Uses of tertiary pyridylamine modulators in cholesterol biosynthesis and for promoting remyelination

Abstract

The subject matter described herein relates to myelin-promoting compounds of formula A and their pharmaceutically acceptable salts, methods for preparing the compounds, pharmaceutical compositions comprising the compounds, and methods for administering the compounds to treat disorders such as myelin-related disorders. In certain embodiments, the subject matter described herein relates to a method for promoting myelin formation in a subject requiring myelin formation promotion, comprising administering to the subject an effective amount of a compound of formula A or formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of formula A or formula I or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable additive. In certain embodiments, the subject has a myelin-related disorder. TIFF2026530180000305.tif65126

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 579,221, filed on 28 August 2023, the contents of which are incorporated in their entirety by reference for all purposes.

[0002] field The subject matter described herein relates to myelin-promoting compounds of formula I, methods for producing such compounds, pharmaceutical compositions thereof, and their use in the treatment of myelin-related disorders. [Background technology]

[0003] background Myelin-related disorders are disorders that result in abnormalities of the myelin sheath (e.g., hypomyelination, demyelination, and hypomyelination) in the nerve cells of the affected area, such as CNS neurons including their axons. The loss or breakdown of the myelin sheath in such disorders results in delayed or cessation of nerve cell conduction. The resulting myelin-related disorders are characterized by deficits in sensory, motor, cognitive, or other physiological functions. Myelin-related disorders include multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, childhood leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander disease, Pelizaeus-Merzbacher disease (PMD), white matter disappearance disease, Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, and Alzheimer's disease. This includes, but is not limited to, Mars' 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, sporadic vitamin E deficiency syndrome, Bassen-Kohnzweig syndrome, Marquiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barré syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination.

[0004] MS is the most common myelin-related disorder, affecting millions of people worldwide and causing an estimated 18,000 deaths annually. MS is a complex neurological disorder characterized by the deterioration of central nervous system (CNS) myelin. Myelin, composed mostly of lipids (70% lipids, 30% protein), protects axons, enables saltatory conduction, and accelerates axonal electrical impulses. Demyelination of axons in chronic MS can lead to axonal degeneration and neuronal cell death. Furthermore, MS destroys oligodendrocytes, which are highly specialized CNS cells that produce and maintain myelin. A repair process called remyelination occurs in the early stages of the disease, but over time, oligodendrocytes become unable to fully rebuild and restore the myelin sheath. Repeated attacks result in successive, less effective remyelination until scar-like plaques accumulate around damaged axons.

[0005] Currently, there is no treatment for myelin-related disorders, and current treatments do not prevent the progression of MS. Therefore, new therapeutic approaches to address myelin-related disorders, including promoting remyelination, are needed. The subject matter described herein addresses this unmet need. [Overview of the project]

[0006] concise summary In certain embodiments, the subject matter described herein is a compound of formula A. [ka] [In the formula, A is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, 5-6 member heteroaryl, and 5-6 member heterocyclyl, and each of these is R A1 , R A2 and R A3 It is arbitrarily replaced with one or more of the following: R A1 , R A2 and R A3each independently represents 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 selected from the group consisting of, R A4 is C1-C6 alkyl or C3-C8 cycloalkyl, and when present, said oxo is formed together with the carbon to which each is bonded by two of A1 , R A2 and R A3 ; G is -CH, C-OH, or N; when present, E 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 other than C1-C6 alkyl; R 1 is 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 is selected from the group consisting of hydrogen, halo, and C1-C6 alkyl; R 2 is selected from the group consisting of halo, halo-C1-C6 alkyl, halo-C1-C6 alkoxy and -S(O)2-(C1-C6 alkyl); R 2a is selected from the group consisting of hydrogen and halo; and R 3 is hydrogen, halo, or C1-C6 alkyl] or a pharmaceutically acceptable salt or solvate thereof.

[0007] In certain embodiments, the subject matter described herein relates to a compound of formula I [ka] [In the formula, A is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, 5-6 member heteroaryl, and 5-6 member heterocyclyl, and each of these is R A1 , R A2 and R A3 It is arbitrarily replaced with one or more of the following: R A1 , R A2 and R A3 These are, independently, C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, oxo, and -C(O)-R. A4 ,-S(O)-R A4 and -S(O)2-R A4 Selected from the group consisting of, R A4 These are C1-C6 alkyl or C3-C8 cycloalkyl, and If the aforementioned oxo exists, R A1 , R A2 and R A3 Two of them are formed together with the carbon atoms to which they are bonded; G is either -CH or N; Y is either -CH or N; p is 1, 2, or 3; q is either 1 or 0; r is either 1 or 0; Here, if r is 0, then A is not a C1-C6 alkyl group; R 1 This is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, and halo-C1-C6 alkyl; R 1a This is selected from the group consisting of hydrogen, halo, and C1-C6alkyl; R 2 This is selected from the group consisting of halo, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and -S(O)2-(C1-C6 alkyl); R 2ais selected from the group consisting of hydrogen and halos; and R 3 [These are hydrogen, halos, or C1-C6 alkyl groups.] or relating to pharmaceutically acceptable salts or solvates thereof.

[0008] In certain embodiments, the subject matter described herein relates to pharmaceutical compositions comprising a compound of formula A or formula I or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive.

[0009] In certain embodiments, the subject matter described herein relates to a method for promoting myelin formation in a subject requiring myelin formation promotion, comprising administering to the subject an effective amount of a compound of formula A or formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of formula A or formula I or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable additive. In certain embodiments, the subject has a myelin-related disorder.

[0010] In certain embodiments, the subject matter described herein relates to a pharmaceutical composition for use in treating myelin-related disorders, comprising a compound of formula A or formula I or a pharmaceutically acceptable salt or solvate thereof, or a compound of formula A or formula I or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive.

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

[0012] In certain embodiments, the subject matter described herein relates to methods for preparing compounds of formula A or formula I or pharmaceutically acceptable salts or solvates thereof.

[0013] In certain embodiments, the subject matter described herein relates to a method for inhibiting CYP51 (lanosterol demethylase), comprising contacting CYP51 with a compound of formula A or formula I or a pharmaceutically acceptable salt or solvate thereof, or with a pharmaceutical composition comprising a compound of formula A or formula I or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable additive.

[0014] Other embodiments are also described. [Modes for carrying out the invention]

[0015] Detailed explanation Myelin-promoting compounds of formulas A and I, methods for producing the compounds, pharmaceutical compositions thereof, and their use in the treatment of myelin-related disorders are described herein.

[0016] Enhancement and / or induction of the accumulation of Δ8,9-unsaturated sterol intermediates in the cholesterol biosynthesis pathway in oligodendrocyte progenitor cells (OPCs) may induce oligodendrocyte formation. Enhancement and / or induction of Δ8,9-unsaturated sterol intermediate accumulation can be provided by enhancing and / or inducing the accumulation of Δ8,9-unsaturated sterol intermediates and / or regulating and / or inhibiting enzymes in the cholesterol biosynthesis pathway in OPCs for which Δ8,9-unsaturated sterol intermediates are substrates, as well as by directly and / or indirectly administering Δ8,9-unsaturated sterol intermediates to OPCs. Enhancement and / or induction of Δ8,9-unsaturated sterol intermediate accumulation can promote OPC differentiation, survival, proliferation and / or maturation, and can treat diseases and / or disorders of subjects for which myelination is beneficial.

[0017] Therefore, in some embodiments, agents such as compounds of formula A or I or pharmaceutically acceptable salts or solvates thereof, which can enhance and / or induce the accumulation of Δ8,9-unsaturated sterol intermediates in the cholesterol biosynthesis pathway in OPCs, can be administered to subjects and / or OPCs in amounts effective for promoting and / or inducing OPC differentiation, proliferation and / or maturation, and oligodendrocyte formation. In certain embodiments, the agent, for example, compounds of formula A or I or pharmaceutically acceptable salts or solvates thereof, is a compound that inhibits the enzymatic synthesis of one or more sterol intermediates in the cholesterol biosynthesis pathway of OPCs and / or promotes the accumulation of Δ8,9-unsaturated sterol intermediates.

[0018] In certain embodiments, compounds of formula A or formula I, or pharmaceutically acceptable salts or solvates thereof, can modulate and / or inhibit one or more enzyme-mediated conversion steps in the cholesterol biosynthesis pathway, such as the lanosterol-to-cholesterol pathway (e.g., between lanosterol and / or lathosterol), and modulating and / or inhibiting one or more of these steps in OPCs can promote and / or induce oligodendrocyte formation. For example, compounds of formula A or formula 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 certain embodiments, compounds of formula A or formula I can inhibit CYP51, sterol 14 reductase, and / or EBP. In certain embodiments, compounds of formula A or formula I can inhibit CYP51.

[0019] For example, in certain 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 certain embodiments, the compound of formula I used in the methods described herein can inhibit sterol C14 reductase enzyme activity in the cholesterol biosynthesis pathway, or inhibit the enzyme-mediated conversion of thymothenol to lathosterol by inhibiting emopamyl-binding protein (EBP) isomerase enzyme activity.

[0020] CYP51 belongs to the cytochrome P450 (CYP) monooxygenase superfamily and mediates essential steps in the sterol biosynthesis pathway. The CYP51 protein is the most conserved protein in the CYP superfamily. Unlike other CYP enzymes, CYP51 has strong substrate specificity. CYP51 catalyzes the demethylation of a narrow range of substrates, including lanosterol and 24,25-dihydrolanosterol. The CYP51 protein, also known as sterol 14α-demethylase, is the only invariant P450 present in all sterol biosynthesis pathways.

[0021] While not bound by any particular theory, compounds of formulas A and I, or their pharmaceutically acceptable salts or solvates, are thought 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 OPCs, resulting in enhanced and / or induction of Δ8,9-unsaturated sterol intermediate accumulation. In some embodiments, enhanced and / or induction of Δ8,9-unsaturated sterol intermediate accumulation can promote OPC differentiation, survival, proliferation, and / or maturation, and can treat diseases and / or disorders of subjects where myelination or myelination development is beneficial to the subject. This mechanism of promoting myelination is distinct from the primary action of immunomodulators often used to treat myelin-related disorders.

[0022] Herein, the subject matter disclosed herein is fully described below. However, those skilled in the art will be able to conceive of many modifications and other embodiments of the subject matter disclosed herein, taking advantage of the benefits of the teachings presented in the foregoing description. Therefore, it should be understood that the subject matter disclosed herein should not be 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 substitutes, modifications and equivalents. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All publications, patent applications, patents, and other references referred to herein are incorporated in their entirety by reference. If one or more of the incorporated documents, patents, and similar materials differ from or conflict with this application, including, but not limited to, the terms defined, the usage of terms, the technology described, etc., this application shall prevail.

[0023] I. Definition Where used herein, the following words, phrases, and symbols are intended to have the meanings set forth below in general, except to the extent that the context in which they are used indicates otherwise.

[0024] A dash ("-") without a space between two letters or symbols is used to indicate the bonding point of a substituent. For example, -C(O)NH2 is bonded via a carbon atom. Dashes at the beginning or end of a chemical group are for convenience. Chemical groups may be shown with or without one or more dashes without losing their usual meaning. A wavy or dashed line drawn perpendicularly through or across the end of a line in a structure indicates a designated attachment point of a group. Unless chemically or structurally required, the order in which chemical groups are listed or named does not indicate or imply orientation or stereochemistry.

[0025] Prefix “C” u -Cv The notation "&" indicates that the following group has u to v carbon atoms. For example, "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0026] References to values ​​or parameters preceded by “approximately” in this specification include (and are described) embodiments relating to the value or parameter itself. In certain embodiments, the term “approximately” includes ±50% of the indicated amount. In certain other embodiments, the term “approximately” includes ±20% of the indicated amount. In certain other embodiments, the term “approximately” includes ±10% of the indicated amount. In other embodiments, the term “approximately” includes ±5% of the indicated amount. In certain other embodiments, the term “approximately” includes ±1% of the indicated amount. In certain other embodiments, the term “approximately” includes ±0.5% of the indicated amount, and in certain other embodiments, 0.1%. Such variations are appropriate for carrying out the disclosed method or for using the disclosed composition. Also, the term “approximately x” includes the description of “x.” Also, the singular forms “a” and “the” include plural references unless otherwise explicitly indicated in the context. Thus, for example, a reference to “compound” includes multiple such compounds, and a reference to “assay” includes a reference to one or more assays and their equivalents known to those skilled in the art.

[0027] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a chain of 1 to 20 carbon atoms (i.e., C1-C1). 20 Alkyl), 1 to 12 carbon atoms (i.e., C1-C 12Alkyl groups have 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, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by its chemical name or identified by its molecular formula, all positional isomers having that number of carbon atoms may be included. 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).

[0028] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups and divalent "aryl" groups may also be referred to as "alkylene" groups, "alkylenyl" groups, "arylene" groups, and "aryrenyl" groups, respectively. Also, unless otherwise specified, when a combination of groups is referred to herein as a single part, for example, arylalkyl or aralkyl, the last group mentioned includes the atom to which that part is bonded to the rest of the molecule.

[0029] "Alkenyl" contains at least one carbon-carbon double bond and 2 to 20 carbon atoms (i.e., C2-C) 20Alkenyls refer to alkyl groups having 2 to 8 carbon atoms (i.e., C2-C8 alkenyls), 2 to 6 carbon atoms (i.e., C2-C6 alkenyls), or 2 to 4 carbon atoms (i.e., C2-C4 alkenyls). Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0030] "Alkynnyl" contains at least one carbon-carbon triple bond and 2 to 20 carbon atoms (i.e., C2-C) 20 Alkynyl refers to an alkyl group having 2 to 8 carbon atoms (i.e., C2-C8 alkynyl), 2 to 6 carbon atoms (i.e., C2-C6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). The term "alkynyl" also includes groups having one triple bond and one double bond.

[0031] "Alkoxy" refers to the group "alkyl-O-" (e.g., C1-C3 alkoxy or C1-C6 alkoxy). Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0032] "Alkylthio" refers to the group "alkyl-S-".

[0033] "Acyl" is the base -C(O)R y It refers to, and in the formula, R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl, each of which may be optionally substituted as defined herein. Examples of acyls include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.

[0034] "Amide" is the group -C(O)NR y Rz The "C-amide" group and the group -NR refer to the "C-amide" group. y C(O)R z It refers to both of the "N-amide" groups, and in the formula, R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl, each of which may be optionally substituted as defined herein, or R y and R z These combine to form heterocyclines, which may be optionally substituted as defined herein.

[0035] "Amino" is the base-NR y R z It refers to, and in the formula, R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0036] "Amidino" is -C(NR y )(NR z 2) refers to, in the formula, R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0037] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including a fused system. As used herein, aryl refers to a ring carbon atom (i.e., C6-C) with 6 to 20 carbon atoms. 20 aryl), 6-12 carbocyclic atoms (i.e., C6-C 12 aryl), or 6-10 carbon ring atoms (i.e., C6-C 10They have an aryl group. Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryls do not include, and never overlap with, heteroaryls as defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl regardless of the bonding site. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl regardless of the bonding site.

[0038] "Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-", for example (C6-C 10 This refers to aryl)-C1-C3 alkyl groups. A non-limiting example of an arylalkyl group is benzyl.

[0039] "Carbamoyl" is based on the base -OC(O)NR y R z The "O-carbamoyl" group and the -NR group refer to the "O-carbamoyl" group and the -NR group. y C(O)OR z It refers to both of the "N-carbamoyl" groups, and in the formula, R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0040] "Carboxyl ester" or "ester" is -OC(O)R x and -C(O)OR x It refers to both, and in the formula, R x is an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0041] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having monocyclic or polycyclic structures, including condensation, crosslinking, and spirocyclic systems. The term "cycloalkyl" refers to a cycloalkenyl group (i.e., a cyclic group having at least one double bond) and at least one sp 3 It comprises a carbocyclic fused ring system having carbon atoms (i.e., at least one non-aromatic ring). As used herein, cycloalkyl refers to a ring with 3 to 20 carbon atoms (i.e., C3-C3). 20 Cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-C 12 Cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-C 10 These groups have cycloalkyl groups, 3 to 8 ring carbon atoms (i.e., C3-C8 cycloalkyl groups), 3 to 7 ring carbon atoms (i.e., C3-C7 cycloalkyl groups), or 3 to 6 ring carbon atoms (i.e., C3-C6 cycloalkyl groups). Examples of monocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic groups include bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, dekalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Furthermore, the term cycloalkyl is intended to encompass any part containing a non-aromatic alkyl ring that can be condensed to an aryl ring, regardless of its bonding to the rest of the molecule. Furthermore, cycloalkyls also include “spirocycloalkyls” when there are two positions for substitution on the same carbon atom (e.g., spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl). As used herein, “halocycloalkyl,” e.g., C3-C7 halocycloalkyl, refers to a C3-C7 cycloalkyl group substituted with one or more halogens.

[0042] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-", for example, (C3-C6 cycloalkyl)-C1-C3 alkyl.

[0043] "Guanidino" refers to -NR y C(=NR z )(NR y R z ), wherein in the formula, each R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl, each of which may be optionally substituted as defined herein.

[0044] "Hydrazino" refers to -NHNH2.

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

[0046] "Imido" refers to the group -C(O)NR y C(O)R z , wherein in the formula, R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl, each of which may be optionally substituted as defined herein.

[0047] "Halogen" or "halo" refers to an atom belonging to Group VIIA of the periodic table, such as fluoro (fluorine), chloro (chlorine), bromo (bromine) or iodo (iodine).

[0048] "Haloalkyl" refers to the unbranched or branched alkyl group defined above, in which one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by halogens. For example, halo-C1-C3 alkyl refers to an alkyl group of 1 to 3 carbon atoms in which at least one hydrogen atom is replaced by a halogen. Halo-C1-C6 alkyl refers to an alkyl group of 1 to 6 carbon atoms in which at least one hydrogen atom is replaced by a halogen. If a residue is substituted with two or more halogens, it may be referred to by using a prefix corresponding to the number of halogen moieties it is bonded to. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halogen groups, which may or may not be the same halogen. Examples of haloalkyls include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0049] A "haloalkoxy" refers to an alkoxy group as defined above in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogens. For example, a halo-C1-C3 alkoxy refers to an alkoxy group of 1 to 3 carbon atoms in which at least one hydrogen atom is replaced by a halogen. A halo-C1-C6 alkoxy refers to an alkoxy group of 1 to 6 carbon atoms in which at least one hydrogen atom is replaced by a halogen. Non-limiting examples of haloalkoxys are -OCH2CF3, -OCF2H, and -OCF3.

[0050] "Hydroxyalkyl" refers to the alkyl group defined above in which one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by hydroxyl groups (e.g., hydroxy-C1-C3-alkyl, hydroxy-C1-C6-alkyl). The term "hydroxy-C1-C3 alkyl" refers to a 1 to 3-carbon alkyl chain in which one or more hydrogen atoms on any carbon are replaced by hydroxyl groups, in particular one carbon atom on one carbon in the chain is replaced by a hydroxyl group. The term "hydroxy-C1-C6 alkyl" refers to a 1 to 6-carbon alkyl chain in which one or more hydrogen atoms on any carbon are replaced by hydroxyl groups, in particular one carbon atom on one carbon in the chain is replaced by a hydroxyl group. Non-limiting examples of hydroxyalkyl include -CH2OH, -CH2CH2OH, and -C(CH3)2CH2OH.

[0051] A "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 heteroatomic groups, provided that the bonding points to the rest of the molecule are via carbon atoms. In certain embodiments, a heteroalkyl 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 heteroatomic groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. As an example, one, two, or three carbon atoms of the alkyl group in a "heteroalkyl" may be independently replaced by the same or different heteroatomic groups. Examples of heteroatomic groups include, but are not limited to, -NR y Examples include -, -O-, -S-, -S(O)-, -S(O)2-, etc., in the formula, R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl, each of which is optionally 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 and the like, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which is optionally substituted as defined herein). In certain embodiments, heteroalkyl can have 1 to 20 carbon atoms, 1 to 15 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms or 1 to 4 carbon atoms, and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0052] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings or multiple fused rings, containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl has 1 to 20 ring carbon atoms (i.e., C1-C 20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-C12A heteroaryl (or a heteroaryl) comprises 3 to 8 carbocyclic atoms (i.e., a C3-C8 heteroaryl) and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. In certain cases, the heteroaryl includes 9 to 10-membered ring systems (i.e., 9 to 10-membered heteroaryls), 5 to 10-membered ring systems (i.e., 5 to 10-membered heteroaryls), 5 to 7-membered ring systems (i.e., 5 to 7-membered heteroaryls), 5 to 6-membered ring systems (i.e., 5 to 6-membered heteroaryls), or 4 to 6-membered ring systems (i.e., 4 to 6-membered heteroaryls), each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl This includes isoquinolyl, isoxazolyl, naphthilidinyl, oxadiazolyl, oxazolyl, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, phenazinyl, phthalazinyl, pteridinyl, prinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of condensed heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl; heteroaryls can be linked via any of the rings in the condensation system.Any aromatic group having one or more fused rings containing at least one heteroatom is considered a heteroaryl, regardless of its bonding to the rest of the molecule (i.e., via any one of the fused rings). Heteroaryls do not encompass and do not overlap with aryls as defined above.

[0053] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-", for example, (5-10 member monocyclic heteroaryl)-C1-C3 alkyl.

[0054] A "heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridging heterocyclyl groups, condensed heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be monocyclic, or may have multiple rings fused, bridging, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of bonding (i.e., it can be bonded via carbon atoms or heteroatoms). Furthermore, the term heterocyclyl is intended to encompass parts containing any non-aromatic ring containing at least one heteroatom, which may be fused to an aryl or heteroaryl ring, regardless of bonding to the rest of the molecule. The term heterocyclyl is also intended to encompass parts containing a cycloalkyl ring fused to a heteroaryl ring, regardless of bonding to the rest of the molecule. Furthermore, the term heterocyclyl is intended to encompass the portion containing a cycloalkyl ring fused to a heterocyclyl ring, regardless of its bonding to the rest of the molecule. As used herein, heterocyclyl refers to a ring containing 2 to 20 carbon atoms (i.e., C2-C2). 20 Heterocyclines), 2 to 12 ring carbon atoms (i.e., C2-C 12 Heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-C10 Heterocyclines), 2-8 ring carbon atoms (i.e., C2-C8 heterocyclines), 3-12 ring carbon atoms (i.e., C3-C 12A heterocyclil has 3 to 8 ring carbon atoms (i.e., a C3-C8 heterocyclil) or 3 to 6 ring carbon atoms (i.e., a C3-C6 heterocyclil) and has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, sulfur, or oxygen. When the heterocyclil ring contains 4 to 6 ring atoms, it is also referred to herein as a 4 to 6 membered heterocyclil. 5 or 6 membered heterocyclils having 5 or 6 ring atoms, respectively, and 5 to 10 membered heterocyclils having 5 to 10 ring atoms are also disclosed herein. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxynyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolidinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolinyl Examples include lyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxylanil, oxetanyl, phenothiazinyl, phenoxadinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianil, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In certain embodiments, the term "heterocyclyl" may include "spiroheterocyclyl" if there are two positions for substitution on the same carbon atom and at least one ring of the spiro system contains at least one heteroatom.Examples of spiro-heterocyclyl rings include, for example, bicyclic and tricyclic rings such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of condensed heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, and heterocyclyls can be linked via any of the rings in the condensed system.

[0055] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0056] "Oxime" is a base-CR y (=NOH) refers to R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl. Each of these may be optionally substituted as defined herein.

[0057] "Oxo" refers to the base (=O).

[0058] "Cyano" refers to the group (-CN).

[0059] "N-oxide" refers to the group (-NO).

[0060] "Thiol" refers to the group (-SH).

[0061] "Sulfonyl" is the group -S(O)2R y It refers to, and in the formula, R yThe group is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. A non-limiting example of a sulfonyl group is -SO2(C1-C6 alkyl), which is referred to herein as alkylsulfonyl. Examples of sulfonyls are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0062] "Sulfinyl" is the group -S(O)R y It refers to, and in the formula, R y These are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0063] "Sulfonamide" is a group with the base -SO2NR y R z and -NR y SO2R z It refers to, and in the formula, R y and R z Each of these is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0064] The terms “optional” or “optionally” mean that the event or situation described thereafter may or may not occur, and that the description includes both cases in which the event or situation occurs and cases in which it does not occur. The term “optionally substituted” means that any one or more hydrogen atoms (e.g., 1 to 5, 1 to 4, or 1 to 3) on the specified atom or group may or may not be replaced by non-hydrogen parts.

[0065] As used herein, the term “substituted” means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl and / or heteroalkyl) in which at least one (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced by bonding to a non-hydrogen atom, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amide, amino, amidino, aryl, aralkyl, azide, and carboxyl. Bamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imide, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamide, thiol, thioxo, N-oxide or -Si(R y )3(in the formula, each R y (These are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl) and are not limited to these.

[0066] In certain embodiments, "substituted" means that one or more (e.g., 1-5, 1-4, or 1-3) hydrogen atoms are independently deuterium, halo, cyano, nitro, azide, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR gS(=O) 1-2 R h -C(=O)R g , -C(=O)OR g , -OC(=O)OR g -OC(=O)R g -C(=O)NR g R h -OC(=O)NR g R h , -OR g , -SR g -S(=O)R g -S(=O)2R g -OS (=O) 1-2 R g -S(=O) 1-2 Ure g , -NR g S(=O) 1-2 NR g R h ,=NSO2R g 、=NOR g -S(=O) 1-2 NR g R h This includes any of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups described above, which are replaced with -SF5, -SCF3, or -OCF3. In certain embodiments, "substituted" also means that one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced with -C(=O)R g , -C(=O)OR g -C(=O)NR g R h ,-CH2SO2R g , or -CH2SO2NR g R h This means any of the above bases that are replaced by R. g and R hThese are the same or different, independently of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, “substituted” also means that one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced by a bond to amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or R g and R h and R i The two groups mentioned above, together with the atom to which they are bonded, form an oxo, halo, or oxo, halo, amino, hydroxyl, or alkoxy-substituted heterocyclyl ring, which is optionally substituted with an alkyl group.

[0067] Polymers or similar non-tertiary structures achieved by defining substituents with an infinitely increasing number of further substituents (e.g., substituted aryls having a substituted alkyl that is itself substituted with a substituted aryl group and further substituted with a substituted heteroalkyl group) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group by two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryls. Similarly, the above definitions are not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term “substituted” may refer to other chemical groups as defined herein.

[0068] In certain embodiments, as used herein, the phrase "one or more" refers to 1 to 5 items. In certain embodiments, as used herein, the phrase "one or more" refers to 1 to 4 items. In certain embodiments, as used herein, the phrase "one or more" refers to 1 to 3 items.

[0069] Any compound or structure given herein is intended to represent both an unlabeled and an isotope-labeled form (isotopolog) of the compound. Compounds in these forms are also called “isotopically enriched analogs” and include “isotopically enriched analogs.” An isotope-labeled compound has the structure shown herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, respectively. 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 is an example. Various isotope-labeled compounds of this disclosure, for example 3 H, 13 C and 14Radioactive isotopes such as 13C are incorporated. Such isotope-labeled compounds may be useful 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 in radioactive treatment of patients.

[0070] The term “isotope-enriched analog” includes “deuterium-containing analogs” of the compounds described herein in which one or more hydrogens are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound when administered to 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 hydrogens are replaced by deuterium.

[0071] The deuterium-labeled or substituted therapeutic compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to adsorption, distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in certain therapeutic benefits arising from greater metabolic stability, e.g., increased in vivo half-life, reduced dose requirements, and / or improved therapeutic index. 18 F, 3 H, 1114C-labeled compounds may be useful in PET or SPECT or other imaging studies. The isotope-labeled compounds of this disclosure can generally be prepared by performing the procedures disclosed in the following schemes or examples and preparations, by using readily available isotope-labeling reagents in place of non-isotope-labeling reagents. In this context, deuterium is understood to be a substituent in the compounds described herein.

[0072] The concentrations of such heavy isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, where a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its naturally occurring isotopic composition. Thus, in the compounds of this disclosure, any atom specifically designated as deuterium(D) is meant to represent deuterium. Furthermore, in some embodiments, corresponding deuterized analogs are provided.

[0073] In many cases, the compounds of this disclosure can form acids and / or base salts in the presence of amino and / or carboxyl groups or similar groups.

[0074] Also provided herein are pharmaceutically acceptable salts, isotopically enriched analogs, deuterized analogs, isomers (such as stereoisomers), and mixtures of isomers (such as mixtures of stereoisomers) of the compounds described herein.

[0075] "Pharmacologically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0076] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. "pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Furthermore, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, in particular a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize the various synthetic methodologies that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Examples of salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of salts derived from organic acids include 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. Examples of salts derived from inorganic bases include sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.Salts derived from organic bases include alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), and tri(substituted alkenyl) Examples of suitable amines include, but are not limited to, salts of primary, secondary, and tertiary amines such as nylamines (i.e., N(substituted alkenyl)3, mono-, di- or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines include, but are not limited to, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0077] The term "hydrate" refers to a complex formed by a combination of the compounds described herein with water.

[0078] A “solvate” refers to the association or complex of one or more solvent molecules with a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. Solvates include hydrates.

[0079] Some of the compounds described herein may exist as tautomers. Tautomers exist in equilibrium with each other. For example, amide-containing compounds may exist in equilibrium with imido acid tautomers. Regardless of which tautomers are shown and the nature of the equilibrium between the tautomers, it will be understood by those skilled in the art that the compounds contain both amide and imido acid tautomers. Thus, amide-containing compounds are understood to contain their imido acid tautomers. Similarly, imido acid-containing compounds are understood to contain their amide tautomers.

[0080] The compounds described herein or their pharmaceutically acceptable salts may contain chiral centers and thus may give rise to other stereoisomeric forms that can be defined in terms of enantiomers, diastereomers, and absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. This disclosure includes all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or they may be resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from optically pure suitable precursors, or resolution of racemic compounds (or racemic salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). If a compound described herein contains an olefinic double bond or other centers due to geometric asymmetry, and unless otherwise specified, the compound is intended to contain both E and Z geometric isomers.

[0081] A "stereoisomer" refers to a compound that is composed of the same atoms bonded together by the same bonds, but has a different three-dimensional structure and is not interchangeable. This disclosure intends various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers that are mirror images of each other and whose molecules cannot be superimposed on each other.

[0082] "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

[0083] The relative centers of the compounds shown herein are graphically indicated using the "thick bond" style (bold lines or parallel lines), and absolute stereochemistry is indicated using wedge bonds (bold lines or parallel lines).

[0084] "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the severity of the disease or condition); b) delaying or stopping the onset 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 (e.g., metastasis) of the disease or condition); and / or c) alleviating the disease or condition, that is, causing regression of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another agent, slowing disease progression, improving quality of life, and / or extending survival).

[0085] "Prevention" or "preventing" means any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. In some embodiments, the compound can be administered to a subject (including humans) who is at risk of the disease or condition or has a family history of the disease or condition.

[0086] "Subject" refers to an animal that has been or will be the subject of treatment, observation, or experimentation, such as a mammal (including humans). The methods described herein may be useful for human therapeutic and / or veterinary use. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0087] The terms “therapeutic effective dose” or “effective dose” of any compound or pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterized analog described herein mean an amount sufficient to perform a treatment when administered to a subject in order to provide a therapeutic benefit such as improvement of symptoms or delay of disease progression. The therapeutic effective dose may vary depending on the subject, the disease or symptoms being treated, the subject’s weight and age, the severity of the disease or symptoms, and the method of administration, which can be readily determined by those skilled in the art. An effective dose of any compound in such a treatment method may be, for example, about 0.01 mg / kg / day to about 1000 mg / kg / day, or about 0.1 mg / kg / day to about 100 mg / kg / day.

[0088] As used herein, the term “additive” means an inert or inactive substance that can be used in the manufacture of a drug or pharmaceutical composition, such as a tablet containing one of the compounds (or pharmaceutically acceptable salts) described herein as an active ingredient. A variety of substances may be included in the term additive, including, but are not limited to, any substance used as a diluent, filler or bulking agent, binder, disintegrant, wetting agent, coating, emulsifier or dispersant, compression / encapsulation aid, cream or lotion, lubricant, parenteral administration solution, material for chewable tablets, sweetener or flavoring agent, suspending / gelling agent, or wet granulator. Binders may include, for example, carbomer, povidone, xanthan gum; coatings may include, for example, cellulose phthalate acetate, ethylcellulose, gellan gum, maltodextrin, enteric coating; compression / encapsulation aids may include, for example, calcium carbonate, dextrose, fructose dc (dc - "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose or microcrystalline cellulose), starch dc, sucrose; disintegrants may include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate; creams or lotions are, for example For example, these include maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, for example, dextrose, fructose dc, lactose (monohydrate, optionally combined with aspartame or cellulose), etc.; suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc. In some cases, the term “additives” encompasses pharmaceutically acceptable carriers.

[0089] Additional definitions may also be provided below as needed.

[0090] II. Compounds In certain embodiments, the subject matter described herein is a compound of formula A. [ka] [In the formula, A is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, 5-6 member heteroaryl, and 5-6 member heterocyclyl, and each of these is R A1 , R A2 and R A3 It is arbitrarily replaced with one or more of the following: R A1 , R A2 and R A3 These are, independently, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo, cyano, oxo, and -C(O)-R. A4 ,-S(O)-R A4 and -S(O)2-R A4 Selected from the group consisting of, R A4 These are C1-C6 alkyl or C3-C8 cycloalkyl, and If the aforementioned oxo exists, R A1 , R A2 and R A3 Two of them are formed together with the carbon atoms to which they are bonded; G is -CH, C-OH, or N; If E exists, it is -C(O)- or -O-; Y is either -CH or N; p is 1, 2, or 3; q is either 1 or 0; r is either 1 or 0; Here, if r is 0, then A is not a C1-C6 alkyl group; R 1 is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl and halo-C1-C6 alkyl; or R 1is halo and q is 0; R 1a is selected from the group consisting of hydrogen, halo, and C1-C6 alkyl; R 2 is selected from the group consisting of halo, halo-C1-C6 alkyl, halo-C1-C6 alkoxy and -S(O)2-(C1-C6 alkyl); R 2a is selected from the group consisting of hydrogen and halo; and R 3 is hydrogen, halo, or C1-C6 alkyl] relates to a compound or a pharmaceutically acceptable salt or solvate thereof.

[0091] In certain embodiments, the compound has the structure of Formula A-i, wherein G is CH, r is 1, and E is -O-

Chemical Formula

[0092] In certain embodiments, the compound is Formula A-i', wherein p is 2; R 1a , R 2a , and R 3 are each hydrogen

Chemical Formula

[0093] In certain embodiments, the compound is Formula A-ii, wherein G is C-OH and r is 0

Chemical Formula

[0094] In certain embodiments, the compound has p is 2; and R1a , R 2a , and R 3 However, each is hydrogen, as in equation A-ii'. [ka] This includes compounds of formula A having the structure shown, or pharmaceutically acceptable salts or solvates thereof.

[0095] In certain embodiments, the compound is such that q is 1 and R 1 The compound comprises compounds of formula Ai, A-i', A-ii, or A-ii', or pharmaceutically acceptable salts or solvates thereof, wherein the compound is CH3. In certain embodiments, the compound is R 2 The compounds include compounds of formula Ai, A-i', A-ii, or A-ii', where Y is CF3 or OCHF2, or pharmaceutically acceptable salts or solvates thereof. In certain embodiments, the compounds include compounds of formula Ai, A-i', A-ii, or A-ii', where Y is CH, or pharmaceutically acceptable salts or solvates thereof.

[0096] In certain embodiments, the compound comprises a compound of formula A having the structure of formula I, where E is -C(O)-, or a pharmaceutically acceptable salt or solvate thereof.

[0097] In certain embodiments, the subject described herein is a compound of formula I. [ka] [In the formula, A is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, 5-6 member heteroaryl, and 5-6 member heterocyclyl, and each of these is R A1 , R A2 and R A3 It is arbitrarily replaced with one or more of the following: R A1 , R A2 and R A3These are, independently, C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, oxo, and -C(O)-R. A4 ,-S(O)-R A4 and -S(O)2-R A4 Selected from the group consisting of, R A4 These are C1-C6 alkyl or C3-C8 cycloalkyl, and If the aforementioned oxo exists, R A1 , R A2 and R A3 Two of them are formed together with the carbon atoms to which they are bonded; G is either -CH or N; Y is either -CH or N; p is 1, 2, or 3; q is either 1 or 0; r is either 1 or 0; Here, if r is 0, then A is not a C1-C6 alkyl group; R 1 This is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, and halo-C1-C6 alkyl; R 1a This is selected from the group consisting of hydrogen, halo, and C1-C6alkyl; R 2 These include halo, halo-C1-C6alkyl, halo-C1-C6alkoxy and --Selected from the group consisting of S(O)2-(C1-C6 alkyl); R 2a is selected from the group consisting of hydrogen and halos; and R 3 is hydrogen, halo, or C1-C6 alkyl. This relates to the compound or its pharmaceutically acceptable salts or solvates.

[0098] In certain embodiments, the compounds include compounds of formulas A and I, where G is CH, or pharmaceutically acceptable salts or solvates thereof.

[0099] In certain embodiments, the compound comprises a compound of formula I where G is N, or a pharmaceutically acceptable salt or solvate thereof, and formula I' [ka] It includes compounds having the structure of [this structure].

[0100] In certain embodiments, the compound comprises a compound of formula I or I' where q is 1, or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the compound comprises a compound of formula I or I' where q is 0, or a pharmaceutically acceptable salt or solvate thereof.

[0101] In a particular embodiment, the compound is R 1 The compound comprises a compound of formula I or I', or a pharmaceutically acceptable salt or solvate thereof, wherein is a C1-C6 alkyl or a C3-C8 cycloalkyl. In certain embodiments, the compound is R 1 However, it includes compounds of formula I or I', which are methyl, ethyl, or cyclopropyl, or pharmaceutically acceptable salts or solvates thereof.

[0102] In certain embodiments, a compound of formula I or I' or a pharmaceutically acceptable salt or solvate thereof is a compound of formula Ia, Ib, or Ic [ka] [ka] [ka] This includes compounds having the structure or pharmaceutically acceptable salts or solvates thereof.

[0103] In certain embodiments, the compound is such that q is 0 and R 1 The compound comprises a compound of formula A or a pharmaceutically acceptable salt or solvate thereof, wherein q is a halogen. In certain embodiments, the compound has q = 0 and R1 The compound comprises a compound of formula A or a pharmaceutically acceptable salt or solvate thereof, wherein r and q are -Cl. In certain embodiments, the compound has r and q, respectively, and R 1a and R 1b However, each is hydrogen, and R 1 The formula Id is a halogen. [ka] This includes compounds of formula A having the structure shown, or pharmaceutically acceptable salts or solvates thereof.

[0104] In a particular embodiment, the compound is R 1 The compound comprises a compound of formula Id where is -Cl. In certain embodiments, the compound is R 2 The compound comprises a compound of formula Id in which CF3 is present. In a particular embodiment, the compound is R 3 The compound includes a compound of formula Id where is hydrogen. In certain embodiments, the compound includes a compound of formula Id where Y is N. In certain embodiments, the compound includes a compound of formula Id where G is N and p is 2.

[0105] In certain embodiments, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', I, I', Ia, Ib, Ic, or Id, in which one or more hydrogen atoms are replaced by deuterium.

[0106] In certain embodiments, the compounds are of formula A-iii. [ka] This includes a compound of formula A having the structure shown.

[0107] In a particular embodiment, the compound is R 1 This includes compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where -CD3.

[0108] In certain embodiments, the compound includes compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where Y is N. In certain embodiments, the compound includes compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where Y is -CH.

[0109] In a particular embodiment, the compound is R 2 The compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, which are halo-C1-C6 alkyl or halo-C1-C6 alkoxy. In certain embodiments, the compound is R 2 The compound comprises compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where is a halo-C1-C6 alkyl group. In certain embodiments, the compound is R 2 The compound comprises compounds of formula I, I', Ia, Ib, or Ic, wherein is -CF3. In certain embodiments, the compound is R 2 The compound comprises compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where is a halo-C1-C6 alkyloxy. In certain embodiments, the compound is R 2 The compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where -O-CHF2.

[0110] In certain embodiments, the compound includes compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where p is 1 or 2. In certain embodiments, the compound includes compounds of formula A, Ai, A-ii, A-iii, I, I', Ia, Ib, Ic, or Id, where p is 1. In certain embodiments, the compound includes compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where p is 2.

[0111] In a particular embodiment, the compound is R 3 The compound comprises compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where is a C1-C6 alkyl group. In certain embodiments, the compound is R 3 The compound comprises compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, wherein the compound is methyl. In certain embodiments, the compound is R 3 This includes compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where hydrogen is present.

[0112] In certain embodiments, the compound includes compounds of formula A, Ai, A-i', A-iii, I, I', Ia, Ib, or Ic, where r is 1. In certain embodiments, the compound includes compounds of formula A, Ai, A-i', A-iii, I, I', Ia, Ib, or Ic, where r is 1 and A is C1-C6 alkyl. In certain embodiments, the compound includes compounds of formula A, Ai, A-i', A-iii, I, I', Ia, Ib, or Ic, where r is 1 and A is -CH3 or -CH2CH3. In certain embodiments, the compound includes compounds of formula A, A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where r is 0. In certain embodiments, the compound includes compounds of formula A, A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where r is 0 and A is R A1 , R A2 and R A3 The compounds include those of formula A, A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, which are C3-C8 cycloalkyls optionally substituted with one or more of the following:

[0113] In certain embodiments, the compound is such that r is 0 or 1, and A is R A1 , R A2 and R A3 The compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, which are C3-C5 cycloalkyls optionally substituted with one or more of the following. In certain embodiments, the compound is such that A is [ka] That is, The compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id. In the examples of the embodiments described above, the compound is R A1 The compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, which are cyano or halo C1-C6 alkyl. In the examples of the embodiments described above, the compound is R A1 The compound comprises compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, or Ic, where r is -CF3. In the examples of the embodiments described above, the compound comprises compounds of formula A, Ai, A-i', A-iii, I, I', Ia, Ib, or Ic, where r is 1.

[0114] In certain embodiments, the compound has r = 0, and A = R A1 , R A2 and R A3 The compounds include those of formula A, A-ii, A-ii', I, I', Ia, Ib, Ic, or Id, which are phenyls optionally substituted with one or more of the following. In certain embodiments, the compounds have r = 0, and A = R A1 and R A2 The compounds include those of formula A, A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, which are phenyls optionally substituted with one or more of the following. In certain embodiments, the compounds have r = 0 and A = structure [ka] The compound comprises compounds of formula A, A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id having R. In the examples of the embodiments described above, the compound is R A1 -S(O)2-R A4 And R A2The compound comprises compounds of formulas A, A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where r is a halo. In certain embodiments, the compound has r = 0 and A is structure [ka] The compound comprises compounds of formula A, A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id having R. In the examples of the embodiments described above, the compound is R A1 However, halo, cyano, -S(O)2-R A4 and -C(O)-R A4 The compound comprises compounds of formula A, A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, selected from the group consisting of the following:

[0115] In certain embodiments, the compound is such that r is 0 or 1, and A is R A1 , R A2 and R A3 The compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, which are 5-6 member heterocyclines optionally substituted with one or more of the following. In the examples of the embodiments above, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where A is a heterocycline containing one or two heteroatoms selected from the group consisting of N, S, and O. In the examples of the embodiments above, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where A is a 5-6 member heterocycline. In the examples of the embodiments described above, the compounds include compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where A is a 5-6 membered heterocycline containing one or two heteroatoms selected from the group consisting of N, S, and O. In the examples of the embodiments described above, the compounds include compounds where A is [ka] This includes compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id.

[0116] In certain embodiments, the compound is such that r is 0 or 1, and A is R A1 , R A2 and R A3 The compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, which are 5-6 membered heterocyclines substituted with R. A2 and R A3 However, each forms an oxo with the carbon it is bonded to, and A, [ka] And R A1 However, it includes compounds of formula A, Ai, A-i', A-ii, A-iii, A-ii', I, I', Ia, Ib, Ic, or Id, which are C1-C6 alkyl. In the example of the above embodiment, the compound is R A2 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 compound is ethyl.

[0117] In certain embodiments, the compound is such that r is 0 or 1, and A is R A1 , R A2 and R A3 The compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, or Ic, which are 5-6 member heteroaryls optionally substituted with one or more of the following: A1 , R A2 and R A3The compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, and thiazolyl, which are optionally substituted with one or more of the following. In the examples of the embodiments described above, the compounds are such that A is R A1 , R A2 and R A3 The compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, and pyrrolyl, which are optionally substituted with one or more of the following. In the examples of the embodiments described above, the compounds are such that A is R A1 , R A2 and R A3 The compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, which are pyridinyl compounds optionally substituted with one or more of the following: A1 The compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, which are pyridinyl compounds optionally substituted with. In the examples of the embodiments described above, the compounds are such that A is [ka] [ka] The compound comprises compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id. In the above embodiment, the compound is R A1 However, C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano and -S(O)2-R A4 The compound comprises a compound of formula I, I', Ia, Ib, or Ic, selected from the group consisting of the following. In the example of the above embodiment, the compound is A, [ka] The compound comprises compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id. In the above embodiment, the compound is A, R A1 , R A2 and R A3 The compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, which are pyrimidinyl or pyrazinyl compounds optionally substituted with one or more of the following: A1 The compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, which are pyrimidinyl or pyrazinyl compounds optionally substituted with. In the examples of the embodiments described above, the compounds are such that A is [ka] [ka] The compound comprises compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id. In the above embodiment, the compound is R A1 However, C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano and -S(O)2-R A4 The compound comprises a compound of formula I, I', Ia, Ib, Ic, or Id, selected from the group consisting of . In the example of the above embodiment, the compound is R A1 The compound comprises compounds of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where is CH2OCH3. In the examples of the embodiments above, the compound is A, [ka] This includes compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id. In the above embodiment, the compound is A, R A1 , R A2 and R A3The compounds include those of formula I, I', Ia, Ib, or Ic, which are oxadiazolyl and pyrrolyl, optionally substituted with one or more of the following. In the examples of the embodiments described above, the compounds include those of formula A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, or Id, where oxadiazolyl and pyrrolyl are R A1 It may be optionally substituted with. In the example of the above embodiment, the compound is A, [ka] [ka] This includes compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id.

[0118] The subject matter described herein includes the following compounds in Table 1, or their pharmaceutically acceptable salts. Individual enantiomers and diastereomers are included in the following table by compound name, from which their corresponding structures can be readily determined. In some cases, the enantiomers or diastereomers of this disclosure may be identified by their respective properties, e.g., retention time by chiral HPLC, NMR peaks, and / or biological activity (e.g., further described in the Examples), but without the assignment of absolute configurations for one or more chiral centers.

[0119] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16]

[0120] The subjects described herein include the following compounds in Table A, or pharmaceutically acceptable salts thereof.

[0121] [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table A-6] [Table A-7] [Table A-8] [Table A-9]

[0122] In certain embodiments, the subject matter described herein relates to compounds selected from Table 1. In certain embodiments, the subject matter described herein relates to compounds selected from Table A. In certain embodiments, the subject matter described herein relates to compounds selected from Table 1 and Table A.

[0123] III. Pharmaceutical Compositions and Dosage Modes The compounds provided 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 additives are also provided herein. Suitable pharmaceutically acceptable additives include, for example, inert solid diluents and fillers, liquid diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared by methods well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & C.T. Rhodes, Eds.).

[0124] In some embodiments, the pharmaceutical composition comprises a compound of formula A or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive. In some embodiments, the pharmaceutical composition comprises a compound of formula Ai or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive. In some embodiments, the pharmaceutical composition comprises a compound of formula A-i' or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive. In some embodiments, the pharmaceutical composition comprises a compound of formula A-ii or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive. In some embodiments, the pharmaceutical composition comprises a compound of formula A-ii' or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive. In some embodiments, the pharmaceutical composition comprises a compound of formula A-iii or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive. In some embodiments, the pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive. In some embodiments, the pharmaceutical composition comprises a compound of formula I' or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive. In some embodiments, the pharmaceutical composition comprises a compound of formula Ia or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive. In some embodiments, the pharmaceutical composition comprises a compound of formula Ib or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive. In some embodiments, the pharmaceutical composition comprises a compound of formula Ic or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive. In some embodiments, the pharmaceutical composition comprises a compound of formula Id or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive. In some embodiments, the pharmaceutical composition comprises a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive. In some embodiments, the pharmaceutical composition comprises a compound of Table A or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive.In some embodiments, the pharmaceutical composition comprises a compound from Table 1 and Table A or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive.

[0125] The pharmaceutical composition may be administered in single or multiple doses. The pharmaceutical composition may be administered by various methods, including, for example, rectally, buccally, intranasally, and transdermally. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0126] One mode of administration is, for example, parenteral administration by injection. Forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous suspensions or oil 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 vehicles.

[0127] Oral administration may be another route for administering the compounds described herein. Administration may be carried out, for example, via capsules or tablets such as enteric-coated tablets. When preparing a pharmaceutical composition comprising at least one of the compounds described herein or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, the active ingredient is usually diluted with an additive and / or encapsulated in such a carrier, which may be in the form of a capsule, sachet, paper or other container. Where the additive acts as a diluent, the additive may be in the form of a solid, semi-solid or liquid material acting as a vehicle, carrier or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium), ointments, soft and hard gelatin capsules, sterile injections, and sterile packaged powders, for example, containing up to 10% by weight of the active compound.

[0128] Some examples of suitable additives include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may further contain lubricants, wetting agents, emulsifiers and suspending agents such as talc, magnesium stearate, and mineral oil, as well as preservatives, sweeteners, and flavoring agents such as methyl hydroxybenzoate and propyl hydroxybenzoate.

[0129] Compositions comprising at least one compound described herein or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject by using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are given in U.S. Patents 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods disclosed herein uses transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutically active substances are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0130] To prepare solid compositions such as tablets, a main active ingredient can be mixed with pharmaceutical additives to form a solid pre-formulation composition containing a homogeneous mixture of the compound described herein or its pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers. When these pre-formulation compositions are referred to as homogeneous, the active ingredient can be uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0131] Tablets or pills of the compounds described herein may be coated or otherwise formulated to provide a dosage form that offers the advantage of a longer-acting effect or to protect from the acidic conditions of the stomach. For example, a tablet or pill may contain an internally administered component and an externally administered component, the latter in the form of an envelope covering the former. The two components may be separated by a single enteric coating, which serves to withstand disintegration in the stomach, allowing the internal component to pass through the duodenum intact or to delay its release. Various materials may be used for such enteric coatings or coatings, including numerous polymer acids and mixtures of polymer acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0132] 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 appropriate pharmaceutically acceptable additives as described herein. In some embodiments, compositions are administered orally or via nasal respiratory routes for topical or systemic effects. In other embodiments, compositions in pharmaceutically acceptable solvents may be sprayed using an inert gas. Sprayed solutions may be inhaled directly from a spraying device, or the spraying device may be attached to a face mask tent or an intermittent positive airway pressure (PAP) respirator. Solutions, suspensions, or powder compositions may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0133] The specific dose level of the compounds of this application for any particular subject depends on a variety of factors, including the activity of the specific compound used, age, body weight, overall health, sex, diet, administration time, route of administration, and excretion rate, drug combinations, and the severity of the specific disease in the subject being treated. For example, the dose may be expressed as the number of milligrams (mg / kg) of the compound described herein per kilogram of body weight of the subject. A dose of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, a dose of about 0.1 to 100 mg / kg may be appropriate. In other embodiments, a dose of 0.5 to 60 mg / kg may be appropriate. Normalizing according to the body weight of the subject is particularly useful when adjusting doses between subjects of significantly different sizes, such as when using the drug in both children and adults, or when converting an effective dose in a non-human subject such as a dog to a dose suitable for a human subject. The dose may be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including the absorption, distribution, metabolism, and excretion of the specific compound. In addition, toxic factors may affect the dosage and administration regimen. When administered orally, pills, capsules, or tablets may be taken orally daily or at longer intervals according to the specified time cycle. This regimen can be repeated for a predetermined number of treatment cycles.

[0134] IV. Treatment Methods This specification describes a method for promoting myelination of central nervous system neurons in subjects suffering from myelin-related disorders, comprising administering 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 containing the same, to the subject. In certain 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 for the manufacture of pharmaceuticals for promoting myelination of central nervous system neurons in subjects suffering from myelin-related disorders.

[0135] In certain embodiments, in a method for promoting myelination of central nervous system neurons in subjects 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 containing them, inhibit the enzymatic synthesis of one or more sterol intermediates in the cholesterol biosynthesis pathway.

[0136] In certain embodiments, in a method for promoting myelination of central nervous system neurons in subjects 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 containing them, promote the accumulation of Δ8,9-unsaturated sterol intermediates in the cholesterol biosynthesis pathway.

[0137] In certain embodiments, in a method for promoting myelination of central nervous system neurons in subjects 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 their pharmaceutically acceptable salts or solvates, or pharmaceutical compositions containing them, inhibit one or more of the CYP51, sterol-14-reductase, or EBP enzyme-mediated synthesis of sterol intermediates in the cholesterol biosynthesis pathway. In certain embodiments, compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id or their pharmaceutically acceptable salts or solvates, or pharmaceutical compositions containing them, inhibit CYP51.

[0138] In certain embodiments, in a method for promoting myelination of central nervous system neurons in subjects 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 containing them, induce, promote, and / or regulate the differentiation, proliferation, and / or maturation of oligodendrocyte progenitor cells (OPCs). In certain embodiments, the induction of OPC differentiation is characterized by increased myelin basic protein (MBP) expression.

[0139] In certain embodiments, the subject matter described herein relates to a method for treating a disorder in a subject requiring treatment of the disorder, comprising administering 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 solvate thereof to the subject requiring treatment of the disorder. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of formula A is the compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula Ai or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-i' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-ii or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-ii' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of formula A-iii or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of formula Id or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of formula I' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of formula Ia or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of formula I is a compound of formula Ib or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of formula I is a compound of formula Ic or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of Table A or a pharmaceutically acceptable salt or solvate thereof.

[0140] In certain 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 for use in the treatment of disorders in subjects requiring treatment of the disorder. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of formula A is the compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula Ai or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-i' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-ii or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-ii' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of formula A-iii or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of formula Id or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of formula I' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of formula Ia or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of formula I is a compound of formula Ib or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of formula I is a compound of formula Ic or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of Table A or a pharmaceutically acceptable salt or solvate thereof.

[0141] In certain 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 pharmaceuticals for treating disorders in subjects requiring such treatment. In certain embodiments, subjects have myelin-related disorders. In some embodiments, the compound of formula A is the compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula Ai or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-i' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-ii or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-ii' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of formula A-iii or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of formula Id or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of formula I' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of formula Ia or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of formula I is a compound of formula Ib or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of formula I is a compound of formula Ic or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of Table A or a pharmaceutically acceptable salt or solvate thereof.

[0142] In certain embodiments, the subject disclosed herein relates to a method for promoting myelination in a subject requiring myelination, comprising administering 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 solvate thereof to the subject. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of formula A is the compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula Ai or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-i' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-ii or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-ii' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of formula A-iii or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of formula Id or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of formula I' or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the subject has myelin-related disorders. In some embodiments, the compound of formula I is a compound of formula Ia or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of formula I is a compound of formula Ib or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of formula I is a compound of formula Ic or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of Table A or a pharmaceutically acceptable salt or solvate thereof.

[0143] In certain 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, or pharmaceutical compositions comprising such compounds, for use in promoting myelin formation in subjects requiring it. In certain embodiments, the subjects have myelin-related disorders. In some embodiments, the compound of formula A is the compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula Ai or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-i' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-ii or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-ii' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of formula A-iii or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of formula Id or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of formula I' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of formula Ia or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of formula I is a compound of formula Ib or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of formula I is a compound of formula Ic or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of Table A or a pharmaceutically acceptable salt or solvate thereof.

[0144] In certain 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, or pharmaceutical compositions containing such compounds, in the manufacture of pharmaceuticals for promoting myelin formation in subjects requiring myelin formation promotion. In certain embodiments, the subjects have myelin-related disorders. In some embodiments, the compound of formula A is the compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula Ai or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-i' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-ii or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-ii' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of formula A-iii or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of formula Id or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of formula I' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of formula Ia or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of formula I is a compound of formula Ib or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of formula I is a compound of formula Ic or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound of Table A or a pharmaceutically acceptable salt or solvate thereof.

[0145] In certain embodiments, the subject disclosed herein relates to a method for inducing differentiation of endogenous oligodendrocyte progenitor cells (OPCs) in subjects requiring differentiation of OPCs, 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 solvate thereof, or a pharmaceutical composition containing the same. In certain embodiments, the subject suffers from a myelin-related disorder. In certain embodiments, the myelin-related disorder is multiple sclerosis.

[0146] Myelin-related disorders include multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, childhood leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander disease, Pelizaeus-Merzbacher disease (PMD), white matter disappearance disease, Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, and Alzheimer's disease. This includes, but is not limited to, Heimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post-radiation injury, neurological complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, sporadic vitamin E deficiency syndrome, Bassen-Kohnzweig syndrome, Marchia-Fava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barré syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination.

[0147] Compounds of formulas A, Ai, A-i', A-ii, A-ii', A-iii, I, I', Ia, Ib, Ic, and Id, or their pharmaceutically acceptable salts or solvates, can be administered alone or in combination with other agents 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 resulting from traumatic spinal cord injury and cerebral infarction), or disorder that results in abnormalities of the myelin sheath. Abnormalities may be caused by loss of myelin, called demyelination; dysfunction of myelin, called hypomyelination; or inability to form sufficient myelin, called hypomyelination. The myelin-related disorders described herein may result from hereditary disorders or one or more different neurotoxic injuries. In some embodiments, the compound of formula A is a compound of formula I or its pharmaceutically acceptable salt or solvate. In some embodiments, the compound of formula A is the compound of formula Ai or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-i' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-ii or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-ii' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula A-iii or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is the compound of formula Id or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is the compound of formula I' or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is the compound of formula Ia or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of formula I is the compound of formula Ib or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of formula I is the compound of formula Ic or a pharmaceutically acceptable salt or solvate thereof.In some embodiments, the compound of formula I is a compound from Table 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula A is a compound from Table A or a pharmaceutically acceptable salt or solvate thereof.

[0148] As used herein, “demyelination” refers to activity that causes loss of myelin, i.e., damage or loss of part or all of the myelin sheath that insulates nerves, and is a prominent feature of myelin-related disorders. In certain embodiments, demyelination refers to damage or loss of part or all of the myelin sheath that insulates a subset of nerves in an individual, such as one or more nerves localized in a particular area of ​​the body (e.g., the brain or spinal cord, or neurons in both the brain and spinal cord, or the optic nerve).

[0149] Oligodendritic cells are required for neuronal myelination. As used herein, the term “myelination” refers to the formation of the myelin sheath of a nerve by replacing or restoring the function of myelin-producing cells. Neurons undergoing remyelination may be located in the brain, spinal cord, or both. Restoring the function of myelin-producing cells may include, for example, increasing the rate of myelin production in one or more cells that have below-average production levels. Such an increase may include raising the rate of myelin production to or above the average production level, but may also include raising the rate of myelin production to a level that is still below average but higher than the previous level.

[0150] As used herein, “promote myelinization” means increasing the rate of myelin production, rather than merely a net increase in the amount of myelin compared to a baseline level of myelin production rate in a subject. The increase in myelin production rate can be determined using imaging techniques or functional measurements. In some embodiments, myelinization is promoted by increasing the differentiation of OPCs, increasing the accumulation of 8,9-unsaturated sterol intermediates in the biosynthetic pathway, increasing the formation of OPCs, or any combination thereof. Such activity can be evaluated, for example, using one or more in vitro assays, e.g., assays described herein or assays known to those skilled in the art.

[0151] As used herein, “baseline level of myelin production rate” refers to the myelin production rate in the subject being treated before the initiation of treatment.

[0152] V. Methods for preparing compounds of formulas A and I and their pharmaceutically acceptable salts. The compounds can be synthesized by synthetic routes involving processes similar to those well known in the chemical art, particularly in light of the descriptions contained herein, and processes for other heterocycles described below: Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, e.g., Volume 3; Liebigs Annalen der Chemie, (9):1910-16, (1985); Helvetica Chimica Acta, 41:1052-60, (1958); Arzneimittel-Forschung, 40(12):1328-31, (1990) (each of these is explicitly incorporated by reference). The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or can be readily prepared using methods well known to those skilled in the art (e.g., Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-23, Wiley, NY (1967-2006 ed.) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed., Springer-Verlag, Berlin, including the supplement (also available through the Beilstein online database)).

[0153] Synthetic chemical transformations and protecting group methodologies (protection and deprotection) useful for synthesizing compounds and necessary reagents and intermediates are known in the art, for example, R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and PGMWuts, Protective Groups in Organic Synthesis, 3 rdEd., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

[0154] The compounds can be prepared individually or as a compound library containing at least two compounds, for example, 5 to 1,000 compounds, or 10 to 100 compounds. Libraries of compounds of formulas A and I or their pharmaceutically acceptable salts can be prepared by procedures known to those skilled in the art, by a combinatorial "split and mix" approach, or by multiple parallel synthesis using either solution-phase or solid-phase chemistry. Thus, according to further embodiments, compound libraries containing at least two compounds or their pharmaceutically acceptable salts are provided.

[0155] VI. Further Embodiments The subject matter described herein includes the following embodiments: 1. Compounds of formula I [ka] [In the formula, A is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, 5-6 member heteroaryl, and 5-6 member heterocyclyl, and each of these is R A1 , R A2 and R A3 It is arbitrarily replaced with one or more of the following: R A1 , R A2 and R A3 These are, independently, C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, oxo, and -C(O)-R. A4 ,-S(O)-R A4 and -S(O)2-R A4 Selected from the group consisting of, R A4 These are C1-C6 alkyl or C3-C8 cycloalkyl, and If the aforementioned oxo exists, R A1 , R A2 and R A3 Two of them are formed together with the carbon atoms to which they are bonded; G is either -CH or N; Y is either -CH or N; p is 1, 2, or 3; q is either 1 or 0; r is either 1 or 0; Here, if r is 0, then A is not a C1-C6 alkyl group; R 1 This is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, and halo-C1-C6 alkyl; R 1a This is selected from the group consisting of hydrogen, halo, and C1-C6alkyl; R 2 These include halo, halo-C1-C6alkyl, halo-C1-C6alkoxy and --Selected from the group consisting of S(O)2-(C1-C6 alkyl); R 2a is selected from the group consisting of hydrogen and halos; and R 3 [These are hydrogen, halos, or C1-C6 alkyl groups.] or a pharmaceutically acceptable salt or solvate thereof. 2. G is N, and the structure of equation I' [ka] A compound according to Embodiment 1 or a pharmaceutically acceptable salt or solvate thereof having the above. 3. A compound according to Embodiment 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. 4. A compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. 5.R 1A compound according to any one of Embodiments 1 to 4, wherein the compound is a C1-C6 alkyl or a C3-C8 cycloalkyl compound, or a pharmaceutically acceptable salt or solvate thereof. 6.R 1 The compound described in Embodiment 5 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is methyl, ethyl, or cyclopropyl. 7. Structure of Formula Ia, Ib, or Ic [ka] [ka] [ka] A compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt or solvate thereof having the above. 8. A compound according to any one of Embodiments 1 to 7, wherein Y is N, or a pharmaceutically acceptable salt or solvate thereof. 9. A compound according to any one of Embodiments 1 to 7, wherein Y is -CH, or a pharmaceutically acceptable salt or solvate thereof. 10.R 2 A compound according to any one of Embodiments 1 to 9, wherein the compound is a halo-C1-C6 alkyl or a halo-C1-C6 alkoxy, or a pharmaceutically acceptable salt or solvate thereof. 11.R 2 A compound according to Embodiment 10 or a pharmaceutically acceptable salt or solvate thereof, wherein is a halo-C1-C6 alkyl group. 12.R 2 A compound according to Embodiment 11 or a pharmaceutically acceptable salt or solvate thereof, wherein is -CF3. 13.R 2 A compound according to Embodiment 10 or a pharmaceutically acceptable salt or solvate thereof, wherein is a halo-C1-C6 alkoxy. 14.R 2 A compound according to Embodiment 11 or a pharmaceutically acceptable salt or solvate thereof, wherein is -O-CHF2. 15. A compound according to any one of Embodiments 1 to 14, wherein p is 1 or 2, or a pharmaceutically acceptable salt or solvate thereof. 16. A compound according to any one of Embodiments 1 to 15, wherein p is 1, or a pharmaceutically acceptable salt or solvate thereof. 17. A compound according to any one of Embodiments 1 to 15, wherein p is 2, or a pharmaceutically acceptable salt or solvate thereof. 18.R 3 A compound according to any one of Embodiments 1 to 17, wherein the compound is a C1-C6 alkyl group, or a pharmaceutically acceptable salt or solvate thereof. 19.R 3 A compound according to Embodiment 18 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is methyl. 20.R 3 A compound according to any one of Embodiments 1 to 17, wherein the compound is hydrogen, or a pharmaceutically acceptable salt or solvate thereof. 21. A compound according to any one of Embodiments 1 to 20, wherein r is 1, or a pharmaceutically acceptable salt or solvate thereof. 22. The compound according to Embodiment 21, wherein A is a C1-C6 alkyl group, or a pharmaceutically acceptable salt or solvate thereof. 23. The compound according to Embodiment 22 or a pharmaceutically acceptable salt or solvate thereof, wherein A is -CH3 or -CH2CH3. 24. A compound according to any one of Embodiments 1 to 20, wherein r is 0, or a pharmaceutically acceptable salt or solvate thereof. 25. A is R A1 , R A2 and R A3 A compound according to Embodiment 21 or 24, or a pharmaceutically acceptable salt or solvate thereof, which is a C3-C8 cycloalkyl optionally substituted with one or more of the following. 26. A is R A1 , R A2 and R A3A compound according to Embodiment 25, or a pharmaceutically acceptable salt or solvate thereof, which is a C3-C5 cycloalkyl optionally substituted with one or more of the above. 27.A is, [ka] [ka] The compound described in Embodiment 26 or a pharmaceutically acceptable salt or solvate thereof. 28.R A1 The compound described in Embodiment 27 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is cyano or halo-C1-C6 alkyl. 29.R A1 A compound according to Embodiment 28 or a pharmaceutically acceptable salt or solvate thereof, wherein is -CF3. 30.A is R A1 , R A2 and R A3 A compound according to Embodiment 21 or 24, or a pharmaceutically acceptable salt or solvate thereof, which is a phenyl optionally substituted with one or more of the following. 31. A is R A1 and R A2 A compound according to Embodiment 30 or a pharmaceutically acceptable salt or solvate thereof, wherein the phenyl is optionally substituted with one or more of the following. 32.A is, [ka] The compound described in Embodiment 31 or a pharmaceutically acceptable salt or solvate thereof. 33.R A1 -S(O)2-R A4 And R A2 A compound or a pharmaceutically acceptable salt or solvate thereof according to Embodiment 32, wherein the compound is a halo. 34.A is, [ka] The compound described in Embodiment 31 or a pharmaceutically acceptable salt or solvate thereof. 35.R A1 However, halo, cyano, -S(O)2-R A4 and -C(O)-R A4 A compound according to Embodiment 34 or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of the above. 36.A is R A1 , R A2 and R A3 A compound according to Embodiment 21 or 24, or a pharmaceutically acceptable salt or solvate thereof, which is a 5-6 membered heterocycline optionally substituted with one or more of the above. 37. The compound according to Embodiment 36 or a pharmaceutically acceptable salt or solvate thereof, wherein the heterocyclyl comprises one or two heteroatoms selected from the group consisting of N, S, and O. 38. The compound according to Embodiment 36, wherein A is a 5-6 member heterocycline, or a pharmaceutically acceptable salt or solvate thereof. 39. The compound according to Embodiment 38 or a pharmaceutically acceptable salt or solvate thereof, wherein A is a 5- to 6-membered heterocycline containing one or two heteroatoms selected from the group consisting of N, S, and O. 40.A is, [ka] The compound described in Embodiment 39 or a pharmaceutically acceptable salt or solvate thereof. 41. A is R A1 , R A2 and R A3 A compound according to Embodiment 21 or 24, or a pharmaceutically acceptable salt or solvate thereof, which is a 5-6 member heteroaryl optionally substituted with one or more of the above. 42.A is, R A1 , R A2 and R A3A compound according to Embodiment 41 or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, and thiazolyl, which is optionally substituted with one or more of the following. 43.A is R A1 , R A2 and R A3 A compound according to Embodiment 42 or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, and pyrrolyl, which is optionally substituted with one or more of the above. 44.A is R A1 , R A2 and R A3 A compound according to Embodiment 43, or a pharmaceutically acceptable salt or solvate thereof, which is a pyridinyl optionally substituted with one or more of the above. 45.A is R A1 A compound according to Embodiment 44, which is a pyridinyl substituted with the compound or a pharmaceutically acceptable salt or solvate thereof. 46.A is, [ka] [ka] The compound described in Embodiment 45 or a pharmaceutically acceptable salt or solvate thereof. 47.R A1 However, C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano and -S(O)2-R A4 A compound according to Embodiment 46 or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of the above. 48.A is R A1 , R A2 and R A3 A compound according to Embodiment 43 or a pharmaceutically acceptable salt or solvate thereof, which is a pyrimidinyl or pyrazinyl optionally substituted with one or more of the above. 49.A is R A1A compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, which is a pyrimidinyl or pyrazinyl optionally substituted with. 50.A is, [ka] [ka] The compound described in Embodiment 49 or a pharmaceutically acceptable salt or solvate thereof. 51.R A1 However, C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano and -S(O)2-R A4 A compound according to Embodiment 50 or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of the above. 52.A is R A1 , R A2 and R A3 A compound according to Embodiment 43 or a pharmaceutically acceptable salt or solvate thereof, wherein oxadiazolyl and pyrrolyl are optionally substituted with one or more of the above. 53.A is R A1 The compounds of Embodiment 52 or pharmaceutically acceptable salts or solvates thereof, wherein oxadiazolyl and pyrrolyl are optionally substituted with oxadiazolyl and pyrrolyl. 54.A is, [ka] The compound described in Embodiment 53 or a pharmaceutically acceptable salt or solvate thereof. 55.R A1 C1-C6, the compounds described in Embodiment 54, or pharmaceutically acceptable salts or solvates thereof. 56. A compound of Embodiment 1 selected from Table 1, or a pharmaceutically acceptable salt or solvate thereof. 57. A pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 56 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive. 58. A method for promoting myelin formation in a subject requiring myelin formation, comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt or solvate described in any one of Embodiments 1 to 56, or a pharmaceutical composition described in Embodiment 57, to the subject requiring myelin formation. 59. A compound according to any one of Embodiments 1 to 56 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to Embodiment 57, for use in treating a disorder in a subject requiring treatment of the disorder. 60. A compound according to any one of Embodiments 1 to 56 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to Embodiment 57, for use in promoting myelin formation in subjects requiring myelin formation promotion. 61. Use of a compound according to any one of Embodiments 1 to 56 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to Embodiment 57, in the manufacture of a pharmaceutical for treating a disorder in a subject requiring treatment of the disorder. 62. Use of a compound according to any one of Embodiments 1 to 56 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to Embodiment 57, in the manufacture of a pharmaceutical for promoting myelin formation in subjects requiring promotion of myelin formation. 63. The method according to Embodiment 58, wherein the subject has myelin-related disorders. 64. The compound for use according to Embodiment 59 or 60, wherein the subject has myelin-related disorders. 65. The use according to embodiment 61 or 62, wherein the subject has myelin-related disorders. 66. The myelin-related disorders described above include multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, childhood leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander disease, Pelizaeus-Merzbacher disease (PMD), white matter disappearance disease, Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, and spinal cord injury. The method according to Embodiment 63, the compound for use described in Embodiment 64, or the use described in Embodiment 65, which is a condition of traumatic brain injury, post-radiation injury, neurological complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, sporadic vitamin E deficiency syndrome, Bassen-Kohnzweig syndrome, Marquiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barré syndrome, Charcot-Marie-Tooth disease, Bell's palsy, or radiation-induced demyelination. 67. The method according to Embodiment 63, the compound according to Embodiment 64, or the use according to Embodiment 65, wherein the disorder is multiple sclerosis. 68. A method for inhibiting CYP51 (lanosterol demethylase), comprising contacting CYP51 with a compound described in any one of Embodiments 1 to 56 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of Embodiment 57. [Examples]

[0156] The examples provide exemplary methods for preparing the compounds. Those skilled in the art will understand that other synthetic routes may be used to synthesize the compounds. While specific starting materials and reagents are shown and discussed in the schemes, general procedures and examples, they can be readily substituted with other starting materials and reagents to provide a variety of derivatives and / or reaction conditions. Furthermore, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0157] Example A: (S)-4-cyclopropyl-N-(4-(trifluoromethyl)phenyl)-N-(1-(5-(trifluoromethyl)pyrrolidine-2-yl)pyrrolidine-3-yl)pyridine-3-amine (Compound 1): [ka]

[0158] Step 1: tert-butyl(S)-3-((4-chloropyridine-3-yl)amino)pyrrolidine-1-carboxylate [ka]

[0159] To a mixture of tert-butyl(3S)-3-aminopyrrolidine-1-carboxylate (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% in toluene) were added. The mixture was degassed, purged three times with N2, and then stirred at 100°C for 12 hours under an N2 atmosphere. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by silica flash chromatography (using 0-25% ethyl acetate in petroleum ether as an eluent) to obtain the title compound (633 mg, 2.13 mmol, 41% yield). LCMS[M+H]+=298.2.

[0160] Step 2: tert-butyl(S)-3-((4-chloropyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)pyrrolidine-1-carboxylate [ka]

[0161] To a mixture of tert-butyl(3S)-3-[(4-chloro-3-pyridyl)amino]pyrrolidine-1-carboxylate (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% in toluene) were added. The mixture was degassed, purged three times with N2, and then stirred at 120°C for 16 hours under an N2 atmosphere. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by silica flash chromatography (using 0-25% ethyl acetate in petroleum ether as an eluent) to obtain the title compound (409 mg, 925.60 μmol, 69% yield). LCMS(ESI)[M+H]+=386.1

[0162] Step 3: tert-butyl(S)-3-((4-cyclopropylpyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)pyrrolidine-1-carboxylate [ka]

[0163] A mixture of tert-butyl(3S)-3-[N-(4-chloro-3-pyridyl)-4-(trifluoromethyl)anilino]pyrrolidine-1-carboxylate (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)-butyl-phosphane (32 mg, 0.091 mmol) in toluene (1 mL) and H2O (0.1 mL) was degassed, purged three times with N2, and then stirred in a microwave reactor under an N2 atmosphere at 120°C for 1 hour. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by preparative TLC (SiO2, 50% ethyl acetate in petroleum ether) to obtain the title compound (100.4 mg, 224 μmol, 50% yield). LC-MS (ESI)[M+H]+=448.3.

[0164] Step 4: (S)-4-cyclopropyl-N-(pyrrolidine-3-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride [ka]

[0165] To a mixture of tert-butyl(3S)-3-[N-(4-cyclopropyl-3-pyridyl)-4-(trifluoromethyl)anilino]pyrrolidine-1-carboxylate (180 mg, 402.24 μmol), HCl / dioxane (4 M, 3.00 mL) was added all at once at 25°C and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (130 mg, 374.23 μmol, yield 93.04%), which was used in the next step without further purification. LCMS(ESI)[M+H]+=348.2

[0166] Step 5: (S)-4-cyclopropyl-N-(4-(trifluoromethyl)phenyl)-N-(1-(5-(trifluoromethyl)pyrrolidine-2-yl)pyrrolidine-3-yl)pyridine-3-amine (Compound 1) [ka]

[0167] 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), DIEA (131.31 mg, 1.02 mmol) was added all at once at 25 °C. The mixture was stirred at 80 °C for 4 hours. The reaction 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%-50% ethyl acetate in petroleum ether) to obtain the title compound (140 mg, 284.29 μmol, yield 83.94%) as a yellow solid. (SFC:30:70). A mixture of enantiomers (130 mg, 263.98 μmol) was purified by SFC (SFC-12; DAIEL CHIRALCEL OD (250 mm*30 mm, 10 μm), 0.1% NH3H2O ​​ETOH; 30%~30%, 60 mL / min) to obtain the title compound-1 (first peak on SFC, compound 1, 50.7 mg, 101.92 μmol, yield 38.61%). LCMS(ESI)[M+H] + =493.1. Only the above enantiomer of compound 1 showed activity.

[0168] Compound 1: 1HNMR:(400MHz,CDCl3)δ8.50-8.20(m,3H), 7.63-7.57(m,1H), 7.49-7.41(m,2 H), 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).

[0169] Example B: 2-(4-((4-cyclopropylpyridine-3-yl)(6-(trifluoromethyl)pyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (Compound 2): [ka]

[0170] Step 1: tert-butyl 4-((4-chloropyridine-3-yl)amino)piperidine-1-carboxylate [ka]

[0171] A mixture of tert-butyl 4-amino-1-piperidine carboxylate (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% in toluene), and Pd(OAc)2 (350 mg, 1.56 mmol) in toluene (50 mL) was degassed, purged three times with N2, and then stirred under N2 at 80°C for 19 hours.

[0172] The mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica flash chromatography (silica gel, 100-200 mesh, 50% ethyl acetate in petroleum ether) to obtain the title compound (2200 mg, 7.056 mmol, 45% yield). LCMS(ESI)[M+H]+=312.1. 1 H NMR(400MHz,CDCl3)δppm 8.07(s,1H), 7.89(s,1H), 7.23(d,J=5.2Hz,1H), 4.15(d,J=6.8Hz,1H), 4.00-4.12(m,2H), 3.5 1-3.65(m,1H), 2.98(t,J=11.6Hz,2H), 2.05-2.10(m,2H), 1.50(d,J=1.6Hz,2H), 1.48(s,9H).

[0173] Step 2: tert-butyl 4-((4-chloropyridine-3-yl)(6-(trifluoromethyl)pyridine-3-yl)amino)piperidine-1-carboxylate [ka]

[0174] 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]piperidine-1-carboxylate (600.0 mg, 1.92 mmol), tBu3P (1.81 mL, 0.77 mmol, 10 wt% in toluene), and Pd(OAc)2 (86.4 mg, 0.38 mmol) in toluene (10 mL) was stirred at 120°C for 12 hours under N2. The mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica flash chromatography (0-50% ethyl acetate in petroleum ether) to obtain the title compound (600 mg, 1.31 mmol, yield 68%). LCMS(ESI)[M+H]+=401.2.

[0175] Step 3: tert-butyl 4-((4-cyclopropylpyridine-3-yl)(6-(trifluoromethyl)pyridine-3-yl)amino)piperidine-1-carboxylate [ka]

[0176] A mixture of cyclopropylboronic acid (594 mg, 2.5 mmol), tert-butyl 4-((4-chloropyridine-3-yl)(6-(trifluoromethyl)pyridine-3-yl)amino)piperidine-1-carboxylate (1000.0 mg, 2.28 mmol), Cs2CO3 (2.224 g, 6.83 mmol), di(adamantan-1-yl)(butyl)phosphan (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 N2 for 3 minutes. The mixture was heated in a microwave reactor under N2 at 120°C for 1 hour. Water (20 mL) was added to the mixture and 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 silica flash chromatography (0-50% ethyl acetate in petroleum ether) to obtain the title compound (600 mg, 1.30 mmol, 57% yield). LCMS(ESI)[M+H]+=463.2.

[0177] Step 4: 4-Cyclopropyl-N-(piperidine-4-yl)-N-(6-(trifluoromethyl)pyridine-3-yl)pyridine-3-amine hydrochloride [ka]

[0178] To a solution of tert-butyl 4-[(4-cyclopropyl-3-pyridyl)-[6-(trifluoromethyl)-3-pyridyl]amino]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 hours. The reaction mixture was concentrated under vacuum to obtain the title compound (517 mg, 1.3 mmol, 100% yield) as a white solid. LC-MS(ESI)[M+H]+=363.2.

[0179] Step 5: 2-(4-((4-cyclopropylpyridine-3-yl)(6-(trifluoromethyl)pyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (compound 2): [ka]

[0180] To a solution of N-(4-cyclopropyl-3-pyridyl)-N-(4-piperidyl)-6-(trifluoromethyl)pyridine-3-amine (50.0 mg, 0.14 mmol) and 2-chloropyrimidine-5-carbonitrile (23.1 mg, 0.17 mmol) in N,N-dimethylformamide (1 mL) at 0°C, N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) was added and the mixture was 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 matter was 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) to obtain the title compound (10.5 mg, 0.0205 mmol, yield 15%). LC-MS (ESI) [M+H]+ = 466.3.

[0181] Compound 2: 1H NMR(400MHz,CDCl3)δppm 8.49(s,3H), 8.28(s,1H), 8.11(s,1H), 7.50(d,J=9.2Hz,1H), 6.83(d,J=6.4Hz,2H), 5.06(d,J=14.0Hz,2H), 4.35(s,1H), 3.0 9(t,J=12.8Hz,2H), 2.23(d,J=12.0Hz,2H), 1.91(s,1H), 1.48(d,J=13.6Hz,2H), 1.15(d,J=6.4Hz,2H), 0.89(d,J=6.4Hz,2H).

[0182] Example C: 4-Cyclopropyl-N-(1-(4-(methylsulfonyl)phenyl)piperidine-4-yl)-N-(6-(trifluoromethyl)pyridine-3-yl)pyridine-3-amine (Compound 3): [ka]

[0183] Step 1: 4-Cyclopropyl-N-(piperidine-4-yl)-N-(6-(trifluoromethyl)pyridine-3-yl)pyridine-3-amine [ka]

[0184] To a solution of N-(4-cyclopropyl-3-pyridyl)-N-(4-piperidyl)-6-(trifluoromethyl)pyridine-3-amine hydrochloride (500.0 mg, 1.25 mmol) in methanol (10 mL), basic resin (1.0 g) was added and the mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered, and the methanol was concentrated under vacuum to obtain the title compound (420 mg, 1.16 mmol, 93% yield).

[0185] Step 2: 4-Cyclopropyl-N-(1-(4-(methylsulfonyl)phenyl)piperidine-4-yl)-N-(6-(trifluoromethyl)pyridine-3-yl)pyridine-3-amine (Compound 3): [ka]

[0186] A solution of N-(4-cyclopropyl-3-pyridyl)-N-(4-piperidyl)-6-(trifluoromethyl)pyridine-3-amine (50.0 mg, 0.14 mmol), RuPhos Pd G3 (12 mg, 0.01 mmol), 1-bromo-4-(methylsulfonyl)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 hours. The resulting residue was concentrated under reduced pressure, and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether) to obtain the title compound (53 mg, 0.0995 mmol, yield 72%). LCMS(ESI)[M+H]+=517.3.

[0187] Compound 3: 1 H NMR(400MHz,CDCl3)δppm 8.53(d,J=5.6Hz,1H), 8.30(s,1H), 8.10(d,J=2.4Hz,1H), 7.77(d,J=8.8Hz,2H), 7.4 9(d,J=8.8Hz,1H), 7.28(s,1H), 6.93(d,J=9.2Hz,2H), 6.78-6.86(m,1H), 4.24(t,J=1 1.6Hz,1H), 4.00(d,J=12.8Hz,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=6.4Hz,2H), 0.88(d,J=6.0Hz,2H).

[0188] Example D: 2-(4-((4-ethylpyridine-3-yl)(6-(trifluoromethyl)pyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (compound 4): [ka]

[0189] Step 1: tert-butyl 4-((6-(trifluoromethyl)pyridine-3-yl)(4-vinylpyridine-3-yl)amino)piperidine-1-carboxylate [ka]

[0190] 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)-butyl-phosphane (23.5 mg, 0.066 mmol), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (303.0 mg, 1.97 mmol) in water (1 mL) and toluene (9 mL) was purged three times with N2. The mixture was heated to 120°C for 1 hour under microwave conditions.

[0191] The reaction 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 flash chromatography (0-50% ethyl acetate in petroleum ether) to obtain the title compound (200 mg, 0.646 mmol, 68%). LC-MS (ESI)[M+H]+=449.2.

[0192] Step 2: tert-butyl 4-((4-ethylpyridine-3-yl)(6-(trifluoromethyl)pyridine-3-yl)amino)piperidine-1-carboxylate [ka]

[0193] 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 obtain the title compound (180 mg, 0.40 mmol, 90% yield). LC-MS (ESI)[M-56+H]+=395.1.

[0194] Step 3: 4-Ethyl-N-(piperidine-4-yl)-N-(6-(trifluoromethyl)pyridine-3-yl)pyridine-3-amine hydrochloride [ka]

[0195] 180.0 mg, 0.40 mmol of tert-butyl-4-[(4-ethyl-3-pyridyl)-[6-(trifluoromethyl)-3-pyridyl]amino]piperidine-1-carboxylate was dissolved in HCl / dioxane (4 mL, 4 M) and stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (200 mg, 0.0034 mmol, yield 0.90%). LC-MS(ESI)[M+H]+=350.2.

[0196] Step 4: 2-(4-((4-ethylpyridine-3-yl)(6-(trifluoromethyl)pyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (compound 4): [ka]

[0197] To a solution of N-(4-ethyl-3-pyridyl)-N-(4-piperidyl)-6-(trifluoromethyl)pyridine-3-amine (80.0 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (0.12 mL, 0.68 mol) was added at 0°C, and the mixture was stirred at 0°C for 5 minutes. Then, 2-chloropyrimidine-5-carbonitride (32 mg, 0.23 mmol) was added. The reaction mixture was then stirred at 25°C for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by silica flash chromatography (0-30% ethyl acetate in petroleum ether) to obtain the title compound (11.6 mg, 0.0026 mmol, yield 12%). LCMS(ESI)[M+H]+=454.2.

[0198] Compound 4: 1 H NMR(400MHz,CD3OD)δ8.57-8.52(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), 4.99(d,J) =13.6Hz,2H), 4.64-4.48(m,1H), 3.22-3.11(m,2H), 2.65(s,2H), 2.22-2.02(m,2H), 1.39-1.28(m,2H), 1.18(t,J=7.6Hz,3H).

[0199] Example E: 2-(4-((4-methoxypyridine-3-yl)(6-(trifluoromethyl)pyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (Compound 5): [ka]

[0200] Step 1: tert-butyl 4-[(4-methoxy-3-pyridyl)amino]piperidine-1-carboxylate [ka]

[0201] To a solution of 4-methoxypyridine-3-amine (10 g, 80.55 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (19.26 g, 96.66 mmol) in isopropyl acetate (100 mL), NaBH(OAc)3 (20.49 g, 96.66 mmol) was added and the mixture was stirred at 0°C for 0.1 hours. 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 hours, and then stirred at 30°C for 24 hours. The reaction mixture was prepared with saturated aqueous NaHCO3 (200 mL) and stirred for 30 minutes. The resulting mixture was extracted with ethyl acetate (150 mL x 3) and the combined organic layer was 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 changed to using 3% to 10% methanol in DCM) to obtain 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=6.0Hz,1H), 8.05(s,1H), 7.32(d,J=6.0Hz,1H), 5.84(d,J=8.4Hz,1 H), 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).

[0202] Step 2: tert-butyl 4-((4-methoxypyridine-3-yl)(5-(trifluoromethyl)pyridine-2-yl)amino)piperidine-1-carboxylate [ka]

[0203] 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, purged three times with N2, and then stirred at 120°C for 12 hours under an N2 atmosphere. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica flash chromatography (0-60% ethyl acetate in petroleum ether) to obtain the title compound (2.78 g, 6.14 mmol, yield 63%). LCMS(ESI)[M+H]+=453.3

[0204] Step 3: 4-Methoxy-N-(piperidine-4-yl)-N-(6-(trifluoromethyl)pyridine-3-yl)pyridine-3-amine [ka]

[0205] To a solution of tert-butyl 4-[(4-methoxy-3-pyridyl)-[6-(trifluoromethyl)-3-pyridyl]amino]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 obtain the title compound (510 mg, 1.31 mmol, 99% yield). LCMS(ESI)[M+H]+=353.2.

[0206] Step 4: 2-(4-((4-methoxypyridine-3-yl)(6-(trifluoromethyl)pyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (compound 5): [ka]

[0207] To a solution of N-(4-methoxy-3-pyridyl)-N-(4-piperidyl)-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) at 0°C, 2-chloropyrimidine-5-carbonitrile (22 mg, 0.15 mmol) was added and the mixture was stirred for 1 hour. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic matter was 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) to obtain the title compound (27.8 mg, 0.0574 mmol, yield 45%). LCMS(ESI)[M+H]+=456.2

[0208] Compound 5: 1 H NMR(400MHz,CDCl3)δppm 8.58(d,J=5.2Hz,1H), 8.47(s,2H), 8.28(s,1H), 8.01(s,1H), 7.45(d,J=8.8Hz,1H), 7.00(d,J=5.2Hz,1H), 6.84(d,J=7.2Hz,1H) ), 5.01(d,J=13.2Hz,2H), 4.23(t,J=11.6Hz,1H), 3.82(s,3H), 3.01-3.10(m,1H), 2.15(d,J=13.2Hz,2H), 1.40(d,J=9.2Hz,2H).

[0209] Example F: 1-(4-((4-cyclopropylpyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)ethane-1-one (compound 6): [ka]

[0210] Step 1: tert-butyl 4-[N-(4-chloro-3-pyridyl)-4-(trifluoromethyl)anilino]piperidine-1-carboxylate [ka]

[0211] 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, purity 10%) and tBuONa (740 mg, 7.70 mmol) in toluene (20 mL) was degassed, purged three times with N2, and then stirred at 120 °C for 12 hours under an N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-40% ethyl acetate in petroleum ether) to obtain the title compound (420 mg, 921.25 μmol, yield 47.88%). LCMS(ESI)[M-56+H]+=400.2

[0212] Step 2: tert-butyl 4-((4-cyclopropylpyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate [ka]

[0213] 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)-butyl-phosphane (39 mg, 110 μmol), and Cs2CO3 (536.00 mg, 1.65 mmol) in H2O (0.4 mL) and toluene (4 mL) was degassed, purged three times with N2, and then stirred at 120°C for 1 hour under microwave conditions. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (using 0-45% ethyl acetate in petroleum ether as an eluent) to obtain the title compound (240 mg). LCMS(ESI)[M+H]+=462.3.

[0214] Step 3: 4-Cyclopropyl-N-(piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine [ka]

[0215] To a solution of tert-butyl 4-[N-(4-cyclopropyl-3-pyridyl)-4-(trifluoromethyl)anilino]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 obtain the title compound (200 mg, crude) as the HCl salt. LCMS(ESI): [M+H]+=362.2.

[0216] Step 4: 1-(4-((4-cyclopropylpyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)ethane-1-one (compound 6): [ka]

[0217] To a solution of 4-cyclopropyl-N-(4-piperidyl)-N-[4-(trifluoromethyl)phenyl]pyridine-3-amine (100 mg, 277 μmol) and acetyl chloride (43.44 mg, 553.40 μmol) in dichloromethane (2 mL), triethylamine (84 mg, 830 μmol) was added at 0 °C, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified by reverse-phase HPLC (Welch Xtimate C18 150*30 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 29%~59%, 7 min) to obtain the title compound (33.3 mg, 82.54 μmol, yield 30%). LC-MS (ESI) [M+H]+=403.9.

[0218] Compound 6: 1 H NMR (400MHz, CDCl3) δ8.57-8.41(m,1H), 8.29-8.14(m,1H), 7.46-7.39(m,2H), 6. 80-6.68(m,1H), 6.54(d,J=8.8Hz,2H), 4.79-4.75(m,1H), 4.26-4.16(m,1H), 3.9 6-3.88(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).

[0219] Example G: 1-(4-((4-cyclopropylpyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)propan-1-one (compound 7) [ka]

[0220] To a solution of 4-cyclopropyl-N-(4-piperidyl)-N-[4-(trifluoromethyl)phenyl]pyridine-3-amine (50 mg, 125.67 μmol) and propanoyl chloride (23.26 mg, 251.34 μmol) in dichloromethane (2 mL), triethylamine (38 mg, 377.01 μmol) was added, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (Welch Xtimate C18 150*30 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 29%~59%, 7 min) to obtain the title compound (compound 7, 33.3 mg, 79.77 μmol, yield 63%). LCMS(ESI)[M+H]+=418.0

[0221] Compound 7: 1 H NMR (400MHz, CDCl3) δ8.54-8.41(m,1H), 8.27-8.17(m,1H), 7.45-7.39(m,2H), 6.80-6.7 2(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=7.2Hz,2H), 2.16-2.08(m,2H), 1.92-1.85 (m,1H), 1.41-1.30(m,2H), 1.12(t,J=7.6Hz,3H), 1.08-1.03(m,2H), 0.82-0.81(m,2H).

[0222] Example H: 2-(4-((4-cyclopropoxypyridine-3-yl)(6-(trifluoromethyl)pyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (compound 8): [ka]

[0223] Step 1: 4-Cyclopropoxy-3-nitropyridine [ka]

[0224] 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), 4-chloro-3-nitropyridine (2.2 g, 13.88 mmol) was added at 0°C and the mixture was stirred at that temperature for 2 hours under an N2 atmosphere. 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 flash silica gel chromatography (using 0-30% ethyl acetate in petroleum ether as an eluent) to obtain the title compound (1.93 g, 10.50 mmol, 76% yield). LCMS(ESI)[M+H]+=181.0.

[0225] Step 2: 4-Cyclopropoxypyridine-3-amine [ka]

[0226] 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, purged three times with H2, and then stirred at 25°C for 1 hour under an H2 (15 psi) atmosphere. The reaction mixture was filtered and concentrated under vacuum to obtain the title compound (1.73 g, 11.52 mmol, 97% yield). LCMS(ESI)[M+H]+=151.2.

[0227] Step 3: tert-butyl 4-((4-cyclopropoxypyridine-3-yl)amino)piperidine-1-carboxylate [ka]

[0228] To a solution of 4-(cyclopropoxy)pyridine-3-amine (1.73 g, 11.52 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (3.44 g, 17.28 mmol) in isopropyl acetate (30 mL), NaBH(OAc)3 (2.93 g, 13.82 mmol) was added at 0°C, and then TFA (3.94 g, 34.56 mmol, 2.56 mL) was added dropwise to the mixture at °C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was prepared with saturated NaOH aqueous solution (50 mL) and stirred for 10 minutes. The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (using 0-3% methanol in dichloromethane as an eluent) to obtain the title compound (1.65 g, 4.95 mmol, 43% yield). LC-MS(ESI)[M+H]+=334.3.

[0229] Step 4: tert-butyl 4-((4-cyclopropoxypyridine-3-yl)(6-(trifluoromethyl)pyridine-3-yl)amino)piperidine-1-carboxylate [ka]

[0230] 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, purged three times with N2, and then stirred at 120°C for 24 hours under an N2 atmosphere. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (using 0-60% ethyl acetate in petroleum ether as an eluent) to obtain the title compound (319 mg, 667 μmol, 44% yield). LC-MS(ESI)[M+H]+=479.3.

[0231] Step 5: 4-Cyclopropoxy-N-(piperidine-4-yl)-N-(6-(trifluoromethyl)pyridine-3-yl)pyridine-3-amine. [ka]

[0232] To a solution of tert-butyl 4-[[4-(cyclopropoxy)-3-pyridyl]-[6-(trifluoromethyl)-3-pyridyl]amino]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 obtain the title compound (78 mg, 206.14 μmol crude product) as a yellow solid. LC-MS(ESI)[M+H]+=379.2.

[0233] Step 6: 2-(4-((4-cyclopropoxypyridine-3-yl)(6-(trifluoromethyl)pyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (compound 8): [ka]

[0234] To a solution of N-[4-(cyclopropoxy)-3-pyridyl]-N-(4-piperidyl)-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), 2-chloropyrimidine-5-carbonitrile (28.76 mg, 206.14 μmol) was added at 0°C, and the mixture was stirred at °C for 0.5 hours. 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 obtain the crude residue. The residue was purified by reverse-phase HPLC (Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 39%~69%, 7 min) to obtain the title compound (55.1 mg, 114.44 μmol, yield 56%). LC-MS(ESI)[M+H]+=482.4

[0235] Compound 8: 1 H NMR(400MHz,CDCl3)δ8.55(d,J=5.6Hz,1H), 8.47(s,2H), 8.24(s,1H), 7.98(d, J=2.8Hz,1H), 7.46-7.41(m,1H), 7.31(d,J=5.6Hz,1H), 6.80(dd,J=2.8,8.8Hz ,1H), 5.04-4.96(m,2H), 4.25-4.16(m,1H), 3.80-3.74(m,1H), 3.09-3.00(m,2 H), 2.15-2.10(m,2H), 1.44-1.36(m,2H), 0.85-0.77(m,2H), 0.60-0.53(m,2H).

[0236] Example I: 4-(4-((4-methoxypyridine-3-yl)(4-(methylsulfonyl)phenyl)amino)piperidine-1-yl)benzonitrile: (Compound 9) [ka]

[0237] Step 1: tert-butyl 4-((4-methoxypyridine-3-yl)(4-(methylsulfonyl)phenyl)amino)piperidine-1-carboxylate: [ka]

[0238] A mixture of tert-butyl 4-[(4-methoxy-3-pyridyl)amino]piperidine-1-carboxylate (1 g, 3.25 mmol), 1-bromo-4-methylsulfonylbenzene (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 for 12 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (0-5% MeOH in DCM) to obtain the title compound (430 mg, 931.60 μmol, yield 29%). LC-MS (ESI), [M+H]+=462.3.

[0239] Step 2: 4-Methoxy-N-(4-(methylsulfonyl)phenyl)-N-(piperidine-4-yl)pyridine-3-amine: [ka]

[0240] Tert-butyl-4-(N-(4-methoxy-3-pyridyl)-4-methylsulfonyl-anilino)piperidine-1-carboxylate (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 obtain the title compound (336 mg, 929.57 μmol, yield 99.78%).

[0241] Step 3: 4-(4-((4-methoxypyridine-3-yl)(4-(methylsulfonyl)phenyl)amino)piperidine-1-yl)benzonitrile (compound 9): [ka]

[0242] A mixture of 4-methoxy-N-(4-methylsulfonylphenyl)-N-(4-piperidyl)pyridine-3-amine (50 mg, 138.33 μmol), 4-fluorobenzonitrile (25.13 mg, 207.49 μmol), and K2CO3 (95.59 mg, 691.64 μmol) in DMSO (3 mL) was then stirred at 120 °C for 12 hours. The reaction mixture was purified by pre-HPLC (column: Welch Xtimate C18 150*30 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 22%~52%, 7 min) to obtain the title compound (25 mg, 54.05 μmol, yield 39%). LC-MS (ESI), [M+H]+=463.3.

[0243] Compound 9: 1 H NMR(400MHz,CD3OD)8.51(s,1H), 8.19(s,1H), 7.68(d,J=8.8Hz,3H), 7.48(d,J=8.4Hz,2H), 7.27(d,J=5.6Hz,1H), 6.97(d,J=8.4Hz,2H), 6.7 0(d,J=8.0Hz,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).

[0244] Example J: 4-Cyclopropyl-N-(1-(4-(cyclopropylsulfonyl)phenyl)piperidine-4-yl)-N-(6-(trifluoromethyl)pyridine-3-yl)pyridine-3-amine (Compound 10): [ka]

[0245] The title compound was synthesized following the same procedure as in Example C (Compound 3).

[0246] The compound was purified by reverse-phase HPLC (Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 37%~67%, 7 min) to obtain the title compound (1 mg, 1.84 μmol, yield 2.23%). LC-MS (ESI), [M+H]+=543.0.

[0247] Compound 10: 1 H NMR(400MHz,CDCl3)δ8.54-8.48(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=9.2Hz,2H), 6.82-6.76(m,2H), 4.27-4.1 7(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).

[0248] Example K: 6-(4-((4-methoxypyridine-3-yl)(6-(trifluoromethyl)pyridine-3-yl)amino)piperidine-1-yl)nicotinonitrile (compound 11): [ka]

[0249] The title compound was synthesized following the same procedure as in Example E (Compound 5).

[0250] The title compound was purified by flash silica gel chromatography (using 0-30% ethyl acetate in petroleum ether as an eluent) to obtain the title compound (30 mg, 66.01 μmol, 32% yield). LC-MS (ESI), [M+H]+ = 455.3.

[0251] Compound 11: 1 H NMR (400MHz, CDCl3) δ8.58-8.54(m,1H), 8.39-8.36(m,1H), 8.26-8.24(m,1H) ), 8.01(d,J=2.8Hz,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).

[0252] Example L: 4-Methoxy-N-(1-(5-(methylsulfonyl)pyrimidine-2-yl)piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 12): [ka]

[0253] Step 1: tert-butyl 4-[N-(4-methoxy-3-pyridyl)-4-(trifluoromethyl)anilino]piperidine-1-carboxylate [ka]

[0254] To a mixture of tert-butyl 4-[(4-methoxy-3-pyridyl)amino]piperidine-1-carboxylate (2 g, 6.51 mmol) and 1-bromo-4-(trifluoromethyl)benzene (2.93 g, 13.01 mmol) in toluene (20 mL), tBu3P Pd G2 (333.39 mg, 650.65 μmol) and tBuONa (1.88 g, 19.52 mmol) were added in one batch under N2, and the reaction was stirred at 120 °C for 24 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica flash chromatography (0-40% ethyl acetate in petroleum ether) to obtain the title compound (2.9 g, 6.42 mmol, 99% yield). LC-MS (ESI), [M+H]+=452.2.

[0255] Step 2: 4-Methoxy-N-(piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride [ka]

[0256] tert-butyl-4-[N-(4-methoxy-3-pyridyl)-4-(trifluoromethyl)anilino]piperidine-1-carboxylate (2.9 g, 6.42 mmol) was dissolved in dioxane (3.0 mL), and HCl / dioxane (4 M, 10 mL) was added. The mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain the title compound (2.4 g, 6.19 mmol, 96% yield) as a yellow solid. LC-MS (ESI), [M+H]+=352.1.

[0257] Step 3: 4-Methoxy-N-(1-(5-(methylsulfonyl)pyrimidine-2-yl)piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 12): [ka]

[0258] To a solution of 4-methoxy-N-(4-piperidyl)-N-[4-(trifluoromethyl)phenyl]pyridine-3-amine (50 mg, 128.92 μmol) and 2-chloro-5-methylsulfonylpyrimidine (24.83 mg, 128.92 μmol) in DMF (1 mL), DIEA (49.99 mg, 386.77 μmol) was added all at once at 0°C, and the mixture was stirred at 0°C for 0.5 hours. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (water (NH3H2O+NH4HCO3)-ACN); B%: 45%~75%, 7 min) to obtain the title compound (36.2 mg, 71.33 μmol, yield 55.32%). LC-MS (ESI), [M+H]+=508.1.

[0259] Compound 12: 1 H NMR(400MHz,CDCl3)δ8.66(s,2H), 8.53(d,J=5.6Hz,1H), 8.22(s,1H), 7.40(d,J=8.8Hz,2H), 7.00-6.98(m,1H), 7.00-6.93(m,1H), 6.55(d, J=8.8Hz,2H), 5.04(d,J=13.6Hz,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).

[0260] Example M: ​​4-Methoxy-N-(4-(trifluoromethyl)phenyl)-N-(1-(5-(trifluoromethyl)pyridine-2-yl)piperidine-4-yl)pyridine-3-amine (Compound 13): [ka]

[0261] The title compound was synthesized following the same procedure as in Example L (Compound 12).

[0262] The title compound was purified by preparative HPLC (50% acetonitrile / 0.2% formic acid in water) to obtain the title compound (120 mg, 241.72 μmol, yield 42.58%). LC-MS (ESI) showed [M+H]+=497.2.

[0263] Compound 13: 1 H NMR(400MHz,CD3OD)8.46(d,J=5.6Hz,1H), 8.28(s,1H), 8.16(s,1H), 7.69-7.60(m,1H), 7.39(d,J=8.8Hz,2H), 7.23(d,J=5.6Hz,1H), 6.85(d,J =9.2Hz,1H), 6.65(d,J=8.8Hz,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).

[0264] Example N: 6-(4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)nicotinonitrile (compound 14): [ka]

[0265] The title compound was synthesized following the same procedure as in Example L (Compound 12).

[0266] The title compound was purified by preparative HPLC (50% acetonitrile / 0.2% formic acid in water) to obtain the title compound (120 mg, 264.63 μmol, yield 46.49%). LC-MS (ESI), [M+H]+=454.2.

[0267] Compound 14: 1H NMR(400MHz,CD3OD)8.46(d,J=5.6Hz,1H), 8.34(d,J=1.6Hz,1H), 8.16(s,1H), 7.69-7.6(m,1H), 7.39(d,J=8.8Hz,2H), 7.22(d,J=5.6Hz,1H), 6.82( d,J=8.8Hz,1H), 6.65(d,J=8.8Hz,2H), 4.59-4.56(m,2H), 4.44-4.34(m,1 H), 3.83(s,3H), 3.18-3.05(m,2H), 2.14-2.12(m,2H), 1.36-1.28(m,2H).

[0268] Example O: 2-(4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (Compound 15): [ka]

[0269] The title compound was synthesized following the same procedure as in Example L (Compound 12).

[0270] The title compound was purified by preparative HPLC (35-50% acetonitrile / 0.2% formic acid in water) to obtain the title compound (120 mg, 264.06 μmol, yield 46.39%). LC-MS (ESI), [M+H]+=455.2.

[0271] Compound 15: 1 H NMR(400MHz,CD3OD)8.54(s,2H), 8.46(d,J=6.4Hz,1H), 8.16(s,1H), 7.39(d,J=8.4Hz,2H), 7.22(d,J=2.0Hz,1H), 6.65(d,J=8.4Hz, 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).

[0272] Example P: 4-Methoxy-N-(1-(4-(methylsulfonyl)phenyl)piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 16): [ka]

[0273] The title compound was synthesized following the same procedure as in Example C (Compound 3).

[0274] The title compound was purified by preparative HPLC (Welch Xtimate C18 150*30mm*5um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 50%~80%, 8 min) to obtain the title compound (82.5 mg, 163.19 μmol, yield 48.53%). LC-MS (ESI), [M+H]+=506.1.

[0275] Compound 16: 1 H NMR(400MHz,CD3OD)8.47(d,J=6.0Hz,1H), 8.18(s,1H), 7.69(d,J=8.8Hz,2H), 7.39(d,J=8.8Hz,2H), 7.24(d,J=6.4Hz,1H), 7.03(d,J=8.8Hz,2H) , 6.64(d,J=8.8Hz,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).

[0276] Example Q: 4-Methoxy-N-(1-(5-(methylsulfonyl)pyrimidine-2-yl)piperidine-4-yl)-N-(6-(trifluoromethyl)pyridine-3-yl)pyridine-3-amine (Compound 17): [ka]

[0277] The title compound was synthesized following the same procedure as in Example E (Compound 5).

[0278] The title compound was purified by pre-HPLC (column: Welch Xtimate C18 150*30mm×5um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 37%~67%, 8 min) to obtain the title compound (180 mg, 353.97 μmol, yield 44.40%). LC-MS (ESI), [M+H]+=509.1.

[0279] Compound 17: 1 H NMR(400MHz,CD3OD)8.65(s,2H), 8.51(d,J=5.6Hz,1H), 8.24(s,1H), 7.87(d,J=2.8Hz,1H), 7.58(d,J=8.8Hz,1H), 7.27(d,J=5.6Hz,1H), 7.18( dd,J=2.8,8.8Hz,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).

[0280] Example R: 2-(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (compound 18): [ka]

[0281] Step 1: tert-butyl 4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate [ka]

[0282] 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, purged three times with N2, and then stirred at 120°C for 24 hours under an N2 atmosphere. The mixture was concentrated under reduced pressure, and the residue was purified by silica flash chromatography (0-40% ethyl acetate in petroleum ether) to obtain the title compound (1600 mg, 3.45 mmol, yield 52.98%). LC-MS (ESI), [M+H]+=450.1.

[0283] Step 2: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(piperidine-4-yl)pyridine-3-amine hydrochloride [ka]

[0284] tert-butyl-4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate (1.6 g, 3.56 mmol) was dissolved in dioxane (3.0 mL), and HCl / dioxane (4 M, 6 mL) was added. The mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain the title compound (1.37 g, 3.56 mmol, 100% yield). LC-MS (ESI), [M+H]+=350.1.

[0285] Step 3: 2-(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)-pyrimidine-5-carbonitrile (compound 18): [ka]

[0286] To a mixture of N-[4-(difluoromethoxy)phenyl]-4-methoxy-N-(4-piperidyl)pyridine-3-amine (260 mg, 744.19 μmol) and triethylamine (301.22 mg, 2.98 mmol) in DMF (5 mL), 2-chloropyrimidine-5-carbonitrile (103.85 mg, 744.19 μmol) was added under N2 at 0°C. The mixture was stirred at 0°C for 30 minutes. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (water (NH3H2O+NH4HCO3)-ACN); B%: 45%~75%, 7 min) to obtain the title compound (153.4 mg, 339.04 μmol, yield 45.56%). LC-MS (ESI), [M+H]+=453.2.

[0287] Compound 18: 1 H NMR(400MHz,CD3OD)δ8.53(s,2H), 8.41(d,J=5.6Hz,1H), 8.14(s,1H), 7.18(d,J=5.6Hz,1H), 6.94(d,J=9.2Hz,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).

[0288] Example S: 2-(4-((4-(difluoromethoxy)phenyl)(4-methylpyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (compound 19): [ka]

[0289] Step 1: tert-butyl-4-((4-(difluoromethoxy)phenyl)(4-methylpyridine-3-yl)amino)piperidine-1-carboxylate [ka]

[0290] 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, purged three times with N2, and then stirred at 120°C for 12 hours under an N2 atmosphere. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (using 0-35% ethyl acetate in petroleum ether as an eluent) to obtain the title compound (0.99 g, 2.28 mmol, yield 66.55%). LC-MS (ESI), [M+H]+=434.2.

[0291] Step 2: N-(4-(difluoromethoxy)phenyl)-4-methyl-N-(piperidine-4-yl)pyridine-3-amine [ka]

[0292] To a solution of tert-butyl-4-[4-(difluoromethoxy)-N-(4-methyl-3-pyridyl)anilino]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 at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.9 g, crude, HCl salt).

[0293] Step 3: 2-(4-((4-(difluoromethoxy)phenyl)(4-methylpyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (compound 19): [ka]

[0294] DIEA (524.19 mg, 4.06 mmol) was added to a solution of N-[4-(difluoromethoxy)phenyl]-4-methyl-N-(4-piperidyl)pyridine-3-amine (300 mg, 811.17 μmol) and 2-chloropyrimidine-5-carbonitrile (135.83 mg, 973.40 μmol) in acetonitrile (5 mL). The mixture was stirred at 0°C for 0.5 hours. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (Boston Prime C18 150*30 mm*5 μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 60%~90%, 7 min]) to obtain the title compound (100.8 mg, 230.95 μmol, yield 28.47%). LCMS(ESI), [M+H]+=437.1

[0295] Compound 19: 1 H NMR(400MHz,CD3OD)δ8.59-8.46(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).

[0296] Example T: 4-Methoxy-N-(1-(1-methyl-1H-pyrazole-5-yl)piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 20): [ka]

[0297] The title compound was synthesized following the same procedure as in Example C (Compound 3).

[0298] The title compound was purified by preparative HPLC (Welch Xtimate C18 150*30mm*5um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 25%~40%, 8 min) to obtain the title compound (75 mg, 173.83 μmol, yield 20.36%). LC-MS (ESI), [M+H]+=432.2.

[0299] Compound 20: 1 H NMR(400MHz,CD3OD)8.51(d,J=6.0Hz,1H), 8.23(s,1H), 7.39(d,J=8.8Hz,2H), 7.30-7.27(m,2H), 6.63(d,J=8.8Hz,2H), 5.90(d,J=2 .0Hz,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).

[0300] Example U: (R)-(4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)(tetrahydrofuran-3-yl)methanone (compound 21): [ka]

[0301] To a mixture of 4-methoxy-N-(4-piperidyl)-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), DIEA (220.70 mg, 1.71 mmol) and HATU (324.65 mg, 853.82 μmol) were added in one step at 20°C. The mixture was stirred at 20°C for 1 hour. The reaction mixture was purified by pre-HPLC (water (NH3H2O+NH4HCO3)-ACN]; B%: 45%~75%, 7 min) to obtain the title compound (45.9 mg, 102.12 μmol, yield 17.94%, purity 100%). LC-MS (ESI), [M+H]+=450.2.

[0302] Compound 21: 1 H NMR(400MHz, CDCl3) δ8.55(d,J=5.6Hz,1H), 8.22(s,1H), 7.39(d,J=8.8Hz,2H ), 6.99(d,J=5.6Hz,1H), 6.52(d,J=8.8Hz,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).

[0303] Example V: 1-(4-((4-ethoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)-2-methyl-piperidine-1-yl)propan-1-one (Compound 22): [ka]

[0304] Step 1: tert-butyl-4-[N-(4-ethoxy-3-pyridyl)-4-(trifluoromethyl)anilino]-2-methyl-piperidine-1-carboxylate [ka]

[0305] To a mixture of tert-butyl 4-[(4-ethoxy-3-pyridyl)amino]-2-methylpiperidine-1-carboxylate (500 mg, 1.49 mmol) and 1-bromo-4-(trifluoromethyl)benzene (670.78 mg, 2.98 mmol) in toluene (20 mL), tBu3P Pd G2 (76.38 mg, 149.06 μmol) and tBuONa (429.73 mg, 4.47 mmol) were added in one step, and the mixture was stirred at 120 °C for 19 hours under N2. The mixture was concentrated under vacuum, and the residue was purified by silica flash chromatography (0-30% ethyl acetate in petroleum ether) to obtain the title compound (600 mg, 1.25 mmol, yield 83.94%). LCMS (ESI), [M+H]+=480.2.

[0306] 1 H NMR (400MHz, CD3CN) δ8.50-8.45(m,1H), 8.19(s,1H), 7.40(d,J=8.8Hz,2H), 7.10-7.04(m,1H), 6.60(d,J=8.8Hz,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).

[0307] Step 2: 4-Ethoxy-N-(2-methyl-4-piperidyl)-N-[4-(trifluoromethyl)phenyl]pyridine-3-amine [ka]

[0308] To a solution of tert-butyl 4-[N-(4-ethoxy-3-pyridyl)-4-(trifluoromethyl)anilino]-2-methyl-piperidine-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 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (520 mg, 1.25 mmol, yield 99.93%, HCl salt) as a yellow solid. LC-MS (ESI), [M+H]+=380.1.

[0309] Step 3: 1-(4-((4-ethoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)-2-methyl-piperidine-1-yl)propan-1-one (compound 22): [ka]

[0310] To a solution of 4-ethoxy-N-(2-methyl-4-piperidyl)-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) at 0°C, propanoyl chloride (182.89 mg, 1.98 mmol) was added dropwise. The mixture was stirred at 0°C for 1 hour. The mixture was concentrated under vacuum, and the resulting residue was purified by pre-HPLC (water (0.05% FA)-ACN, 35%~65%) to obtain the title compound (280 mg, 623.68 μmol, yield 47.33%). LC-MS (ESI), [M+H]+=436.2.

[0311] Compound 22: 1H NMR (400MHz, CDCl3) δ8.55(d,J=5.6Hz,1H), 8.29(s,1H), 8.15(s,1H), 7.38(d,J =8.8Hz,2H), 7.00(d,J=5.6Hz,1H), 6.53(d,J=8.8Hz,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=7.2Hz,3H), 1.22-1.16(m,6H).

[0312] Example W: 1-(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3yl)amino)piperidine-1-yl)propan-1-one (compound 23): [ka]

[0313] The title compound was synthesized following the same procedure as in Example V (Compound 22).

[0314] The title compound was purified by pre-HPLC (column: Welch Xtimate C18 150*30mm×5um; mobile phase: water (0.05% FA)-ACN, 20%~50%, 8 min) to obtain the title compound (87.1 mg, 214.83 μmol, yield 41.44%, purity 100%). LC-MS (ESI), [M+H]+=406.1.

[0315] Compound 23: 1H NMR(400MHz, CDCl3)8.50(d,J=5.6Hz,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=8.8Hz,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=7.6Hz,3H).

[0316] Example X: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(5-(methylsulfonyl)pyrimidine-2-yl)piperidine-4-yl)pyridine-3-amine (Compound 24): [ka]

[0317] The title compound was synthesized following the same procedure as in Example L (Compound 12).

[0318] The title compound was purified by preparative HPLC (26-35% acetonitrile / 0.2% formic acid in water) to obtain the title compound (172.4 mg, 334.20 μmol, yield 42.98%, purity 98%). LC-MS (ESI), [M+H]+=506.0.

[0319] Compound 24: 1 H NMR(400MHz,CDCl3)8.66(s,2H), 8.49(d,J=5.6Hz,1H), 8.23(s,1H), 7.00-6.93(m,3H), 6.58(s,1H), 6.54-6.49(m,2H), 6.4 1-6.18(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).

[0320] Example Y: 2-(4-((6-(difluoromethoxy)pyridine-3-yl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (compound 25): [ka]

[0321] Step 1: tert-butyl 4-((6-chloropyridine-3-yl)(4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate [ka]

[0322] 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 toluene (20 mL)) was degassed, purged three times with N2, and then stirred at 120°C for 12 hours under an N2 atmosphere. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by silica flash chromatography (20-70% ethyl acetate in petroleum ether) to obtain the title compound (4.0 g, 9.55 mmol, yield 73.39%). LCMS(ESI)[M+H]+=419.2.

[0323] Step 2: tert-butyl 4-((6-hydroxypyridine-3-yl)(4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate [ka]

[0324] To a solution of tert-butyl-4-[(6-chloro-3-pyridyl)-(4-methoxy-3-pyridyl)amino]piperidine-1-carboxylate (2000 mg, 4.77 mmol) in dioxane (20 mL) and H2O (4 mL), ditert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphan (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 obtain the title compound (1.91 g, 3.86 mmol, yield 80.99%, purity 81%), and the crude product was used directly in the next step. LCMS(ESI)[M+H]+=401.2.

[0325] Step 3: tert-butyl 4-((6-(difluoromethoxy)pyridine-3-yl)(4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate [ka]

[0326] A mixture of tert-butyl 4-[(6-hydroxy-3-pyridyl)-(4-methoxy-3-pyridyl)amino]piperidine-1-carboxylate (700 mg, 1.29 mmol, purity 74%) was dissolved in CH3CN (6 mL), KOH (6 M, 2.58 mL), and difluoromethyltrifluoromethanesulfonate (776 mg, 3.88 mmol), and the mixture was then stirred at 25°C for 0.03 hours. 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 flash silica gel chromatography (0-60% ethyl acetate / petroleum ether eluent), and then purified by preparative TLC (petroleum ether / ethyl acetate / ETOH = 4 / 3 / 1) to obtain the title compound (240 mg, yield 41%). LCMS(ESI)[M+H]+=451.1.

[0327] Step 4: 6-(difluoromethoxy)-N-(4-methoxypyridine-3-yl)-N-(piperidine-4-yl)pyridine-3-amine hydrochloride [ka]

[0328] To a solution of tert-butyl 4-[[6-(difluoromethoxy)-3-pyridyl]-(4-methoxy-3-pyridyl)amino]piperidine-1-carboxylate (215.07 mg, 477.42 μmol) in dioxane (2 mL), HCl / dioxane (4 M, 2 mL) was added at 25°C, and the mixture was stirred at 25°C for 1 hour. The reaction was concentrated under reduced pressure to obtain the title compound (184 mg, 475.67 μmol, yield 99.63%, HCl salt). LCMS(ESI)[M+H]+=351.1.

[0329] Step 5: 2-(4-((6-(difluoromethoxy)pyridine-3-yl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (compound 25): [ka]

[0330] A mixture of 6-(difluoromethoxy)-N-(4-methoxy-3-pyridyl)-N-(4-piperidyl)pyridine-3-amine (40 mg, 103.41 μmol, HCl salt), 2-chloropyrimidine-5-carbonitride (17.32 mg, 124.09 μmol), and DIEA (40.09 mg, 310.22 μmol) was placed in DMF (2.0 mL), and the mixture 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 layer was washed with brine (30 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude residue. The residue was purified by flash silica gel chromatography (using 0-5% methanol in dichloromethane as an eluent) to obtain the title compound (34 mg, 72.73 μmol, yield 70.34%, purity 97%). LCMS(ESI)[M+H]+=454.1.

[0331] Compound 25: 1 HNMR(400MHz,DMSO-d6):8.71(s,2H), 8.46(d,J=5.6Hz,1H), 8.20(s,1H), 7.54(s,1H), 7.48(t,J=74Hz,1H), 7.19(d,J=5.6Hz,1H), 7.02(d,J= 3.2Hz,1H), 6.87(d,J=8.8Hz,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).

[0332] Example Z: 6-(difluoromethoxy)-N-(4-methoxypyridine-3-yl)-N-(1-(5-(methylsulfonyl)pyrimidine-2-yl)piperidine-4-yl)pyridine-3-amine (compound 26): [ka]

[0333] The title compound was synthesized following the same procedure as in Example Y (Compound 25).

[0334] The residue was purified by flash silica gel chromatography (using 0-5% methanol in dichloromethane as an eluent) to obtain the title compound (40 mg, 77.39 μmol, yield 74.84%). LCMS(ESI)[M+H]+=507.1.

[0335] Compound 26: 1 H NMR(400MHz,CDCl3)8.66(s,2H), 8.49(d,J=5.2Hz,1H), 8.25(s,1H), 7.58(s,1H), 7.27(t,J=75.2Hz,1H), 6.93-6.88(m,2H), 6. 74(d,J=8.8Hz,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).

[0336] Example AA: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(1-methyl-1H-pyrazole-5-yl)piperidine-4-yl)pyridine-3-amine (Compound 27): [ka]

[0337] The title compound was synthesized following the same procedure as in Example C (Compound 3).

[0338] The title compound was purified by preparative TLC (ethanol:ethyl acetate:petroleum ether = 1:3:4) to obtain the title compound (41 mg, 92.60 μmol, yield 16.18%). LC-MS (ESI), [M+H]+ = 430.2.

[0339] Compound 27: 1H NMR(400MHz,CDCl3)8.53(d,J=5.6Hz,1H), 8.30(s,1H), 7.36(d,J=2.0Hz,1H), 7.05-6.93(m,3H), 6.59(s,1H), 6.53(d,J=9.2Hz,2H), 6.43-6.18(m, 1H), 5.80(d,J=2.0Hz,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).

[0340] Example AB: (4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)(pyridine-4-yl)methanone (compound 28): [ka]

[0341] The title compound was synthesized following the same procedure as in Example U (Compound 21).

[0342] The title compound was purified by preparative TLC (10% methanol in dichloromethane) to obtain the title compound (129.8 mg, 285.61 μmol, yield 66.52%). LC-MS (ESI), [M+H]+=455.2.

[0343] Compound 28: 1 H NMR(400MHz,CD3OD)δ8.69-8.59(m,2H), 8.46(d,J=5.6Hz,1H), 8.18(s,1H), 7.43 -7.35(m,2H), 7.22(d,J=5.6Hz,1H), 7.00-6.89(m,2H), 6.80-6.39(m,3H), 4.68( d,J=13.6Hz,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).

[0344] Example AC: (4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)(pyridine-4-yl)methanone (compound 29): [ka]

[0345] The title compound was synthesized following the same procedure as in Example U (Compound 21).

[0346] The title compound was purified by preparative TLC (10% methanol in dichloromethane) to obtain the title compound (135 mg, 295.75 μmol, yield 69.28%). LC-MS (ESI), [M+H]+=457.2.

[0347] Compound 29: 1 H NMR(400MHz,CD3OD)δ8.63(d,J=6.0Hz,2H), 8.51(d,J=5.6Hz,1H), 8.20(s,1H ), 7.42-7.34(m,4H), 7.26(d,J=5.6Hz,1H), 6.64(d,J=8.8Hz,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).

[0348] Example AD: 6-(difluoromethoxy)-N-(4-methoxypyridine-3-yl)-N-(1-(1-methyl-1H-pyrazole-5-yl)piperidine-4-yl)pyridine-3-amine (compound 30): [ka]

[0349] Step 1: N-(1-(3-bromo-1-methyl-4-nitro-1H-pyrazole-5-yl)piperidine-4-yl)-6-(difluoromethoxy)-N-(4-methoxypyridine-3-yl)pyridine-3-amine [ka]

[0350] A mixture of 6-(difluoromethoxy)-N-(4-methoxy-3-pyridyl)-N-(4-piperidyl)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) was added to CH3CN (2.0 mL), and the mixture was then stirred at 80°C for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude residue, and the residue was purified by flash silica gel chromatography (10-45% ethyl acetate in petroleum ether) to obtain the title compound (56 mg, 101.02 μmol).

[0351] Step 2: N-(1-(4-amino-3-bromo-1-methyl-1H-pyrazole-5-yl)piperidine-4-yl)-6-(difluoro-methoxy)-N-(4-methoxypyridine-3-yl)pyridine-3-amine [ka]

[0352] A solution of N-[1-(5-bromo-2-methyl-4-nitropyrazole-3-yl)-4-piperidyl]-6-(difluoromethoxy)-N-(4-methoxy-3-pyridyl)pyridine-3-amine (56 mg, 101.02 μmol) in EtOH (5 mL) and H2O (1 mL) was added in one step, along with NH4Cl (27.02 mg, 505.10 μmol) and Fe (28.21 mg, 505.10 μmol). The mixture was then stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature and then filtered over a diatomaceous earth plug. The filtrate was concentrated. The residue was diluted with ethyl acetate, and the suspension was filtered. The filtrate was concentrated to obtain the title compound (52 mg, 99.17 μmol, yield 98.17%). This was used in the next step without further purification. LCMS(ESI)[M+H]+=513.9.

[0353] Step 3: N-(1-(3-bromo-1-methyl-1H-pyrazole-5-yl)piperidine-4-yl)-6-(difluoromethoxy)-N-(4-methoxypyridine-3-yl)pyridine-3-amine [ka]

[0354] At 0°C, concentrated H2SO4 (103.67 mg, 1.06 mmol) was slowly added to a stirred solution of N-[1-(4-amino-5-bromo-2-methylpyrazole-3-yl)-4-piperidyl]-6-(difluoromethoxy)-N-(4-methoxy-3-pyridyl)pyridine-3-amine (52 mg, 99.17 μmol) in EtOH (6 mL). The reaction mixture was stirred at 0°C for 5 minutes, and then 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 minutes, and then heated to 100°C and stirred for 1 hour. H3PO2 (128.90 mg, 991.68 μmol, 50% purity) was added, and the resulting reaction mixture was stirred at 0-100°C for 3 hours. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (30 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude residue. The residue was purified by flash silica gel chromatography (using 25-45% EE (ethanol / ethyl acetate) in petroleum ether as an eluent) to obtain the title compound (38 mg, 74.61 μmol, yield 75.23%) as a white solid. LC-MS (ESI) [M+H]+ = 511.1.

[0355] Step 4: 6-(difluoromethoxy)-N-(4-methoxypyridine-3-yl)-N-(1-(1-methyl-1H-pyrazole-5-yl)piperidine-4-yl)pyridine-3-amine (compound 30): [ka]

[0356] A mixture of N-[1-(5-bromo-2-methylpyrazole-3-yl)-4-piperidyl]-6-(difluoromethoxy)-N-(4-methoxy-3-pyridyl)pyridine-3-amine (38 mg, 74.61 μmol) and Pd / C (25 mg, 74.61 μmol, purity 10%) in methanol (10 mL) was degassed, purged three times with H2, and then stirred under H2 (15 psi) at 28 °C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by silica gel chromatography (elution with petroleum ether / ethyl acetate / ethanol = 4:3:1, followed by purification by preparative TLC) to obtain the title compound (22 mg, 48.04 μmol, yield 64.40%). LCMS(ESI)[M+H]+=431.2.

[0357] Compound 30: 1 H NMR(400MHz,CDCl3)8.54(d,J=5.6Hz,1H), 8.32(s,1H),7.55(d,J=3.2Hz,1 H), 7.36-7.27(m,2H), 6.96(d,J=5.6Hz,1H), 6.88(d,J=3.2Hz,1H), 6.73(d ,J=8.8Hz,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).

[0358] Example AE: (4-chlorophenyl)(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)methanone (compound 31): [ka]

[0359] The title compound was synthesized following the same procedure as in Example U (Compound 21).

[0360] The title compound was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 50%~80%, 10 min) to obtain the title compound (125 mg, 255.16 μmol, yield 44.57%). LC-MS (ESI), [M+H]+=488.0.

[0361] Compound 31: 1 H NMR (400MHz, CDCl3) δ8.53(s,1H), 8.24(s,1H), 7.43-7.34(m,2H), 7.33-7.28(m,2H), 6.95(d,J=9.2Hz,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).

[0362] Example AF: 4-(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-carbonyl)benzonitrile (compound 32): [ka]

[0363] The title compound was synthesized following the same procedure as in Example U (Compound 21).

[0364] The title compound was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 38%~50%, 10 min) to obtain the title compound (110 mg, 227.59 μmol, yield 39.76%). LC-MS (ESI), [M+H]+=479.0.

[0365] Compound 32: 1H NMR(400MHz,CDCl3)δ8.53(d,J=4.8Hz,1H), 8.24(s,1H), 7.70(d,J=8.0Hz,2H), 7.46(d,J=8.0Hz,2H), 6.96(d,J=9.2Hz,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), 3.2 0-3.16(m,1H), 2.95-2.89(m,1H), 2.22-1.93(m,2H), 1.52-1.12(m,2H).

[0366] Example AG: (4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)(4-(methylsulfonyl)phenyl)methanone (compound 33): [ka]

[0367] The title compound was synthesized following the same procedure as in Example U (Compound 21).

[0368] The title compound was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 44%~74%, 10 min) to obtain the title compound (130 mg, 242.11 μmol, yield 42.29%). LC-MS (ESI), [M+H]+=532.0.

[0369] Compound 33: 1H NMR(400MHz,CDCl3)δ8.53(d,J=5.2Hz,1H), 8.25(s,1H), 7.99(d,J=8.4Hz, 2H), 7.54(d,J=8.4Hz,2H), 6.96(d,J=8.8Hz,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).

[0370] Example AH: 6-(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)nicotinonitrile (compound 34): [ka]

[0371] The title compound was synthesized following the same procedure as in Example R (Compound 18).

[0372] The title compound was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 55%~85%, 10 min) to obtain the title compound (104 mg, 223.45 μmol, yield 39.03%). LC-MS (ESI), [M+H]+=452.0.

[0373] Compound 34: 1H NMR(400MHz,CDCl3)δ8.53(d,J=4.8Hz,1H), 8.24(s,1H), 7.70(d,J=8.0Hz,2H), 7.46(d,J=8.0Hz,2H), 6.96(d,J=9.2Hz,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), 3.2 1-3.18(m,1H), 2.94-2.88(m,1H), 2.22-1.93(m,2H), 1.52-1.12(m,2H).

[0374] Example AI: Cyclobutyl(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)methanone (Compound 35): [ka]

[0375] The title compound was synthesized following the same procedure as in Example U (Compound 21).

[0376] The title compound was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 50%~80%, 10 min) to obtain the title compound (115.0 mg, 261.20 μmol, yield 45.63%). LC-MS (ESI), [M+H]+=432.2.

[0377] Compound 35: 1 H NMR(400MHz,CD3OD)δ8.43(d,J=5.6Hz,1H), 8.14(s,1H), 7.19(d,J=5.6Hz,1H), 6.93(d,J=9.2Hz,2H), 6.79-6.39(m,3H), 4.57-4.46(m,

[0378] 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).

[0379] Example AJ: Cyclobutyl(4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)methanone (compound 36): [ka]

[0380] The title compound was synthesized following the same procedure as in Example U (Compound 21).

[0381] The title compound was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 50%~80%, 10 min) to obtain the title compound (131.8 mg, 304.06 μmol, yield 53.42%). LC-MS (ESI), [M+H]+=434.1.

[0382] Compound 36: 1 H NMR(400MHz,CD3OD)δ8.56-8.44(m,1H), 8.25-8.12(m,1H), 7.40(d,J=8.8Hz,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), 3.9 2-3.89(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).

[0383] Example AK: (4-Fluoro-2-(methylsulfonyl)phenyl)(4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)methanone (Compound 37): [ka]

[0384] Step 1: Preparation of tert-butyl 4-((4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate: [ka]

[0385] To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (12.03 g, 60.41 mmol, 1.5 equivalents) in anhydrous dichloromethane (75 mL), 4-methoxypyridine-3-amine (5.0 g, 40.27 mmol, 1.0 equivalent), acetic acid (2.53 mL, 44.30 mmol, 1.1 equivalents), and sodium triacetoxyborohydride (12.80 g, 60.41 mmol, 1.5 equivalents) were sequentially added at room temperature. The resulting reaction mixture was refluxed and stirred for 20 hours. The progress of the reaction was monitored by TLC and ULC-MS, which showed product formation upon complete consumption of the starting materials. The reaction mixture was then cooled to room temperature, the pH was adjusted to approximately 8 with 2 M aqueous sodium hydroxide (100 mL), and the mixture was extracted with dichloromethane (2 × 200 mL). The combined organic layers were dried over anhydrous Na2SO4, the drying agent was filtered, and the solution was concentrated under reduced pressure to obtain the crude residue. The crude material was purified by combiflash chromatography using silica gel eluted with siRNA, and the pure fraction was concentrated under reduced pressure to obtain tert-butyl 4-((4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate (7.80 g, 63%). MS(ESI):C 16 H 25 Calculated mass for N3O3: 307.39; measured value (m / z): 308.2 [M+H] + .

[0386] 1 H NMR(400MHz,CDCl3)δ7.88(s,1H), 7.76(d,J=5.2Hz,1H), 6.83(d,J=5.2Hz,1H), 4.61(d,J=8.4Hz,1H), 3.90(d,J=12.4Hz,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).

[0387] Step 2: Preparation of tert-butyl 4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate: [ka]

[0388] In a sealed tube, tert-butyl 4-((4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate (7.80 g, 25.37 mmol, 1.0 equivalent), 1-bromo-4-(trifluoromethyl)benzene (5.71 g, 25.37 mmol, 1.0 equivalent), sodium tert-butoxide (4.80 g, 50.74 mmol, 2.0 equivalent), and toluene (150 mL) were added at room temperature under an argon atmosphere. The resulting mixture was degassed for 10 minutes using an argon balloon, and then Ruphos-Pd-G3 (1.06 g, 1.26 mmol, 0.05 equivalent) was added under argon. The tube was then sealed and stirred at 120°C for 16 hours. The reaction was monitored by TLC and ULC-MS to show product formation. The reaction mixture was cooled to room temperature and passed through a Celite pad. The filtrate was concentrated under reduced pressure to obtain the crude material. The crude material was purified by combiflash chromatography using silica gel eluted with 80% toluene in hexane, and the pure fraction was concentrated under reduced pressure to obtain tert-butyl 4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (5, 4.40 g, 38%). MS(ESI):C 23 H 28 Calculated mass for F3N3O3: 451.49; measured value (m / z): 452.2 [M+H] + .

[0389] 1 H NMR(400MHz,CDCl3)δ8.54(d,J=5.6Hz,1H), 8.21(s,1H), 7.36(d,J=8.8Hz,2H), 6.96(d,J=6.0Hz,1H), 6.47(d,J=8.8Hz,2H), 4.18(br s,2H), 4.06-3.97(tt,J=11.6Hz,J=3.6Hz,1H), 3.79(s,3H), 2.81(m,2H), 1.32-1.2 5(td,J=12.4Hz,J=4.0Hz,2H), 1.42(s,9H), 1.32-1.25(td,J=12.4Hz,J=4.0Hz,2H).

[0390] Step 3: Preparation of 4-methoxy-N-(piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride: [ka]

[0391] To a solution of tert-butyl 4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (4.40 g, 9.74 mmol, 1.0 equivalent) in 2,2,2-trifluoroethanol (25.0 mL) at 0°C, chlorotrimethylsilane (6.80 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC, which indicated the complete consumption of the starting materials. The crude material was obtained by removing volatile substances under reduced pressure. Tracturing of the crude product with acetonitrile (10.0 mL) yielded 4-methoxy-N-(piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride (3.10 g (crude)). MS(ESI):C 18 H 20 Calculated mass for F3N3O: 351.16; measured value in m / z: 352.1 [M+H] + .

[0392] 1 H NMR(400MHz,DMSO-d6)δ9.11(d,J=8.8Hz,1H), 8.92-8.90(m,2H), 8.74(s,1H), 7.79(d,J=6.4Hz,1H), 7.46(d,J=8.4Hz,2H), 6.78(d,J= 8.4Hz,2H), 4.43(t,J=11.6Hz,1H), 4.00(s,3H), 3.25(d,J=12.0Hz,2H), 3.11-3.02(m,2H), 2.03(d,J=12.8Hz,2H), 1.68-1.59(m,2H).

[0393] Step 4: Preparation of 4-fluoro-2-(methylsulfonyl)benzoic acid (7) [ka]

[0394] To a solution of 2-bromo-4-fluorobenzoic acid (0.25 g, 1.14 mmol, 1.0 equivalent) in dimethyl sulfoxide (15.0 mL), sodium methanesulfonate (0.47 g, 3.99 mmol, 3.5 equivalents), CuI (0.86 g, 4.56 mmol, 4.0 equivalents), and sodium hydroxide (5N in H2O, 0.22 mL, 1.14 mmol, 1.0 equivalent) were added at room temperature, and the mixture was stirred at 120 °C for 2 hours. The progress of the reaction 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 siRNA (2 × 10 mL). The aqueous layer was acidified with 2N aqueous HCl (2.0 mL) and extracted with siRNA (2 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, the drying agent was filtered, and the solution was concentrated under reduced pressure to obtain 4-fluoro-2-(methylsulfonyl)benzoic acid (0.15 g, crude). MS(ESI): Calculated mass relative to C8H7FO4S, 218.00; measured value at m / z, 216.98 [MH] - .

[0395] 1 H NMR (400MHz, DMSO-d6) δ7.93-7.88(m,2H), 7.40-7.37(m,1H), 3.44(s,3H).

[0396] Step 5: Preparation of (4-fluoro-2-(methylsulfonyl)phenyl)(4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)methanone (compound 37): [ka]

[0397] To a stirred solution of 4-methoxy-N-(piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride (0.10 g, 0.25 mmol, 1.0 equivalent) and 4-fluoro-2-(methylsulfonyl)benzoic acid (0.06 g, 0.30 mmol, 1.2 equivalents) in N,N-dimethylformamide (2.0 mL), diisopropylethylamine (0.17 mL, 1.02 mmol, 4.0 equivalents) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.11 g, 0.30 mmol, 1.2 equivalents) were added at 0°C. The resulting reaction mixture was then stirred at room temperature for 8 hours. The reaction progress was monitored by TLC and ULC-MS, which showed product formation along with the complete consumption of the starting materials. The reaction mixture was poured into ice-cold water (5.0 mL). The resulting solid was collected by filtration, the solid cake was washed with an excess of cold water (5.0 mL), and dried under vacuum to obtain (4-fluoro-2-(methylsulfonyl)phenyl)(4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)methanone (0.14 g, yield 66%). MS(ESI):C 26 H 25 Calculated mass for F4N3O4S: 551.15; measured value (m / z): 552.3 [M+H] + , HPLC purity: 95.77%

[0398] Compound 37: Rotational isomer 1H NMR (400MHz, CDCl3) δ8.53(dd,J=18.0Hz,J=5.6Hz,1H), 8.17(d,J=38.4Hz,1H), 7.74-7.60(m,2H) , 7.59-7.53(m,1H), 7.40(d,J=8.8Hz,2H), 7.25(dd,J=16.8Hz,J=6.0Hz,1H), 6.62-6.57(m,2H), 4. 59-4.46(m,1H), 4.33-4.24(dd,J=24.0Hz,J=11.6Hz,1H), 3.76(d,J=14.8Hz,3H), 3.26(d,J=7.6H z,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=56.0Hz,J=12.0Hz 1H), 1.48-1.23(m,2H).

[0399] Example AL: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(4-(methylsulfonyl)phenyl)piperidine-4-yl)pyridine-3-amine (compound 38): [ka]

[0400] Step 1: Preparation of tert-butyl 4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate: [ka]

[0401] In a sealed tube, tert-butyl 4-((4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate (1.50 g, 4.88 mmol, 1.0 equivalent), 1-bromo-4-(difluoromethoxy)benzene (1.30 g, 5.86 mmol, 1.2 equivalents), sodium tert-butoxide (0.93 g, 9.76 mmol, 2.0 equivalents), and toluene (30.0 mL) were added at room temperature under an argon atmosphere. The resulting mixture was degassed by argon purging for 10 minutes, and then P(t-Bu)3Pd-G2 (0.15 g, 0.29 mmol, 0.05 equivalents) was added. The cap was then sealed, and the mixture was stirred at 120°C for 16 hours. The reaction was monitored by UPLC showing product formation. The reaction mixture was cooled to room temperature and passed through a Celite pad. The filtrate was concentrated under reduced pressure to obtain the crude material. The crude material was purified by combiflash chromatography using silica gel eluted with 60% ethyl hexane, and the pure fraction was concentrated under reduced pressure to obtain tert-butyl 4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate (0.40 g, yield 17%). MS(ESI):C 23 H 29 Calculated mass for F2N3O4: 449.21; measured value (m / z): 450.2 [M+H] + .

[0402] 1 H NMR(400MHz,DMSO-d6)δ8.48(d,J=5.6Hz,1H), 8.15(s,1H), 7.21(d,J=7.2Hz,1H), 7.16-6.97( t,J=75Hz,1H), 6.96-6.93(d,J=9.2Hz,2H), 6.45(d,J=9.2Hz,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=12.0Hz,2H), 1.33(s,9H), 1.10-1.08(m,2H).

[0403] Step 2: Preparation of N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(piperidine-4-yl)pyridine-3-amine hydrochloride (11) [ka]

[0404] To a solution of tert-butyl 4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate (0.40 g, 0.89 mmol, 1.0 equivalent) in 2,2,2-trifluoroethanol (3.0 mL), chlorotrimethylsilane (0.70 mL) was added dropwise at 0°C. The reaction mixture was then stirred at room temperature for 1 hour. Volatile substances were removed under reduced pressure to obtain the crude material. The obtained crude material was triturated with acetonitrile (10.0 mL) to obtain N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(piperidine-4-yl)pyridine-3-amine hydrochloride (crude product, 0.25 g). MS(ESI):C 18 H 21 Calculated mass for F2N3O2: 349.16; measured value (m / z): 350.1 [M+H] +

[0405] 1 H NMR(400MHz,DMSO-d6)δ9.14(d,J=9.2Hz,1H), 8.84-8.82(m,2H), 8.69(s,1H), 7.73(d,J=6.8Hz,1H), 7.25-6.88(t,J=75Hz,1H), 7.01(d,J=9.2H) z,2H), 6.74(d,J=12Hz,2H), 4.31-4.25(m,1H), 3.97(s,3H), 3.25(d,J= 12Hz,2H), 3.08-2.99(m,2H), 2.01(d,J=12.4Hz,2H), 1.67-1.58(m,2H).

[0406] Step 3: Preparation of N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(4-(methylsulfonyl)phenyl)piperidine-4-yl)pyridine-3-amine (compound 38) [ka]

[0407] In a sealed tube, N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(piperidine-4-yl)pyridine-3-amine hydrochloride (0.21 g, 0.54 mmol, 1.0 equivalent), 1-bromo-4-(methylsulfonyl)benzene (0.19 g, 0.81 mmol, 1.5 equivalents), sodium tert-butoxide (0.15 g, 1.62 mmol, 3.0 equivalents), and anhydrous 1,4-dioxane (10.0 mL) were added at room temperature under an argon atmosphere. The reaction mixture was degassed with argon for 10 minutes, and then Ruphos-Pd-G3 (0.02 g, 0.027 mmol, 0.05 equivalents) was added under argon. The tube was capped and stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, passed through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude material. The obtained crude material was purified by combiflash chromatography using silica gel eluted with 60% ethyl hexane to obtain N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(4-(methylsulfonyl)phenyl)piperidine-4-yl)pyridine-3-amine (0.08 g, yield 22%). MS(ESI):C 25 H 27 Calculated mass for F2N3O4S: 503.56; measured value (m / z): 504.1 [M+H] + , HPLC purity: 98.27%.

[0408] Compound 38: 1H NMR(400MHz,DMSO-d6)δ8.46(d,J=5.6Hz,1H), 8.16(s,1H), 7.61(d,J=9.2Hz,2H) , 7.20(d,J=5.6Hz,1H), 7.17(t,J=75Hz,1H), 7.02-7.00(d,J=9.2Hz,2H), 6.97-6 .94(d,J=9.2Hz,2H), 6.49(d,J=9.2Hz,2H), 4.20-4.14(m,1H), 3.97(d,J=13.2Hz ,2H), 3.75(s,3H), 3.02-2.99(m,5H), 1.98(d,J=11.6Hz,2H), 1.29-1.21(m,2H).

[0409] Example AM: N-(1-(5-(difluoromethyl)pyridine-2-yl)piperidine-4-yl)-4-methoxy-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 39): [ka]

[0410] 4-methoxy-N-(piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrogen chloride (0.60 g, 1.54 mmol, 1.0 equivalent), 2-chloro-5-(difluoromethyl)pyridine (0.25 g, 1.54 mmol, 1.3 equivalents), sodium tert-butoxide (0.297 g, 3.09 mmol, 2.0 equivalents), and toluene (5.0 mL) were added to a microwave tube under an argon atmosphere at room temperature. The resulting reaction mixture was then degassed with argon for 10 minutes, and Ruphos-Pd-G3 (0.06 g, 0.077 mmol, 0.05 equivalents) was added under argon. The microwave tube was sealed with a cap and stirred under microwave at 130°C for 2 hours. The progress of the reaction was monitored by TLC, and the complete consumption of the starting materials was observed. The reaction mixture was cooled to room temperature, passed through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude material. The crude material was purified by combiflash chromatography using silica gel eluted with 100% ammonium hexane to obtain N-(1-(5-(difluoromethyl)pyridine-2-yl)piperidine-4-yl)-4-methoxy-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (0.23 g, yield 31%). MS(ESI):C 24 H 23 Calculated mass for F5N4O: 478.47; measured value in m / z: 479.3 [M+H] + , HPLC purity: 95.15%.

[0411] Compound 39: 1H NMR(400MHz,DMSO-d6)δ8.49(d,J=5.6Hz,1H), 8.20(d,J=8.4Hz,1H), 8.18(s,1H), 7.61 (dd,J=9.2Hz,J=2.4Hz,1H), 7.42(d,J=8.8Hz,2H), 7.23(d,J=5.6Hz,1H), 7.06-6.74(t ,J=50Hz,1H), 6.89-6.87(m,1H), 6.61(d,J=8.8Hz,2H), 4.44(d,J=13.6Hz,2H), 4.36-4 .31(m,1H), 3.76(s,3H), 3.07-3.01(m,2H), 2.10(d,J=12.0Hz,2H), 1.23-1.16(m,2H).

[0412] Example AN: 6-(4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)-1-methylpyridine-2(1H)-one (compound 40): [ka]

[0413] Step 1: Preparation of 6-bromo-1-methylpyridine-2(1H)-one [ka]

[0414] To a solution of 6-bromopyridine-2-ol (0.25 g, 1.43 mmol, 1.0 equivalent) in N,N-dimethylformamide (5.0 mL), K2CO3 (0.99 g, 7.18 mmol, 5.0 equivalent) and CH3I (0.44 mL, 7.18 mmol, 5.0 equivalent) were added 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 indicated the complete consumption of the starting materials. The reaction mixture was quenched with water (5.0 mL) and extracted with siRNA (2 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, the drying agent was filtered, and the solution was concentrated under reduced pressure to obtain the crude material. The crude material obtained was purified by combi-flash chromatography using silica gel eluted with 30-35% ammonium hexane, and the pure fraction was concentrated under reduced pressure to obtain 6-bromo-1-methylpyridine-2(1H)-one (0.23 g, yield 31%).

[0415] 1 H NMR (400MHz, CDCl3) δ7.16-7.12(dd,J=9.2Hz,J=7.2Hz,1H), 6.53-6.48(m,2H), 6.68(d,J=8.0Hz,1H), 3.74(s,3H).

[0416] Step 2: Preparation of 6-(4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)-1-methylpyridine-2(1H)-one (compound 40): [ka]

[0417] 4-methoxy-N-(piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride (0.15 g, 0.38 mmol, 1.0 equivalent, Curia lot number IN-NRM-G-39), 6-bromo-1-methylpyridine-2(1H)-one (0.07 g, 0.42 mmol, 1.1 equivalent), sodium tert-butoxide (0.11 g, 1.15 mmol, 3.0 equivalent), and anhydrous toluene (3.0 mL) were added to a microwave tube under an argon atmosphere at room temperature. The resulting reaction mixture was degassed with argon for 10 minutes, and Ruphos-Pd-G3 (0.016 g, 0.01 mmol, 0.05 equivalent) was added under argon. The microwave tube was sealed with a cap and stirred under microwave at 120°C for 2 hours. The reaction progress was monitored by TLC and ULC-MS, which showed product formation. The reaction mixture was cooled to room temperature, passed through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude material. The crude material was purified by combiflash chromatography using silica gel eluted with 4% MeOH in CH2Cl2, and the pure fraction was concentrated under reduced pressure to obtain 6-(4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)-1-methylpyridine-2(1H)-one (0.15 g, yield 51%). MS(ESI):C 24 H 25 Calculated mass for F3N4O2: 458.49; measured value (m / z): 459.2 [M+H] + . HPLC purity: 99.73%.

[0418] Compound 40: 1H NMR(400MHz,DMSO-d6)δ8.55(d,J=5.6Hz,1H), 8.26(s,1H), 7.43(d,J=8.8H z,2H), 7.35-7.28(m,2H), 6.60(d,J=8.8Hz,2H), 6.08(d,J=8.4Hz,1H), 5.8 3-5.81(m,1H), 4.22-4.16(m,1H), 3.80(s,3H), 3.27(s,3H), 3.16(d,J=12. 0Hz,2H), 2.83(t,J=11.6Hz,2H), 2.03(d,J=12.0Hz,2H), 1.47-1.39(m,2H).

[0419] Example AO: Bicyclo[1.1.1]pentan-1-yl(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)methanone (compound 41): [ka]

[0420] The title compound was synthesized following the same procedure as in Example U (Compound 21).

[0421] The title compound was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm×5um; mobile phase: [water(FA)-ACN]; B%: 22%~52%, 7 min) to obtain the title compound (49.4 mg, 109.16 μmol, yield 84.24%). LC-MS (ESI), [M+H]+=444.1.

[0422] Compound 41: 1H NMR(400MHz,CD3OD)δ8.59(d,J=6.4Hz,1H), 8.49(s,1H), 7.58(d,J=6.8Hz, 1H), 7.02(d,J=9.2Hz,2H), 6.88-6.45(m,3H), 4.52-4.48(m,1H), 4.35-4.3 1(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).

[0423] Example AP: (4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)(3-fluorobicyclo[1.1.1]pentan-1-yl)methanone (compound 42): [ka]

[0424] The title compound was synthesized following the same procedure as in Example U (Compound 21).

[0425] The title compound was purified by preparative HPLC (column: Phenomenex C18 80*40mm*3μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 50%~80%, 7 min) to obtain the title compound (26 mg, 55.05 μmol, yield 70.79%). LC-MS (ESI), [M+H]+=462.0.

[0426] Compound 42: 1H NMR(400MHz,CD3OD)δ8.45(s,1H), 8.16(s,1H), 7.20(d,J=4.4Hz,1H), 6.93(d,J=9.2Hz,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,6H), 2.13-2.09(m,1H), 2.08-2.06(m,1H), 1.33-1.09(m,3H).

[0427] Example AQ: 3-(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-carbonyl)bicyclo[1.1.1]pentane-1-carbonitrile (compound 43): [ka]

[0428] The title compound was synthesized following the same procedure as in Example U (Compound 21).

[0429] The title compound was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm×5um; mobile phase: [water(FA)-ACN]; B%: 20%~50%, 7 min) to obtain the title compound (56.6 mg, 118.40 μmol, yield 91.36%). LC-MS (ESI), [M+H]+=469.0.

[0430] Compound 43: 1 H NMR(400MHz,CD3OD)δ8.60(d,J=6.4Hz,1H), 8.51(s,1H), 7.61(d,J=6.8Hz,1H), 7.03(d,J=9.2Hz,2H), 6.94-6.43(m,3H), 4.49-4.4 6(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).

[0431] Example AR: 4-Methoxy-N-(1-(pyrazine-2-yl)piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (compound 44): [ka]

[0432] The title compound was synthesized following the same procedure as in Example C (Compound 3).

[0433] The title compound was purified by preparative TLC (SiO2, dichloromethane:methanol = 10:1) to obtain the title compound (129.2 mg, 288.82 μmol, yield 50.74%). LC-MS (ESI) showed [M+H]+ = 430.1.

[0434] Compound 44: 1 H NMR(400MHz,CD3OD)δ8.47(d,J=6.0Hz,1H), 8.16(d,J=4.4Hz,2H), 8.04-8.03(m,1H), 7.71(d,J=2.4Hz,1H), 7.39(d,J=8.8Hz,2H), 7.23(d,J= 5.6Hz,1H), 6.64(d,J=8.8Hz,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).

[0435] Example AS: Bicyclo[1.1.1]pentan-1-yl(4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)methanone (compound 45): [ka]

[0436] The title compound was synthesized following the same procedure as in Example U (Compound 21).

[0437] The title compound was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 26%~56%, 7 min) to obtain the title compound (56 mg, 125.71 μmol, yield 97.51%). LC-MS (ESI), [M+H]+=446.1.

[0438] Compound 45: 1 H NMR(400MHz,CD3OD)δ8.60(d,J=6.0Hz,1H), 8.35(s,1H), 7.45-7.39(m,3H), 6.70(d,J=8.8Hz,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).

[0439] Example AT: (3-Fluorobicyclo[1.1.1]pentan-1-yl)(4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)methanone (Compound 46): [ka]

[0440] The title compound was synthesized following the same procedure as in Example U (Compound 21).

[0441] The title compound was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 26%~56%, 7 min) to obtain the title compound (69.9 mg, 150.82 μmol, yield 97.49%). LC-MS (ESI), [M+H]+=464.1.

[0442] Compound 46: 1H NMR(400MHz,CD3OD)δ8.76-8.74(m,1H), 8.60(s,1H), 7.71(d,J=7.2Hz,1H), 7.46(d,J=8.8Hz,2H), 6.79(d,J=8.8Hz,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).

[0443] Example AU: 3-(4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-carbonyl)bicyclo[1.1.1]pentan-1-carbonitrile (compound 47): [ka]

[0444] The title compound was synthesized following the same procedure as in Example U (Compound 21).

[0445] The title compound was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 25%~55%, 7 min) to obtain the title compound (65 mg, 125.72 μmol, yield 97.52%). LC-MS (ESI), [M+H]+=471.1.

[0446] Compound 47: 1H NMR(400MHz,CD3OD)δ8.75(dd,J=0.8,6.8Hz,1H), 8.60(d,J=0.8Hz,1H), 7.71(d,J=6.8Hz,1H), 7.46(d,J=8.8Hz,2H), 6.79(d,J=8.8Hz,2H), 4.61-4.5 5(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).

[0447] Example AV: (4-((4-(trifluoromethyl)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methanone (compound 48): [ka]

[0448] The title compound was synthesized following the same procedure as in Example U (Compound 21).

[0449] The title compound was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 33%~63%, 7 min) to obtain the title compound (74.2 mg, 141.62 μmol, yield 82.93%) as a white solid. LC-MS (ESI), [M+H]+=514.1.

[0450] Compound 48: 1H NMR(400MHz,CD3OD)δ8.52(d,J=7.6Hz,1H), 8.19(s,1H), 7.39(d,J=8.8Hz,2H), 7.27(d,J=6.0Hz,1H), 6.63(d,J=8.8Hz,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).

[0451] Example AW: (4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methanone (compound 49): [ka]

[0452] The title compound was synthesized following the same procedure as in Example U (Compound 21).

[0453] The title compound was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 29%~59%, 7 min) to obtain the title compound (56.45 mg, 110.37 μmol, yield 77.12%). LC-MS (ESI), [M+H]+=512.0.

[0454] Compound 49: 1H NMR(400MHz,CD3OD)δ8.59(d,J=6.8,1H), 8.511(s,1H), 7.61(d,J=6.8Hz,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).

[0455] Example AX: 4-Methoxy-N-(1-(5-methylpyrazine-2-yl)piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 50): [ka]

[0456] The title compound was synthesized following the same procedure as in Example C (Compound 3).

[0457] The title compound was purified by reverse-phase HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (FA)-ACN]; B%: 32%~62%, 6 min) to obtain the title compound (136.4 mg, 298.35 μmol, yield 52.42%). LC-MS (ESI), [M+H]+=444.1.

[0458] Compound 50: 1 H NMR(400MHz,CD3OD)δ8.47(d,J=4.4Hz,1H), 8.17(s,1H), 8.05(s,1H), 7.95(s,1H), 7.39(d,J=7.6Hz,2H), 7.23(d,J=4.0Hz,1H ), 6.64(d,J=8.0Hz,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).

[0459] Example AY: 4-Methoxy-N-(1-(pyrimidine-5-yl)piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 51): [ka]

[0460] The title compound was synthesized following the same procedure as in Example C (Compound 3).

[0461] The title compound was purified by reverse-phase HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (FA)-ACN]; B%: 32%~62%, 6 min) to obtain the title compound (156.6 mg, 364.66 μmol, yield 64.07%). LC-MS (ESI), [M+H]+=430.1.

[0462] Compound 51: 1 H NMR(400MHz,CD3OD)δ8.54-8.46(m,2H), 8.44(s,2H), 8.22(s,1H), 7.39(d,J=8.8Hz,2H), 7.25(d,J=6.0Hz,1H), 6.64(d,J =8.8Hz,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).

[0463] Example AZ: 4-Methoxy-N-(1-(2-methylpyrimidine-5-yl)piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 52): [ka]

[0464] The title compound was synthesized following the same procedure as in Example C (Compound 3).

[0465] The title compound was purified by reverse-phase HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (FA)-ACN]; B%: 30%~60%, 6 min) to obtain the title compound (126.6 mg, 279.77 μmol, yield 49.15%). LC-MS (ESI), [M+H]+=444.1.

[0466] Compound 52: 1 H NMR(400MHz,CD3OD)δ8.49(d,J=6.0Hz,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,2 H), 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).

[0467] Example BA: 5-(4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)pyrimidine-2-carbonitrile (compound 53): [ka]

[0468] The title compound was synthesized following the same procedure as in Example L (Compound 12).

[0469] The title compound was purified by flash silica gel chromatography (SepaFlash® Silica Flash Column, 0-50% ethyl acetate / petroleum ether eluent, 40 mL / min) to obtain the title compound (164.2 mg, 328.80 μmol, yield 63.76%). LC-MS (ESI), [M+H]+=455.1.

[0470] Compound 53: 1H NMR(400MHz,CD3OD)δ8.48(d,J=5.6Hz,1H), 8.44(s,2H), 8.19(s,1H), 7.39(d,J=8.8Hz,2H), 7.24(d,J=5.6Hz,1H), 6.65(d ,J=8.8Hz,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).

[0471] Example BB: 4-Methoxy-N-(4-(trifluoromethyl)phenyl)-N-(1-(2-(trifluoromethyl)pyrimidine-5-yl)piperidine-4-yl)pyridine-3-amine (Compound 54): [ka]

[0472] The title compound was synthesized following the same procedure as in Example C (Compound 3).

[0473] The title compound was purified by reverse-phase HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (FA)-ACN]; B%: 40%~70%, 6 min) to obtain the title compound (160 mg, 308.78 μmol, yield 54.25%). LC-MS (ESI), [M+H]+=498.1.

[0474] Compound 54: 1 H NMR(400MHz,CD3OD)δ8.49-8.48(m,3H), 8.20(s,1H), 7.39(d,J=8.4Hz,2H), 7.25(d,J=6.0Hz,1H), 6.65(d,J=8.4H) z,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).

[0475] Example BC: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(pyrazine-2-yl)piperidine-4-yl)pyridine-3-amine (compound 55): [ka]

[0476] The title compound was synthesized following the same procedure as in Example C (Compound 3).

[0477] The title compound was purified by reverse-phase HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (FA)-ACN]; B%: 40%~70%, 6 min) to obtain the title compound (0.20 g, 459.77 μmol, yield 80.32%). LC-MS (ESI), [M+H]+=428.0.

[0478] Compound 55: 1 H NMR(400MHz,CD3OD)δ8.41(d,J=5.6Hz,1H), 8.14(d,J=5.6Hz,2H), 8.02(s,1H), 7.69(s,1H), 7.17(d,J=5.6Hz,1H), 6.93(d,J=5.6Hz,2H), 6.78( d,J=5.6Hz,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).

[0479] Example BD: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(5-methylpyrazine-2-yl)piperidine-4-yl)pyridine-3-amine (compound 56): [ka]

[0480] The title compound was synthesized following the same procedure as in Example C (Compound 3).

[0481] The title compound was purified by reverse-phase HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (FA)-ACN]; B%: 23%~53%, 7 min) to obtain the title compound (113.62 mg, 257.37 μmol, yield 44.96%). LC-MS (ESI), [M+H]+=442.3.

[0482] Compound 56: 1 H NMR(400MHz,CD3OD)δ8.41(d,J=5.6Hz,1H), 8.26(s,1H), 8.09(s,1H), 7.95(s,1H), 7.24(d,J=5.6Hz,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).

[0483] Example BE: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(pyrimidine-5-yl)piperidine-4-yl)pyridine-3-amine (compound 57): [ka]

[0484] The title compound was synthesized following the same procedure as in Example C (Compound 3).

[0485] The title compound was purified by reverse-phase HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (FA)-ACN]; B%: 15%~45%, 7 min) to obtain the title compound (238.4 mg, 557.73 μmol, yield 97.43%). LC-MS (ESI), [M+H]+=428.0.

[0486] Compound 57: 1H NMR(400MHz,CD3OD)δ8.55(s,1H), 8.50(s,3H), 8.21(s,1H), 7.25(d,J=6.0Hz,1H), 6.96(d,J=8.8Hz,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).

[0487] Example BF: 5-(4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)pyrimidine-2-carbonitrile (compound 58): [ka]

[0488] The title compound was synthesized following the same procedure as in Example L (Compound 12).

[0489] The title compound was purified by reverse-phase HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (FA)-ACN]; B%: 25%~55%, 7 min) to obtain the title compound (96.63 mg, 213.57 μmol, yield 37.31%). LC-MS (ESI), [M+H]+=455.1.

[0490] Compound 58: 1 H NMR(400MHz,CD3OD)δ8.45-8.41(m,3H), 8.17(s,1H), 7.19(d,J=5.6Hz,1H), 6.94(d,J=8.8Hz,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).

[0491] Example BG: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(2-(trifluoromethyl)pyrimidine-5-yl)piperidine-4-yl)pyridine-3-amine (compound 59): [ka]

[0492] The title compound was synthesized following the same procedure as in Example C (Compound 3).

[0493] The title compound was purified by column chromatography (10%-60% ethyl acetate in petroleum ether) to obtain the title compound (215 mg, 416.60 μmol, yield 72.77%). LC-MS (ESI), [M+H]+=496.0.

[0494] Compound 59: 1 H NMR(400MHz,CD3OD)δ8.48(s,2H), 8.43(d,J=5.6Hz,1H), 8.18(s,1H), 7.19(d,J=5.6Hz,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).

[0495] Example BH: ((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)(2-methylpyridine-4-yl)methanone (compound 60): [ka]

[0496] To a stirred solution of 4-methoxy-N-(piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride (0.20 g, 0.51 mmol, 1.0 equivalent) and 2-methylisonicotinic acid (0.07 g, 0.56 mmol, 1.1 equivalents) in N,N-dimethylformamide (DMF, 2.0 mL), diisopropylethylamine (0.26 g, 2.06 mmol, 4.0 equivalents) and 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 0.29 g, 0.77 mmol, 1.5 equivalents) were added at 0°C. The reaction mixture was then stirred at room temperature for 8 hours. The progress of the reaction was monitored by TLC and ULC-MS, which showed product formation. The crude material was purified by combiflash chromatography using silica gel eluted with 72% ethyl hexane, and the pure fraction was concentrated under reduced pressure to obtain (4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)(2-methylpyridine-4-yl)methanone (0.16 g, yield 66%). MS(ESI):C 25 H 25 Calculated mass for F3N4O2: 470.50; measured value (m / z): 471.5 [M+H] + , HPLC purity: 99.90%.

[0497] Compound 60: 1 H NMR(400MHz, CDCl3) δ8.55(dd,J=13.6,5.6Hz,2H), 8.22(s,1H), 7.37(d,J=8.8Hz,2H ), 7.09(s,1H), 7.00-6.97(m,2H), 6.50(d,J=8.8Hz,2H), 4.81(d,J=12.4Hz,1H), 4.1 9-4.14(m,1H), 3.80(s,3H), 3.70(d,J=12.4Hz,1H), 3.21-3.15(m,1H), 2.90-2.84(m ,1H), 2.57(s,3H), 2.17(d,J=11.6Hz,1H), 1.99(d,J=10.4Hz,1H), 1.43-1.25(m,2H).

[0498] Example BI: 4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)(2-(trifluoromethyl)pyridine-4-yl)methanone (compound 61): [ka]

[0499] To a stirred solution of 4-methoxy-N-(piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride (0.28 g, 0.51 mmol, 1.0 equivalent) and 2-(trifluoromethyl)isonicotinic acid (0.11 g, 0.61 mmol, 1.2 equivalents) in N,N-dimethylformamide (DMF, 2.0 mL), diisopropylethylamine (0.33 mL, 2.06 mmol, 4.0 equivalents) and 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 0.29 g, 0.77 mmol, 1.5 equivalents) were added at 0°C. The reaction mixture was then stirred at room temperature for 2 hours. The progress of the reaction 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 resulting solid was collected by filtration, and the solid cake was washed with an excess of cold water (5.0 mL). The solid was dried under vacuum to obtain (4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)(2-(trifluoromethyl)pyridine-4-yl)methanone (0.18 g, yield 67%). MS(ESI):C 25 H 22 Calculated mass for F6N4O2: 524.47; measured value (m / z): 525.1 [M+H] + , HPLC purity: 99.76%.

[0500] Compound 61: 1H NMR (400MHz, CDCl3) δ8.79(d,J=4.8Hz,1H), 8.58(d,J=5.6Hz,1H), 8.22(s,1H), 7.64(s,1H) ), 7.42(d,J=4.8Hz,1H), 7.38(d,J=8.8Hz,2H), 6.99(d,J=5.6Hz,1H), 6.50(d,J=8.8Hz,2H ), 4.82(d,J=13.2Hz,1H), 4.22-4.14(m,1H), 3.80(s,3H), 3.63(d,J=8.4Hz,1H), 3.29-3.2 3(m,1H), 2.95-2.80(m,1H), 2.19(d,J=11.2Hz,1H), 2.04-2.02(m,1H), 1.50-1.25(m,2H).

[0501] Example BJ: 4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)(2-methylpyridine-4-yl)methanone (compound 62): [ka]

[0502] To a stirred solution of N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(piperidine-4-yl)pyridine-3-amine hydrochloride (0.15 g, 0.38 mmol, 1.0 equivalent) in anhydrous N,N-dimethylformamide (DMF, 2.0 mL), diisopropylethylamine (0.27 mL, 1.55 mmol, 4.0 equivalents), 2-methylisonicotinic acid (0.05 g, 0.42 mmol, 1.1 equivalents), and 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 0.22 g, 0.58 mmol, 1.50 equivalents) were added 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 the crude material. The obtained crude material was purified by combiflash chromatography using silica gel and eluted with 72% siRNA in hexane to obtain (4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)(2-methylpyridine-4-yl)methanone (0.07 g, yield 39%). MS(ESI):C 25 H 26 Calculated mass for F2N4O3: 468.50; measured value in m / z: 469.4 [M+H] + , HPLC purity: 98.95%.

[0503] Compound 62: 1 H NMR (400MHz, CDCl3) δ8.52(s,2H), 8.22(s,1H), 7.09(s,1H), 7.09-6.93(m,4H), 6.56-6.19(t,J=75Hz,1H), 6.47(d,J=8.8Hz,2H), 4.78(d,J=11.6Hz,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=10.8Hz,1H), 1.97(d,J=12.8Hz,1H), 1.68-1.25(m,2H).

[0504] Example BK: 4-Methoxy-N-(1-(4-(methylsulfinyl)phenyl)piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 63): [ka]

[0505] In a sealed tube, 4-methoxy-N-(piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride (0.25 g, 0.64 mmol, 1.0 equivalent), 1-bromo-4-(methylsulfinyl)benzene (0.18 g, 0.83 mmol, 1.3 equivalents), sodium tert-butoxide (0.18 g, 1.92 mmol, 3.0 equivalents), and anhydrous 1,4-dioxane (10.0 mL) were added at room temperature under an argon atmosphere. The reaction mixture was degassed with argon for 10 minutes, and then Ruphos-Pd-G3 (0.026 g, 0.032 mmol, 0.05 equivalents) was added under argon. The tube was capped and stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, passed through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude material. The obtained crude material was purified by combiflash chromatography using silica gel and eluted with 10% MeOH in toluene to obtain 4-methoxy-N-(1-(4-(methylsulfinyl)phenyl)piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (0.18 g, yield 48%). MS(ESI):C 25 H 26 Calculated mass for F3N3O2S: 489.56; measured value (m / z): 490.5 [M+H] + , HPLC purity: 98.39%.

[0506] Compound 63: 1H NMR(400MHz,DMSO-d6)δ8.52(d,J=5.6Hz,1H), 8.21(s,1H), 7.47-7.41(m,4H), 7.25(d,J=5.6Hz,1H), 7.04(d,J=9.2Hz,2H), 6.60(d,J=8 .8Hz,2H), 4.26-4.21(m,1H), 3.87(d,J=12.8Hz,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).

[0507] Example BL: N-(1-(2-fluoro-4-(methylsulfonyl)phenyl)piperidine-4-yl)-4-methoxy-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (compound 64): [ka]

[0508] 4-methoxy-N-(piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine hydrochloride (0.25 g, 0.64 mmol, 1.0 equivalent), 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (0.21 g, 0.83 mmol, 1.3 equivalents), sodium tert-butoxide (0.18 g, 1.92 mmol, 3.0 equivalents), and anhydrous 1,4-dioxane (10.0 mL) were added to a microwave tube under an argon atmosphere at room temperature. The resulting reaction mixture was degassed with argon for 10 minutes, and Ruphos-Pd-G3 (0.026 g, 0.032 mmol, 0.05 equivalents) was added under argon. The microwave tube was sealed with a cap, and the mixture was stirred under microwave at 120°C for 2 hours. The reaction progress was monitored by TLC and ULC-MS to observe product formation. The reaction mixture was cooled to room temperature, passed through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude material. The crude material was purified by combiflash chromatography using silica gel and eluted with 80% ethyl acetate in hexane to obtain N-(1-(2-fluoro-4-(methylsulfonyl)phenyl)piperidine-4-yl)-4-methoxy-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (0.18 g, yield 45%) as a grayish-white solid. MS(ESI):C 25 H 25 Calculated mass for F4N3O3S: 523.55; measured value in m / z: 524.1 [M+H] + , HPLC purity: 99.52%.

[0509] Compound 64: 1H NMR(400MHz,DMSO-d6)δ8.52(d,J=5.6Hz,1H), 8.21(s,1H), 7.62(bs,1H), 7.5 9(s,1H), 7.43(d,J=8.8Hz,2H), 7.28(d,J=5.6Hz,1H), 7.19(t,J=8.4Hz,1H), 6 .61(d,J=8.4Hz,2H), 4.27-4.21(m,1H), 3.79(s,3H), 3.57(d,J=12.4Hz,2H), 3 .17(s,3H), 3.03(t,J=11.6Hz,2H), 2.03(d,J=12.4Hz,2H), 1.45-1.36(m,2H).

[0510] Example BM: 2-(4-((4-fluorophenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (compound 65): [ka]

[0511] Step 1: Preparation of tert-butyl 4-((4-fluorophenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate (22) [ka]

[0512] In a microwave tube, tert-butyl 4-((4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate (0.45 g, 1.46 mmol, 1.0 equivalent), 1-bromo-4-fluorobenzene (0.30 g, 1.75 mmol, 1.2 equivalents), sodium tert-butoxide (0.28 g, 2.92 mmol, 2.0 equivalents), and toluene (5.0 mL) were added at room temperature under an argon atmosphere. The resulting reaction mixture was degassed with argon for 10 minutes, and Ruphos-Pd-G3 (0.06 g, 0.07 mmol, 0.05 equivalents) was added under argon. The tube was sealed with a cap and stirred at 130°C for 2 hours under microwave. TLC analysis showed new nonpolar spots along with some unreacted starting material. The reaction mixture was cooled to room temperature, passed through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude material. The crude material obtained was purified by combiflash chromatography using silica gel and eluted with 60-65% ethyl hexane to obtain tert-butyl 4-((4-fluorophenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate (0.30 g, yield 35%). MS(ESI):C 22 H 28 Calculated mass for FN3O3: 401.48; measured value (m / z): 402.2 [M+H] + .

[0513] 1 H NMR (400MHz, CDCl3) δ8.47(d,J=5.6Hz,1H), 8.22(s,1H), 6.90(d,J=5.6Hz,1H), 6.87-6.83(m,2H), 6.47-6.44(m,2H), 4.16 -4.11(m,2H), 3.92(tt,J=3.6Hz,1H), 3.77(s,3H), 2.83-2.77(m,2H), 1.96(d,J=12Hz,2H), 1.42(s,9H), 1.34-1.25(m,2H).

[0514] Step 2: Preparation of N-(4-fluorophenyl)-4-methoxy-N-(piperidine-4-yl)pyridine-3-amine hydrochloride [ka]

[0515] To a solution of tert-butyl 4-((4-fluorophenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate (0.30 g, 0.77 mmol, 1.0 equivalent) in 2,2,2-trifluoroethanol (2.0 mL) at 0°C, chlorotrimethylsilane (0.45 mL) was added dropwise at room temperature. The reaction mixture was then stirred at room temperature for 1 hour. TLC analysis showed new polar spots along with complete conversion of the starting material. The volatile substances were removed under reduced pressure to obtain the crude material. The obtained crude material was triturated with ACN (10.0 mL) to obtain N-(4-fluorophenyl)-4-methoxy-N-(piperidine-4-yl)pyridine-3-amine hydrochloride (0.21 g, yield 81%). MS(ESI):C 17 H 20 Calculated mass for FN3O: 301.37; measured value (m / z): 302.1 [M+H] + .

[0516] 1 H NMR(400MHz,DMSO-d6)δ9.10(d,J=10Hz,1H), 8.81-8.79(m,2H), 8.64(s,1H), 7.70(d,J=6.8Hz,1H), 7.04(t,J=8.8Hz,2H), 6.79 -6.75(m,2H), 4.28-4.22(m,1H), 3.94(s,3H), 3.25(d,J=14.4Hz,2H), 3.07-2.98(m,2H), 2.02-1.99(m,2H), 1.65-1.58(m,2H).

[0517] Step 3: Preparation of 2-(4-((4-fluorophenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (compound 65): [ka]

[0518] To a stirred solution of N-(4-fluorophenyl)-4-methoxy-N-(piperidine-4-yl)pyridine-3-amine hydrochloride (0.15 g, 0.44 mmol, 1.0 equivalent) in anhydrous N,N-dimethylformamide (DMF, 2.0 mL), diisopropylethylamine (0.31 mL, 1.77 mmol, 2.0 equivalent) and 2-chloropyrimidine-5-carbonitrile (0.07 g, 0.35 mmol, 1.0 equivalent) were added at room temperature, and the mixture was stirred at 90°C for 4 hours. TLC testing showed new nonpolar spots along with 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, the drying agent was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude material. The crude material was purified by combiflash chromatography using silica gel and eluted with 65-70% ethyl hexane to obtain 2-(4-((4-fluorophenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (0.12 g, yield 51%). MS(ESI):C 22 H 21 Calculated mass for FN6O: 404.45; measured value in m / z: 405.1 [M+H] + , HPLC purity: 98.93%.

[0519] Compound 65: 1 H NMR(400MHz,CDCI3)δ8.46(d,J=5.6Hz,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=13.2Hz,2H), 1.42-1.29(m,2H).

[0520] Example BN: 4-Cyclopropoxy-N-(4-(difluoromethoxy)phenyl)-N-(1-(1-methyl-1H-pyrazole-5-yl)piperidine-4-yl)pyridine-3-amine (Compound 66): [ka]

[0521] The title compound was synthesized following the same procedure as in Example AD (Compound 30).

[0522] The title compound was purified by column chromatography (10%-80% ethyl acetate in petroleum ether) to obtain the title compound (110.7 mg, 243.03 μmol, yield 44.78%). LC-MS (ESI), [M+H]+=456.2.

[0523] Compound 66: 1 H NMR(400MHz,CD3OD)δ8.45(d,J=5.6Hz,1H), 8.21(s,1H), 7.50(d,J=5.6Hz,1H ), 7.29(s,1H), 6.93(d,J=8.8Hz,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).

[0524] Example BO:4-Cyclopropoxy-N-(1-(1-methyl-1H-pyrazole-5-yl)piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 67): [ka]

[0525] The title compound was synthesized following the same procedure as in Example AD (Compound 30).

[0526] The title compound was purified by column chromatography (10% to 80% ethyl acetate in petroleum ether) to obtain the title compound (70.1 mg, 153.23 μmol, yield 43.26%). LC-MS (ESI), [M+H]+=458.2.

[0527] Compound 67: 1 H NMR(400MHz,CD3OD)8.51(d,J=5.6Hz,1H),8.24(s,1H),7.56(d,J=5.6Hz,1H),7. 38(d,J=8.8Hz,2H), 7.30(d,J=2.4Hz,1H), 6.61(d,J=8.8Hz,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).

[0528] Example BP: 6-[4-[N-[4-(cyclopropoxy)-3-pyridyl]-4-(difluoromethoxy)anilino]-1-piperidyl]pyridine-3-carbonitrile (compound 68): [ka]

[0529] The title compound was synthesized following the same procedure as in Example R (Compound 18).

[0530] The title compound was purified by Silica Flash Column (10-50% ethyl acetate in petroleum ether) to obtain the title compound (162.9 mg, 320.68 μmol, yield 60.19%). LC-MS (ESI), [M+H]+=478.1.

[0531] Compound 68: 1H NMR(400MHz,CD3OD)δ8.40(d,J=5.6Hz,1H), 8.33(s,1H), 8.15(s,1H), 7.65(d,J=2 .0Hz,1H), 7.44(d,J=5.6Hz,1H), 6.93(d,J=8.8Hz,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).

[0532] Example BQ: (4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methanone (compound 69): [ka]

[0533] The title compound was synthesized following the same procedure as in Example L (Compound 12).

[0534] The title compound was purified by reverse-phase HPLC (Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 32%~62%, 7 min) to obtain the title compound (73.5 mg, 150.54 μmol, yield 28.26%). LC-MS (ESI), [M+H]+=479.2.

[0535] Compound 69: 1H NMR(400MHz,CD3OD)δ8.54(s,2H), 8.41(d,J=5.6Hz,1H), 8.16(s,1H), 7.46(d,J=5.6Hz,1H), 6.94(d,J=8.8Hz,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), 2.1 1-2.07(m,2H), 1.29-1.24(m,2H), 0.79-0.74(m,2H), 0.47-0.43(m,2H).

[0536] Example BR:N-(1-(1,2,4-oxadiazole-3-yl)piperidine-4-yl)-4-cyclopropoxy-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (compound 70): [ka]

[0537] Step 1: 4-((4-cyclopropoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-carbonitrile [ka]

[0538] To a solution of 4-(cyclopropoxy)-N-(4-piperidyl)-N-[4-(trifluoromethyl)phenyl]pyridine-3-amine (400 mg, 966.50 μmol, HCl salt) in dichloromethane (4.0 mL), NaHCO3 (405.96 mg, 4.83 mmol) in H2O (1 mL) was added at °C. Then, cyanogen bromide (1.1 g, 10.39 mmol) was added and the mixture was stirred at 0 °C for 1 hour. Sodium carbonate (2 g) was added to ensure complete neutralization. MgSO4 (5 g) was added and the mixture was vigorously stirred for 15 minutes. The resulting suspension was filtered and rinsed with dichloromethane (50 mL x 2). The organic layer was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (using 0-85% ethyl acetate in petroleum ether as an eluent) to obtain the title compound (200 mg, 497.00 μmol, yield 51.42%). LC-MS (ESI), [M+H]+=403.1.

[0539] Step 2: (E)-4-((4-cyclopropoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)-N'-hydroxypiperidine-1-carboximidoamide [ka]

[0540] To a solution of 4-[N-[4-(cyclopropoxy)-3-pyridyl]-4-(trifluoromethyl)anilino]piperidine-1-carbonitrile (200 mg, 497.00 μmol) in THF (5 mL), NH2OH (164.01 mg, 2.49 mmol, 50% purity in water) was added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (eluting agent: 30-100% ethyl acetate in petroleum ether) to obtain the title compound (190 mg, 436.34 μmol, yield 87.79%). LC-MS (ESI), [M+H]+=436.2

[0541] Step 3: N-(1-(1,2,4-oxadiazole-3-yl)piperidine-4-yl)-4-cyclopropoxy-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 70): [ka]

[0542] To a solution of 4-[N-[4-(cyclopropoxy)-3-pyridyl]-4-(trifluoromethyl)anilino]-N'-hydroxy-piperidine-1-carboxamidine (190 mg, 436.34 μmol) in triethoxymethane (5 mL), diethoxymethoxyethane (129.33 mg, 872.68 μmol) was added, followed by the addition of HCl (12 M, 36.36 μL). The resulting mixture was stirred at 110°C for 0.5 hours. Sodium carbonate (2 g) was added to ensure complete neutralization. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (using 0-60% ethyl acetate in petroleum ether as an eluent) to obtain the title compound (80.5 mg, 180.72 μmol, yield 41.42%). LC-MS (ESI), [M+H]+=446.1

[0543] Compound 70: 1 H NMR(400MHz,CD3OD)δ8.72(s,1H), 8.48(d,J=5.6Hz,1H), 8.18(s,1H), 7.52(d,J=5.6Hz,1H), 7.38(d,J=8.8Hz,2H), 6.62(d,J=8.8Hz,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), 2.0 7-2.03(m,2H), 1.41-1.37(m,2H), 0.81-0.77(m,2H), 0.53-0.49(m,2H).

[0544] Example BS: 6-(4-((4-cyclopropoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)nicotinonitrile (compound 71): [ka]

[0545] The title compound was synthesized following the same procedure as in Example R (Compound 18).

[0546] The title compound was purified by Silica Flash Column (10-40% ethyl acetate in petroleum ether, 40 mL / min) to obtain the title compound (114.5 mg, 224.46 μmol, yield 42.36%). LC-MS (ESI), [M+H]+=480.1.

[0547] Compound 71: 1 H NMR(400MHz,CD3OD)δ8.46(d,J=5.6Hz,1H), 8.33(d,J=1.6Hz,1H), 8.15(s,1H), 7.68 -7.65(m,1H), 7.50(d,J=5.6Hz,1H), 7.38(d,J=8.8Hz,2H), 6.83-6.81(m,1H), 6.63( d,J=8.8Hz,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).

[0548] Example BT: 2-(4-((4-cyclopropoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (compound 72): [ka]

[0549] The title compound was synthesized following the same procedure as in Example L (Compound 12).

[0550] The title compound was purified by reverse-phase HPLC (Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 35%~65%, 7 min) to obtain the title compound (130.3 mg, 271.18 μmol, yield 56.12%). LC-MS (ESI), [M+H]+=481.2.

[0551] Compound 72: 1 H NMR(400MHz,CD3OD)δ8.54(s,2H), 8.47(d,J=6.0Hz,1H), 8.17(s,1H), 7.50(d,J=6.0Hz,1H), 7.39(d,J=8.4Hz,2H), 6.63(d,J=8.4Hz,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), 2.1 5-2.08(m,2H), 1.32-1.23(m,2H), 0.81-0.76(m,2H), 0.51-0.45(m,2H).

[0552] Example BU:N-(1-(1,2,4-oxadiazole-3-yl)piperidine-4-yl)-4-cyclopropoxy-N-(4-(difluoromethoxy)phenyl)pyridine-3-amine (compound 73): [ka]

[0553] The title compound was synthesized following the same procedure as in Example BS (Compound 70).

[0554] The title compound was purified by Silica Flash Column (10-40% ethyl acetate in petroleum ether, 40 mL / min) to obtain the title compound (67.5 mg, 152.22 μmol, yield 21.28%). LC-MS (ESI), [M+H]+=444.1.

[0555] Compound 73: 1H NMR(400MHz,CD3OD)δ8.71(s,1H), 8.42(d,J=5.6Hz,1H), 8.17(s,1H), 7.47(d,J=5.6Hz,1H), 6.94(d,J=8.8Hz,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), 2.0 4-2.01(m,2H), 1.39-1.32(m,2H), 0.79-0.75(m,2H), 0.49-0.47(m,2H).

[0556] Example BV: 2-(4-((4-(difluoromethoxy)-3-fluorophenyl)(4-methoxypyridine-3-yl)amino)piperidine-1-yl)pyrimidine-5-carbonitrile (compound 74): [ka]

[0557] The title compound was synthesized following the same procedure as in Example L (Compound 12).

[0558] The title compound was purified by reverse-phase HPLC (Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 28%~58%, 7 min) to obtain the title compound (153.3 mg, 319.34 μmol, yield 64.48%). LC-MS (ESI), [M+H]+=471.2.

[0559] Compound 74: 1 H NMR(400MHz,CD3OD)δ8.55(s,2H), 8.47(d,J=5.6Hz,1H), 8.18(s,1H), 7.23(d,J=5.6Hz,1H), 7.05-7.03(m,1H), 6.64(t,J=74Hz,1H), 6.44-6.3 9(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).

[0560] Example BW: N-(4-(difluoromethoxy)phenyl)-4-methoxy-N-(1-(5-(methylsulfonyl)pyridine-2-yl)piperidine-4-yl)pyridine-3-amine (compound 75): [ka]

[0561] The title compound was synthesized following the same procedure as in Example C (Compound 3).

[0562] The title compound was purified by reverse-phase HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (FA)-ACN]; B%: 15%~45%, 7 min) to obtain the title compound (238.4 mg, 435.42 μmol, yield 76.06%). LC-MS (ESI), [M+H]+=505.2.

[0563] Compound 75: 1 H NMR(400MHz,CD3OD)δ8.59(d,J=2.4Hz,1H), 8.48(d,J=5.6Hz,1H),8.24(s,1 H), 7.82(d,J=5.6Hz,1H), 6.98-6.93(m,3H), 6.62(d,J=9.2Hz,1H), 6.53(d,J =8.8Hz,2H), 6.40(t,J=74Hz,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).

[0564] Example BX: 4-Methoxy-N-(1-(5-(methylsulfonyl)pyridine-2-yl)piperidine-4-yl)-N-(4-(trifluoromethyl)phenyl)pyridine-3-amine (Compound 76): [ka]

[0565] The title compound was synthesized following the same procedure as in Example C (Compound 3).

[0566] The title compound was purified by reverse-phase HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (FA)-ACN]; B%: 7%~37%, 7 min) to obtain the title compound (153.9 mg, 300.79 μmol, yield 48.04%). LC-MS (ESI), [M+H]+=507.6.

[0567] Compound 76: 1 H NMR(400MHz,CD3OD)δ8.48(d,J=5.6Hz,1H), 8.43(s,1H),8.18(s,1H), 7.82(d,J=8.0Hz,1H), 7.42(d,J=8.8Hz,2H), 7.23(d,J=5.6Hz,1H), 6.92(d ,J=9.2Hz,1H), 6.61(d,J=8.8Hz,2H), 4.55-4.52(m,2H), 4.41-4.35(m,1 H), 3.76(s,3H), 3.15-3.09(m,5H), 2.04-2.01(m,2H), 1.23-1.13(s,2H).

[0568] Example BY: ((trans)-4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)cyclohexyl)(morpholino)methanone (compound 77): [ka]

[0569] Step 1: Ethyl 4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)cyclohexane-1-carboxylate [ka]

[0570] 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, purity 10%), Pd(OAc)2 (32.26 mg, 143.71 μmol), and tBuONa (207.16 mg, 2.16 mmol) in toluene (8 mL) was degassed, purged three times with N2, and then stirred at 120°C for 24 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by Silica Flash Column (0-30% ethyl acetate in petroleum ether) to obtain the title compound (136 mg, 322.51 μmol, yield 45%). LCMS(ESI), [M+H]+=421.3.

[0571] Step 2: 4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)cyclohexane-1-carboxylic acid [ka]

[0572] To a solution of ethyl 4-[4-(difluoromethoxy)-N-(4-methoxy-3-pyridyl)anilino]cyclohexanecarboxylate (403 mg, 958.50 μmol) in THF (5 mL) and methanol (5 mL), lithium hydroxide monohydrate (201.11 mg, 4.79 mmol) in H2O (5 mL) was added, and the mixture was stirred at 25°C for 2 hours. 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 times), the combined organic matter was dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (376.11 mg, 958.50 μmol, yield 100.00%). LC-MS (ESI), [M+H]+=393.1.

[0573] Step 3: ((trans)-4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)cyclohexyl)(morpholino)methane (compound 77) and ((cis)-4-((4-(difluoromethoxy)phenyl)(4-methoxypyridine-3-yl)amino)cyclohexyl)(morpholino)methane [ka]

[0574] 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), DIEA (169.75 mg, 1.31 mmol) and HATU (332.95 mg, 875.65 μmol) were added 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*30mm×5um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 40%~70%, 7 min) to obtain the title compound-1 (peak 1 on HPLC, compound 77, 31.9 mg, 68.63 μmol, yield 15.67%) and compound-2 (peak 2 on HPLC, isomer of compound 77, 64.3 mg, 136.29 μmol, yield 31.13%). LC-MS (ESI), [M+H]+=462.2. Only the trans isomer, compound 77, showed activity.

[0575] Compound 77: 1H NMR(400MHz,CD3OD)δ8.41(d,J=5.6Hz,1H), 8.15(s,1H), 7.18(d,J=5.6Hz,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).

[0576] Compound 77 cis isomer: 1 H NMR(400MHz,CD3OD)δ8.38(d,J=5.6Hz,1H), 8.22(s,1H), 7.15(d,J=5.6Hz,1H), 6.91(d,J=9.2,2H), 6.7 8-6.41(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).

[0577] Example BZ: (cis)-4-((4-methoxypyridine-3-yl)(4-(trifluoromethyl)phenyl)amino)cyclohexyl)(morpholino)methanone (compound 78): [ka]

[0578] The title compound was synthesized following the same procedure as in Example BY (Compound 77).

[0579] The title compound was purified by reverse-phase HPLC (column: Welch Xtimate C18 150*30mm×5um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 40%~70%, 7 min) to obtain title compound-1 (peak 1 on HPLC, 125 mg, 269.69 μmol, yield 66.48%) and compound-2 (compound 78, peak 2 on HPLC, 60 mg, 129.45 μmol, yield 31.91%). LC-MS (ESI), [M+H]+=464.3. Only compound 78, the cis isomer, showed activity.

[0580] Compound 78: 1 H NMR(400MHz,CD3OD)δ8.45(d,J=5.6Hz,1H), 8.18(s,1H), 7.35(d,J=8.8Hz,2H), 7.22(d,J=5.6,1H), 6.57(d,J=5.6,2H), 4.0 1-3.98(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).

[0581] Isomers of compound 78: 1 H NMR(400MHz,CD3OD)δ8.47(d,J=5.6Hz,1H), 8.18(s,1H), 7.36(d,J=8.8Hz,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).

[0582] Example CA:N-(4-(difluoromethoxy)phenyl)-5-fluoro-4-methoxy-N-(1-(5-(methylsulfonyl)pyrimidine-2-yl)piperidine-4-yl)pyridine-3-amine (compound 79): [ka]

[0583] Step 1: 3-Bromo-5-fluoro-4-methoxypyridine [ka]

[0584] To a solution of 3-bromo-4-chloro-5-fluoropyridine (3.0 g, 14.26 mmol, 1 equivalent) in THF (30 mL), NaOMe (5.4 M, 2.64 mL, 1 equivalent) was added. The mixture was stirred at 50°C for 1 hour. LCMS (5~95 AB / 1.5 min): RT = 0.656 min, [M+H] + The reaction yielded 206.1%, showing 58% of the desired product. The reaction was diluted with brine (50 mL). The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash chromatography on silica gel (0-12.5% ​​ethyl acetate in petroleum ether) to obtain the title compound (760 mg, 26%).

[0585] 1 H NMR(400MHz, CDCl3): δ8.44(s,1H), 8.34(d,J=2.8Hz,1H), 4.21(d,J=4.4Hz,3H);LCMS(ESI):m / z206.1(M+H) + .

[0586] Step 2: tert-butyl 4-((5-fluoro-4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate [ka]

[0587] A mixture of 3-bromo-5-fluoro-4-methoxypyridine (850 mg, 4.13 mmol, 1 equivalent), tert-butyl 4-aminopiperidine-1-carboxylate (992 mg, 4.95 mmol, 1.2 equivalents), Pd(OAc)2 (93 mg, 412.60 μmol, 0.1 equivalent), BINAP (514 mg, 825.19 μmol, 0.2 equivalents), and t-BuONa (1.19 g, 12.38 mmol, 3 equivalents) in toluene (20 mL) was stirred at 100°C for 12 hours under an N2 atmosphere. LCMS (5~95AB / 1.5 min): RT = 0.655 min, [M+H] + The desired product was obtained at a concentration of 326.3 and 57%. The reaction was diluted with brine (50 mL), and the mixture was extracted with RINKAN (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate = 2:1) to obtain the title compound (830 mg, 62%). LC-MS (ESI): m / z 326.3 (M + H) + .

[0588] Step 3: tert-butyl 4-((4-(difluoromethoxy)phenyl)(5-fluoro-4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate [ka]

[0589] A mixture of tert-butyl 4-((5-fluoro-4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate (250 mg, 768.34 μmol, 1 equivalent), 1-bromo-4-(difluoromethoxy)benzene (343 mg, 1.54 mmol, 210.12 μL, 2 equivalents), t-Bu3P-Pd-G2 (79 mg, 153.67 μmol, 0.2 equivalents), and t-BuONa (222 mg, 2.31 mmol, 3 equivalents) in toluene (5 mL) was stirred at 120 °C for 16 hours under an N2 atmosphere. LCMS (5~95 AB / 1.5 min): RT = 0.885 min, [M+H] +The reaction yielded 46% of the desired product, with a coefficient of 468.3. The reaction was diluted with brine (50 mL), and the mixture was extracted with HCl (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash chromatography on silica gel (0-5% EE in petroleum ether (ethanol:HCl = 1:3)) to obtain the title compound (350 mg, crude). LC-MS (ESI): m / z 468.3 (M + H) + .

[0590] Step 4: N-(4-(difluoromethoxy)phenyl)-5-fluoro-4-methoxy-N-(piperidine-4-yl)pyridine-3-amine hydrochloride [ka]

[0591] To a solution of tert-butyl 4-((4-(difluoromethoxy)phenyl)(5-fluoro-4-methoxypyridine-3-yl)amino)piperidine-1-carboxylate (350 mg, 748.69 μmol, 1 equivalent) in dioxane (0.5 mL), HCl / dioxane (4 M, 5 mL, 26.71 equivalents) was added. The mixture was stirred at 25°C for 1 hour. LC-MS (5~95 AB / 1.5 min): RT = 0.747 min, [M+H] + =368.2, showing 94% of the desired product. The mixture was concentrated under reduced pressure to obtain the title compound (275 mg, crude, HCl salt). The crude product was used directly in the next step. LCMS(ESI): m / z 368.2(M+H) + .

[0592] Step 5: N-(4-(difluoromethoxy)phenyl)-5-fluoro-4-methoxy-N-(1-(5-(methylsulfonyl)pyrimidine-2-yl)piperidine-4-yl)pyridine-3-amine (compound 79) [ka]

[0593] To a solution of N-(4-(difluoromethoxy)phenyl)-5-fluoro-4-methoxy-N-(piperidine-4-yl)pyridine-3-amine hydrochloride (132 mg, 359.32 μmol, 1 equivalent) and 2-chloro-5-(methylsulfonyl)pyrimidine (70 mg, 359.32 μmol, 1 equivalent) in MeCN (5 mL), TEA (181.79 mg, 1.80 mmol, 250.06 μL, 5 equivalents) was added at 0°C. The mixture was stirred at 0°C for 1 hour. LCMS (5~95 AB / 1.5 min): RT = 0.811 min, [M+H] + =524.2, showing 70% of the desired product. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash chromatography on silica gel (0-45% siRNA in petroleum ether) to obtain the title compound (97.68 mg, 52%).

[0594] Compound 79: 1 H NMR (400MHz, CD3OD): δ8.65(s,2H), 8.38(d,J=3.2Hz,1H), 8.09(s,1H), 7.00(d,J=9.2Hz,2H), 6.84-6.39(m,3H), 5.01-4.97(m,2H), 4.3 3-4.30(m,1H), 3.93(d,J=4.4Hz,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) + .

[0595] Using appropriate reagents, the following compounds were prepared according to the same protocol as described above.

[0596] Example CB: (4-methyl-3-pyridyl)[p-(trifluoromethyl)phenyl]{1-[5-(trifluoromethyl)-2-pyridyl]-4-piperidyl}amine: [ka]

[0597] Compound 100:29.9mg; 1 H NMR(400MHz,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.

[0598] Example CD: 2-{4-[(4-methyl-3-pyridyl)[6-(trifluoromethyl)-3-pyridyl]amino]-1-piperidyl}-5-pyrimidine carbonitrine: [ka]

[0599] Compound 101:26.6mg; 1 H NMR(400MHz,CD3OD)d8.55(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.

[0600] Example CE: 2-{4-[(4-chloro-3-pyridyl)[6-(trifluoromethyl)-3-pyridyl]amino]-1-piperidyl}-5-pyrimidine carbonitrine: [ka]

[0601] Compound 102: 95mg; 1H NMR(400MHz,CDCl3)d8.58(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.

[0602] Example CF: (p-difluoromethoxyphenyl)(4-methoxy-3-pyridyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidyl]amine: [ka]

[0603] Compound 103:538mg; 1 H NMR(400MHz,CD3OD)d8.44(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.

[0604] Example CG: 5-{4-[(p-difluoromethoxyphenyl)(4-methoxy-3-pyridyl)amino]cyclohexyloxy}-2-pyridinecarbonitride: [ka]

[0605] Compound 104-isomer 1: 7.5mg; 1H NMR (400MHz, CD3OD)d8.5(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.

change

[0606] Compound 104-Iridoid 2: 51 mg; 1 H NMR (400MHz, CD3OD)d8.6(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.

[0607] Example CH: 5-{4-[(4-メトキシ-3-ピリジル)[p-(トリフルオロメチル)フェニル]アミノ]シクロヘキシルオキシ}-2-ピリジンカルボニトリル:

change

[0608] Compound 105-Iridoid 1: 9.3 mg; 1 H NMR (400MHz, CDCl3)d8.28(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.

change

[0609] Compound 105-isomer 2: 68mg; 1 H NMR(400MHz,CDCl3)d8.6(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.

[0610] Example CI: (p-difluoromethoxyphenyl)(4-methoxy-3-pyridyl){1-[p-(methylsulfinyl)phenyl]-4-piperidyl}amine: [ka]

[0611] Compound 106: 150mg; 1 H NMR(400MHz,DMSO-d6)d8.48(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.

[0612] Example CJ: p-difluoromethoxyphenyl)[1-(2-fluoro-4-mesylphenyl)-4-piperidyl](4-methoxy-3-pyridyl)amine: [ka]

[0613] Compound 107: 150mg; 1H NMR(400MHz,DMSO-d6)d8.50(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.

[0614] Example CK: 5-{4-[(p-difluoromethoxyphenyl)(4-methoxy-3-pyridyl)amino]cyclohexyl}-2-pyridinecarbonitride: [ka]

[0615] Compound 108:21.4 mg (1:1 mixture of diastereomers); 1 H NMR(400MHz,CD3OD)d8.65(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

[0616] Example CL: (p-difluoromethoxyphenyl)(4-methoxy-3-pyridyl)[1-(4-pyridyl)-4-piperidyl]amine: [ka]

[0617] Compound 109:152mg; 1H NMR(400MHz,CD3OD)d8.45(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.

[0618] Example CM: (4-Methoxy-3-pyridyl)[1-(4-pyridyl)-4-piperidyl][p-(trifluoromethyl)phenyl]amine: [ka]

[0619] Compound 110: 159mg; 1 H NMR(400MHz,CD3OD)d8.5(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.

[0620] Example CN: 5-{4-[(4-methoxy-3-pyridyl)[p-(trifluoromethyl)phenyl]amino]cyclohexyl}-2-pyridinecarbonitride: [ka]

[0621] Compound 111:34.2 mg (a mixture of 41:59 diastereomers); 1H NMR(400MHz,CD3OD)d8.65(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.

[0622] Example CO: (4-cyclopropoxy-3-pyridyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidyl][p-(trifluoromethyl)phenyl]amine: [ka]

[0623] Compound 112: 96mg; 1 H NMR(400MHz,CD3OD)d8.2-8.55(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.

[0624] Example CP: 3-{4-[(4-methoxy-3-pyridyl)[p-(trifluoromethyl)phenyl]amino]-1-piperidyl}bicyclo[1.1.1]pentane-1-carbonitride: [ka]

[0625] Compound 113: 10mg; 1H NMR(400MHz,CD3OD)d8.53(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.

[0626] Example CQ: 2-{4-[(p-difluoromethoxyphenyl)(4-methoxy-3-pyridyl)amino]cyclohexyloxy}-5-pyrimidine carbonitrin [ka]

[0627] Compound 114: 40mg; 1 H NMR(400MHz,CD3OD)d8.87(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.

[0628] Example CR: (4-methyl-3-pyridyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidyl][p-(trifluoromethyl)phenyl]amine: [ka]

[0629] Compound 115:126mg; 1 H NMR(400MHz,CD3OD)d8.45(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.

[0630] Example CS: (p-difluoromethoxyphenyl)(4-methyl-3-pyridyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidyl]amine: [ka]

[0631] Compound 116:48mg; 1 H NMR(400MHz,CD3OD)d8.35(br.m,4H), 7.45(s,1H), 6.95(s,2H), 6.55(m,3H), 4.2(m,1H), 3.85( LCMS(ESI)[M+H]+=426.

[0632] Example CT: {1-[2-(methoxymethyl)-5-pyrimidinyl]-4-piperidyl}(4-methoxy-3-pyridyl)[p-(trifluoromethyl)phenyl]amine: [ka]

[0633] Compound 117: 142mg; 1 H NMR(400MHz,CD3OD)d8.4-8.55(m,3H), 8.21(s,1H), 7.45(m,2H), 7.25(d,1H), 6.65(m,2H), 4.5(m,2H), 4.25( LCMS(ESI)[M+H]+=474.

[0634] Example CU: (4-Cyclopropyl-3-pyridyl)(p-difluoromethoxyphenyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidyl]amine: [ka]

[0635] Compound 118: 125mg; 1 H NMR(400MHz,CD3OD)d8.35(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.

[0636] Example CV: (4-Cyclopropyl-3-pyridyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidyl][p-(trifluoromethyl)phenyl]amine: [ka]

[0637] Compound 119:78mg; 1 H NMR(400MHz,CD3OD)d8.2-8.4(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.

[0638] Example CW: 2-{4-[(4-methoxy-3-pyridyl)[p-(trifluoromethyl)phenyl]amino]cyclohexyloxy}-5-pyrimidine carbonitride: [ka]

[0639] Compound 120:26mg; 1H NMR(400MHz,CD3OD)d8.89(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.

[0640] Example CX: (4-ethyl-3-pyridyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidyl][p-(trifluoromethyl)phenyl]amine: [ka]

[0641] Compound 121:83mg; 1 H NMR(400MHz,CD3OD)d8.25-8.65(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.

[0642] Example CY:2-{4-[(4-cyclopropyl-3-pyridyl)[6-(difluoromethyl)-3-pyridyl]amino]-1-piperidyl}-5-pyrimidine carbonitrine: [ka]

[0643] Compound 122: 157mg; 1H NMR(400MHz,CD3OD)d8.75(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,1H), 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.

[0644] Example CZ: (p-difluoromethoxyphenyl)(4-ethyl-3-pyridyl)[1-(2-methyl-5-pyrimidinyl)-4-piperidyl]amine: [ka]

[0645] Compound 123:49mg; 1 H NMR(400MHz,CD3OD)d8.25-8.5(m,4H), 7.55(s,1H), 7.00(m,2H), 6.4-6.8(m,3H), 4.2(m,1H), 3.85(m,2) LCMS(ESI)[M+H]+=440.

[0646] Example DA: 2-(4-{[6-(difluoromethyl)-3-pyridyl](4-ethyl-3-pyridyl)amino}-1-piperidyl)-5-pyrimidine carbonitrine: [ka]

[0647] Compound 124: 102 mg; 1H NMR(400MHz,CD3OD)d8.60(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.

[0648] Example DB: (R)-4-{4-[(p-difluoromethoxyphenyl)(4-methoxy-3-pyridyl)amino]-1-piperidyl}1-ethyl-2-pyrrolidinone: [ka]

[0649] Compound 126:84mg; 1 H NMR(400MHz,CDCl3)d8.50(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(m ,2H), 3.1(m,1H), 2.95(m,2H), 2.55(m,1H), 2.40(m,1H), 2.2(m,2H), 2.05(m,2H), 1.5(m,2H), 1.1(t,3H)LCMS(ESI)[M+H]+=461.

[0650] Example DC: [1-(5-mesyl-2-pyrimidinyl)-4-piperidyl](4-methyl-3-pyridyl)[p-(trifluoromethyl)phenyl]amine: [ka]

[0651] Compound 127: 147mg; 1H NMR(400MHz,DMSO-d6)d8.7(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.

[0652] Example DD: 5-{4-[(4-methyl-3-pyridyl)[p-(trifluoromethyl)phenyl]amino]-1-piperidyl}-2-pyrimidine carbonitride: [ka]

[0653] Compound 128:192mg; 1 H NMR(400MHz,DMSO-d6)d8.55(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.

[0654] Example DE: (S)-1'-ethyl-4-[(4-methoxy-3-pyridyl)[p-(trifluoromethyl)phenyl]amino][1,3'-bipiperidyl]-6'-one: [ka]

[0655] Compound 129: 108 mg; 1H NMR(400MHz,CD3OD)d8.55(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(b r.m,6H), 2.80(m,2H), 2.5(m,1H), 2.4(m,1H), 2.05-2.2(m,3H), 1.85(m,1H), 1.55(m,1H), 1.15(t,3H)LCMS(ESI)[M+H]+=477.

[0656] Example DF: [4-(2H3)methoxy(2,5,6-2H3)-3-pyridyl][1-(2-methyl-5-pyrimidinyl)-4-piperidyl][p-(trifluoromethyl)phenyl]amine: [ka]

[0657] Compound 130: 230mg; 1 H NMR(400MHz,CD3OD)d8.32(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.

[0658] Example DG: (p-difluoromethoxyphenyl)[1-(5-mesyl-2-pyrimidinyl)-4-piperidyl][4-(2H3)methoxy(2,5,6-2H3)-3-pyridyl]amine: [ka]

[0659] Compound 131: 300mg; 1H NMR(400MHz,CD3OD)d8.62(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.

[0660] Example DH: [4-(2H3)methoxy-3-pyridyl][1-(2-methyl-5-pyrimidinyl)-4-piperidyl][p-(trifluoromethyl)phenyl]amine: [ka]

[0661] Compound 132: 185mg; 1 H NMR(400MHz,CD3OD)d8.5(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.

[0662] Example DI: (p-difluoromethoxyphenyl)[1-(5-mesyl-2-pyrimidinyl)-4-piperidyl][4-(2H3)methoxy-3-pyridyl]amine: [ka]

[0663] Compound 133: 300mg; 1 H NMR(400MHz,CD3OD)d8.85(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.

[0664] Example DJ: 2-{1-hydroxy-4-[(4-methoxy-3-pyridyl)[p-(trifluoromethyl)phenyl]amino]cyclohexyl}-5-pyrimidine carbonitrine: [ka]

[0665] Compound 134-isomer 1:80mg; 1 H NMR(400MHz,CD3CN)d9.1(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. [ka]

[0666] Compound 134-isomer 2: 78 mg; 1 H NMR(400MHz,CD3CN)d9.1(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.

[0667] Example DK: 2-{4-[(p-difluoromethoxyphenyl)(4-methoxy-3-pyridyl)amino]-1-hydroxycyclohexyl}-5-pyrimidine carbonitrile: [ka]

[0668] Compound 135-isomer 1:36 mg; 1H NMR(400MHz,CD3OD)d9.1(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. [ka]

[0669] Compound 135-isomer 2: 60 mg; 1 H NMR(400MHz,CD3OD)d9.01(s,2H), 8.51(br.s,1H), 8.32(br.s,1H), 6.97(m,3H), 6.2-6.6(br. LCMS(ESI)[M+H]+=468.

[0670] Examples of biological assays Preparation of mouse OPCs To evaluate the effect of treatment on OPCs, all treatments were assayed using two or more independent platings of epiblast stem cell-derived OPCs (EpiSCs). EpiSC-derived OPCs were obtained using previously described in vitro differentiation protocols and culture conditions (Najm et al, 2011, Nature Methods). The OPCs were expanded and frozen in aliquots. Before use in further assays, the OPCs were thawed under growth conditions for at least one passage.

[0671] EC of compounds 50 Determining the value A: In vitro phenotypic screening of OPC The ability of each compound to induce maturation of mouse OPCs into oligodendrocytes was evaluated. Before harvesting for the experiment, EpiSC-derived OPCs were grown and expanded in poly-L-ornithine (PO) and laminin-coated flasks in N2B27 medium (DMEM / F12 (Gibco), N2-MAX (R&D Systems), B-27 (ThermoFisher), 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). Poly-L-ornithine or poly-D-lysine-coated Cell Carrier Ultra plates (PerkinElmer) coated with laminin (Sigma, L2020) were used to grow 150,000 / cm³ of growth factor-free N2B27 medium. 2 Cells were seeded at a density of . For dose-response testing, a 1000-fold compound stock in dimethyl sulfoxide (DMSO) was added to assay plates, and an 8-point dose curve was obtained. A positive control and a DMSO vehicle control were included in each assay plate. Cells were incubated for 3 days under standard conditions (37°C, 5% CO2) and fixed with 4% paraformaldehyde (PFA) in phosphate-buffered saline (PBS) for 20 minutes. The fixed plates were washed with PBS, permeabilized with 0.1% Triton® X-100, and blocked with 10% donkey serum (v / v) in PBS for 40 minutes. Cells were then labeled with MBP antibody (Abcam, ab7349; 1:200) overnight at 4°C, washed with PBS, and stained with Alexa Fluor conjugate secondary antibody (1:500) for 45 minutes. Nuclei were visualized by DAPI staining (Sigma; 1 g / ml), followed by further washing with PBS.

[0672] B: High-Content Imaging and Analysis Cells and cell culture plates were imaged using the Operetta High Content Imaging and Analysis system (PerkinElmer). Analysis (PerkinElmer Harmony and Columbus software) began by identifying intact nuclei stained with DAPI. Subsequently, the perinuclear region of each cell was cross-referenced with mature myelin protein (MBP) staining to identify oligodendrocyte nuclei, from which the percentage of oligodendrocytes was calculated. The Levenberg-Marquardt algorithm was used to fit Hill's equation to the 8-point dose-response curves. 50 The values ​​were calculated. The results are shown in Table 3 (OPC EC). 50}) is shown.

[0673] Determination of efficacy and enzyme target GC / MS-based sterol profiling A: Mouse sterol profiling assay The ability of each compound to induce the accumulation of key sterol intermediates in the cholesterol biosynthesis 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 / well in PO and laminin-coated 96-well plates in growth factor-free N2B27 medium. After 24 hours, cells were rinsed with saline and the plates were frozen. Cholesterol-d7 standard was then added to each well, followed by drying under a stream of nitrogen and derivatization with 55 μl of bis(trimethylsilyl)trifluoroacetamide. After derivatization, 2 μl was analyzed by gas chromatography / mass spectrometry using an Agilent 5973 network mass-selective detector with a 6890 gas chromatography system and an HP-5MS capillary column (30 m × 0.25 mm × 0.25 mm). Samples were analyzed in full scan mode using electron ionization, and sterol abundances were calculated by integrating ion fragment peaks and compared with cholesterol-d7. Each metabolite was quantified using the following ion fragments: cholesterol-d7 (465), FF-Mas (482), cholesterol (368), thymostenol (458), thymosterol (456), desmosterol (456, 343), 7-dehydrocholesterol (456, 325), lanosterol (393), lathosterol (458), 14-dehydrothymostenol (456, 351), and dihydrolanosterol (395). For reference, Table 2 shows the sterol GC-MS analytes and their relationship with inhibitors of cholesterol biosynthesis. Unless otherwise indicated, all standards were obtained from Avanti Polar Lipids. Calibration curves were created by injecting sterol standards of various concentrations and maintaining a constant amount of cholesterol-D7. For normalized lanosterol accumulation results, the total amount of lanosterol measured after drug treatment was divided by the total amount of lanosterol accumulated after 24 hours of treatment with a 100 nM positive control standard. The Levenberg-Marquardt algorithm was used to fit Hill's equation to the 8-point dose-response curves. 50The value was calculated. EC of lanosterol 50 Value (mouse GCMS EC) 50 The results are shown in Table 3.

[0674] [Table 2]

[0675] B: Human sterol profiling assay 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 / well in Nunc MicroWell 96-well plates in hMSC High Performance Media Kit medium (RoosterBio). After 24 hours, cells were rinsed with saline and the plates were frozen. Cholesterol-d7 standard was then added to each well, followed by drying under a stream of nitrogen and derivatization with 55 μl of bis(trimethylsilyl)trifluoroacetamide. After derivatization, 2 μl was analyzed by gas chromatography / mass spectrometry using an Agilent 5973 network mass selective detector with an HP-5MS capillary column (30 m × 0.25 mm × 0.25 mm) on a 6890 gas chromatograph system. Samples were analyzed in full scan mode using electron ionization, and sterol abundances were calculated by integrating ion fragment peaks and compared with cholesterol-d7. Each metabolite was quantified using the following ion fragments: cholesterol-d7 (465), FF-Mas (482), cholesterol (368), thymostenol (458), thymosterol (456), desmosterol (456, 343), 7-dehydrocholesterol (456, 325), lanosterol (393), lathosterol (458), 14-dehydrothymostenol (456, 351), and dihydrolanosterol (395). For reference, Table 2 above shows the sterol GC-MS analytes and their relationship with inhibitors of cholesterol biosynthesis. Unless otherwise indicated, all standards were obtained from Avanti Polar Lipids. Calibration curves were created by injecting sterol standards of various concentrations and maintaining a constant level of cholesterol-D7. For normalized lanosterol accumulation results, the total amount of lanosterol measured after drug treatment was divided by the total amount of lanosterol accumulated after 24 hours of treatment with a 100 nM positive control standard.The Levenberg-Marquardt algorithm was used to fit Hill's equation to the 8-point dose-response curve, and EC. 50 The value was calculated. EC of lanosterol 50 Value (Human GCMS EC) 50 The results are shown in Table 3.

[0676] [Table 3-1] [Table 3-2] [Table 3-3]

[0677] While efforts have been made to ensure accuracy regarding the numerical values ​​used (e.g., quantities, temperatures, etc.), some experimental error and deviation should be taken into consideration.

[0678] Those skilled in the art will understand a number of methods and materials similar to or equivalent to those described herein that can be used to carry out the subject matter described herein. This disclosure is not limited to the methods and materials described herein.

[0679] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the subject matter, and are consistent with 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.

[0680] Throughout this specification and the claims, the words “comprise / comprises, and comprising” are used in a non-restrictive sense unless the context contradicts it. Embodiments described herein are understood to include embodiments that “consist of” and / or “essentially consist of.”

[0681] When a range of values ​​is provided, unless otherwise explicitly indicated in the context, it should be understood that the upper and lower limits of that range encompass each intervening value up to one-tenth of the lower limit unit between that range and any other described or intervening value within that range. The upper and lower limits of these smaller ranges, which may independently fall within smaller ranges, are also encompassed, subject to any specifically excluded restrictions within the described range. If the stated range includes one or both of the upper and lower limits, the range excluding one or both of the encompassed upper and lower limits is also included.

[0682] Those skilled in the art, having received the teachings presented in the preceding description and accompanying drawings, will likely conceive of many modifications and other embodiments described herein. Therefore, it will be understood that the present invention is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the accompanying claims. Certain terms are used herein, but these are used in a general and descriptive sense only and are not intended to be limiting.

Claims

1. Compound of formula A [Chem. 233] [In the formula, A is C １ -C ６ Alkyl, C ３ -C ８ Selected from the group consisting of cycloalkyl, phenyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, each of which is R Ａ１ , R Ａ２ and R Ａ３ It is arbitrarily replaced with one or more of the following: R Ａ１ , R Ａ２ and R Ａ３ are each independently C １ -C ６ alkyl, halo-C １ -C ６ alkyl, C １ -C ６ alkoxy, halo, cyano, oxo, -C(O)-R Ａ４ , -S(O)-R Ａ４ and -S(O) ２ -R Ａ４ selected from the group consisting of, R Ａ４ C １ -C ６ Alkyl or C ３ -C ８ It is a cycloalkyl, and If the aforementioned oxo exists, R Ａ１ , R Ａ２ and R Ａ３ Two of them are formed together with the carbon atoms to which they are bonded; G is -CH, C-OH, or N; If E exists, it is -C(O)- or -O-; Y is -CH or N; p is 1, 2, or 3; q is either 1 or 0; r is either 1 or 0; Here, if r is 0, then A is C １ -C ６ It is not alkyl; R １ C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl and Halo-C １ -C ６ Selected from the group consisting of alkyl groups; or R １ is a halo, and q is 0; R １ａ is hydrogen, halo, C １ -C ６ Selected from the group consisting of alkyl groups; R ２ Hello, Hello-C １ -C ６ Alkyl, Halo-C １ -C ６ Alkoxy and -S(O) ２ - (C １ -C ６ Selected from the group consisting of alkyl; R ２ａ is selected from the group consisting of hydrogen and halos; and R ３ is hydrogen, halo, or C １ -C ６ It is alkyl. or a pharmaceutically acceptable salt or solvate thereof.

2. Structure of formula I, formula A-i, or formula A-ii 【Chemistry 234】 【Chemical 235】 【Chemistry 236】 A compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, having the above.

3. Structure of Equation I 【Chemistry 237】 It has, During the ceremony, R Ａ１ , R Ａ２ and R Ａ３ Each of them is independent of C １ -C ６ Alkyl, Halo-C １ -C ６ Alkyl, halo, cyano, oxo, -C(O)-R Ａ４ , -S(O)-R Ａ４ and -S(O) ２ -R Ａ４ Selected from the group consisting of; G is -CH or N; and R １ C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl and Halo-C １ -C ６ Selected from the group consisting of alkyl groups, The compound according to claim 2 or a pharmaceutically acceptable salt or solvate thereof.

4. G is N, and the structure of equation I' [Chem. 238] A compound according to claim 3 or a pharmaceutically acceptable salt or solvate thereof, having the above.

5. A compound according to any one of claims 1 to 4, wherein q is 1, or a pharmaceutically acceptable salt or solvate thereof.

6. A compound according to any one of claims 1 to 4, wherein q is 0, or a pharmaceutically acceptable salt or solvate thereof.

7. R １ However, C １ -C ６ Alkyl or C ３ -C ８ A compound according to any one of claims 1 to 6, which is a cycloalkyl compound, or a pharmaceutically acceptable salt or solvate thereof.

8. R １ The compound according to claim 7 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is methyl, ethyl, or cyclopropyl.

9. Structure of formulas Ia, Ib, or Ic 【Chemistry 239】 【Chemistry 240】 【Chemistry 241】 A compound according to any one of claims 1 to 8, having the above, or a pharmaceutically acceptable salt or solvate thereof.

10. A compound according to any one of claims 1 to 9, wherein Y is N, or a pharmaceutically acceptable salt or solvate thereof.

11. A compound according to any one of claims 1 to 9, wherein Y is -CH, or a pharmaceutically acceptable salt or solvate thereof.

12. R ２ However, Hello C １ -C ６ Alkyl or Halo-C １ -C ６ A compound according to any one of claims 1 to 11, which is an alkoxy, or a pharmaceutically acceptable salt or solvate thereof.

13. R ２ However, Hello C １ -C ６ A compound according to claim 12, wherein it is alkyl, or a pharmaceutically acceptable salt or solvate thereof.

14. R ２ ga-CF ３ The compound according to claim 13 or a pharmaceutically acceptable salt or solvate thereof.

15. R ２ is halo-C １ -C ６ alkoxy, the compound according to claim 12 or a pharmaceutically acceptable salt or solvate thereof.

16. R ２ ga-O-CHF ２ The compound according to claim 15 or a pharmaceutically acceptable salt or solvate thereof.

17. A compound according to any one of claims 1 to 16, wherein p is 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

18. A compound according to any one of claims 1 to 17, wherein p is 1, or a pharmaceutically acceptable salt or solvate thereof.

19. A compound according to any one of claims 1 to 17, wherein p is 2, or a pharmaceutically acceptable salt or solvate thereof.

20. R ３ C １ -C ６ A compound according to any one of claims 1 to 19, which is alkyl, or a pharmaceutically acceptable salt or solvate thereof.

21. R ３ The compound according to claim 20, wherein is methyl, or a pharmaceutically acceptable salt or solvate thereof.

22. R ３ is hydrogen, the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt or solvate thereof.

23. A compound according to any one of claims 1 to 22, wherein r is 1, or a pharmaceutically acceptable salt or solvate thereof.

24. A is C １ -C ６ A compound according to claim 23, wherein it is alkyl, or a pharmaceutically acceptable salt or solvate thereof.

25. A is -CH ３ or -CH ２ CH ３ The compound according to claim 24 or a pharmaceutically acceptable salt or solvate thereof.

26. A compound according to any one of claims 1 to 22, wherein r is 0, or a pharmaceutically acceptable salt or solvate thereof.

27. The compound according to claim 23 or 26, wherein G is -CH, or a pharmaceutically acceptable salt or solvate thereof.

28. A is R Ａ１ , R Ａ２ and R Ａ３ C is arbitrarily replaced with one or more of the following ３ -C ５ A cycloalkyl compound according to claim 27, or a pharmaceutically acceptable salt or solvate thereof.

29. A, 【Chemistry 242】 The compound according to claim 28 or a pharmaceutically acceptable salt or solvate thereof.

30. R Ａ１ However, cyano or halo-C １ -C ６ A compound according to claim 29, wherein it is alkyl, or a pharmaceutically acceptable salt or solvate thereof.

31. R Ａ１ ga-CF ３ The compound according to claim 30 or a pharmaceutically acceptable salt or solvate thereof.

32. A is R Ａ１ , R Ａ２ and R Ａ３ The compound according to claim 23 or 26, wherein the compound is a phenyl optionally substituted with one or more of the following, or a pharmaceutically acceptable salt or solvate thereof.

33. A is R Ａ１ and R Ａ２ The compound according to claim 32, wherein the phenyl is optionally substituted with one or more of the following, or a pharmaceutically acceptable salt or solvate thereof.

34. A, 【Chemistry 243】 The compound according to claim 33 or a pharmaceutically acceptable salt or solvate thereof.

35. R Ａ１ ga-S(O) ２ -R Ａ４ And R Ａ２ The compound according to claim 34 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is a halo.

36. A, 【Chemistry 244】 The compound according to claim 33 or a pharmaceutically acceptable salt or solvate thereof.

37. R Ａ１ However, halo, cyano, -S(O) ２ -R Ａ４ and -C(O)-R Ａ４ A compound according to claim 36, selected from the group consisting of the above, or a pharmaceutically acceptable salt or solvate thereof.

38. A is R Ａ１ , R Ａ２ and R Ａ３ The compound according to claim 23 or 26, which is a 5-6 member heterocycline optionally substituted with one or more of the above, or a pharmaceutically acceptable salt or solvate thereof.

39. The compound according to claim 38, wherein the heterocyclyl comprises one or two heteroatoms selected from the group consisting of N, S, and O, or a pharmaceutically acceptable salt or solvate thereof.

40. The compound according to claim 38, wherein A is a 5-6 member heterocycline, or a pharmaceutically acceptable salt or solvate thereof.

41. The compound according to claim 40, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a 5- to 6-membered heterocycline comprising one or two heteroatoms selected from the group consisting of N, S, and O.

42. A, 【Chemistry 245】 The compound according to claim 41 or a pharmaceutically acceptable salt or solvate thereof.

43. A is R Ａ１ , R Ａ２ and R Ａ３ The compound according to claim 23 or 26, or a pharmaceutically acceptable salt or solvate thereof, which is a 5-6 member heteroaryl optionally substituted with one or more of the above.

44. A is R Ａ１ , R Ａ２ and R Ａ３ A compound according to claim 43, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl, oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, and thiazolyl, which is optionally substituted with one or more of the above.

45. A is R Ａ１ , R Ａ２ and R Ａ３ A compound according to claim 44, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, and pyrrolyl, which is optionally substituted with one or more of the above.

46. A is R Ａ１ , R Ａ２ and R Ａ３ The compound according to claim 45, which is a pyridinyl optionally substituted with one or more of the above, or a pharmaceutically acceptable salt or solvate thereof.

47. A is R Ａ１ The compound according to claim 46, wherein the pyridinyl is substituted with a pyridinyl compound, or a pharmaceutically acceptable salt or solvate thereof.

48. A, 【Chemistry 246】 The compound according to claim 47 or a pharmaceutically acceptable salt or solvate thereof.

49. R Ａ１ However, C １ -C ６ Alkyl, Halo-C １ -C ６ Alkyl, halo, cyano, and -S(O) ２ -R Ａ４ A compound according to claim 48, selected from the group consisting of the above, or a pharmaceutically acceptable salt or solvate thereof.

50. A is R Ａ１ , R Ａ２ and R Ａ３ The compound according to claim 45, which is a pyrimidinyl or pyrazinyl optionally substituted with one or more of the above, or a pharmaceutically acceptable salt or solvate thereof.

51. A is R Ａ１ The compound according to claim 50, which is optionally substituted with pyrimidinyl or pyrazinyl, or a pharmaceutically acceptable salt or solvate thereof.

52. A, 【Chemistry 247】 The compound according to claim 51 or a pharmaceutically acceptable salt or solvate thereof.

53. R Ａ１ However, C １ -C ６ Alkyl, Halo-C １ -C ６ Alkyl, halo, cyano, and -S(O) ２ -R Ａ４ A compound according to claim 52, selected from the group consisting of the above, or a pharmaceutically acceptable salt or solvate thereof.

54. A is R Ａ１ , R Ａ２ and R Ａ３ The compound according to claim 45, or a pharmaceutically acceptable salt or solvate thereof, wherein oxadiazolyl and pyrrolyl are optionally substituted with one or more of the above.

55. A is R Ａ１ The compound according to claim 54, wherein oxadiazolyl and pyrrolyl are optionally substituted with oxadiazolyl and pyrrolyl, or a pharmaceutically acceptable salt or solvate thereof.

56. A, 【Chemistry 248】 The compound according to claim 55 or a pharmaceutically acceptable salt or solvate thereof.

57. R Ａ１ C １ -C ６ , the compound according to claim 56 or a pharmaceutically acceptable salt or solvate thereof.

58. A, 【Chemistry 249】 And R Ａ１ However, C １ -C ６ A compound according to claim 38, wherein the compound is alkyl, or a pharmaceutically acceptable salt or solvate thereof.

59. R Ａ１ The compound according to claim 58, wherein is ethyl, or a pharmaceutically acceptable salt or solvate thereof.

60. R Ａ１ ga CH ２ OCH ３ The compound according to claim 43 or 52, or a pharmaceutically acceptable salt or solvate thereof.

61. Structure of formula Id [Chemical 250] [In the formula, r and q are both 0; R １ａ and R １ｂ These are hydrogen atoms, and R １ It is a halogen. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, having the above.

62. R １ The compound according to claim 61, wherein -Cl is present, or a pharmaceutically acceptable salt or solvate thereof.

63. R ２ ga CF ３ The compound according to claim 61 or 62, or a pharmaceutically acceptable salt or solvate thereof.

64. R ３ A compound according to any one of claims 61 to 63, wherein is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

65. A compound according to any one of claims 61 to 64, wherein Y is N, or a pharmaceutically acceptable salt or solvate thereof.

66. A compound according to any one of claims 61 to 65, wherein G is N and p is 2, or a pharmaceutically acceptable salt or solvate thereof.

67. E is -O-; r is 1; p is 2; R １ａ , R ２ａ , and R ３ However, each of them is hydrogen, and the structure is given by formula A-i'. 【Chemistry 251】 A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, having the above.

68. r is 0; p is 2; R １ａ , R ２ａ , and R ３ However, each of them is hydrogen, and the structure is given by equation A-ii'. 【Chemistry 252】 A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, having the above.

69. q is 1, and R １ ga CH ３ The compound according to claim 67 or 68, or a pharmaceutically acceptable salt or solvate thereof.

70. R ２ However, CF ３ or OCHF ２ The compound according to any one of claims 67 to 69 or a pharmaceutically acceptable salt or solvate thereof.

71. A compound according to any one of claims 67 to 70, wherein Y is CH, or a pharmaceutically acceptable salt or solvate thereof.

72. A, 【Chemistry 253】 The compound according to any one of claims 52 and 61 to 71, or a pharmaceutically acceptable salt or solvate thereof.

73. A, 【Chemistry 254】 The compound according to any one of claims 48 and 61 to 71, or a pharmaceutically acceptable salt or solvate thereof.

74. The compound according to any one of claims 1 to 73, wherein one or more hydrogen atoms are replaced by deutherium.

75. Structure of formula A-iii 【Chemistry 255】 The compound according to claim 74, having the following characteristics.

76. R １ ga-CD ３ The compound according to claim 74 or 75, or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 77】 【Table 4-1】 Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 A compound according to claim 1, 2, or 3, selected from the group consisting of the above, or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 78】 【Table 5-1】 Table 5-2 Table 5-3 Table 5-4 Table 5-5 A compound according to claim 1, selected from the group consisting of the above, or a pharmaceutically acceptable salt or solvate thereof.

79. A pharmaceutical composition comprising a compound according to any one of claims 1 to 78 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive.

80. A method for promoting myelin formation in a subject requiring promotion of myelin formation, comprising administering to the subject requiring promotion of myelin formation a therapeutically effective amount of a compound according to any one of claims 1 to 78 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 79.

81. A compound according to any one of claims 1 to 78 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 79, for use in treating a disorder in a subject requiring treatment of the disorder.

82. A compound according to any one of claims 1 to 78 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 79, for use in promoting myelin formation in subjects requiring promotion of myelin formation.

83. Use of a compound according to any one of claims 1 to 78 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 79, in the manufacture of a pharmaceutical for treating a disorder in a subject requiring treatment of the disorder.

84. Use of a compound according to any one of claims 1 to 78 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 79, in the manufacture of a pharmaceutical for promoting myelin formation in subjects requiring promotion of myelin formation.

85. The method according to claim 80, wherein the subject has myelin-related disorders.

86. The compound for use according to claim 81 or 82, wherein the subject has myelin-related disorders.

87. The use according to claim 83 or 84, wherein the subject has myelin-related disorders.

88. The aforementioned myelin-related disorders include multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, childhood leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander disease, Pelizaeus-Merzbacher disease (PMD), white matter disappearance disease, Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, and spinal cord injury. The method according to claim 85, the compound for use according to claim 86, or the use according to claim 87, which is a traumatic brain injury, post-radiation injury, neurological complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, sporadic vitamin E deficiency syndrome, Bassen-Kohnzweig syndrome, Marquiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barré syndrome, Charcot-Marie-Tooth disease, Bell's palsy, or radiation-induced demyelination.

89. The method according to claim 85, the compound according to claim 86, or the use according to claim 87, wherein the disorder is multiple sclerosis.

90. A method for inhibiting CYP51 (lanosterol demethylase), comprising contacting CYP51 with a compound according to any one of claims 1 to 78 or a pharmaceutically acceptable salt or solvate thereof, or with a pharmaceutical composition according to claim 79.

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