (m,3H), 4.29 - 4.21 (m, 1H), 3.93 - 3.89 (m, 2H), 3.85 (s, 3H), 3.07 - 2.98 (m,2H), 2.18 - 2.15 (m, 2H), 1.54 - 1.48 (m, 2H).

[0800] Example BF: 5-(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)pyrimidin-2-carboxynitrile (Compound 58):

[0801]

[0802] The title compound was synthesized using a method similar to that used in Example L (Compound 12).

[0803] The title compound was purified by reversed-phase HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 25% to 55%, 7 min) to provide the title compound (96.63 mg, 213.57 μmol, 37.31% yield). LCMS (ESI), [M+H]+ = 455.1.

[0804] Compound 58: 1 H NMR (400 MHz, CD3OD) δ 8.45 - 8.41 (m, 3H), 8.17 (s, 1H), 7.19 (d, J = 5.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.79 - 6.42 (m, 3H), 4.26- 4.20 (m, 1H), 4.10 - 4.07 (m, 2H), 3.82 (s, 3H), 3.17 - 3.11 (m, 2H), 2.17- 2.13 (m, 2H), 1.50 - 1.43 (m, 2H).

[0805] Example BG: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(2-(trifluoromethyl)pyridin-5-yl)piperidin-4-yl)pyridin-3-amine (compound 59):

[0806]

[0807] The title compound was synthesized using a method similar to that used in Example C (Compound 3).

[0808] The title compound was purified by column chromatography (10% to 60% ethyl acetate in petroleum ether solution) to provide the title compound (215 mg, 416.60 μmol, 72.77% yield). LCMS (ESI), [M+H]+ = 496.0.

[0809] Compound 59: 1 H NMR (400 MHz, CD3OD) δ 8.48 (s, 2H), 8.43 (d, J = 5.6 Hz,1H), 8.18 (s, 1H), 7.19 (d, J = 5.6 Hz, 1H), 6.96 (d, J = 8.8, 2H), 6.60 -6.58 (m, 3H), 4.64 - 4.56 (m, 1H), 4.26 - 4.16 (m, 1H), 4.06 - 4.03 (m, 2H), 3.82 (s, 3H), 3.16 - 3.11 (m, 2H), 2.17 - 2.14 (m, 2H), 1.56 - 1.42 (m, 2H).

[0810] Example BH: ((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)(2-methylpyridin-4-yl)methyl ketone (compound 60):

[0811]

[0812] Diisopropylethylamine (0.26 g, 2.06 mmol, 4.0 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 0.29 g, 0.77 mmol, 1.5 eq) were added to a stirred solution of 4-methoxy-N-(piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride (0.20 g, 0.51 mmol, 1.0 eq) and 2-methylisonicotinic acid (0.07 g, 0.56 mmol, 1.1 eq) in N,N-dimethylformamide (DMF, 2.0 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 8 h. The reaction progress was monitored by TLC and UPLC-MS, which showed product formation. The crude material was purified by rapid chromatography using silica gel by elution with a hexane solution of 72% EtOAc, and the pure fraction was concentrated under reduced pressure to give (4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)(2-methylpyridin-4-yl) methyl ketone (0.16 g, 66% yield). MS (ESI): against C 25 H 25 F3N4O2, calculated mass 470.50; measured m / z 471.5 [M+H] + HPLC purity: 99.90%.

[0813] Compound 60: 1 H NMR (400 MHz, CDCl3) δ 8.55 (dd, J = 13.6, 5.6 Hz, 2H), 8.22 (s, 1H), 7.37 (d, J = 8.8 Hz, 2H), 7.09 (s, 1H), 7.00 - 6.97 (m, 2H), 6.50 (d, J = 8.8 Hz, 2H), 4.81 (d, J = 12.4 Hz, 1H), 4.19 - 4.14 (m, 1H), 3.80 (s, 3H), 3.70 (d, J = 12.4 Hz, 1H), 3.21 - 3.15 (m, 1H), 2.90 - 2.84 (m,1H), 2.57 (s, 3H), 2.17 (d, J = 11.6 Hz, 1H), 1.99 (d, J = 10.4 Hz, 1H), 1.43-1.25 (m, 2H).

[0814] Example BI: 4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)(2-(trifluoromethyl)pyridin-4-yl)methyl ketone (compound 61):

[0815]

[0816] Diisopropylethylamine (0.33 mL, 2.06 mmol, 4.0 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 0.29 g, 0.77 mmol, 1.5 eq) were added to a stirred solution of 4-methoxy-N-(piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride (0.28 g, 0.51 mmol, 1.0 eq) and 2-(trifluoromethyl)isonicotinic acid (0.11 g, 0.61 mmol, 1.2 eq) in N,N-dimethylformamide (DMF, 2.0 mL) (0.33 mL, 2.06 mmol, 4.0 eq) at 0 °C. The reaction mixture was then stirred at room temperature for 2 h. The reaction progress was monitored by TLC and UPLC-MS, and the complete consumption of the starting materials was observed. The reaction mixture was poured into cold water (5.0 mL). The obtained solid was collected by filtration, and the solid filter cake was washed with excess cold water (5.0 mL). The solid was dried under vacuum to give (4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)(2-(trifluoromethyl)pyridin-4-yl) methyl ketone (0.18 g, 67% yield). MS (ESI): against C 25 H 22 F6N4O2, calculated mass 524.47; measured m / z 525.1 [M+H] + HPLC purity: 99.76%.

[0817] Compound 61: 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 4.8 Hz, 1H), 8.58 (d,J = 5.6 Hz, 1H), 8.22 (s, 1H), 7.64 (s, 1H), 7.42 (d, J = 4.8 Hz, 1H), 7.38(d, J = 8.8 Hz, 2H), 6.99 (d, J = 5.6 Hz, 1H), 6.50 (d, J = 8.8 Hz, 2H), 4.82 (d, J = 13.2 Hz, 1H), 4.22 - 4.14 (m, 1H), 3.80 (s, 3H), 3.63 (d, J =8.4 Hz, 1H), 3.29 - 3.23 (m, 1H), 2.95 - 2.80 (m, 1H), 2.19 (d, J = 11.2 Hz,1H), 2.04 - 2.02 (m, 1H), 1.50 - 1.25 (m, 2H).

[0818] Example BJ: 4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)(2-methylpyridin-4-yl)methyl ketone (compound 62):

[0819]

[0820] Diisopropylethylamine (0.27 mL, 1.55 mmol, 4.0 eq), 2-methylnicotinic acid (0.05 g, 0.42 mmol, 1.1 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 0.22 g, 0.58 mmol, 1.50 eq) were added to a stirred solution of N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(piperidin-4-yl)pyridine-3-amine hydrochloride (0.15 g, 0.38 mmol, 1.0 eq) in dry N,N-dimethylformamide (DMF, 2.0 mL) at 0 °C. The resulting mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with ice-cold water (10.0 mL) and extracted with ethyl acetate (2 × 10.0 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude product. The crude product was purified by combined rapid chromatography using silica gel and eluted with a 72% EtOAc solution in hexane to give (4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)(2-methylpyridin-4-yl)methyl ketone (0.07 g, 39% yield). MS (ESI): against C 25 H 26 F₂N₄O₃, calculated mass 468.50; measured m / z 469.4 [M+H] + HPLC purity: 98.95%.

[0821] Compound 62: 1 H NMR (400 MHz, CDCl3) δ 8.52 ( s, 2H), 8.22 ( s, 1H), 7.09 (s, 1H), 7.09 - 6.93 (m, 4H), 6.56 - 6.19 (t, J = 75 Hz, 1H), 6.47 (d, J =8.8 Hz, 2H), 4.78 (d, J = 11.6 Hz, 1H), 4.11- 4.06 (m,1H), 3.79 (s, 3H), 3.70- 3.67 (m, 1H), 3.26 - 3.16 (m, 1H), 2.90 - 2.87 (m, 1H), 2.57 (s, 3H), 2.16(d, J = 10.8 Hz, 1H), 1.97 (d, J = 12.8 Hz, 1H), 1.68 - 1.25 (m, 2H).

[0822] Example BK: 4-methoxy-N-(1-(4-(methylsulfinyl)phenyl)piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (compound 63):

[0823]

[0824] 4-Methoxy-N-(piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride (0.25 g, 0.64 mmol, 1.0 eq), 1-bromo-4-(methylsulfinyl)benzene (0.18 g, 0.83 mmol, 1.3 eq), sodium tert-butoxide (0.18 g, 1.92 mmol, 3.0 eq), and dry 1,4-dioxane (10.0 mL) were added to a sealed tube under an argon atmosphere at room temperature. The reaction mixture was degassed with argon for 10 min, and then Ruphos-Pd-G3 (0.026 g, 0.032 mmol, 0.05 eq) was added under argon. The tube was sealed with a cap and stirred at 110 °C for 16 h. The reaction mixture was cooled to room temperature, passed through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude material was purified by a combination of rapid chromatography using silica gel and eluted with 10% MeOH in EtOAc solution to give 4-methoxy-N-(1-(4-(methylsulfinyl)phenyl)piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (0.18 g, 48% yield). MS (ESI): against C 25 H 26 F3N3O2S, calculated mass value 489.56; measured m / z value 490.5 [M+H] + HPLC purity: 98.39%.

[0825] Compound 63: 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 5.6 Hz, 1H), 8.21(s, 1H), 7.47 - 7.41 (m, 4H), 7.25 (d, J = 5.6 Hz, 1H), 7.04 (d, J = 9.2 Hz, 2H), 6.60 (d, J = 8.8 Hz, 2H), 4.26 - 4.21 (m, 1H), 3.87 (d, J = 12.8 Hz,2H), 3.77 (s, 3H), 2.98 - 2.93 (m, 2H), 2.64 (s, 3H), 2.07 - 1.99 (m, 2H),1.36 - 1.23 (m, 2H).

[0826] Example BL: N-(1-(2-fluoro-4-(methanesulfonyl)phenyl)piperidin-4-yl)-4-methoxy-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (compound 64):

[0827]

[0828] 4-Methoxy-N-(piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride (0.25 g, 0.64 mmol, 1.0 eq), 1-bromo-2-fluoro-4-(methanesulfonyl)benzene (0.21 g, 0.83 mmol, 1.3 eq), sodium tert-butoxide (0.18 g, 1.92 mmol, 3.0 eq), and dry 1,4-dioxane (10.0 mL) were added to a microwave tube under an argon atmosphere at room temperature. The resulting mixture was degassed with argon for 10 min, and Ruphos-Pd-G3 (0.026 g, 0.032 mmol, 0.05 eq) was added under argon atmosphere. The microwave tube was sealed and stirred at 120 °C for 2 h. The reaction progress was monitored by TLC and UPLC-MS, which showed product formation. The reaction mixture was cooled to room temperature, passed through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to obtain a crude substance. The obtained crude substance was purified by a combined rapid chromatography using silica gel and eluted with 80% EtOAc in hexane to give N-(1-(2-fluoro-4-(methanesulfonyl)phenyl)piperidin-4-yl)-4-methoxy-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (0.18 g, 45% yield), which was a grayish-white solid. MS (ESI): against C 25 H 25F4N3O3S, calculated mass value 523.55; measured m / z value 524.1 [M+H] + HPLC purity: 99.52%.

[0829] Compound 64: 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 5.6 Hz, 1H), 8.21(s, 1H), 7.62 (bs, 1H), 7.59 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.28 (d, J =5.6 Hz, 1H), 7.19 (t, J = 8.4 Hz, 1H), 6.61 (d, J = 8.4 Hz, 2H), 4.27 - 4.21(m, 1H), 3.79 (s, 3H), 3.57 (d, J = 12.4 Hz, 2H), 3.17 (s, 3H), 3.03 (t, J =11.6 Hz, 2H), 2.03 (d, J = 12.4 Hz, 2H), 1.45 - 1.36 (m, 2H).

[0830] Example BM: 2-(4-((4-fluorophenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)pyridin-5-carboxynitrile (Compound 65):

[0831]

[0832] Step 1: Preparation of tert-butyl 4-((4-fluorophenyl)(4-methoxypyridin-3-yl)amino)piperidine-1-carboxylic acid (22)

[0833]

[0834] 4-((4-methoxypyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (0.45 g, 1.46 mmol, 1.0 eq), 1-bromo-4-fluorobenzene (0.30 g, 1.75 mmol, 1.2 eq), sodium tert-butoxide (0.28 g, 2.92 mmol, 2.0 eq), and toluene (5.0 mL) were added to a microwave-safe tube under an argon atmosphere at room temperature. The resulting mixture was degassed with argon for 10 min, and Ruphos-Pd-G3 (0.06 g, 0.07 mmol, 0.05 eq) was added under argon atmosphere. The tube was sealed with a cap and stirred in a microwave oven at 130 °C for 2 h. TLC analysis revealed new nonpolar spots and some unreacted starting material. The reaction mixture was cooled to room temperature, passed through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude material was purified by a combination of rapid chromatography using silica gel and eluted with a hexane solution of 60% to 65% EtOAc to give tert-butyl 4-((4-fluorophenyl)(4-methoxypyridin-3-yl)amino)piperidine-1-carboxylate (0.30 g, 35% yield). MS (ESI): against C 22 H 28 FN3O3, calculated mass value 401.48; measured m / z value 402.2 [M+H] + .

[0835] 1 H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 5.6 Hz, 1H), 8.22 (s, 1H), 6.90 (d, J = 5.6 Hz, 1H), 6.87 - 6.83 (m, 2H), 6.47 - 6.44 (m, 2H), 4.16 - 4.11(m, 2H), 3.92 (tt, J = 3.6 Hz, 1H), 3.77 (s, 3H), 2.83 - 2.77 (m, 2H), 1.96(d, J = 12 Hz, 2H), 1.42 (s, 9H), 1.34 - 1.25 (m, 2H).

[0836] Step 2: Preparation of N-(4-fluorophenyl)-4-methoxy-N-(piperidin-4-yl)pyridine-3-amine hydrochloride

[0837]

[0838] Trimethylchlorosilane (0.45 mL) was added dropwise to a solution of tert-butyl 4-((4-fluorophenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-carboxylate (0.30 g, 0.77 mmol, 1.0 eq) in 2,2,2-trifluoroethanol (2.0 mL) at room temperature. The reaction mixture was then stirred at room temperature for 1 hour. TLC analysis showed new polar spots and complete conversion of the starting material. The volatiles were removed under reduced pressure to obtain the crude product. The obtained crude product was milled with ACN (10.0 mL) to give N-(4-fluorophenyl)-4-methoxy-N-(piperidin-4-yl)pyridin-3-amine hydrochloride (0.21 g, 81% yield). MS (ESI): against C 17 H 20 FN3O, calculated mass value 301.37; measured m / z value 302.1 [M+H] + .

[0839] 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 10 Hz, 1H), 8.81 - 8.79 (m,2H), 8.64 ( s, 1H), 7.70 (d, J = 6.8 Hz, 1H), 7.04 (t, J = 8.8 Hz, 2H), 6.79- 6.75 (m, 2H), 4.28 - 4.22 (m, 1H), 3.94 (s, 3H), 3.25 (d, J = 14.4 Hz, 2H), 3.07 - 2.98 (m, 2H), 2.02 - 1.99 (m, 2H), 1.65 - 1.58 (m, 2H).

[0840] Step 3: Preparation of 2-(4-((4-fluorophenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (compound 65):

[0841]

[0842] Diisopropylethylamine (0.31 mL, 1.77 mmol, 2.0 eq) and 2-chloropyrimidin-5-carboxynitrile (0.07 g, 0.35 mmol, 1.0 eq) were added to a stirred solution of N-(4-fluorophenyl)-4-methoxy-N-(piperidin-4-yl)pyridine-3-amine hydrochloride (0.15 g, 0.44 mmol, 1.0 eq) in dry N,N-dimethylformamide (DMF, 2.0 mL) and stirred at 90 °C for 4 h. TLC analysis showed new nonpolar spots and complete conversion of the starting material. The reaction mixture was cooled to room temperature, diluted with ice-cold water (10.0 mL), and extracted with ethyl acetate (2 × 10.0 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered through the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude substance. The crude material was purified by a combination of rapid chromatography using silica gel and eluted with a hexane solution of 65–70% EtOAc to give 2-(4-((4-fluorophenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (0.12 g, 51% yield). MS (ESI): against C 22 H 21 FN6O, calculated mass value 404.45; measured m / z value 405.1 [M+H] + HPLC purity: 98.93%.

[0843] Compound 65: 1 H NMR (400 MHz, CDCI3) δ 8.46 (d, J = 5.6 Hz, 1H), 8.44 (s,2H), 8.22 (s, 1H), 6.90 - 6.85 (m, 3H), 6.51-6.48 (m, 2H), 4.94 - 4.90 (m,2H), 4.16 - 4.09 (m, 1H), 3.77 (s, 3H), 3.07 - 3.00 (m, 2H), 2.12 (d, J =13.2 Hz, 2H), 1.42 - 1.29 (m, 2H).

[0844] Example BN: 4-Cyclopropoxy-N-(4-(difluoromethoxy)phenyl)-N-(1-(1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)pyridine-3-amine (Compound 66):

[0845]

[0846] The title compound was synthesized using a method similar to that used in Example AD (Compound 30).

[0847] The title compound was purified by column chromatography (10% to 80% ethyl acetate in petroleum ether solution) to provide the title compound (110.7 mg, 243.03 μmol, 44.78% yield). LCMS (ESI), [M+H]+ = 456.2.

[0848] Compound 66: 1 H NMR (400 MHz, CD3OD) δ 8.45 (d, J = 5.6 Hz, 1H), 8.21 (s,1H), 7.50 (d, J = 5.6 Hz, 1H), 7.29 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.79 -6.41 (m, 3H), 5.89 (s, 1H), 4.06 - 4.03 (m, 1H), 3.94 - 3.92 (m, 1H), 3.62(s, 3H), 3.20 - 3.17 (m, 2H), 2.88 - 2.82 (m, 2H), 2.08 - 2.05 (m, 2H), 1.59- 1.54 (m, 2H), 0.80 - 0.76 (m, 2H), 0.52 - 0.49 (m, 2H).

[0849] Example BO: 4-Cyclopropoxy-N-(1-(1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 67):

[0850]

[0851] The title compound was synthesized using a method similar to that used in Example AD (Compound 30).

[0852] The title compound was purified by column chromatography (10% to 80% ethyl acetate in petroleum ether solution) to provide the title compound (70.1 mg, 153.23 μmol, 43.26% yield). LCMS (ESI), [M+H]+ = 458.2.

[0853] Compound 67: 1H NMR (400 MHz, CD3OD) 8.51 (d, J = 5.6 Hz, 1H), 8.24 (s,1H), 7.56 (d, J = 5.6 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 2.4 Hz,1H), 6.61 (d, J = 8.8 Hz, 2H), 5.90 (s, 1H), 4.09 - 4.05 (m, 1H), 3.96 - 3.89(m, 1H), 3.62 (s, 3H), 3.22 - 3.18 (m, 2H), 2.91 - 2.85 (m, 2H), 2.10 - 2.07(m, 2H), 1.59 - 1.55 (m, 2H), 0.82 - 0.76 (m, 2H), 0.53 - 0.48 (m, 2H).

[0854] Example BP: 6-[4-[N-[4-(cyclopropoxy)-3-pyridinyl]-4-(difluoromethoxy)anilino]-1-piperidinyl]pyridine-3-carboxynitrile (compound 68):

[0855]

[0856] The title compound was synthesized using a method similar to that used in Example R (Compound 18).

[0857] The title compound was purified by a silica gel rapid column chromatography (10% to 50% ethyl acetate in petroleum ether solution) to provide the title compound (162.9 mg, 320.68 μmol, 60.19% yield). LCMS (ESI), [M+H]+ = 478.1.

[0858] Compound 68: 1H NMR (400 MHz, CD3OD) δ 8.40 (d, J = 5.6 Hz, 1H), 8.33 (s,1H), 8.15 (s, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 5.6 Hz, 1H), 6.93(d, J = 8.8 Hz, 2H), 6.83 - 6.79 (m, 1H), 6.61 - 6.41 (m, 3H), 4.55 - 4.52(m, 2H), 4.26 - 4.22 (m, 1H), 3.89 - 3.87 (m, 1H), 3.12 - 3.06 (m, 2H), 2.08- 2.05 (m, 2H), 1.31 - 1.27 (m, 2H), 0.79 - 0.73 (m, 2H), 0.46 - 0.42 (m, 2H).

[0859] Example BQ: (4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl ketone (compound 69):

[0860]

[0861] The title compound was synthesized using a method similar to that used in Example L (Compound 12).

[0862] The title compound was purified by reversed-phase HPLC (Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 32% to 62%, 7 min) to provide the title compound (73.5 mg, 150.54 μmol, 28.26% yield). LCMS (ESI), [M+H]+ = 479.2.

[0863] Compound 69: 1H NMR (400 MHz, CD3OD) δ 8.54 (s, 2H), 8.41 (d, J = 5.6 Hz,1H), 8.16 (s, 1H), 7.46 (d, J = 5.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.60 -6.42 (m, 3H), 4.60 - 4.59 (m, 2H), 4.29 - 4.22 (m, 1H), 3.92 - 3.88 (m, 1H), 3.15 - 3.06 (m, 2H), 2.11 - 2.07 (m, 2H), 1.29 - 1.24 (m, 2H), 0.79 - 0.74(m, 2H), 0.47 - 0.43 (m, 2H).

[0864] Example BR: N-(1-(1,2,4-oxadiazol-3-yl)piperidin-4-yl)-4-cyclopropoxy-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (compound 70):

[0865]

[0866] Step 1: 4-((4-cyclopropoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxynitrile

[0867]

[0868] At ℃, a solution of NaHCO3 (405.96 mg, 4.83 mmol) in H2O (1 mL) was added to a solution of 4-(cyclopropoxy)-N-(4-piperidinyl)-N-[4-(trifluoromethyl)phenyl]pyridine-3-amine (400 mg, 966.50 μmol, HCl salt) in dichloromethane (4.0 mL). Then, carbonitride bromide (1.1 g, 10.39 mmol) was added and the mixture was stirred at 0℃ for 1 hour. Sodium carbonate (2 g) was added to ensure neutralization was complete. MgSO4 (5 g) was added and the mixture was stirred vigorously for 15 minutes. The resulting suspension was filtered and washed with dichloromethane (50 mL x 2). The organic layer was concentrated under reduced pressure, and the residue was purified by rapid silica gel chromatography (petroleum ether eluent for 0% to 85% ethyl acetate) to provide the title compound (200 mg, 497.00 μmol, 51.42% yield). LCMS (ESI), [M+H]+ = 403.1.

[0869] Step 2: (E)-4-((4-cyclopropoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-N'-hydroxypiperidine-1-carboxamide

[0870]

[0871] NH₂OH (164.01 mg, 2.49 mmol, 50% purity, aqueous solution) was added to a solution of 4-[N-[4-(cyclopropoxy)-3-pyridyl]-4-(trifluoromethyl)anilinoyl]piperidine-1-carboxynitrile (200 mg, 497.00 μmol) in THF (5 mL), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel chromatography (petroleum ether eluent from 30% to 100% ethyl acetate) to provide the title compound (190 mg, 436.34 μmol, 87.79% yield). LCMS (ESI), [M+H]⁺ = 436.2

[0872] Step 3: N-(1-(1,2,4-oxadiazol-3-yl)piperidin-4-yl)-4-cyclopropoxy-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (compound 70):

[0873]

[0874] Add diethoxymethoxyethane (129.33 mg, 872.68 μmol) to a solution of 4-[N-[4-(cyclopropoxy)-3-pyridyl]-4-(trifluoromethyl)anilino]-N'-hydroxy-piperidine-1-carbamate (190 mg, 436.34 μmol) in triethoxymethane (5 mL), followed by the addition of HCl (12 M, 36.36 μL). Stir the resulting mixture at 110 °C for 0.5 h. Add sodium carbonate (2 g) to ensure neutralization is complete. Filter the reaction mixture and concentrate under reduced pressure. Purify the residue by rapid silica gel chromatography (0% to 60% ethyl acetate eluent in petroleum ether) to provide (80.5 mg, 180.72 μmol, 41.42% yield). LCMS (ESI), [M+H]+ = 446.1

[0875] Compound 70: 1H NMR (400 MHz, CD3OD) δ 8.72 (s, 1H), 8.48 (d, J = 5.6 Hz,1H), 8.18 (s, 1H), 7.52 (d, J = 5.6 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 6.62(d, J = 8.8 Hz, 2H), 4.27 - 4.19 (m, 1H), 4.07 - 4.03 (m, 2H), 3.94 - 3.92(m, 1H), 3.17 - 3.11 (m, 2H), 2.07 - 2.03 (m, 2H), 1.41 - 1.37 (m, 2H), 0.81- 0.77 (m, 2H), 0.53 - 0.49 (m, 2H).

[0876] Example BS: 6-(4-((4-cyclopropoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)nicotinonitrile (Compound 71):

[0877]

[0878] The title compound was synthesized using a method similar to that used in Example R (Compound 18).

[0879] The title compound was purified by a silica gel rapid column (10% to 40% ethyl acetate in petroleum ether solution, 40 mL / min) to provide the title compound (114.5 mg, 224.46 μmol, 42.36% yield). LCMS (ESI), [M+H]+ = 480.1.

[0880] Compound 71: 1H NMR (400 MHz, CD3OD) δ 8.46 (d, J = 5.6 Hz, 1H), 8.33 (d,J = 1.6 Hz, 1H), 8.15 (s, 1H), 7.68 - 7.65 (m, 1H), 7.50 (d, J = 5.6 Hz, 1H),7.38 (d, J = 8.8 Hz, 2H), 6.83 - 6.81 (m, 1H), 6.63 (d, J = 8.8 Hz, 2H), 4.59- 4.55 (m, 2H), 4.38 - 4.35 (m, 1H), 3.93 - 3.89 (m, 1H), 3.14 - 3.08 (m, 2H), 2.11 - 2.07 (m, 2H), 1.32 - 1.28 (m, 2H), 0.81 - 0.76 (m, 2H), 0.49 -0.45 (m, 2H).

[0881] Example BT: 2-(4-((4-cyclopropoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 72):

[0882]

[0883] The title compound was synthesized using a method similar to that used in Example L (Compound 12).

[0884] The title compound was purified by reversed-phase HPLC (Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 35% to 65%, 7 min) to provide the title compound (130.3 mg, 271.18 μmol, 56.12% yield). LCMS (ESI), [M+H]+ = 481.2.

[0885] Compound 72: 1H NMR (400 MHz, CD3OD) δ 8.54 (s, 2H), 8.47 (d, J = 6.0 Hz,1H), 8.17 (s, 1H), 7.50 (d, J = 6.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 6.63(d, J = 8.4 Hz, 2H), 4.61 - 4.59 (m, 2H), 4.40 - 4.37 (m, 1H), 3.95 - 3.92(m, 1H), 3.18 - 3.09 (m, 2H), 2.15 - 2.08 (m, 2H), 1.32 - 1.23 (m, 2H), 0.81- 0.76 (m, 2H), 0.51 - 0.45 (m, 2H).

[0886] Example BU: N-(1-(1,2,4-oxadiazol-3-yl)piperidin-4-yl)-4-cyclopropoxy-N-(4-(difluoromethoxy)phenyl)pyridine-3-amine (compound 73):

[0887]

[0888] The title compound was synthesized using a method similar to that used in example BS (compound 70).

[0889] The title compound was purified by a silica gel rapid column (10% to 40% ethyl acetate in petroleum ether solution, 40 mL / min) to provide the title compound (67.5 mg, 152.22 μmol, 21.28% yield). LCMS (ESI), [M+H]+ = 444.1.

[0890] Compound 73: 1H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 8.42 (d, J = 5.6 Hz,1H), 8.17 (s, 1H), 7.47 (d, J = 5.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.79 -6.41 (m, 3H), 4.18 - 4.14 (m, 1H), 4.05 - 4.02 (m, 2H), 3.91 - 3.89 (m, 1H), 3.15 - 3.07 (m, 2H), 2.04 - 2.01 (m, 2H), 1.39 - 1.32 (m, 2H), 0.79 - 0.75(m, 2H), 0.49 - 0.47 (m, 2H).

[0891] Example BV: 2-(4-((4-(difluoromethoxy)-3-fluorophenyl)(4-methoxypyridin-3-yl)amino)piperidin-1-yl)pyrimidin-5-carboxynitrile (Compound 74):

[0892]

[0893] The title compound was synthesized using a method similar to that used in Example L (Compound 12).

[0894] The title compound was purified by reversed-phase HPLC (Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 28% to 58%, 7 min) to provide the title compound (153.3 mg, 319.34 μmol, 64.48% yield). LCMS (ESI), [M+H]+ = 471.2.

[0895] Compound 74: 1H NMR (400 MHz, CD3OD) δ 8.55 (s, 2H), 8.47 (d, J = 5.6 Hz,1H), 8.18 (s, 1H), 7.23 (d, J = 5.6 Hz, 1H), 7.05 - 7.03 (m, 1H), 6.64 (t, J= 74 Hz, 1H), 6.44 - 6.39 (m, 1H), 6.33 - 6.30 (m, 1H), 4.61 - 4.59 (m, 2H), 4.32 - 4.28 (m, 1H), 3.86 (s, 3H), 3.16 - 3.10 (m, 2H), 2.14 - 2.11 (d, J = 6Hz, 2H), 1.32 - 1.22 (m, 2H).

[0896] Example BW: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(5-(methanesulfonyl)pyridin-2-yl)piperidin-4-yl)pyridin-3-amine (compound 75):

[0897]

[0898] The title compound was synthesized using a method similar to that used in Example C (Compound 3).

[0899] The title compound was purified by reversed-phase HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 15% to 45%, 7 min) to provide the title compound (238.4 mg, 435.42 μmol, 76.06% yield). LCMS (ESI), [M+H]+ = 505.2.

[0900] Compound 75: 1H NMR (400 MHz, CD3OD) δ 8.59 (d, J = 2.4 Hz, 1H), 8.48 (d,J = 5.6 Hz, 1H), 8.24 (s, 1H), 7.82 (d, J = 5.6 Hz, 1H), 6.98 - 6.93 (m, 3H), 6.62 (d, J = 9.2 Hz, 1H), 6.53 (d, J = 8.8 Hz, 2H), 6.40 (t, J = 74 Hz, 1H), 4.59 - 4.51 (m, 2H), 4.18 - 4.14(m, 1H), 3.80 (s, 3H), 3.18 - 3.6 (m, 2H), 3.03 (s, 3H), 2.15 - 2.10 (m, 2H), 1.42 - 1.38 (m, 2H).

[0901] Example BX: 4-methoxy-N-(1-(5-(methanesulfonyl)pyridin-2-yl)piperidin-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridin-3-amine (compound 76):

[0902]

[0903] The title compound was synthesized using a method similar to that used in Example C (Compound 3).

[0904] The title compound was purified by reversed-phase HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 7% to 37%, 7 min) to provide the title compound (153.9 mg, 300.79 μmol, 48.04% yield). LCMS (ESI), [M+H]+ = 507.6.

[0905] Compound 76: 1H NMR (400 MHz, CD3OD) δ 8.48 (d, J = 5.6 Hz, 1H), 8.43 (s,1H), 8.18 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.23(d, J = 5.6 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H), 6.61 (d, J = 8.8 Hz, 2H), 4.55- 4.52 (m, 2H), 4.41 - 4.35 (m, 1H), 3.76 (s, 3H), 3.15 - 3.09 (m, 5H), 2.04- 2.01 (m, 2H), 1.23 - 1.13 (s, 2H).

[0906] Example BY: ((trans)-4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)cyclohexyl)(morpholino)methyl ketone (compound 77):

[0907]

[0908] Step 1: Ethyl 4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)cyclohexane-1-carboxylate

[0909]

[0910] A mixture of ethyl 4-[(4-methoxy-3-pyridyl)amino]cyclohexanecarboxylate (200 mg, 718.53 μmol), 1-bromo-4-(difluoromethoxy)benzene (320.49 mg, 1.44 mmol), t-Bu3P (581.48 mg, 287.41 μmol, 674.58 μL, 10% purity), Pd(OAc)2 (32.26 mg, 143.71 μmol), and tBuONa (207.16 mg, 2.16 mmol) in toluene (8 mL) was degassed and purged three times with N2. The mixture was then stirred at 120 °C under N2 atmosphere for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel rapid column chromatography (0% to 30% ethyl acetate in petroleum ether solution) to provide the title compound (136 mg, 322.51 μmol, 45% yield). LCMS (ESI), [M+H]+ = 421.3.

[0911] Step 2: 4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)cyclohexane-1-carboxylic acid

[0912]

[0913] A solution of ethyl 4-[4-(difluoromethoxy)-N-(4-methoxy-3-pyridyl)anilino]cyclohexylcarboxylate (403 mg, 958.50 μmol) in THF (5 mL) and methanol (5 mL) was added to a solution of lithium hydroxide monohydrate (201.11 mg, 4.79 mmol) in H₂O (5 mL), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was adjusted to pH 6 with HCl (4 M). The resulting mixture was extracted with ethyl acetate (25 mL x 3), and the combined organic matter was dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to provide the title compound (376.11 mg, 958.50 μmol, 100.00% yield). LCMS (ESI), [M+H]⁺ = 393.1.

[0914] Step 3: ((trans)-4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)cyclohexyl)(morpholino) methyl ketone (compound 77) and ((cis)-4-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)cyclohexyl)(morpholino) methyl ketone

[0915]

[0916] DIEA (169.75 mg, 1.31 mmol) and HATU (332.95 mg, 875.65 μmol) were added to a solution of 4-[4-(difluoromethoxy)-N-(4-methoxy-3-pyridyl)anilino]cyclohexanecarboxylic acid (200 mg, 437.82 μmol) and morpholine (57.21 mg, 656.74 μmol) in dichloromethane (4 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Welch Xtimate C18 150 * 30 mm * 5 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 40% to 70%, 7 min) to provide title compound-1 (peak 1 on HPLC, compound 77, 31.9 mg, 68.63 μmol, 15.67% yield) and compound-2 (peak 2 on HPLC, isomer of compound 77, 64.3 mg, 136.29 μmol, 31.13% yield). LCMS (ESI), [M+H]+ = 462.2. Only the trans isomer, compound 77, showed activity.

[0917] Compound 77: 1 H NMR (400 MHz, CD3OD) δ 8.41 (d, J = 5.6 Hz, 1H), 8.15 (s,1H), 7.18 (d, J = 5.6 Hz, 1H), 6.90 (d, J = 9.2 ,2H), 6.76 - 6.38 (m, 3H), 3.98 - 3.86 (m, 1H), 3.81 (s, 3H), 3.62 - 3.53 (m, 8H), 2.60 - 2.44 (m, 1H), 2.11 - 2.09 (m, 2H), 1.87 - 1.74 (m, 2H), 1.74 - 1.60 (m, 2H), 1.26 - 1.22(m, 2H).

[0918] Compound 77 cis isomer: 1H NMR (400 MHz, CD3OD) δ 8.38 (d, J = 5.6 Hz,1H), 8.22 (s, 1H), 7.15 (d, J = 5.6 Hz, 1H), 6.91 (d, J = 9.2 ,2H), 6.78 -6.41 (m, 3H), 3.96 - 3.93 (m, 1H), 3.81 (s, 3H), 3.61 - 3.46 (m, 8H), 2.86 -2.84 (m, 1H), 1.90 - 1.67 (m, 8H).

[0919] Example BZ: (cis)-4-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)cyclohexyl)(morpholino) methyl ketone (compound 78):

[0920]

[0921] The title compound was synthesized using a method similar to that used in Example BY (Compound 77).

[0922] The title compounds were purified by reversed-phase HPLC (column: Welch Xtimate C18 150 * 30 mm * 5 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 40% to 70%, 7 min) to provide title compound-1 (peak 1 on HPLC, 125 mg, 269.69 μmol, 66.48% yield) and compound-2 (compound 78, peak 2 on HPLC, 60 mg, 129.45 μmol, 31.91% yield). LCMS (ESI), [M+H]+ = 464.3. Only the cis isomer, compound 78, showed activity.

[0923] Compound 78: 1H NMR (400 MHz, CD3OD) δ 8.45 (d, J = 5.6 Hz, 1H), 8.18 (s,1H), 7.35 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 5.6 ,1H), 6.57 (d, J = 5.6 ,2H),4.01 - 3.98 (m, 1H), 3.83 (s, 3H), 3.65 - 3.60 (m, 4H), 3.52 - 3.46 (m, 4H), 2.91 - 2.88 (m, 1H), 1.90 - 1.86 (m, 4H), 1.76 - 1.71 (m, 4H).

[0924] Compound 78 isomer: 1 H NMR (400 MHz, CD3OD) δ 8.47 (d, J = 5.6 Hz, 1H),8.18 (s, 1H), 7.36 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 5.6 ,1H), 6.57 (d, J =8.8 ,2H), 4.27 - 4.16 (m, 1H), 3.84 (s, 3H), 3.63- 3.60 (m, 4H), 3.58 - 3.53(m, 4H), 2.59 - 2.51 (m, 1H), 2.14 - 2.11 (m, 2H), 1.85 - 1.83 (m, 2H), 1.74- 1.60 (m, 4H).

[0925] Example CA: N-(4-(difluoromethoxy)phenyl)-5-fluoro-4-methoxy-N-(1-(5-(methanesulfonyl)pyrimidin-2-yl)piperidin-4-yl)pyridine-3-amine (compound 79):

[0926]

[0927] Step 1: 3-Bromo-5-fluoro-4-methoxypyridine

[0928]

[0929] Add NaOMe (5.4 M, 2.64 mL, 1 eq) to a solution of 3-bromo-4-chloro-5-fluoropyridine (3.0 g, 14.26 mmol, 1 eq) in THF (30 mL). Stir the mixture at 50 °C for 1 hour. LCMS (5-95AB / 1.5 min): RT = 0.656 min, [M+H] + = 206.1 shows 58% of the desired product. The reaction mixture was diluted with brine (50 mL). The mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel rapid chromatography (0% to 12.5% ​​ethyl acetate in petroleum ether solution) to provide the title compound (760 mg, 26%).

[0930] 1 H NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 8.34 (d, J = 2.8 Hz, 1H), 4.21 (d, J = 4.4 Hz, 3H); LCMS (ESI): m / z 206.1 (M+H) + .

[0931] Step 2: 4-((5-fluoro-4-methoxypyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0932]

[0933] A mixture of 3-bromo-5-fluoro-4-methoxypyridine (850 mg, 4.13 mmol, 1 eq), tert-butyl 4-aminopiperidine-1-carboxylate (992 mg, 4.95 mmol, 1.2 eq), Pd(OAc)₂ (93 mg, 412.60 μmol, 0.1 eq), BINAP (514 mg, 825.19 μmol, 0.2 eq), and t-BuONa (1.19 g, 12.38 mmol, 3 eq) in toluene (20 mL) was stirred at 100 °C under a nitrogen atmosphere for 12 hours. LCMS (5-95AB / 1.5 min): RT = 0.655 min, [M+H] += 326.3 shows 57% of the desired product. The reaction mixture was diluted with brine (50 mL), and the mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 2:1) to provide the title compound (830 mg, 62%). LCMS (ESI): m / z 326.3 (M+H) + .

[0934] Step 3: 4-((4-(difluoromethoxy)phenyl)(5-fluoro-4-methoxypyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0935]

[0936] A mixture of tert-butyl 4-((5-fluoro-4-methoxypyridin-3-yl)amino)piperidin-1-carboxylate (250 mg, 768.34 μmol, 1 eq), 1-bromo-4-(difluoromethoxy)benzene (343 mg, 1.54 mmol, 210.12 μL, 2 eq), t-Bu3P-Pd-G2 (79 mg, 153.67 μmol, 0.2 eq), and t-BuONa (222 mg, 2.31 mmol, 3 eq) in toluene (5 mL) was stirred at 120 °C under a nitrogen atmosphere for 16 hours. LCMS (5-95AB / 1.5 min): RT = 0.885 min, [M+H] + = 468.3 shows 46% of the desired product. The reaction was diluted with brine (50 mL), and the mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel rapid chromatography (0% to 5% EE (ethanol:EtOAc = 1:3) in petroleum ether solution) to provide the title compound (350 mg, crude). LCMS (ESI): m / z 468.3 (M+H) + .

[0937] Step 4: N-(4-(difluoromethoxy)phenyl)-5-fluoro-4-methoxy-N-(piperidin-4-yl)pyridine-3-amine hydrochloride

[0938]

[0939] To a solution of tert-butyl 4-((4-(difluoromethoxy)phenyl)(5-fluoro-4-methoxypyridin-3-yl)amino)piperidin-1-carboxylate (350 mg, 748.69 μmol, 1 eq) in dioxane (0.5 mL), HCl / dioxane (4 M, 5 mL, 26.71 eq) was added. The mixture was stirred at 25 °C for 1 hour. LCMS (5-95AB / 1.5 min): RT = 0.747 min, [M+H] + = 368.2 shows 94% of the desired product. The mixture was concentrated under reduced pressure to provide the title compound (275 mg, crude, HCl salt). The crude was used directly for the next step. LCMS(ESI): m / z 368.2(M+H) + .

[0940] Step 5: N-(4-(difluoromethoxy)phenyl)-5-fluoro-4-methoxy-N-(1-(5-(methanesulfonyl)pyrimidin-2-yl)piperidin-4-yl)pyridine-3-amine (compound 79)

[0941]

[0942] TEA (181.79 mg, 1.80 mmol, 250.06 μL, 5 eq) was added to a solution of N-(4-(difluoromethoxy)phenyl)-5-fluoro-4-methoxy-N-(piperidin-4-yl)pyridine-3-amine hydrochloride (132 mg, 359.32 μmol, 1 eq) and 2-chloro-5-(methanesulfonyl)pyrimidine (70 mg, 359.32 μmol, 1 eq) in MeCN (5 mL). The mixture was stirred at 0 °C for 1 hour. LCMS (5-95AB / 1.5 min): RT = 0.811 min, [M+H] + = 524.2 shows 70% of the desired product. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel rapid chromatography (0% to 45% EtOAc in petroleum ether solution) to provide the title compound (97.68 mg, 52%).

[0943] Compound 79: 1H NMR (400 MHz, CD3OD): δ 8.65 (s, 2H), 8.38 (d, J = 3.2Hz, 1H), 8.09 (s, 1H), 7.00 (d, J = 9.2 Hz, 2H), 6.84 - 6.39 (m, 3H), 5.01 -4.97 (m, 2H), 4.33 - 4.30 (m, 1H), 3.93 (d, J = 4.4 Hz, 3H), 3.19 - 3.12 (m,2H), 3.11 (s, 3H), 2.15 - 2.11 (m, 2H), 1.37 - 1.29 (m, 2H); LCMS (ESI): m / z524.2 (M+H) + .

[0944] The following compounds were prepared using appropriate reagents following a similar procedure as described above.

[0945] Example CB: (4-methyl-3-pyridyl)[p-(trifluoromethyl)phenyl]{1-[5-(trifluoromethyl)-2-pyridyl]-4-piperidinyl}amine:

[0946]

[0947] Compound 100: 29.9 mg; 1 H NMR (400 MHz, CD3OD) d 8.42 (d, 1H), 8.25 (m,2H), 7.67 (d,1H), 7.44 (m, 3H), 6.86 (d, 1H), 6.62 (m, 2H), 4.50 (m, 2H), 4.46 (m, 1H), 3.11 (m, 2H), 2.19 (s, 3H), 2.12 (m, 2H), 1.4 (m, 2H); LCMS(ESI) [M+H]+ = 481.

[0948] Example CD: 2-{4-[(4-methyl-3-pyridyl)[6-(trifluoromethyl)-3-pyridyl]amino]-1-piperidinyl}-5-pyrimidinecarboxynitrile:

[0949]

[0950] Compound 101: 26.6 mg; 1H NMR (400 MHz, CD3OD) d 8.55 (s, 2H), 8.47 (d,1H), 8.31 (s,1H), 7.87 (s, 1H), 7.59 (d, 1H), 7.49 (d, 1H), 7.10 (d, 1H), 5.00 (m, 2H), 4.53 (m, 1H), 3.17 (m, 2H), 2.21 (s, 3H), 2.17 (m, 2H), 1.37(m, 2H) LCMS (ESI) [M+H]+ = 440.

[0951] Example CE: 2-{4-[(4-chloro-3-pyridyl)[6-(trifluoromethyl)-3-pyridyl]amino]-1-piperidinyl}-5-pyrimidinecarboxynitrile:

[0952]

[0953] Compound 102: 95 mg; 1 H NMR (400 MHz, CDCl3) d 8.58 (m, 1H), 8.48 (m,3H), 8.20 (s,1H), 7.54 (dd, 2H), 6.84 (d, 1H), 5.03 (m, 2H), 4.30 (m, 1H), 3.08 (m, 2H), 2.22 (m, 2H), 1.41-1.50 (br. m, 2H); LCMS (ESI) [M+H]+ = 460.

[0954] Example CF: (p-Difluoromethoxyphenyl)(4-methoxy-3-pyridyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidinyl]amine:

[0955]

[0956] Compound 103: 538 mg; 1 H NMR (400 MHz, CD3OD) d 8.44 (d, 1H), 8.43 (s,2H), 8.42 (s, 1H), 6.97 (m, 1H), 6.96 (m, 2H), 6.92 (m, 3H), 4.11 (m, 1H), 3.84 (s, 3H), 3.83 (m, 2H), 2.98 (m, 2H), 2.20 (s, 3H), 2.14 (m, 2H), 1.5 (m,2H); LCMS (ESI) [M+H]+ = 442.

[0957] Example CG: 5-{4-[(p-difluoromethoxyphenyl)(4-methoxy-3-pyridyl)amino]cyclohexyloxy}-2-pyridinecarboxynitrile:

[0958]

[0959] Compound 104-isomer 1: 7.5 mg; 1 H NMR (400 MHz, CD3OD) d 8.5 (d, 1H), 8.3(d, 1H), 8.2 (d, 1H), 7.8 (d, 1h), 7.5 (d, 1H), 7.2 (d, 1H), 6.9 (d, 2H),6.4-6.6 (m, 3H), 4.6 (m, 1H), 4.1 (m, 1H), 3.8 (s, 3H), 2.15 (m, 2H), 1.9(br. m, 4H), 1.6 (m, 2H); LCMS (ESI) [M+H]+ = 467.

[0960]

[0961] Compound 104-Isomer 2: 51 mg; 1 H NMR (400 MHz, CD3OD) d 8.6 (d, 1H), 8.30(d, 1H), 8.20 (s, 1H), 7.75 (d, 1H), 7.50 (d, 1H), 7.20 (s, 1H), 6.9 (d, 2H),6.3-6.7 (m, 3H), 4.3 (m, 1H), 4.05 (m, 1H), 3.8 (s, 3H), 2.2 (m, 4H), 1.7 (m,2H), 1.4 (m, 2H); LCMS (ESI) [M+H]+ = 467.

[0962] Example CH: 5-{4-[(4-methoxy-3-pyridyl)[p-(trifluoromethyl)phenyl]amino]cyclohexyloxy}-2-pyridinecarboxynitrile:

[0963]

[0964] Compound 105-isomer 1: 9.3 mg; 1H NMR (400 MHz, CDCl3) d 8.28 (d, 1H),7.59 (d, 1H), 7.38 (d, 2H), 7.2-7.3 (br. m, 4H), 4.67 (m, 1H), 4.0 (m, 1H),3.81 (s, 3H), 2.17 (m, 2H), 1.93 (m, 2H), 1.77 (m, 2H), 1.6 (m, 2H); LCMS(ESI) [M+H]+ = 469.

[0965]

[0966] Compound 105-isomer 2: 68 mg; 1 H NMR (400 MHz, CDCl3) d 8.6 (br. s, 1H),8.35 (s, 1H), 8.30 (br. s, 1H), 7.6 (d, 1H), 7.4 (d, 2H), 7.15 (m, 1H), 7.0(m, 1H), 6.5 (d, 2H) 4.2 (m, 1H), 4.0 (m, 1H), 3.80 (s, 3H), 2.2 (m, 4H), 1.7(m, 2H), 1.3 (m, 2H)LCMS (ESI) [M+H]+ = 469.

[0967] Example CI: (p-difluoromethoxyphenyl)(4-methoxy-3-pyridyl){1-[p-(methylenesulfinyl)phenyl]-4-piperidinyl}amine:

[0968]

[0969] Compound 106: 150 mg; 1 H NMR (400 MHz, DMSO-d6) d 8.48 (m, 1H), 8.20 (s,1H), 7.45 (m, 2H), 7.2 (m, 1H), 6.8-7.1 (m, 5H), 6.5 (m, 2H), 4.15 (m, 1H),3.85 (m, 2H), 3.75 (s, 3H), 2.95 (m, 2H), 2.68 (s, 3H), 2.0 (m, 2H), 1.3 (m,2H); LCMS (ESI) [M+H]+ = 488.

[0970] Example CJ: p-Difluoromethoxyphenyl)[1-(2-fluoro-4-methylsulfonylphenyl)-4-piperidinyl](4-methoxy-3-pyridinyl)amine:

[0971]

[0972] Compound 107: 150 mg; 1 H NMR (400 MHz, DMSO-d6) d 8.50 (d, 1H), 8.20 (s,1H), 7.60 (m, 2H), 6.8-7.3 (m, 5H), 6.5 (m, 2H), 4.15 (m, 1H), 3.80 (s, 3H), 3.55 (m, 2H), 3.20 (s, 3H), 3.00 (m, 2H), 2.0 (m, 2H), 1.4 (m, 2H); LCMS(ESI) [M+H]+ = 522.

[0973] Example CK: 5-{4-[(p-difluoromethoxyphenyl)(4-methoxy-3-pyridyl)amino]cyclohexyl}-2-pyridinecarboxynitrile:

[0974]

[0975] Compound 108: 21.4 mg (a 1:1 mixture of diastereomers); 1 H NMR (400 MHz, CD3OD)d 8.65 (m, 1H), 8.25-8.5 (m, 2H), 7.8-7.9 (m, 2H), 7.1-7.2 (m, 1H), 6.9 (m,2H), 6.4-6.7 (m, 3H), 4.0-4.25 (m, 1H), 3.80 (s, 3H), 2.6-2.95 (m, m, 1H), 2.2 (m, 1H), 2.0 (m, 2H), 1.7-1.9 (m, 5H); LCMS (ESI) [M+H]+ = 451

[0976] Example CL: (p-difluoromethoxyphenyl)(4-methoxy-3-pyridyl)[1-(4-pyridyl)-4-piperidinyl]amine:

[0977]

[0978] Compound 109: 152 mg; 1H NMR (400 MHz, CD3OD) d 8.45 (s, 1H), 8.2 (s,1H), 8.10 (d, 2H), 7.2 (d, 1H), 6.9 (m, 4H), 6.6 (m, 3H), 4.25 (m, 1H) 4.1(m, 2H), 3.80 (s, 3H), 3.1 (m, 2H), 2.1 (m, 2H), 1.4 (m, 2H) LCMS (ESI) [M+H]+ = 427.

[0979] Example CM: (4-methoxy-3-pyridyl)[1-(4-pyridyl)-4-piperidinyl][p-(trifluoromethyl)phenyl]amine:

[0980]

[0981] Compound 110: 159 mg; 1 H NMR (400 MHz, CD3OD) d 8.5 (m, 1H), 8.2 (s, 1H), 8.15 (d, 2H), 7.45 (d, 2H), 7.25 (s, 1H), 6.95 (d, 2H), 6.65 (d, 2H) 4.4 (m, 1H), 4.15 (m, 2H), 3.80 (s, 3H), 3.2 (m, 2H), 2.2 (m, 2H), 1.4 (m, 2H); LCMS(ESI) [M+H]+ = 429.

[0982] Example CN: 5-{4-[(4-methoxy-3-pyridyl)[p-(trifluoromethyl)phenyl]amino]cyclohexyl}-2-pyridinecarboxynitrile:

[0983]

[0984] Compound 111: 34.2 mg (a mixture of 41:59 diastereomers); 1H NMR (400 MHz, CD3OD) d 8.65 (m, 1H), 8.4 (m, 1H), 7.9 (m, 1H), 7.8 (m, 1H), 7.35-7.55 (m,4H), 6.65 (d, 2H), 4.2-4.3 (br. m, 1H), 3.85, 3.95 (s, s, 3H), 2.6-3.1 (m, m,1H), 2.4 (br. s, 2H), 1.4-2.25 (m, 6H); LCMS (ESI) [M+H]+ = 453.

[0985] Example CO: (4-cyclopropoxy-3-pyridyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidinyl][p-(trifluoromethyl)phenyl]amine:

[0986]

[0987] Compound 112: 96 mg; 1 H NMR (400 MHz, CD3OD) d 8.2-8.55 (m, 4H), 7.55 (d,1H), 7.35 (d, 2H), 6.62 (d, 2H), 4.2 (m, 1H), 3.95 (m, 1H), 3.80 (m, 2H), 3.0(m, 2H), 2.55 (s, 3H), 2.15 (m, 2H), 1.55 (m, 2H), 0.83 (m, 2H), 0.55 (m,2H); LCMS (ESI) [M+H]+ = 470.

[0988] Example CP: 3-{4-[(4-methoxy-3-pyridyl)[p-(trifluoromethyl)phenyl]amino]-1-piperidinyl}bicyclo[1.1.1]pentane-1-carboxynitrile:

[0989]

[0990] Compound 113: 10 mg; 1H NMR (400 MHz, CD3OD) d 8.53 (d, 1H), 8.24 (s,1H), 7.38 (d, 2H), 7.32 (d, 1H), 6.60 (d, 2H), 4.04 (m, 1H), 3.87 (s, 3H), 2.37 (m, 2H), 2.31 (m, 2H), 2.27 (s, 6H), 2.05 (m, 2H), 1.38 (m, 2H) LCMS(ESI) [M+H]+ = 443.

[0991] Example CQ: 2-{4-[(p-difluoromethoxyphenyl)(4-methoxy-3-pyridyl)amino]cyclohexyloxy}-5-pyrimidinecarboxynitrile

[0992]

[0993] Compound 114: 40 mg; 1 H NMR (400 MHz, CD3OD) d 8.87 (d, 2H), 8.44 (d,1H), 8.18 (s, 1H), 7.22 (d, 1H), 6.91 (d, 2H), 6.52 (m, 3H), 4.95 (m, 1H), 4.03 (m, 1H), 4.02 (s, 3H), 2.16 (m, 4H), 1.79 (m, 2H), 1.33 (m, 2H) LCMS(ESI) [M+H]+ = 468.

[0994] Example CR: 4-methyl-3-pyridyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidinyl][p-(trifluoromethyl)phenyl]amine:

[0995]

[0996] Compound 115: 126 mg; 1 H NMR (400 MHz, CD3OD) d 8.45 (d, 1H), 8.30 (m,3H), 7.48 (d, 1H), 7.43 (d, 2H), 6.61 (d, 2H), 4.3 (m, 1H), 3.84 (m, 2H), 2.99 (m, 2H), 2.54 (s, 3H), 2.20 (s, 3H), 2.13 (m, 2H), 1.56 (m, 2H); LCMS(ESI) [M+H]+ = 428.

[0997] Example CS: (p-Difluoromethoxyphenyl)(4-methyl-3-pyridyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidinyl]amine:

[0998]

[0999] Compound 116: 48 mg; 1 H NMR (400 MHz, CD3OD) d 8.35 (br. m, 4H), 7.45 (s,1H), 6.95 (s, 2H), 6.55 (m, 3H), 4.2 (m, 1H), 3.85 (m, 2H), 3.0 (m, 2H), 2.55(s, 3H), 2.20 (s, 3H), 2.05 (m, 2H), 1.55 (m, 2H); LCMS (ESI) [M+H]+ = 426.

[1000] Example CT: {1-[2-(methoxymethyl)-5-pyrimidinyl]-4-piperidinyl}(4-methoxy-3-pyridinyl)[p-(trifluoromethyl)phenyl]amine:

[1001]

[1002] Compound 117: 142 mg; 1 H NMR (400 MHz, CD3OD) d 8.4-8.55 (m, 3H), 8.21(s, 1H), 7.45 (m, 2H), 7.25 (d, 1H), 6.65 (m, 2H), 4.5 (m, 2H), 4.25 (m, 1H),3.90 (m, 2H), 3.85 (s, 3H), 3.42 (s, 3H), 3.05 (m, 2H), 2.15 (m, 2H), 1.50(m, 2H); LCMS (ESI) [M+H]+ = 474.

[1003] Example CU: (4-Cyclopropyl-3-pyridyl)(p-difluoromethoxyphenyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidinyl]amine:

[1004]

[1005] Compound 118: 125 mg; 1H NMR (400 MHz, CD3OD) d 8.35 (m, 3H), 8.20 (s,1H), 7.0 (m, 3H), 6.56 (m, 3H), 4.25 (m, 1H), 3.85 (m, 2H), 3.0 (m, 2H), 2.55(s, 3H), 2.25 (m, 2H), 2.05 (m, 1H), 1.5 (m, 2H), 1.05 (m, 2H), 0.85 (m, 2H)LCMS (ESI) [M+H]+ = 452.

[1006] Example CV: (4-cyclopropyl-3-pyridyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidinyl][p-(trifluoromethyl)phenyl]amine:

[1007]

[1008] Compound 119: 78 mg; 1 H NMR (400 MHz, CD3OD) d 8.2-8.4 (m, 4H), 7.45 (d,2H), 7.05 (d, 1H), 6.65 (d, 2H), 4.35 (m, 1H), 3.85 (m, 2H), 3.05 (m, 2H), 2.55 (s, 3H), 2.25 (m, 2H), 2.0 (m, 1H), 1.55 (m, 2H), 1.05 (m, 2H), 0.85 (m,2H); LCMS (ESI) [M+H]+ = 454.

[1009] Example CW: 2-{4-[(4-methoxy-3-pyridyl)[p-(trifluoromethyl)phenyl]amino]cyclohexyloxy}-5-pyrimidinecarboxynitrile:

[1010]

[1011] Compound 120: 26 mg; 1H NMR (400 MHz, CD3OD) d 8.89 (s, 2H), 8.54 (br. s,1H), 8.23 ​​(br. s, 1H), 7.39 (d, 2H), 7.33 (m, 1H), 6.60 (d, 2H), 4.95 (s,1H), 4.60 (m, 1H), 4.12 (s, 3H), 2.17 (m, 4H), 1.76 (m, 2H), 1.29 (m, 2H); LCMS (ESI) [M+H]+ = 470.

[1012] Example CX: (4-Ethyl-3-pyridyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidinyl][p-(trifluoromethyl)phenyl]amine:

[1013]

[1014] Compound 121: 83 mg; 1 H NMR (400 MHz, CD3OD) d 8.25-8.65 (m, 4H), 7.55(m, 1H), 7.4 (m, 2H), 6.65 (m, 2H), 4.31 (m, 1H), 3.85 (m, 2H), 3.0 (m, 2H),2.55 (m, 2H), 2.50 (s, 3H), 2.15 (m, 2H), 1.55 (q, 2H), 1.15 (t, 3H); LCMS(ESI) [M+H]+ = 442.

[1015] Example CY: 2-{4-[(4-cyclopropyl-3-pyridyl)[6-(difluoromethyl)-3-pyridyl]amino]-1-piperidinyl}-5-pyrimidinecarboxynitrile:

[1016]

[1017] Compound 122: 157 mg; 1H NMR (400 MHz, CD3OD) d 8.75 (s, 2H), 8.42 (m,1H), 8.25 (s, 1H), 7.85 (m, 1H), 7.52 (m, 1H), 7.20 (m, 1H), 6.95 (m, 1H0,6.65 (m, 1H), 5.05 (m, 2H), 4.55 (m, 1H), 3.20 (m, 2H), 2.25 (m, 2H), 1.95(m, 1H), 0.85-1.545 (br. m, 6H) LCMS (ESI) [M+H]+ = 448.

[1018] Example CZ: (p-difluoromethoxyphenyl)(4-ethyl-3-pyridyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidinyl]amine:

[1019]

[1020] Compound 123: 49 mg; 1 H NMR (400 MHz, CD3OD) d 8.25-8.5 (m, 4H), 7.55 (s,1H), 7.00 (m, 2H), 6.4-6.8 (m, 3H), 4.2 (m, 1H), 3.85 (m, 2H), 2.95 (m, 2H),2.55 (s, 3H), 2.10 (q, 2H), 1.55 (m, 2H), 1.4 (m, 2H), 1.15 (t, 3H); LCMS(ESI) [M+H]+ = 440.

[1021] Example DA: 2-(4-{[6-(difluoromethyl)-3-pyridyl](4-ethyl-3-pyridyl)amino}-1-piperidinyl)-5-pyrimidinecarboxynitrile:

[1022]

[1023] Compound 124: 102 mg; 1H NMR (400 MHz, CD3OD) d 8.60 (s, 2H), 8.50 (m,1H), 8.30 (s, 1H), 7.85 (d, 1H), 7.60 (d, 1H), 7.50 (d, 1H), 7.15 (d, 1H), 6.60 (m, 1H), 5.05 (m, 2H), 4.55 (m, 1H), 3.20 (m, 2H), 2.6 (m, 2H), 2.15 (m,2H), 1.35 (m, 2H), 1.15 (t, 3H); LCMS (ESI) [M+H]+ = 436.

[1024] Example DB: (R)-4-{4-[(p-difluoromethoxyphenyl)(4-methoxy-3-pyridyl)amino]-1-piperidinyl}-1-ethyl-2-pyrrolidone:

[1025]

[1026] Compound 126: 84 mg; 1 H NMR (400 MHz, CDCl3) d 8.50 (d, 1H), 8.2 (s, 1H), 6.95 (m, 3H), 6.18 -6.55 (br. m, 3H), 3.85 (m, 1H), 3.70 (s, 3H), 3.45 (m,2H), 3.30 LCMS (ESI) LCMS (ESI) [M+H]+ = 461.

[1027] Example DC: [1-(5-Methylsulfonyl-2-pyrimidinyl)-4-piperidinyl](4-methyl-3-pyridinyl)[p-(trifluoromethyl)phenyl]amine:

[1028]

[1029] Compound 127: 147 mg; 1H NMR (400 MHz, DMSO-d6) d 8.7 (s, 2H), 8.49 (d,1H), 8.3 (s, 1H), 7.45 (m, 3H), 6.60 (d, 2H), 4.85 (m, 2H), 4.50 (m, 1H), 3.25 (m, 2H), 3.1 (s, 3H), 2.1 (s, 3H), 2.05 (m, 2H), 1.25 (m, 2H) LCMS (ESI)[M+H]+ = 492.

[1030] Example DD: 5-{4-[(4-methyl-3-pyridyl)[p-(trifluoromethyl)phenyl]amino]-1-piperidinyl}-2-pyrimidinecarboxynitrile:

[1031]

[1032] Compound 128: 192 mg; 1 H NMR (400 MHz, DMSO-d6) d 8.55 (s, 2H), 8.3 (m,2H), 7.45 (m, 3H), 6.60 (m, 2H), 4.45 (m, 1H), 4.15 (m, 2H), 3.15 (m, 2H), 2.15 (s, 3H), 2.0 (m, 2h), 1.35 (m, 2H); LCMS (ESI) [M+H]+ = 439.

[1033] Example DE: (S)-1'-Ethyl-4-[(4-methoxy-3-pyridyl)[p-(trifluoromethyl)phenyl]amino][1,3'-bipiperidinyl]-6'-one:

[1034]

[1035] Compound 129: 108 mg; 1H NMR (400 MHz, CD3OD) d 8.55 (d, 1H), 8.25 (m,2H)< 7.45 (d, 2H), 7.30 (d, 1H), 6.65 (d, 2H), 4.2 (m, 1H), 3.92 (s, 3H),3.05-3.55 (br. LCMS (ESI) [M+H]+ = 477.

[1036] Example DF: [4-( 2 H3)Methoxy(2,5,6- 2 [H3)-3-pyridyl][1-(2-methyl-5-pyrimidinyl)-4-piperidinyl][p-(trifluoromethyl)phenyl]amine:

[1037]

[1038] Compound 130: 230 mg; 1 H NMR (400 MHz, CD3OD) d 8.32 (s, 2H), 7.41 (d,2H), 6.65 (d, 2H), 4.21 (m, 1H), 3.82 (m, 2H), 3.0 (m, 2H), 2.55 (s, 3H), 2.15 (m, 2H), 1.52 (m, 2H); LCMS (ESI) [M+H]+ = 450.

[1039] Example DG: (p-difluoromethoxyphenyl)[1-(5-methyl-2-pyrimidinyl)-4-piperidinyl][4-( 2 H3)Methoxy(2,5,6- 2 [H3)-3-pyridyl]amine:

[1040]

[1041] Compound 131: 300 mg; 1H NMR (400 MHz, CD3OD) d 8.62 (s, 2H), 6.95 (d,2H), 6.60 (m, 3H), 4.95 (m, 2H), 4.30 (m, 1H), 3.15 (m, 2H), 3.10 (s, 3H), 2.12 (m, 2H), 1.32 (m, 2H); LCMS (ESI) [M+H]+ = 512.

[1042] Example DH: [4-( 2 [H3)methoxy-3-pyridyl][1-(2-methyl-5-pyrimidinyl)-4-piperidinyl][p-(trifluoromethyl)phenyl]amine:

[1043]

[1044] Compound 132: 185 mg; 1 H NMR (400 MHz, CD3OD) d 8.5 (d, 1H), 8.40 (s,2H), 8.25 (s, 1H), 7.45 (d, 2H), 7.25 (d, 1H), 6.65 (d, 2H), 4.25 (m, 1H), 3.82 (m, 2H), 2.95 (m, 2H), 2.55 (s, 3H), 2.15 (m, 2H), 1.55 (m, 2H); LCMS(ESI) [M+H]+ = 447.

[1045] Example DI: (p-Difluoromethoxyphenyl)[1-(5-methyl-2-pyrimidinyl)-4-piperidinyl][4-( 2 [H3)methoxy-3-pyridyl]amine:

[1046]

[1047] Compound 133: 300 mg; 1 H NMR (400 MHz, CD3OD) d 8.85 (s, 2H), 8.56 (d,1H), 8.32 (s, 1H), 7.4 (d, 1H), 7.15 (d, 2H), 6.8 (m, 3H), 5.20 (m, 2H), 4.52(m, 1H), 3.35 (m, 2H), 3.28 (s, 3H), 2.45 (m, 2H), 1.50 (m, 2H); LCMS (ESI)[M+H]+ = 509.

[1048] Example DJ: 2-{1-hydroxy-4-[(4-methoxy-3-pyridyl)[p-(trifluoromethyl)phenyl]amino]cyclohexyl}-5-pyrimidinecarboxynitrile:

[1049]

[1050] Compound 134-Isomer 1: 80 mg; 1 H NMR (400 MHz, CD3CN) d 9.1 (s, 2H), 8.52(d, 1H), 8.28 (d, 1H), 7.40 (d, 2H), 7.15 (d, 1H), 6.61 (d, 2H), 4.15 (m,1H), 3.85 (m, 1H), 3.70 (s, 3H), 2.5 (m, 2H), 2.0 (m, 2H), 1.85 (m, 2H), 1.32(m, 2H); LCMS (ESI) [M+H]+ = 470.

[1051]

[1052] Compound 134-isomer 2: 78 mg; 1 H NMR (400 MHz, CD3CN) d 9.1 (s, 2H), 8.52(d, 1H), 8.28 (d, 1H), 7.40 (d, 2H), 7.15 (d, 1H), 6.61 (d, 2H), 4.15 (m,1H), 4.05 (m, 1H), 3.80 (s, 3H), 2.22 (m, 2H), 2.02 (m, 2H), 1.6-1.8 (br. m,4H); LCMS (ESI) [M+H]+ = 470.

[1053] Example DK: 2-{4-[(p-difluoromethoxyphenyl)(4-methoxy-3-pyridyl)amino]-1-hydroxycyclohexyl}-5-pyrimidinecarboxynitrile:

[1054]

[1055] Compound 135-isomer 1: 36 mg; 1H NMR (400 MHz, CD3OD) d 9.1 (s, 2H), 8.35 (d, 1H), 8.06 (s, 1H), 7.10 (d, 1H), 6.9 (m, 2H), 6.56 (m, 3H), 4.12 (m, 1H), 3.75 (s, 3H), 2.66 (m, 2H), 1.97 (m, 2H), 1.85 (m, 2H), 1.29 (m, 2H); LCMS(ESI) [M+H]+ = 468.

[1056]

[1057] Compound 135-isomer 2: 60 mg; 1 H NMR (400 MHz, CD3OD) d 9.01 (s, 2H),8.51 (br. s, 1H), 8.32 (br. s, 1H), 6.97 (m, 3H), 6.2-6.6 (br. m, 3H), 4.0(m, 2H), 3.8 (s, 3H), 2.24 (m, 2H), 2.04 (m, 2H), 1.78 (m, 4H); LCMS (ESI) [M+H]+ = 468.

[1058] Examples of bioassays

[1059] Mouse OPC preparation

[1060] To assess the effects of treatments on OPCs, all treatments were measured in two or more independent platings of ectoderm stem cell-derived OPCs (EpiSCs). EpiSC-derived OPCs were obtained using the previously described in vitro differentiation protocol and culture conditions (Najm et al., 2011, Nature Methods). OPCs were amplified and frozen in aliquots. OPCs were thawed to growth conditions and passaged at least once before use for further assays.

[1061] Compound EC 50 Determining the value

[1062] A: OPC morphology screening

[1063] The ability of each compound to induce mouse OPCs to mature into oligodendrocytes was evaluated. EpiSC-derived OPCs were grown and expanded in N2B27 medium (DMEM / F12 (Gibco), N2-MAX (R&D Systems), B-27 (ThermoFisher), and GlutaMax (Gibco)) supplemented with FGF2 (10 µg / mL, R&D Systems, 233-FB-025) and PDGF-AA (10 µg / mL, R&D Systems, 233-AA-050) in poly-L-ornithine (PO) and laminin-coated flasks, and then harvested for experiments. Cells were grown at 150,000 / cm². 2 Cells were seeded at a density of [insert density here] into growth factor-free N2B27 medium in CellCarrier Ultra (PerkinElmer) plates (Sigma, L2020) coated with poly-L-ornithine or poly-D-lysine and laminin. For dose-response assays, 1000x of the compound stock solution in dimethyl sulfoxide (DMSO) was added to the assay plates to generate an 8-point dose curve. Each assay plate included a positive control and a DMSO mediator control. Cells were incubated for 3 days under standard conditions (37°C, 5% CO2) and fixed for 20 minutes with 4% paraformaldehyde (PFA) in phosphate-buffered saline (PBS). The fixed plates were washed with PBS, permeabilized with 0.1% Triton X-100, and blocked for 40 minutes with 10% donkey serum (v / v) in PBS. Then, cells were labeled overnight at 4°C with MBP antibody (Abcam, ab7349; 1:200), washed with PBS, and stained with Alexa Fluor-conjugated secondary antibody (1:500) for 45 minutes. Cell nuclei were visualized by DAPI staining (Sigma; 1 g / ml), followed by further washing with PBS.

[1064] B: High-content imaging and analysis

[1065] Cells and cell culture plates were imaged on the Operetta High Content Imaging and Analysis System (PerkinElmer). Analysis (PerkinElmer Harmony and Columbus software) first identified intact nuclei stained with DAPI. Then, the perinuclear region of each cell was cross-referenced with mature myelin (MBP) staining to identify oligodendrocyte nuclei, and the percentage of oligodendrocytes was calculated from this. EC was calculated using the Levenberg–Marquardt algorithm.50 Values ​​were used to fit the Hill equation to an 8-point dose-response curve. The results are provided in Table 3 (OPC EC). 50 ).

[1066] Efficacy and determination of enzyme targets

[1067] Sterol analysis based on GC / MS

[1068] A: Analysis and determination of rat sterols

[1069] The ability of each compound to induce the accumulation of key sterol intermediates in the cholesterol biosynthetic pathway was evaluated. Sterols were monitored using a modified Folch washing protocol (Hubler et al., 2018, Nature). EpiSC-derived OPCs were seeded at 100,000 cells per well in PO and laminin-coated 96-well plates in growth factor-free N2B27 medium. After 24 hours, the cells were washed with saline and the plates were frozen. Cholesterol-d7 standards were then added to each well, dried under a nitrogen stream, and derivatized with 55 µl of bis(trimethylsilyl)trifluoroacetamide. Following derivatization, 2 µl of the derivatized material was analyzed by gas chromatography / mass spectrometry using an Agilent 5973 network quality-selective detector equipped with a 6890 gas chromatography system and an HP-5MS capillary column (30 m x 0.25 mm x 0.25 mm). Samples were analyzed in full-scan mode using electron impact ionization; ion fragment peaks were integrated to calculate sterol abundance and quantified relative to cholesterol-d7. Each metabolite was quantified using the following ion fragments: cholesterol-d7 (465), FF-Mas (482), cholesterol (368), dihydroyamsterol (458), yamsterol (456), demosterol (456, 343), 7-dehydrocholesterol (456, 325), lanosterol (393), 7-encholesterol (458), 14-dehydrodihydroyamsterol (456, 351), and dihydrolanosterol (395). For reference, Table 2 shows the sterol GC-MS analytes and their relationships with cholesterol biosynthesis inhibitors. Unless otherwise stated, all standards were obtained from Avanti PolarLipids. Calibration curves were generated by injecting different concentrations of sterol standards while maintaining a constant level of cholesterol-D7. For normalized lanosterol accumulation results, the total lanosterol measured after drug treatment was divided by the total lanosterol accumulated 24 hours after treatment with the 100 nM positive control reference. EC was calculated using the Levenberg–Marquardt algorithm. 50The values ​​were used to fit the Hill equation to an 8-point dose-response curve. The EC50 of lanosterol was... 50 Value (mouse GCMS EC) 50 (This information is provided in Table 3.)

[1070] Table 2. Sterol Analytes

[1071]

[1072] B: Human sterol analysis and determination

[1073] The ability of each compound to induce the accumulation of key sterol intermediates in the cholesterol biosynthesis pathway was evaluated in human cells. Sterols were monitored using a modified Folch washing protocol (Hubler et al., 2018, Nature). Human mesenchymal stem cells (hMSCs) were seeded at 50,000 cells per well in Nunc microplates in a high-performance hMSC culture kit (RoosterBio). After 24 hours, the cells were washed with saline and the plates were frozen. Cholesterol-d7 standard was then added to each well, dried under a nitrogen stream, and derivatized with 55 µl of bis(trimethylsilyl)trifluoroacetamide. Following derivatization, 2 µl of the derivatized material was analyzed by gas chromatography / mass spectrometry using an Agilent 5973 network quality-selective detector equipped with a 6890 gas chromatography system and an HP-5MS capillary column (30 m x 0.25 mm x 0.25 mm). Samples were analyzed in full-scan mode using electron impact ionization; ion fragment peaks were integrated to calculate sterol abundance and quantified relative to cholesterol-d7. Each metabolite was quantified using the following ion fragments: cholesterol-d7 (465), FF-Mas (482), cholesterol (368), dihydroyamsterol (458), yamsterol (456), demosterol (456, 343), 7-dehydrocholesterol (456, 325), lanosterol (393), 7-encholesterol (458), 14-dehydrodihydroyamsterol (456, 351), and dihydrolanosterol (395). For reference, Table 2 above shows the sterol GC-MS analytes and their relationships with cholesterol biosynthesis inhibitors. Unless otherwise stated, all standards were obtained from Avanti Polar Lipids. Calibration curves were generated by injecting different concentrations of sterol standards while maintaining a constant level of cholesterol-D7. For normalized lanosterol accumulation results, the total lanosterol measured after drug treatment was divided by the total lanosterol accumulated 24 hours after treatment with a 100 nM positive control reference. EC was calculated using the Levenberg–Marquardt algorithm.50 The values ​​were used to fit the Hill equation to an 8-point dose-response curve. The EC50 of lanosterol was... 50 Value (human GCMS EC) 50 (See Table 3 for details.)

[1074] Table 3. Measured values

[1075]

[1076] Efforts have been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but some experimental errors and biases should be taken into account.

[1077] Those skilled in the art will recognize that many methods and materials similar to or equivalent to those described and materials herein can be used to implement the subject matter described herein. This disclosure is by no means limited to the methods and materials described herein.

[1078] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject pertains, and are consistent with the following references: Singleton et al. (1994) Dictionary of Microbiology and Molecular Biology, 2nd ed., J. Wiley & Sons, New York, NY; and Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immunobiology, 5th ed., Garland Publishing, New York.

[1079] In this specification and claims, unless the context otherwise requires, the words “comprising,” “including,” and “containing” are used in a non-exclusive sense. It should be understood that the embodiments described herein include “consisting of the embodiments” and / or “substantially consisting of the embodiments.”

[1080] If a range of values ​​is provided, it should be understood that it includes every intermediate value between the upper and lower limits of the range (to one-tenth of the unit of the lower limit, unless the context explicitly specifies otherwise), as well as any other specified value or intermediate value within the specified range. It also includes the upper and lower limits of these smaller ranges that can be independently included within the smaller range, based on any explicitly excluded limits within the specified range. Where the specified range includes one or two limits, it also includes the range excluding one or both of those included limits.

[1081] Many variations and other embodiments set forth herein will come to mind for those skilled in the art to which this subject matter pertains, taking advantage of the teachings presented in the foregoing description and the accompanying drawings. Therefore, it should be understood that this subject matter is not limited to the specific embodiments disclosed, and that variations and other embodiments are intended to be included within the scope of the appended claims. Although specific terminology is used herein, it is used only in a general and descriptive sense and not for limiting purposes.

Claims

1. A compound of Formula A: wherein, A is selected from the group consisting of Ci-C6alkyl, C3-C8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl, each of which is optionally substituted with one or more of R A1 , R A2 , and R A3 , wherein R A1 , R A2 and R A3 are each independently selected from the group consisting of C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo, cyano, oxo, -C(O)-R A4 , -S(O)-R A4 and -S(O)2-R A4 , wherein R A4 is C1-C6 alkyl or C3-C8 cycloalkyl, and wherein said oxo, if present, is formed by R A1 , R A2 and R A3 together with the carbon to which each is attached; G is -CH, C-OH, or N; E, if present, is -C(O)- or -O-; Y is -CH or N; p is 1, 2, or 3; q is 1 or 0; r is 1 or 0; wherein when r is 0, A is not C1-C6 alkyl; R 1 R1is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, and halo-C1-C6 alkyl; or R 1 is halo, and q is 0; R 1a selected from the group consisting of hydrogen, halo, Ci-C6alkyl; R 2 halo, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, and -S(0)2-(Ci-C6 alkyl); R 2a selected from the group consisting of hydrogen and halo; and, R 3 R is hydrogen, halo or C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula I, Formula A-i, or Formula A-ii:

3. The compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula I: wherein, R A1 , R A2 and R A3 are each independently selected from the group consisting of Ci-C6alkyl, halo-Ci-C6alkyl, halo, cyano, oxo, -C(O)-R A4 , -S(O)-R A4 and -S(O)2-R A4 ; G is -CH or N; and R 1 Ci-C6-alkyl, C3-C8-cycloalkyl, and halo-Ci-C6-alkyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt or solvate thereof, wherein G is N, and the compound has the structure of Formula I':

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C1-C6alkyl or C3-C8cycloalkyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is methyl, ethyl, or cyclopropyl.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula la, lb, or Ic:

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is N.

11. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -CH.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halo-Ci-C6 alkyl or halo-Ci-C6 alkoxy.

13. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halo-Ci-C6 alkyl.

14. The compound of claim 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -CF3.

15. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halo-Ci-C6alkoxy.

16. The compound of claim 15, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -O-CHF2.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1 or 2.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

19. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C1-C6 alkyl.

21. The compound of claim 20, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is methyl.

22. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is hydrogen.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein r is 1.

24. The compound of claim 23, or a pharmaceutically acceptable salt or solvate thereof, wherein A is C1-C6 alkyl.

25. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof, wherein A is -CH3 or -CH2CH3.

26. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein r is 0.

27. The compound of claim 23 or 26, or a pharmaceutically acceptable salt or solvate thereof, wherein G is -CH.

28. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein A is C3-C5 cycloalkyl, optionally substituted with one or more of R A1 , R A2 , and R A3 .

29. The compound of claim 28, or a pharmaceutically acceptable salt or solvate thereof, wherein A is , , or .

30. The compound of claim 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R A1 is cyano or halo-Ci-C6 alkyl.

31. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R A1 is -CF3.

32. The compound of claim 23 or 26, or a pharmaceutically acceptable salt or solvate thereof, wherein A is phenyl, which is optionally substituted with one or more of R A1 , R A2 , and R A3 .

33. The compound of claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein A is phenyl, which is optionally substituted with one or more of R A1 and R A2 .

34. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein A is 。 35. The compound of claim 34, or a pharmaceutically acceptable salt or solvate thereof, wherein R A1 is -S(O)2-R A4 ; and R A2 is halo.

36. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein A is 。 37. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein R A1 is selected from the group consisting of halo, cyano, -S(O)2-R A4 and -C(O)-R A4 .

38. The compound of claim 23 or 26, or a pharmaceutically acceptable salt or solvate thereof, wherein A is 5- to 6-membered heterocyclyl, optionally substituted with one or more of R A1 , R A2 , and R A3 .

39. The compound of claim 38, or a pharmaceutically acceptable salt or solvate thereof, wherein the heterocyclyl comprises 1 or 2 heteroatoms selected from the group consisting of N, S, and O.

40. The compound of claim 38, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a 5- to 6-membered heterocyclyl.

41. The compound of claim 40, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a 5- to 6-membered heterocyclyl comprising 1 or 2 heteroatoms selected from the group consisting of N, S, and O.

42. The compound of claim 41, or a pharmaceutically acceptable salt or solvate thereof, wherein A is or .

43. The compound of claim 23 or 26, or a pharmaceutically acceptable salt or solvate thereof, wherein A is 5- to 6-membered heteroaryl, which is optionally substituted with one or more of R A1 , R A2 , and R A3 .

44. The compound of claim 43, or a pharmaceutically acceptable salt or solvate thereof, wherein A is selected from the group consisting of pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, and thiazolyl, optionally substituted with one or more of R A1 , R A2 , and R A3 .

45. The compound of claim 44, or a pharmaceutically acceptable salt or solvate thereof, wherein A is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, oxadiazolyl, and pyrrolyl, optionally substituted with one or more of R A1 , R A2 , and R A3 .

46. The compound of claim 45, or a pharmaceutically acceptable salt or solvate thereof, wherein A is pyridyl, which is optionally substituted with one or more of R A1 , R A2 , and R A3 .

47. The compound of claim 46, or a pharmaceutically acceptable salt or solvate thereof, wherein A is substituted pyridyl. A1 substituted pyridyl.

48. The compound of claim 47, or a pharmaceutically acceptable salt or solvate thereof, wherein A is , , or .

49. The compound or pharmaceutically acceptable salt or solvate thereof of claim 48, wherein R A1 is selected from the group consisting of C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, and -S(O)2-R A4 .

50. The compound of claim 45, or a pharmaceutically acceptable salt or solvate thereof, wherein A is pyrimidinyl or pyrazinyl, optionally substituted with one or more of R A1 , R A2 , and R A3 .

51. The compound of claim 50, or a pharmaceutically acceptable salt or solvate thereof, wherein A is pyrimidinyl or pyrazinyl, optionally substituted with R A1 .

52. The compound of claim 51, or a pharmaceutically acceptable salt or solvate thereof, wherein A is , , , , or .

53. The compound or pharmaceutically acceptable salt or solvate thereof of claim 52, wherein R A1 is selected from the group consisting of C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, and -S(O)2-R A4 .

54. The compound of claim 45, or a pharmaceutically acceptable salt or solvate thereof, wherein A is oxadiazolyl and pyrrolyl, optionally substituted with one or more of R A1 , R A2 , and R A3 .

55. The compound of claim 54, or a pharmaceutically acceptable salt or solvate thereof, wherein A is oxadiazolyl and pyrrolyl, which are optionally substituted with R A1 .

56. The compound of claim 55, or a pharmaceutically acceptable salt or solvate thereof, wherein A is or .

57. The compound of claim 56, or a pharmaceutically acceptable salt or solvate thereof, wherein R A1 is C1-C6 alkyl.

58. The compound of claim 38, or a pharmaceutically acceptable salt or solvate thereof, wherein A is or and R A1 is Ci-C6alkyl.

59. The compound or a pharmaceutically acceptable salt or solvate thereof of claim 58, wherein R A1 is ethyl.

60. The compound or pharmaceutically acceptable salt or solvate thereof of claim 43 or 52, wherein R A1 is CH2OCH3.

61. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula Id: wherein: r and q are each 0; R 1a and R 1b each is hydrogen; and R 1 R is halogen.

62. The compound of claim 61, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -Cl.

63. The compound of claim 61 or 62, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is CF3.

64. The compound or pharmaceutically acceptable salt or solvate thereof of any one of claims 61 to 63, wherein R 3 is hydrogen.

65. The compound of any one of claims 61-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is N.

66. The compound of any one of claims 61-65, or a pharmaceutically acceptable salt or solvate thereof, wherein G is N and p is 2.

67. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein E is -0-; r is 1; p is 2; R 1a , R 2a and R 3 are each hydrogen, and the compound has the structure of Formula A-i':

68. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein r is 0; p is 2; R 1a , R 2a and R 3 are each hydrogen, and the compound has the structure of Formula A-ii’:

68. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein r is 0; p is 2; R 1a , R 2a and R 3 are each hydrogen, and the compound has the structure of Formula A-ii’:

68. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof 69. The compound of claim 67 or 68, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1 and R 1 is CH3.

70. The compound of any one of claims 67 to 69, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is CF3or OCHF2.

71. The compound of any one of claims 67-70, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is CH.

72. The compound of any one of claims 52 and 61-71, or a pharmaceutically acceptable salt or solvate thereof, wherein A is 。 73. The compound of any one of claims 48 and 61-71, or a pharmaceutically acceptable salt or solvate thereof, wherein A is .

74. The compound of any one of claims 1-73, wherein one or more hydrogen atoms are replaced by deuterium.

75. The compound of claim 74, having the structure of Formula A-iii:

76. The compound of claim 74 or 75, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -CD3.

77. The compound of claim 1, 2, or 3, selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof.

78. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof.

79. A pharmaceutical composition, comprising: a compound of any one of claims 1-78, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

80. A method of promoting myelination in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-78, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 79.

81. A compound of any one of claims 1-78, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 79, for use in treating a condition in a subject in need thereof.

82. A compound of any one of claims 1-78, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 79, for use in promoting myelination in a subject in need thereof.

83. Use of a compound of any one of claims 1-78, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 79, in the manufacture of a medicament for treating a condition in a subject in need thereof.

84. Use of a compound of any one of claims 1-78, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 79, in the manufacture of a medicament for promoting myelination in a subject in need thereof.

85. The method of claim 80, wherein the subject has a myelin-related condition.

86. The compound for use of claim 81 or 82, wherein the subject has a myelin-related condition.

87. The use of claim 83 or 84, wherein the subject has a myelin-related condition.

88. The method of claim 85, the compound for use of claim 86, or the use of claim 87, wherein the myelin-related disorder is multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophy, white matter injury in the newborn, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander disease, Pelizaeus-Merzbacher disease (PMD), vanishing white matter disease, Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, spinal cord injury, traumatic brain injury, post-radiation injury, neurological complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Mal de Meleda, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barre syndrome, Charcot-Marie-Tooth disease, Bell’s palsy, or radiation-induced demyelination.

89. The method of claim 85, the compound for use of claim 86, or the use of claim 87, wherein the disorder is multiple sclerosis.

90. A method of inhibiting CYP51 (lanosterol demethylase), comprising contacting CYP51 with a compound of any one of claims 1-78, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 79.

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