Quinoline derivatives and related products as modulators of MAS-associated G protein receptor X2

Abstract

In general, a method for modulating MRGPRX2, or more specifically for treating an MRGPRX2 or MRGPRX2 ortholog dependent condition, is provided by contacting MRGPRX2 or an MRGPRX2 ortholog, respectively, by administering to a subject in need of such treatment an effective amount of a compound having structure (I), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein W, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R x is as defined herein. Pharmaceutical compositions containing such compounds are also provided, as well as the compounds themselves. JPEG2025512839000280.jpg5981

Description

[Technical field]

[0001] The present invention relates to modulators of the Mas-related G protein-coupled receptor X2, products containing same, and methods of their use and preparation. [Background technology]

[0002] The Mas-related G protein receptors (MRGPRs) are a group of orphan receptors with restricted expression in very specific tissues. Little is known about the function of most of these receptors. There are eight related receptors in this class that are expressed in humans, only four of which have readily identifiable orthologues in other species (i.e., MRGPRs D, E, F, and G). Although some of the other four receptors (MRGPRs X1, X2, X3, and X4) have counterparts in higher species, including dogs and horses, they do not have a single corresponding orthologue in rodents. Summary of the Invention

[0003] The present invention is based, in part, on the identification of MRGPRX2 or MRGPRX2 ortholog modulator compounds. Among the rodent orthologs, mouse mrgprb2 and rat mrgprb3 functionally correspond to human MRGPRX2 in mast cells. MRGPRX2 and its ortholog receptors mediate disorders including pseudoallergic drug reactions, chronic itch (e.g., pruritus), inflammatory disorders, pain disorders, cancer-related conditions, skin disorders, wound healing, cardiovascular disease, and pulmonary inflammation / COPD. In one embodiment, expression of MRGPRX2 and its orthologs is primarily restricted to mast cells. Mast cells are innate immune cells that are primarily present at sites exposed to the external environment, such as the skin, oral / gastrointestinal mucosa, and airways. Mast cells express a large number of receptors that respond to mechanical and chemical stimuli. Classically, when activated by IgE, mast cells release preformed mediators from granules (e.g., histamine, proteases, and heparin) as well as newly synthesized mediators (e.g., thromboxanes, prostaglandin D2, leukotriene C4, tumor necrosis factor alpha, eosinol chemotactic factor, and platelet activating factor) that trigger allergic and inflammatory responses. Histamine dilates postcapillary venules, activates the endothelium, and increases vascular permeability. This causes local edema, warmth, redness, and chemotaxis of other inflammatory cells to the site of release. Histamine also contributes to neuronal sensitization that results in pain or itch. MRGPRX2 and its orthologues mediate immunoglobulin E (IgE)-independent activation of mast cells. MRGPRX2 and its orthologues are receptors for (or are sensitive to activation by) a variety of ligands, including basic secretagogues (small cationic molecules), certain drugs (e.g., cationic peptide agonists), neuropeptides, and antimicrobial peptides, and are therefore important in non-IgE-mediated pseudoallergic reactions, inflammation, pain, and itch conditions. Mast cells also promote chronic inflammation in the local tissue microenvironment, ultimately resulting in the development of T. h17 It may contribute to the progression of autoimmune disorders by polarizing the immune response. Thus, modulating MRGPRX2 or MRGPRX2 orthologues allows for the treatment of autoimmune diseases, pseudoallergic drug reactions, pain, itch, and inflammatory disorders such as inflammatory bowel disease, urticaria, sinusitis, asthma, rosacea, endometriosis, and other MRGPRX2 or MRGPRX2 orthologue-dependent conditions as described in more detail below.

[0004] In one embodiment there is provided a method of treating a MRGPRX2 or MRGPRX2 ortholog dependent condition by administering to a subject in need thereof a pharmaceutical composition of an effective amount of a modulator compound of the invention.

[0005] Thus, in one embodiment, a compound having structure (I): [ka] or a pharma- ceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein W, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R x is as defined herein.

[0006] In other embodiments, there is provided a compound having formula (Ia), (Ib), (Ic), (Id), (1e), or (If), as defined herein, or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0007] In yet another embodiment, a pharmaceutical composition is provided comprising a carrier or excipient and a compound having structure (I), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0008] In certain embodiments, a pharmaceutical composition is provided comprising a substructure of structure (I) having formula (Ia), (Ib), (Ic), (Id), (1e), or (If), as defined herein, or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0009] In another embodiment, there is provided a method for treating an MRGPRX2 or MRGPRX2 ortholog dependent condition by administering to a subject in need of such treatment an effective amount of a compound having structure (I), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0010] In some embodiments, the MRGPRX2 or MRGPRX2 ortholog dependent condition is one or more of a pseudoallergic reaction, an itch-associated condition, a pain-associated condition, a cancer-associated condition, an inflammation-associated condition, or an autoimmune disorder.

[0011] In one embodiment, there is provided a method of treating an MRGPRX2 or MRGPRX2 ortholog dependent condition comprising administering an effective amount of a compound of structure (I) having formula (Ia), (Ib), (Ic), (Id), (1e), or (If) as defined herein, or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0012] In another embodiment, there is provided a compound having one or more of the structures disclosed herein, or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] As mentioned above, the present invention relates to modulators of MRGPRX2 (or MRGPRX2 orthologues), products containing same, and methods of their use and preparation. The present invention is based, in part, on the identification of MRGPRX2 modulator compounds and MRGPRX2 orthologue modulator compounds. MRGPRX2 and MRGPRX2 orthologues are expressed in mast cells. MRGPRX2 and MRGPRX2 orthologues are receptors for (or susceptible to activation by) a diverse group of ligands, including basic secretagogues, certain drugs, neuropeptides, antimicrobial peptides, and are therefore important for pseudoallergic reactions, itch, pain, or inflammatory disorders upon exposure.

[0014] MRGPR appears to be a sensory receptor that recognizes the external environment for exogenous or endogenous signals / chemicals. These receptors may respond to multiple chemical ligands / agonists. For example, MRGPRX2 recognizes compound 48 / 80, substance P, mastoparan, icatibant, ciprofloxacin, and tracurium as agonist signals. In certain embodiments, the molecules of the present invention modulate MRGPRX2 by functioning as inverse agonists that can block multiple chemicals and / or as competitive antagonists that can specifically block individual ligands. In one embodiment, such modulation is selective to other MRGPRs, such as MRGPR X1, X3, and / or X4.

[0015] definition As used herein, the following terms have the meanings defined below, unless the context indicates otherwise.

[0016] By "modulate" MRGPRX2 it is meant that the compound interacts with MRGPRX2 or an MRGPRX2 orthologue such that it functions as an inverse agonist for the receptor and / or as a competitive antagonist for the receptor. In one embodiment, such modulation is partially or completely selective relative to other MRGPRs, such as MRGPRs X1, X3 and / or X4.

[0017] "MRGPR" refers to one or more of the Mas-related G protein-coupled receptors, which are a group of orphan receptors with restricted expression in very specific tissues (e.g., mast cells and dorsal root ganglia) and barrier tissues. There are eight related receptors in this class that are expressed in humans, only four of which have readily identifiable orthologues in other species (i.e., MRGPR D, E, F, and G). The other four receptors (MRGPR X1, X2, X3, and X4) do not have any orthologues in non-human species based on homology. Of the rodent receptors, mouse mrgprb2 and rat mrgprb3 functionally correspond to human MRGPRX2 on mast cells.

[0018] "MRGPRX2," also known as "MRGX2" or "MGRG3," refers to a member of the MRGPR family that is expressed on mast cells and can mediate IgE-independent activation (e.g., mast cell degranulation) in response to ligand binding. An exemplary human MRGPRX2 amino acid sequence is set forth in Uniprot Q96LB1.

[0019] "Effective amount" refers to the amount of a particular drug sufficient to achieve a desired effect in a subject being treated with that drug. Ideally, an effective amount of a drug is an amount sufficient to inhibit or treat a disease without causing substantial toxicity in the subject. The effective amount of a drug varies depending on the subject being treated, the severity of the affliction, and the method of administration of the pharmaceutical composition. How to determine an effective amount of a disclosed compound sufficient to achieve a desired effect in a subject will be understood by one of skill in the art in light of this disclosure.

[0020] "Alkyl" refers to a saturated or unsaturated, straight or branched chain alkyl group having 1 to 8 carbon atoms, in some embodiments 1 to 6 carbon atoms, in some embodiments 1 to 4 carbon atoms, and in some embodiments 1 to 3 carbon atoms. Examples of saturated straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl-, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Unsaturated alkyl includes alkenyl and alkynyl as defined below.

[0021] "Alkenyl" refers to saturated or straight or branched chain alkenyl groups having 2 to 8 carbon atoms, in some embodiments 2 to 6 carbon atoms, in some embodiments 2 to 4 carbon atoms, and in some embodiments 2 to 3 carbon atoms. An alkenyl group is an unsaturated hydrocarbon containing at least one carbon-carbon double bond. Examples of lower alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

[0022] "Alkynyl" refers to straight or branched chain alkynyl groups having from 2 to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in some embodiments from 2 to 4 carbon atoms, and in some embodiments from 2 to 3 carbon atoms. An alkynyl group is an unsaturated hydrocarbon containing at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0023] "Halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0024] "Hydroxy" refers to --OH.

[0025] "Cyano" refers to -CN.

[0026] Amino refers to -NH2, -NHalkyl, or N(alkyl), where alkyl is as defined above. Examples of amino include, but are not limited to, -NH2, -NHCH3, -N(CH3)2, and the like.

[0027] "Haloalkyl" refers to an alkyl as defined above in which one or more hydrogen atoms have been replaced with a halogen. Examples of lower haloalkyl groups include, but are not limited to, -CF3, -CHF2, and the like.

[0028] "Alkoxy" refers to an alkyl as defined above attached through an oxygen atom (i.e., -O-alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like.

[0029] "Haloalkoxy" refers to a haloalkyl as defined above attached through an oxygen atom (i.e., -O-haloalkyl). Examples of lower haloalkoxy groups include, but are not limited to, -OCF3, and the like.

[0030] "Cycloalkyl" refers to an alkyl group that forms a ring structure, which may be substituted or unsubstituted, and the ring is either fully saturated, partially unsaturated, or fully unsaturated, and where there is unsaturation, conjugation of the π electrons within the ring does not result in aromaticity. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, cycloalkyl groups have 3-8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3-5, 3-6, or 3-7. Cycloalkyl groups further include polycyclic cycloalkyl groups, such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, as well as fused rings, such as, but not limited to, decalinyl.

[0031] An "aryl" group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Representative aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, the aryl group contains 6 to 14 carbons in the ring portion of the group. The terms "aryl" and "aryl group" include fused rings in which at least one ring, but not necessarily all rings, is aromatic, such as fused aromatic aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). In one embodiment, the aryl is phenyl or naphthyl, and in another embodiment, the aryl is phenyl.

[0032] "Carbocycle" refers to an alkyl group that forms a ring structure, which may be substituted or unsubstituted, and the ring is either fully saturated, partially unsaturated, or fully unsaturated, and where there is unsaturation, conjugation of the π electrons within the ring may result in aromaticity. In one embodiment, a carbocycle includes a cycloalkyl, as defined above. In another embodiment, a carbocycle includes an aryl, as defined above.

[0033] "Heterocycle" refers to aromatic and non-aromatic ring moieties containing three or more ring members, one or more of which is a heteroatom, such as, but not limited to, N, O, S, or P. In some embodiments, heterocycles contain 3-20 ring members, while other such groups have 3-15 ring members. At least one ring contains a heteroatom, but not all rings in a polycyclic system need contain heteroatoms. For example, a dioxolanyl ring and a benzdioxolanyl ring system (a methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein.

[0034] Heterocyclyl groups also include fused ring species, including those in which an aromatic group is fused with a non-aromatic group. Heterocyclyl groups also include polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl, and include heterocyclyl groups having substituents, including, but not limited to, alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups, attached to one of the ring members. Heterocyclyl groups, as defined herein, may be heteroaryl groups or partially or fully saturated cyclic groups containing at least one ring heteroatom. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, furanyl, tetrahydrofuran, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0035] In one embodiment, heterocyclyl includes heteroaryl.

[0036] "Heteroaryl" refers to an aromatic ring moiety containing five or more ring members, one or more of which is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups. The terms "heteroaryl" and "heteroaryl group" include fused ring compounds in which at least one ring, but not necessarily all rings, is aromatic, e.g., tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, and 2,3-dihydroindolyl.

[0037] "Isomers" is used herein to encompass all chiral, diastereomeric, or racemic forms of a structure (also referred to as stereoisomers, as opposed to structural or positional isomers) unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds may be optical isomers enriched or resolved at any or all asymmetric atoms, with any degree of enrichment, as is evident from the depiction. Both racemic and diastereomeric mixtures, as well as individual optical isomers, can be synthesized to be substantially free of their enantiomeric or diastereomeric partners, all of which are within the scope of certain embodiments of the present invention. Isomers resulting from the presence of a chiral center include a pair of non-superimposable isomers, referred to as "enantiomers". Single enantiomers of a pure compound are optically active (i.e., they can rotate the plane of plane-polarized light, referred to as R or S).

[0038] "Isolated optical isomer" means a compound that is substantially purified from the corresponding optical isomer(s) of the same formula. For example, the isolated isomer can be at least about 80%, at least 80%, or at least 85% pure by weight. In other embodiments, the isolated isomer is at least 90% pure by weight, at least 98% pure by weight, or at least 99% pure by weight.

[0039] "Substantially enantiomerically or diastereomerically" pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer relative to the other enantiomer of at least about 80%, and more specifically, greater than 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.

[0040] The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. Racemates are labeled "(±)" because they have no optical activity (i.e., they do not rotate plane-polarized light in either direction because the constituent enantiomers cancel each other out). All compounds that have an asterisk (*) adjacent to a tertiary or quaternary carbon are optically active isomers and can be purified from their respective racemates and / or synthesized by appropriate chiral syntheses.

[0041] A "hydrate" is a compound that exists in combination with water molecules. The combination may contain stoichiometric amounts of water, such as a monohydrate or dihydrate, or may contain random amounts of water. As the term is used herein, "hydrate" refers to a solid form, i.e., a compound in an aqueous solution may be hydrated, but is not a hydrate as the term is used herein.

[0042] A "solvate" is similar to a hydrate, except that a solvent other than water is present. For example, methanol or ethanol can form an "alcohol acid," which again can be stoichiometric or non-stoichiometric. As the term is used herein, "solvate" refers to a solid form, i.e., a compound in a solvent solution may be solvated, but is not a solvate as the term is used herein.

[0043] "Isotope" refers to an atom with the same number of protons but a different number of neutrons, and an isotope of a compound of structure (I) includes any such compound in which one or more atoms are replaced by an isotope of that atom. For example, carbon-12 (the most common form of carbon) has six protons and six neutrons, while carbon-13 has six protons and seven neutrons, and carbon-14 has six protons and eight neutrons. Hydrogen has two stable isotopes: deuterium (one proton and one neutron) and tritium (one proton and two neutrons). Fluorine has many isotopes, with fluorine-19 being the longest-lived. Thus, isotopes of compounds having the structure of structure (I) include, but are not limited to, compounds of structure (I) in which one or more carbon-12 atoms are replaced by carbon-13 and / or carbon-14 atoms, compounds of structure (I) in which one or more hydrogen atoms are replaced by deuterium and / or tritium, and / or compounds of structure (I) in which one or more fluorine atoms are replaced by fluorine-19.

[0044] "Salt" generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counterion. For example, salts formed between acids in their anionic form and a cation are called "acid addition salts." Conversely, salts formed between a base in its cationic form and an anion are called "base addition salts."

[0045] The term "pharmaceutically acceptable" refers to an agent that is approved for human consumption and is generally non-toxic. For example, the term "pharmaceutically acceptable salts" refers to non-toxic inorganic or organic acid and / or base addition salts (see, for example, Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated herein by reference).

[0046] Pharmaceutically acceptable base addition salts of the compounds of the invention include metal salts including alkali metal, alkaline earth metal, and transition metal salts, such as, for example, calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

[0047] Pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylalanine ... These include phenylacetic acid, mandelic acid, hippuric acid, malonic acid, oxalic acid, embonic (pamoic) acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, -galactaric acid, and galacturonic acid.

[0048] The compounds of the present disclosure (i.e., compounds of structure (I) and embodiments thereof), or pharma- ceutically acceptable salts thereof, may contain one or more geometrically asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, defined with respect to absolute stereochemistry as (R)- or (S)-, or, in the case of amino acids, as (D)- or (L)-. Thus, the embodiments include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using prior art techniques such as chromatography and fractional crystallization. Prior art techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both the E and Z geometric isomers, as well as all tautomeric forms.

[0049] Salts that are not pharma-ceutically acceptable are generally not useful as pharmaceuticals, although such salts may be useful, for example, as intermediates in the synthesis of compounds having structure (I), for example, in their purification by recrystallization.

[0050] As used herein, the phrase "MRGPRX2-dependent state" refers to a state in which activation, hypersensitization, or desensitization of MRGPRX2 or its orthologues by natural or synthetic ligands initiates, mediates, maintains, or enhances a pathological condition. For example, some cationic peptide agonists are known to cause pseudoallergic reactions in patients in whom MRGPRX2 is sensitive to (or activated by) cationic peptide agonists, including secretagogues, icatibant, leuprolide, or ganirelix, neutral and anionic peptide agonists (e.g., exenatide, glucagon, liraglutide, enfuvirtide, colistimethate), nonsteroidal agonists (atracurium mivacurium), nonsteroidal antagonist drugs, neuropeptides, and antimicrobial peptides. Furthermore, overexpression and / or overactive MRGPRX2 can also make mast cells more sensitive to activation by endogenous and / or exogenous ligands. Without being limited by theory, it should be understood that by modulating MRGPRX2, pseudo-allergic reactions, itch, pain, inflammatory or autoimmune disorders can be alleviated.

[0051] In some embodiments, the MRGPRX2-dependent condition is a condition caused by IgE-independent activation of MRGPRX2 or its orthologue. IgE-independent activation of MRGPRX2 can induce mast cell degranulation. For example, IgE-independent mast cell activation is associated with some cases of chronic urticaria and other mast cell-mediated conditions that do not respond to current anti-IgE or antihistamine therapy. Thus, the compounds of the present disclosure can be used to treat MRGPRX2-dependent conditions caused by IgE-independent activation of MRGPRX2, which would benefit from modulating MRGPRX2.

[0052] In some embodiments, the MRGPRX2-dependent condition is an itch-associated condition, a pain-associated condition, a cancer-associated condition, a pseudo-allergic reaction, or an autoimmune or inflammatory disorder in a human or other mammal.

[0053] As used herein, the phrase "pseudo-allergic reaction" refers to an IgE-independent allergic reaction characterized by histamine release, inflammation, airway constriction, or any combination thereof. A pseudo-allergic reaction may be an anaphylactic reaction. A pseudo-allergic reaction may be caused by a range of cationic substances, collectively referred to as basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. Thus, in one embodiment, the method of the present invention is provided for treating pseudo-allergic reactions, such as those caused by secretagogues, cationic peptide agonists, anionic peptide agonists, neutral peptide agonists, nonsteroidal antagonist drugs, neuropeptides, and antimicrobial peptides. In one embodiment, the pseudoallergic reaction is caused by MCD peptide, substance P, VIP, PACAP, dynorphin, somatostatin, compound 48 / 80, cortistatin-14, mastoparan, meletin, cathelicidin peptide, ciprofloxacin, vancomycin, leuprolide, goserelin, histrelin, triptorelin, cetrorelix, ganirelix, degarelix, octreotide, lanreotide, pasireotide, sermorelin, tesamorelin, icatibant, glatiramer acetate, teriparatide, pramlintide, bleomycin, exenatide, glucagon, liraglutide, enfuvirtide, colistimethate, succinylcholine, tubocurarine, atracurium, mivacurium, and rocuronium.

[0054] As used herein, the phrase "itch-associated condition" refers to any condition associated with pruritus, including acute and chronic pruritus. The itch sensation can arise, for example, from the peripheral nervous system (e.g., cutaneous or neuropathic itch) or the central nervous system (e.g., neuropathic, neurogenic, or psychogenic itch). Thus, in one embodiment, the method of the invention is directed to treating an itch-related condition, such as chronic itch, contact dermatitis, allergic blepharitis, anaphylaxis, anaphylactoid drug reactions, anaphylactic shock, anemia, atopic dermatitis, bullous pemphigoid, candidiasis, chickenpox, end stage renal failure, hemodialysis, cholestatic pruritus, chronic urticaria, contact dermatitis, dermatitis herpetiformis, diabetes, drug allergies, dry skin, dyshidrotic dermatitis, ectopic eczema, eosinophilic fasciitis, epidermolysis bullosa, erythrasma, food allergies, folliculitis, fungal skin infections, hemorrhoids, herpes, HIV infection, Hodgkin's disease, hyperthyroidism, iodine-containing coagulants, In one embodiment, the present invention is provided for treating a variety of conditions, including chronic myelopathy, chronic rhinitis ...

[0055] As used herein, the phrase "pain-related condition" means any pain resulting from a medical condition. Thus, in one embodiment, the method of the invention is directed to treating acute pain, advanced prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, arthrofibrosis, ataxic cerebral palsy, autoimmune atrophic gastritis, avascular necrosis, back pain, Behcet's disease (syndrome), burning mouth syndrome, bursitis, cancer pain, carpal tunnel, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical stenosis, Charcot-Marie-Tooth (CMT) disease, Chronic Fatigue Syndrome (CFS), Chronic Functional Abdominal Pain (CFAP), chronic pain, chronic pancreatitis, chronic pelvic pain syndrome, lung collapse (pneumothorax), Complex Regional Pain Syndrome (RSD), corneal neuropathic pain, Crohn's disease, degenerative disc disease, toothache, Dercum's disease, dermatomyositis, diabetic peripheral neuropathy, Peripheral Neuropathy (DPN), dystonia, Ehlers-Danlos Syndrome (EDS), endometriosis, Eosinophilia-Myalgia Syndrome (EMS), erythromelalgia, fibromyalgia, gout, headache, herniated disc, hydrocephalus, intercostal neuralgia, interstitial cystitis, irritable bowel syndrome (EMS). syndrome, IBS), juvenile dermatitis (dermatomyositis), knee injury, leg pain, low back pain and hematuria syndrome, lupus, Lyme disease, cavernous kidney disease (Medullary Sponge Kidney Disease), Kidney, MSK), dysesthesias, thigh pain, mesothelioma, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, osteoarthritis, Paget's disease, Parsonage-Turner syndrome, pelvic pain, periodontal pain, peripheral neuropathy, phantom limb pain, compressed nerve, polycystic kidney disease, polymyalgia rheumatica, polymyositis, porphyria, postherniorrhaphy pain syndrome, postmastectomy, postoperative pain, pain syndrome, poststroke pain, postthoracotomy pain syndrome, postherpetic neuralgia (shingles), postpolio syndrome, primary lateral sclerosis, psoriatic arthritis, pudendal neuralgia, radiculopathy, Raynaud's disease, rheumatoid arthritisIn one embodiment, the present invention is provided for treating pain-related conditions such as chronic myelitis, rheumatoid arthritis, sacroiliac joint dysfunction, sarcoidosis, Scheuermann's kyphosis, sciatica, scoliosis, shingles (herpes zoster), Sjogren's syndrome, spasmodic torticollis, sphincter of Oddi dysfunction, spinocerebellar ataxia (SCA ataxia), spinal cord injury, lumbar spinal stenosis, syringomyelia, Tarlov's cyst, transverse myelitis, trigeminal neuralgia, neuropathic pain, ulcerative colitis, vascular pain, and vulvodynia.

[0056] As used herein, the term "autoimmune disorder" or "inflammatory disorder" refers to a disease or disorder arising from and / or directed towards an individual's own tissues or organs, or their co-segregation or manifestation, or conditions resulting therefrom. Typically, various clinical and laboratory markers of autoimmune disease may be present, including, but not limited to, hypergammaglobulinemia, high levels of autoantibodies, antigen-antibody complex deposits in tissues, clinical benefit from corticosteroid or immunosuppressive treatment, and lymphoid cell aggregates in affected tissues.Thus, in one embodiment, the methods of the invention are directed to the treatment of autoimmune disorders, such as chronic inflammation, mast cell activation syndrome, multiple sclerosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, appendicitis, bursitis, cutaneous lupus, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (rsd / crps), rhinitis, tendonitis, tonsillitis, acne vulgaris, sinusitis, rosacea, psoriasis, graft-versus-host disease, reactive airway disorder, asthma, airway infections, allergic rhinitis, Autoinflammatory diseases, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, sweat gland abscess, hypersensitivity, intestinal disorders, epithelial intestinal disorders, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, lupus erythematosus, interstitial cystitis, otitis, pelvic inflammatory disease, endometrial pain, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, psoriasis, pneumonia, chronic obstructive pulmonary disease, persistent sputum eosinophilia, eosinophilic leukemia, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic duodenitis, eosinophilic Gastroenteritis, mast cell gastrointestinal disease, hypereosinophilic syndrome, aspirin-exacerbated respiratory disease, nasal polyposis, chronic rhinosinusitis, antibody-dependent cell-mediated cytotoxicity, neurofibromatosis, swannamatosis, tubulointerstitial nephritis, glomerulonephritis, diabetic nephropathy, allograft rejection, amyloidosis, renal vascular ischemia, reflux nephropathy, polycystic kidney disease, hepatic fibrosis / cirrhosis, autoimmune liver disease, biliary atresia, acute and chronic hepatitis B and C viruses, liver tumors and cancer, alcoholic liver disease The present invention is provided to treat chronic myelitis, polycystic liver disease, hepatobiliary cancer, neuromyelitis optica spectrum disorder, cardiovascular disease, inflammation induced by bacterial or viral infections, inflammation associated with SARS-CoV-2 infection or its variants and coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome, pneumonia, long / prolonged / chronic COVID, post-acute COVID-19 sequelae (PASC), myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS "brain fog"), and vasculitis.

[0057] As used herein, the phrase "cancer-related condition" refers to any disease resulting from the proliferation of malignant cancer cells. Thus, in one embodiment, the methods of the present invention are directed to treating cancer-related conditions, including, but not limited to, cancers of the following types: (e.g., adenoid cystic carcinoma, adrenal tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia telangiectasia, Beckwith-Wiedemann syndrome, cholangiocarcinoma, Birt-Hogg-Dube syndrome, bone cancer, brain stem glioma, brain tumor, breast cancer (inflammatory, metastatic, male), prostate, basal cell, melanoma, colon cancer, colorectal cancer, bladder cancer, kidney cancer, lacrimal gland cancer, laryngeal cancer, and Hypopharyngeal cancer, Lung cancer (non-small cell, small cell), Leukemia (acute lymphoblastic, acute lymphocytic, acute myeloid, B-cell prolymphocytic, chronic lymphocytic, chronic myeloid, chronic T-cell lymphocytic, eosinophilic), Liver cancer, Li-Fraumeni syndrome, Lymphoma (Hodgkin and non-Hodgkin), Lynch syndrome, Mastocytosis, Medulloblastoma, Meningioma, Mesothelioma, Multiple endocrine neoplasia, Multiple myeloma, MUTYH-associated polyposis, Myelodysplastic syndrome, Nasal cavity and paranasal sinuses Cancer, neuroblastoma, neuroendocrine tumors), neurofibromatosis, penile cancer, parathyroid carcinoma, ovarian fallopian tube and peritoneal cancer, osteosarcoma, pituitary tumors, pleuropulmonary blastoma, oral cavity and oropharynx, thyroid, uterus, pancreas, Carney complex, brain and spinal cord cancer, cervical cancer, Cowden syndrome, craniopharyngioma, desmoid tumor, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing's sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, family The present invention is provided to treat cancer / tumor related conditions such as pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumors, germ cell tumors, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyomatosis, and renal cell cancer, hereditary pancreatitis, hereditary papillary renal cell carcinoma, hereditary mixed polyposis syndrome, HIV / AIDS-related cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Kaposi's sarcoma, small intestine cancer, gastric cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, vaginal cancer, culver cancer, Werner's syndrome, and xeroderma pigmentosum.

[0058] As used herein, the term "administration" refers to providing a compound or a pharmaceutical composition comprising a compound described herein. The compound or composition can be administered to a subject by another person, or it can be self-administered by the subject. Non-limiting examples of routes of administration are oral, parenteral (e.g., intravenous), or topical.

[0059] As used herein, the term "treatment" refers to an intervention that improves the signs or symptoms of a disease or pathological condition. As used herein, the terms "treatment", "treat" and "treating" in reference to a disease, pathological condition or condition also refer to any observable beneficial effect of the treatment. A beneficial effect may be evidenced, for example, by a delay in the onset of clinical symptoms of the disease in a susceptible subject, a reduction in the severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of recurrences of the disease, an improvement in the overall health or well-being of the subject, or other parameters known in the art specific to a particular disease. A preventive treatment is a treatment administered to a subject who does not show signs of the disease or who shows only early signs, with the aim of reducing the risk of developing a pathological condition. A therapeutic treatment is a treatment administered to a subject after the signs and symptoms of the disease have appeared.

[0060] As used herein, the term "subject" refers to an animal (e.g., a mammal such as a human, dog, or horse), with veterinary use being a specifically contemplated application herein. A subject treated according to the methods described herein may be a subject diagnosed with an MRGPRX2-dependent condition or an MRGPRX2 ortholog-dependent condition, such as a pseudoallergic reaction, an itch-related condition, a pain-related condition, a cancer-related condition, an inflammatory or autoimmune disorder. Diagnosis may be performed by any method or technique known in the art. One of skill in the art will understand that a subject treated according to the present disclosure may be subjected to standard testing or may be identified without testing as at risk due to the presence of one or more risk factors associated with a disease or condition. The term "patient" may be used interchangeably with the term "subject." A subject may refer to an adult subject or a pediatric subject.

[0061] The Federal Food, Drug, and Cosmetic Act defines "pediatric" as a subject who is 21 years of age or younger at the time of diagnosis or treatment. Pediatric subpopulations are further characterized as follows: (i) neonates - birth to 28 days of age, (ii) infants - 29 days to less than 2 years of age, (iii) children - 2 to less than 12 years of age, and (iv) adolescents - 12 to 21 years of age. Notwithstanding this definition, depending on susceptible patient populations and clinical trial evaluation, approved regulatory labeling may include wording that specifically modifies the scope of the pediatric population, for example, pediatric patients up to 22 years of age.

[0062] In another embodiment, the method of treating a subject having a MRGPRX2-dependent condition described herein (e.g., an itch-associated condition, a pain-associated condition, a pseudoallergic reaction, or an inflammatory or autoimmune disorder) further comprises administering to the subject a pharma- ceutical effective amount of a second therapeutic agent. In one embodiment, the itch-associated condition is a pseudoallergic condition.

[0063] In one embodiment, the second therapeutic agent is an antihistamine, such as an H1 receptor antagonist or an H2 receptor antagonist. In one embodiment, the second therapeutic agent is an H1 receptor antagonist antihistamine, such as levocetirizine, loratadine, fexofenadine, cetirizine, desloratadine, olopatadine, diphenhydramine, cyproheptadine, or hydroxyzine pamoate. In one embodiment, the second therapeutic agent is an H2 receptor antagonist, such as cimetidine, nizatidine, ranitidine, or famotidine. In one embodiment, the second therapeutic agent is a leukotriene receptor antagonist or a leukotriene synthesis inhibitor, such as montelukast, zafirlukast, pranlukast, or a 5-lipoxygenase inhibitor (e.g., zileuton, St. John's wort). In one embodiment, the second therapeutic agent is an immunomodulator, such as omalizumab or immunoglobulin therapy. In one embodiment, the second therapeutic agent is a corticosteroid, such as hydrocortisone, cortisone, ethamethasoneb, triamcinolone, prednisone, prednisolone, or fludrocortisone. In one embodiment, the second therapeutic agent is a tricyclic antidepressant that can relieve itch, such as doxepin, amitriptyline, or nortriptyline. In one embodiment, the second therapeutic agent is an anti-inflammatory drug, such as dapsone, sulfasalazine, hydroxychloroquine, or colchicine. In one embodiment, the second therapeutic agent is an immunosuppressant, such as cyclosporine, methotrexate, mycophenolic acid, or tacromilus.

[0064] The second therapeutic agent may be administered simultaneously, separately, or sequentially with the compound of the present disclosure. If administered simultaneously, the second therapeutic agent and the compound of the present disclosure may be administered in separate dosage forms or in the same dosage form.

[0065] In another embodiment, a method of treating a subject having an itch-related condition is provided, the method comprising administering to the subject a pharma- ceutical effective amount of a compound having structure (I), or a pharma- ceutical acceptable salt, isomer, hydrate, solvate, or isotope thereof, or a pharmaceutical composition thereof. In one embodiment, the itch-related condition is urticaria, pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema. In another embodiment, a method of treating a subject having an inflammatory or autoimmune-related condition is provided, the method comprising administering to the subject a pharma- ceutical effective amount of a compound having structure (I), or a pharma- ceutical acceptable salt, isomer, hydrate, solvate, or isotope thereof, or a pharmaceutical composition thereof. In one embodiment, the inflammatory or autoimmune-related condition is sinusitis, asthma, rosacea, or endometriosis.

[0066] In another embodiment, a method of treating a subject having a pain-related condition is provided, the method comprising administering to the subject a therapeutically effective amount of a compound having structure (I), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, or a pharmaceutical composition thereof. In one embodiment, the pain-related condition is chronic pelvic pain syndrome, endometrial pain, fibromyalgia, migraine, or post-operative pain.

[0067] compound As detailed above, the present disclosure provides compounds that exhibit significant activity as MRGPRX2 antagonists. Thus, one embodiment provides a compound having the following structure (I): [ka] During the ceremony, R 1 is cycloalkyl, aryl, heterocyclyl, -(CH2) n Q, -CHQR, -(CH=CH) n Q or -CQ(R)2, where Q is C 1-6alkyl, aryl, cycloalkyl, heterocyclyl, -OR, -CHC(O)OR, -C(O)OR, -C(O)NHR, -OC(O)R, -CX, -CXH, -C(X)H, -CN, -N(R), -N(R)C(O)R, -N(R)C(O)OR, or -N(R)S(O)R; R 1 and / or Q is one or more R q is replaced by Each R is independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -N(R)2, alkylamino, -(CH2) n R', X, aryl, cycloalkyl, heteroaryl, or heterocyclyl, or two R groups taken together with the atoms to which they are attached form a double bond, a carbocycle, or a heterocycle, and R is optionally substituted with one or more of X, haloalkyl, or haloalkoxy; Each R q But independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, oxo, -OR, -SR, -O(CH2) n R, -OX3, -OX2H, -O(X)H2, -C(O)OR, -C(O)R, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -CN, - N(O)2, =NH, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, S(O)2R, -B(OR)2, -C(H)Q'R, -O(CH2) n Q' or -(CH2) n Q', where Q' is C 1-6 alkyl, aryl, cycloalkyl, heterocyclyl, OR', -C(O)OR', -OC(O)R', X, -CX3, -CX2H, -C(X)H2, -C(CH3)2X, -C(CH3)2OH, -CN, -N(R')2, -N(R')C(O)R', or -N(R')S(O)2R'; R q and / or Q' is one or more R Y and is optionally replaced by R2 , R 3 , R 4 , R 5 , and R 6 However, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, X, -CX, -CXH, -C(X)H, C(X)R, -C(X)(R), -CN, -N(R), -N(R)C(O)R, -N(R)S(O)R, or S(O)R; Each R x However, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, X, -CX, -CXH, -C(X)H, -CN, -N(R), -N(R)C(O)R, -N(R)S(O)R, or S(O)R; or R X But R 1 together with the compound to form a heterocycle, Each R Y But independently, C 1-6 alkyl, cycloalkyl, oxo, X, -CX3, -OR, or -C(O)OR; W is N or CR w and Z is N or CR z and R w But, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl; R z But, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl; Each R' is independently H, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 alkynyl, -OR, aryl, cycloalkyl, heteroaryl, or heterocyclyl; each X is independently F, Cl, Br, or I; A compound, or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein each n is independently 0, 1, 2, 3, 4, or 5.

[0068] In some embodiments, R is C optionally substituted with one or more of X, haloalkyl, or haloalkoxy. 1-6 It is an alkyl.

[0069] In yet another embodiment, a compound of formula (1a) is provided, [ka] During the ceremony, R 1a is cycloalkyl, -(CH2) n Q, -CHQR, or -CQ(R), Q is cycloalkyl, -OR, -C(O)OR, -OC(O)R, -CX, -CXH, -C(X)H, -CN, -N(R), -N(R)C(O)R, or -N(R)S(O)R; R 1a and / or Q is one or more R q or a pharma- ceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, is provided, wherein:

[0070] In one embodiment, R 1a is cycloalkyl.

[0071] In some embodiments, R 1a and / or Q is one or more R q In other embodiments, the substituent is optionally substituted with C 1-6 Alkyl, C 2-6 Alkenyl, aryl, cycloalkyl, heterocyclyl, -OR, -O(CH2)n R, -OX3, -OX2H, -O(X)H2, -C(O)OR, -C(O)R, -OC(O)R, n Q′, where Q′ is selected from C 1-6 In yet other embodiments, the substituent is selected from the group consisting of alkyl, aryl, cycloalkyl, heterocyclyl, OR', -C(O)OR', -OC(O)R', X, -CX3, -CX2H, -C(X)H2, -CN, -N(R')2, -N(R')C(O)R', and -N(R')S(O)R'. 1-6 Alkyl, aryl, heterocyclyl, -OR, -CN, -C(O)OR, or -(CH2) n It is Q'.

[0072] In yet other embodiments, one or more R q R optionally substituted with 1a has one of the following structures: [ka]

[0073] In yet another embodiment, R 4 and R 6 But independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, OR, -C(O)OR, -OC(O)R, X, -CX, -CXH, -C(X)H, -CN, -N(R), -N(R)C(O)R, -N(R)S(O)R, or S(O)R. In some embodiments, R 6 is X, -CX, -CXH, or -C(X)H. 6 is -CF3, -CF2H, or CFH2.

[0074] In one embodiment, R x is H.

[0075] In another embodiment, there is provided a compound of formula (1a) where W is N and Z is CH. In yet another embodiment, there is provided a compound of formula (1a) where W is CH and Z is N.

[0076] In one embodiment, a compound of formula (1b) [ka] During the ceremony, R 1b Aryl, -(CH2) n Q, -CHQR, and -CQ(R)2; Q is aryl, -OR, -C(O)OR, -OC(O)R, -CX, -CXH, -C(X)H, -CN, -N(R), -N(R)C(O)R, or -N(R)S(O)R; R 1b and / or Q is one or more R q or a pharma- ceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, is provided, wherein:

[0077] In one embodiment, R 1b is aryl. In another embodiment, R 1b is phenyl.

[0078] In some embodiments, R 1b and / or Q is one or more R q In other embodiments, the substituent is optionally substituted with C 1-6 Alkyl, C 2-6 Alkenyl, aryl, cycloalkyl, heterocyclyl, -OR, -SR, -O(CH2) n R, -OX3, -OX2H, -O(X)H2, -C(O)OR, -C(O)R, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, S(O)2R, -B(OR)2, -C(H)Q'R, or -(CH2) n Q′, where Q′ is selected from C1-6 alkyl, aryl, cycloalkyl, heterocyclyl, OR', -C(O)OR', -OC(O)R', X, -CX3, -CX2H, -C(X)H2, -CN, -N(R')2, -N(R')C(O)R', or -N(R')S(O)2R'; R q and / or Q' is one or more R Y is optionally replaced by

[0079] In yet other embodiments, one or more R q R optionally substituted with 1b has one of the following structures: [ka] [ka] [ka]

[0080] In yet another embodiment, R 4 and R 6 However, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, X, -CX, -CXH, -C(X)H, -CN, -N(R), -N(R)C(O)R, -N(R)S(O)R, or S(O)R. In certain embodiments, R 6 is X, -CX3, -CX2H, or -C(X)H2.

[0081] In some embodiments, R 6 is -CF3, -CF2H, or CFH2.

[0082] In one embodiment, R x is H.

[0083] In another embodiment, there is provided a compound of formula (1b) where W is N and Z is CH. In yet another embodiment, there is provided a compound of formula (1b) where W is CH and Z is N.

[0084] In one embodiment, a compound of formula (1c) [ka] During the ceremony, R 1c Cyclocyclyl, -(CH2) n Q, -CHQR, or -CQ(R), Q is heterocyclyl, -OR, -C(O)OR, -OC(O)R, -CX, -CXH, -C(X)H, -CN, -N(R), -N(R)C(O)R, or -N(R)S(O)R; R 1c and / or Q is one or more R q or a pharma- ceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, is provided, wherein:

[0085] In one embodiment, R 1c is heterocyclyl.

[0086] In another embodiment, heterocyclyl is an aromatic and non-aromatic ring moiety containing three or more ring members, one or more of which is a heteroatom selected from N, O, S, or P.

[0087] In some embodiments, R 1c and / or Q is one or more R q is optionally replaced by

[0088] In other embodiments, the substituent is C 1-6 Alkyl, C 2-6 Alkenyl, aryl, cycloalkyl, heterocyclyl, -OR, -SR, -O(CH2) nR, -OX3, -OX2H, -O(X)H2, -C(O)OR, -C(O)R, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -C N, -N(O)2, =NH, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, S(O)2R, -C(H)Q'R, or -(CH2) n Q′, where Q′ is selected from C 1-6 alkyl, aryl, cycloalkyl, heterocyclyl, OR', -C(O)OR', -OC(O)R', X, -CX3, -CX2H, -C(CH3)2X, -C(CH3)2OH, -C(X)H2, -CN, -N(R')2, -N(R')C(O)R', or -N(R')S(O)2R'; R q and / or Q' is one or more R Y is optionally replaced by

[0089] In some embodiments, one or more R q R optionally substituted with 1c has one of the following structures: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0090] In yet another embodiment, R 4 and R 6 but independently in each occurrence: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, X, -CX, -CXH, -C(X)H, -CN, -N(R), -N(R)C(O)R, -N(R)S(O)R, or S(O)R.

[0091] In certain embodiments, R 6 is X, -CX, -CXH, or -C(X)H. 6 is -CF3, -CF2H, or CFH2.

[0092] In one embodiment, R x is H.

[0093] In another embodiment, there is provided a compound of formula (1c) where W is N and Z is CH. In yet another embodiment, there is provided a compound of formula (1c) where W is CH and Z is N.

[0094] In one embodiment, a compound of formula (1d) [ka] During the ceremony, R 1d But, CQ(R)2, Q is C 1-6 alkyl, aryl, cycloalkyl, heterocyclyl, -OR, -CHC(O)OR, -C(O)OR, -C(O)NHR, -OC(O)R, -CX, -CXH, -C(X)H, -CN, -N(R), -N(R)C(O)R, -N(R)C(O)OR, or -N(R)S(O)R; R 1d and / or Q is one or more Rq or a pharma- ceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, is provided, wherein:

[0095] In certain embodiments, Q is C 1-6 It is selected from alkyl, aryl, cycloalkyl, heterocyclyl, and N(R)C(O)R.

[0096] In other embodiments, R is independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, alkylamino, -(CH2) n R', X, H, aryl, cycloalkyl, or heterocyclyl.

[0097] In some embodiments, one or more R q R optionally substituted with 1d has one of the following structures: [ka] [ka]

[0098] In one embodiment, R 6 is X, -CX, -CXH, or -C(X)H. 6 is -CF3, -CF2H, or CFH2.

[0099] In one embodiment, R x is H.

[0100] In another embodiment, there is provided a compound of formula (1d) where W is N and Z is CH. In yet another embodiment, there is provided a compound of formula (1d) where W is CH and Z is N.

[0101] In one embodiment, a compound of formula (1e) [ka] During the ceremony, R 1e But -CHQR, Q is C 1-6 alkyl, aryl, cycloalkyl, heterocyclyl, -OR, -CHC(O)OR, -C(O)OR, -C(O)NHR, -OC(O)R, -CX, -CXH, -C(X)H, -CN, -N(R), -N(R)C(O)R, -N(R)C(O)OR, or -N(R)S(O)R; Each R 1e and / or Q is one or more R q or a pharma- ceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, is provided, wherein:

[0102] In certain embodiments, Q is C 1-6 It is selected from alkyl, aryl, cycloalkyl, heterocyclyl, -N(R)C(O)R and -N(R)C(O)OR.

[0103] In other embodiments, R is independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, alkylamino, -(CH2) n R', X is aryl, cycloalkyl, or heterocyclyl.

[0104] In some embodiments, one or more R q R optionally substituted with 1e has one of the following structures: [ka]

[0105] In certain embodiments, R 6 is X, -CX, -CXH, or -C(X)H.6 is -CF3, -CF2H, or CFH2.

[0106] In one embodiment, R x is H.

[0107] In another embodiment, there is provided a compound of formula (1e) where W is N and Z is CH. In yet another embodiment, there is provided a compound of formula (1e) where W is CH and Z is N.

[0108] In one embodiment, a compound of formula (1f) [ka] During the ceremony, R W or R z But independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Provided are compounds, or a pharma- ceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, which is alkynyl, H, aryl, cycloalkyl, heteroaryl, or heterocyclyl.

[0109] In certain embodiments, R 6 is X, -CX, -CXH, or -C(X)H. 6 is -CF3, -CF2H, or CFH2.

[0110] In certain embodiments, R w and R z are both H.

[0111] In another embodiment, R x is H.

[0112] In one embodiment, the compound is selected from any one of the compounds listed in the table below, or a pharma- ceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

[0113] In another embodiment, representative compounds of structure (I) and, where applicable, formulas (Ia)-(1f) include, but are not limited to, any one of the compounds listed below by their IUPAC name, and pharma- ceutically acceptable salts, isomers, hydrates, solvates, or isotopes thereof. N-[(1R,3S)-3-{[8-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methoxybenzamide, 4-Methoxy-N-[(1R,3S)-3-{[3-(trifluoromethyl)isoquinolin-1-yl]amino}cyclohexyl]benzamide, 4-Methoxy-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methoxybenzamide, 4-Methoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[7-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methoxybenzamide, N-[(1R,3S)-3-{[5-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methoxybenzamide, 4-fluoro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-[(6-chloro-2-methylquinolin-4-yl)amino]cyclohexyl]-4-methoxybenzamide, N-[(1R,3S)-3-[(2-cyanoquinolin-4-yl)amino]cyclohexyl]-4-methoxybenzamide, N-[(1R,3S)-3-{[2-(difluoromethyl)quinazolin-4-yl]amino}cyclohexyl]-4-methoxybenzamide, N-[(1R,3S)-3-{[3-cyano-6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methoxybenzamide, 4-Methoxy-N-[(1R,3S)-3-{[6-methoxy-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-Methoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinazolin-4-yl]amino}cyclohexyl]benzamide, N-[(1S,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methoxybenzamide, N-[(1S,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methoxybenzamide, N-[(1R,3R)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methoxybenzamide, N-[(1R,3R)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methoxybenzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methoxybenzamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-fluoro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinazolin-4-yl]amino}cyclohexyl]benzamide, 4-Methoxy-N-[(1R,3S)-3-{[5-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-Methoxy-N-[(1R,3S)-3-{[7-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, methyl 4-{[(1S,3R)-3-(4-methoxybenzamido)cyclohexyl]amino}-2-(trifluoromethyl)quinoline-8-carboxylate, 4-Methoxy-N-[(1R,3S)-3-[(naphthalen-1-yl)amino]cyclohexyl]benzamide, 4-Methoxy-N-[(1R,3S)-3-{[3-(trifluoromethyl)naphthalen-1-yl]amino}cyclohexyl]benzamide, 4-Methoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-5-yl]amino}cyclohexyl]benzamide, 4-Methoxy-N-[(1R,3S)-3-{[3-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[2-(difluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methoxybenzamide, 2-Methoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-(dimethylamino)-2-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 3-cyano-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, Methyl 3-{[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}benzoate; 2-cyano-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-cyano-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-chloro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 3-fluoro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-fluoro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2,2-dimethyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]propanamide, 4-chloro-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-cyano-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 3-fluoro-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 3-Methoxy-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-methyl-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-methoxybenzamide, 6-amino-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(morpholine-4-carbonyl)benzamide, 3-Methoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-methylbenzamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-4-carboxamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-3-carboxamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-2-carboxamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]cyclopropanecarboxamide, 2-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]propanamide, 3-methanesulfonamido-N-[(1R,3S)-3-[(2-methoxyquinolin-4-yl)amino]cyclohexyl]benzamide, 3-phenyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]propanamide, 3-(dimethylamino)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-(dimethylamino)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-chloro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-(dimethylamino)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-ethyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 3-chloro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 3-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 3-ethyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 3-acetamido-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-ethyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, methyl 4-{[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}benzoate, 4-acetamido-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-(4-methylpiperazin-1-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 6-(dimethylamino)-2-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-3-carboxamide, 2-(methylamino)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 3-(methylamino)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-(methylamino)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-(morpholin-4-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4H,5H,6H,7H-pyrazolo[1,5-a]pyridine-2-carboxamide, 2-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]acetamide, 1-(pyrazin-2-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]cyclopropane-1-carboxamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,5-a]pyridine-1-carboxamide, 4-benzyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]morpholine-3-carboxamide, 2-[2-(difluoromethoxy)-6-fluorophenyl]-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]acetamide, 2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]acetamide, 5-cyano-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2H-indazole-3-carboxamide, 3-[(4-methoxyphenyl)methoxy]-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,2-oxazole-5-carboxamide, 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 7-(benzyloxy)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-indole-3-carboxamide, 3-{[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}-1-oxa-2,7-diazaspiro[4.5]dec-2-ene-7-carboxylate, 2-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyrazolo[1,5-a]pyrimidine-6-carboxamide, 4-propyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,2,3-thiadiazole-5-carboxamide, (3S,4R)-3-(thiophen-3-yl)-4-{[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}pyrrolidine-1-carboxylate, 4-[(quinolin-2-yl)methoxy]-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2,6-difluoro-3-(propane-1-sulfonamido)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 5-benzoyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2,3-dihydro-1H-pyrrolidine-1-carboxamide, 2,4-dichloro-3-cyano-5-fluoro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 1-[(4-methoxyphenyl)methyl]-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, 3-(2-chloro-6-fluorophenyl)-5-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,2-oxazole-4-carboxamide, 2-benzyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2,3-dihydro-1H-isoindole-4-carboxamide, ethyl 1-{[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}cyclobutane-1-carboxylate, 1-ethyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide, 3,6-difluoro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-2-carboxamide, 2-oxo-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2H-chromene-6-carboxamide, 4-methyl-2-(pyridin-2-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,3-thiazole-5-carboxamide, 5-(trifluoromethyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-3-carboxamide, 6-(2-methoxyphenyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-3-carboxamide, 2-Methoxy-4-(trifluoromethyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,3-thiazole-5-carboxamide, 6-(oxan-4-yloxy)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-2-carboxamide, 2-oxo-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H,2H,3H-pyrido[2,3-b][1,4]thiazine-7-carboxamide, 2-methyl-3-oxo-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide, 5-oxo-1-phenyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyrrolidine-2-carboxamide, 5-(pyridin-3-yloxy)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]furan-2-carboxamide, 3-methyl-4-oxo-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3,4-dihydroquinazoline-7-carboxamide, 1,4-dimethyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-indole-2-carboxamide, 2,6,6-trimethyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]bicyclo[3.1.1]heptane-3-carboxamide, 1-(2,2-difluoroethyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-3-carboxamide, tert-butyl N-methyl-N-[(S)-phenyl({[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl})methyl]carbamate, 2-(cyclobutylformamido)-2-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]propanamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyrazine-2-carboxamide, 1-(3-methoxyphenyl)-5-oxo-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyrrolidine-3-carboxamide, 1-methanesulfonyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]piperidine-4-carboxamide, N-(2,6-difluorophenyl)-N'-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]ethanediamide, N-[3-({[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}methyl)phenyl]benzamide, 1-(2,4-dichlorophenyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]cyclobutane-1-carboxamide, 3-(5-bromo-2-fluorophenyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]propanamide, 1-(3-fluorophenyl)-5-(trifluoromethyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, 1-[(4-fluorophenyl)methyl]-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-indole-3-carboxamide, 5-chloro-1-phenyl-3-(trifluoromethyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, (2R,3R)-2-(2-methoxyphenyl)-5-oxo-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]oxolane-3-carboxamide, 5-(thiophen-2-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-3-carboxamide, 1-(4-chlorophenyl)-5-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, 4-(4-ethylphenyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]butanamide, 3-(4-chloro-3-fluorophenyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]propanamide, (2S)-3-phenyl-2-[(pyrazin-2-yl)formamido]-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]propanamide, 2-chloro-6-fluoro-3-methoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, (2R)-2-(3-acetamidopropanamido)-3-(1H-imidazol-5-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]propanamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4,5,6,7-tetrahydro-1H-1,3-benzodiazole-6-carboxamide, 3-chloro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-benzothiophene-2-carboxamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2H-pyrazolo[3,4-b]pyridine-3-carboxamide, 3-tert-butyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide, 1-methyl-3-(2-methylpropyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide, 3-(2-chlorophenyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide, 1-[5-(trifluoromethyl)pyridin-2-yl]-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]piperidine-4-carboxamide, 2-(1H-indol-1-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]acetamide, 2-(morpholin-4-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-4-carboxamide, 2-(thiophen-3-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]acetamide, 1-(4-methylbenzenesulfonyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrrole-3-carboxamide, 6-chloro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-b]pyridazine-2-carboxamide, 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]acetamide, 6-oxo-2-phenyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3,6-dihydropyrimidine-4-carboxamide, 2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]acetamide, 7-Methoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-benzofuran-2-carboxamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,6-naphthyridine-2-carboxamide, 1-(2-chlorobenzoyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]piperidine-4-carboxamide, 5-(furan-2-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,2-oxazole-3-carboxamide, 2-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2H-indazole-3-carboxamide, 1-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide, 2-[(2,5-dichlorophenyl)formamido]-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]acetamide, (1R,4S)-4,7,7-trimethyl-3-oxo-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-oxabicyclo[2.2.1]heptane-1-carboxamide, 2-methyl-4-(2-methylbenzamido)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3,4-dihydro-2H-pyran-6-carboxamide, 4-oxo-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4H-chromene-3-carboxamide, 4-fluoro-3-(trifluoromethoxy)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-phenoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 5-chloro-2-methoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-4-carboxamide, 3-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-benzofuran-2-carboxamide, 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-chloro-4-(4-methylpiperazin-1-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, (1r,4r)-4-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl]-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]cyclohexane-1-carboxamide, 2-(2,3-dimethylphenyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]acetamide, 7-Methoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-3-carboxamide, 3,4-dichloro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,2-thiazole-5-carboxamide, 3,3-dimethoxy-1-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]cyclobutane-1-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(2-methylpropanamido)benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-methoxybenzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2-difluoroethyl)-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-ethyl-4-methyl-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-fluoroethyl)-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-propyl-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(methylamino)benzamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-indole-4-carboxamide, 4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-(1H-imidazol-1-yl)-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(pyrrolidin-1-yl)benzamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(1H-1,2,3,4-tetrazol-1-yl)benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-cyclobutyl-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyrazolo[1,5-a]pyridine-2-carboxamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyrimidine-3-carboxamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-indole-3-carboxamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-4-carboxamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2,3-dioxo-2,3-dihydro-1H-indole-7-carboxamide, 2-acetamido-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-4-carboxamide, 3-(1-cyanoethyl)-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyridine-6-carboxamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,3-benzothiazole-7-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-ethyl-3-phenyl-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-cyclopropyl-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-ethyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-phenyl-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,3-diethyl-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(propan-2-yl)-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide, 3-acetamido-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 3-hydroxy-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(2-methylpropanamido)benzamide, 3-methanesulfonamido-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(methylamino)benzamide, 3-(dimethylamino)-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-(methylamino)benzamide, 2-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methanesulfonylbenzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-ethyl-1H-pyrazole-5-carboxamide, 2-chloro-4-methanesulfonyl-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 1-ethyl-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-(methylamino)benzamide, 2-cyano-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-Methoxy-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-chloro-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-cyanobenzamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]cyclohexanecarboxamide, 1-ethenyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-oxabicyclo[2.2.2]octane-4-carboxamide, 3-(2-oxopyrrolidin-1-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, tert-butyl (3S)-3-methyl-3-{[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}propanoate, 3-{[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}phenylpropanoate, 4-methyl-2-propyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-1,3-benzodiazole-6-carboxamide, (1R,2R)-2-(2-fluorophenyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]cyclopropane-1-carboxamide, 1-tert-butyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-1,2,3-triazole-4-carboxamide, 4-butanamido-3-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 3-(2-fluorophenyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide, 5-fluoro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 2-(pyridin-4-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-1,3-benzodiazole-6-carboxamide, 3-(propan-2-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide, 1-cyano-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]cyclopropane-1-carboxamide, 5-fluoro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-benzofuran-2-carboxamide, 2-(1,2-benzoxazol-3-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]acetamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyrimidine-3-carboxamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2H-1,3-benzodioxole-4-carboxamide, 2-acetamido-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-4-carboxamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-4-carboxamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide, 2-oxo-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2,3-dihydropyridine-4-carboxamide, 2-chloro-4-methanesulfonyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 3-chloro-1-(3-chloropyridin-2-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide, 1-(pyridin-3-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, 4-fluoro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-indole-3-carboxamide, 3-(1H-1,2,4-triazol-1-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-fluoro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2H-indazole-5-carboxamide, 4-(3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-(4-chlorophenyl)-2-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]propanamide, 1,3-dimethyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,3-benzothiazole-7-carboxamide, 3-(1-cyanoethyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4H-thieno[3,2-b]pyrrole-5-carboxamide, 3-methyl-4-oxo-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3H,4H-imidazo[4,3-d][1,2,3,5]tetrazine-8-carboxamide, 6-fluoro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyrazolo[1,5-a]pyridine-2-carboxamide, 2,3-dioxo-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2,3-dihydro-1H-indole-7-carboxamide, 1-phenyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrrole-2-carboxamide, 6-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-benzothiophene-2-carboxamide, 3-chloro-2-iodo-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-indole-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-cyanobenzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(pyrrolidin-1-yl)benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(methylamino)benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-hydroxybenzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(dimethylamino)benzamide, 4-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-acetamidopyridine-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(1-cyanoethyl)benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(methylamino)benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4,5,6,7-tetrahydro-1H-1,3-benzodiazole-6-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyridine-6-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-indole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2,3-dioxo-2,3-dihydro-1H-indole-7-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,3-benzothiazole-7-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyrimidine-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-fluoro-2H-indazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(propane-2-sulfonamido)benzamide, 2-(1-methyl-1H-indol-3-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]acetamide, 2,6-dimethoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyrimidine-4-carboxamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,2,3-thiadiazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2,6-difluoro-3-(propane-2-sulfonamido)benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2,6-difluoro-3-methanesulfonamidobenzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-ethanesulfonamido-2,6-difluorobenzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-fluoro-5-(propane-1-sulfonamido)benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyrazolo[1,5-a]pyridine-2-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(1H-imidazol-1-yl)benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(1H-1,2,3,4-tetrazol-1-yl)benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-fluorobenzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methanesulfonamidobenzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-ethanesulfonamide benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyrimidine-6-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,5-a]pyridine-7-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,5-a]pyridine-6-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyridine-7-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-oxo-2H-chromene-6-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-fluoro-3-(propane-1-sulfonamido)benzamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2H,4H,6H,7H-pyrano[4,3-c]pyrazole-3-carboxamide, 2-chloro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,3-benzothiazole-6-carboxamide, 2-(cyclohexyloxy)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]acetamide, 5-chloro-3-(difluoromethyl)-1-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, 2-acetamido-3-(1H-indol-3-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]propanamide, 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]propanamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-fluoro-3-methanesulfonamidobenzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-acetamido-5-methoxybenzamide, 5-bromo-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-cyanobenzamide, 4-bromo-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-cyanobenzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,3-benzothiazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2H-pyrazolo[4,3-b]pyridine-7-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-methylimidazo[1,2-a]pyridine-6-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-methylimidazo[1,2-a]pyridine-6-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-methyl-1H-1,3-benzodiazole-6-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-cyano-4-fluorobenzamide, 2-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-acetamidobenzamide, 3-bromo-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-acetamidobenzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2H-indazole-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3,5-dihydroxybenzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(N-methylmethanesulfonamido)benzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-(methylamino)benzamide, 2-cyano-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-chloro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-methylbenzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-methoxybenzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-chloro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-methanesulfonamidobenzamide, 2,6-difluoro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(propane-1-sulfonamido)benzamide, 1-ethyl-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide, 3-(1-cyanoethyl)-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(methylamino)benzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-hydroxybenzamide, 3-(dimethylamino)-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-methoxybenzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(pyrrolidin-1-yl)benzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(1H-1,2,3,4-tetrazol-1-yl)benzamide, 4-chloro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-cyano-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-acetamido-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-4-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(propane-2-sulfonyl)benzamide, 3-chloro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methanesulfonylbenzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methanesulfonyl-3-methylbenzamide, 2-fluoro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methanesulfonylbenzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(1H-imidazol-1-yl)benzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(propane-2-sulfonamido)benzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-indole-3-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyridine-6-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-4-carboxamide, 3-fluoro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methanesulfonylbenzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-methanesulfonamidobenzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(methylamino)benzamide, 3-ethanesulfonamido-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(2-methylpropanamido)benzamide, 3-acetamido-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(N-methylmethanesulfonamido)benzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,3-benzothiazole-7-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyrimidine-3-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3H,3aH-pyrazolo[1,5-a]pyridine-2-carboxamide, 3-fluoro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2,6-difluoro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-methanesulfonamidobenzamide, 3-ethanesulfonamido-2,6-difluoro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 2-fluoro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-(propane-1-sulfonamido)benzamide, 2-fluoro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(propane-1-sulfonamido)benzamide, 4-(1,1-dioxo-1λ 6-thiomorpholin-4-yl)-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methanesulfonamidobenzamide, 2,6-difluoro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(propane-2-sulfonamido)benzamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide, 2-fluoro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 4-fluoro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 1-ethyl-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-methyl-1H-pyrazole-5-carboxamide, 1-cyclopropyl-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-methylpropyl)-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-propyl-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(propan-2-yl)-1H-pyrazole-5-carboxamide, 3-cyclopropyl-1-ethyl-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide, 1-ethyl-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(propan-2-yl)-1H-pyrazole-5-carboxamide, 1,3-diethyl-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide, 1-ethyl-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methyl-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-acetamidobenzamide, 3-cyano-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-cyanobenzamide, 3-cyano-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 3-chloro-4-(propan-2-yloxy)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 3-methyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,2-oxazole-4-carboxamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]furan-3-carboxamide, 6-chloro-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2H-chromene-3-carboxamide, 1,3,5-trimethyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, 2-[5-fluoro-2-(trifluoromethyl)phenyl]-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]acetamide, 2-{5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl}-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]acetamide, 4-iodo-1-methyl-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-3-carboxamide, 2-methyl-5-{[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}pyrazin-1-ium-1-oleate, tert-butyl 7-{[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}-1,2,3,4-tetrahydroisoquinoline-2-carboxylate, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-[(trifluoromethyl)sulfanyl]benzamide, 2-(5-chloro-2H-indazol-3-yl)-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]acetamide, Methyl N-[(R)-{[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}(phenyl)methyl]carbamate, 5-bromo-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-indole-7-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(trifluoromethanesulfonamido)benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(difluoromethanesulfonamido)benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-hydroxypyridine-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(N-methylmethanesulfonamido)benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-fluoro-3-methanesulfonamidobenzamide, 7-bromo-2-methyl-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyridine-3-carboxamide, 2-amino-3-(1H-imidazol-5-yl)-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]propanamide, 2-amino-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4,5-dihydro-1,3-thiazole-4-carboxamide, tert-butyl 7-{[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}-1,2,3,4-tetrahydroisoquinoline-2-carboxylate, (2E)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(2,3,4-trimethoxyphenyl)prop-2-enamide, 6-bromo-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyridine-3-carboxamide, 2-chloro-4-iodo-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-3-carboxamide, 2-(2H-1,2,3-triazol-2-yl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, 5-bromo-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide, tert-butyl N-[(1S)-2-(pent-4-en-1-yloxy)-1-{[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}ethyl]carbamate, 2-benzyl-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]prop-2-enamide, 5-bromo-2-(methylsulfanyl)-N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyrimidine-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-ethyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-ethyl-3-(propan-2-yl)-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-cyclopropyl-1-ethyl-1H-pyrazole-5-carboxamide, 5-{[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}-1-ethyl-1H-pyrazole-3-carboxylate methyl, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-ethyl-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-methylpropyl)-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-cyclohexyl-1H-pyrazole-5-carboxamide, 1-tert-butyl-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-cyclopentyl-1H-pyrazole-5-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-oxo-2,3-dihydropyridine-4-carboxamide, N-[(1R,3S)-3-{[6-methyl-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(N-methylmethanesulfonamido)benzamide, 4-fluoro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2H-indazole-5-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-oxo-2H-chromene-6-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4,5,6,7-tetrahydro-1H-1,3-benzodiazole-6-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2,3-dioxo-2,3-dihydro-1H-indole-7-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-methylimidazo[1,2-a]pyridine-6-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-methylimidazo[1,2-a]pyridine-6-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyridine-7-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,5-a]pyridine-6-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,5-a]pyridine-7-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-oxo-2,3-dihydropyridine-4-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyrimidine-6-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(trifluoromethyl)-1H-pyrrole-3-carboxamide, 5-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrrole-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-chloroethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-[1,2,4]triazolo[4,3-a]pyridine-7-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2H-pyrazolo[4,3-c]pyridine-7-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(difluoromethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,3-dimethyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-methyl-1-(propan-2-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-6-methylpyridine-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-cyclopropyl-1H-pyrazole-4-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(difluoromethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(oxetan-3-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-cyano-1H-pyrrole-3-carboxamide, 2-amino-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-[(dimethylamino)methyl]benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-6-fluoropyridine-3-carboxamide, 2-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-1H-imidazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methoxy-3-(methylamino)benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-6-methoxypyridine-3-carboxamide, 4-(aziridin-1-yl)-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-1H-pyrrole-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,4-dimethyl-1H-pyrrole-3-carboxamide, 5-amino-2-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyridine-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-methylfuran-3-carboxamide, 5-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-cyanoethyl)-1H-pyrazole-4-carboxamide, 4-(dimethylamino)-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]benzamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-(dimethylamino)-1,3-thiazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-[(2-fluoroethyl)amino]pyrimidine-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,3-oxazole-2-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,2-thiazole-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2,5-dimethyl-1H-pyrrole-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-ethyl-1H-pyrrole-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-methylthiophene-2-carboxamide, 2-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrrole-3-carboxamide, (4-{[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}phenyl)boronic acid, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-ethyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,5-dimethyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(propan-2-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-methoxy-1-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-ethyl-1-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-methoxy-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-ethyl-3-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-cyclopropyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-cyclobutyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-cyclopropyl-1-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-ethyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-methoxy-1-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-methoxyethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-ethyl-5-methyl-1H-pyrazole-4-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-phenyl-1H-pyrazole-4-carboxamide, 1-benzyl-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(oxan-4-yl)-1H-pyrazole-4-carboxamide, 3-amino-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-methyl-1H-pyrazole-4-carboxamide, 1-ethyl-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, 5-ethyl-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, 1-ethyl-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,3-dimethyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-ethyl-5-fluoro-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(methoxymethyl)-1-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(pyridin-4-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(1,1-dioxo-1λ 6 -thiolan-3-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-3-phenyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-cyclopropyl-1-ethyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2-difluoroethyl)-3-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2-difluoroethyl)-5-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-cyano-1-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-3-(pyridin-3-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-3-(propan-2-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-cyclopentyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-propyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-[(oxan-4-yl)methyl]-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-[2-(dimethylamino)ethyl]-1H-pyrazole-4-carboxamide, tert-butyl 4-(4-{[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}-1H-pyrazol-1-yl)piperidine-1-carboxylate, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-cyclohexyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(pyridin-3-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2-difluorocyclopropyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-fluoroethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(cyclopropylmethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-[2-(morpholin-4-yl)ethyl]-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(furan-2-yl)-1-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(1,3-thiazol-2-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-5-sulfamoyl-1H-pyrazole-4-carboxamide, 1-tert-butyl-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-methylpropyl)-1H-pyrazole-4-carboxamide, 1-tert-butyl-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-cyanoethyl)-5-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(4-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(1,1-dioxo-1λ 6 -thiolan-3-yl)-3-(propan-2-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-methyl-1-(pyridin-4-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,3-bis(difluoromethyl)-1H-pyrazole-4-carboxamide, 5-amino-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide, 5-amino-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(difluoromethyl)-3-nitro-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-(difluoromethyl)-1H-pyrazole-4-carboxamide, 1-(difluoromethyl)-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, 1,3-bis(difluoromethyl)-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, 5-chloro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3,5-dimethyl-1H-pyrazole-4-carboxamide, 5-amino-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-fluoroethyl)-3-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-fluoroethyl)-5-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2H,3H-pyrazolo[3,2-b][1,3]oxazole-7-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1,3,5-trimethyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(difluoromethyl)-3-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-cyano-1-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-methanesulfonamidobenzamide, 2-amino-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyrimidine-5-carboxamide, N-[(1R,3S)-3-{[2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]propanamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-methoxy-1-methyl-1H-imidazole-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-6-[(2-fluoroethyl)amino]pyridine-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-methyl-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-fluoroethyl)-2-methyl-1H-pyrrole-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-fluoroethyl)-5-methyl-1H-pyrrole-3-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-cyanoethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2-difluoroethyl)-5-methyl-1H-pyrrole-3-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2-difluoroethyl)-2-methyl-1H-pyrrole-3-carboxamide, 5-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-ethyl-1H-pyrrole-3-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(oxetan-3-yl)-1H-pyrazole-4-carboxamide, tert-butyl 3-(4-{[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}-1H-pyrazol-1-yl)azetidine-1-carboxylate, 1-(azetidin-3-yl)-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide, tert-butyl (3S)-3-(4-{[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate, tert-butyl (3S)-3-(4-{[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}-1H-pyrazol-1-yl)piperidine-1-carboxylate, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-[(3S)-pyrrolidin-3-yl]-1H-pyrazole-4-carboxamide, tert-butyl (3R)-3-(4-{[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}-1H-pyrazol-1-yl)piperidine-1-carboxylate, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-[(3S)-piperidin-3-yl]-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazole-4-carboxamide, 5-amino-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide, 5-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-fluoroethyl)-1H-pyrazole-4-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-fluoroethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methanesulfonyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-fluoro-2-methylpropyl)-3-methyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(difluoromethyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-(difluoromethyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-hydroxy-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-ethyl-1H-pyrazole-4-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-fluoro-2-methylpropyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(difluoromethyl)-1-ethyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(fluoromethyl)-1H-pyrazole-4-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(fluoromethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-cyano-1-(2-fluoroethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(difluoromethyl)-1-(2-fluoro-2-methylpropyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-fluoro-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-carboxamide, 5-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-fluoro-2-methylpropyl)-1H-pyrazole-4-carboxamide, 5-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide, 3-amino-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-fluoro-2-methylpropyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-cyano-1-(fluoromethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-cyano-1-(fluoromethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-cyano-1-(difluoromethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(difluoromethyl)-1-(fluoromethyl)-1H-pyrazole-4-carboxamide, 5-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methyl-1H-pyrrole-3-carboxamide, 5-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2-difluoroethyl)-1H-pyrrole-3-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-methanesulfonyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazole-4-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-cyano-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-(difluoromethyl)-1-(fluoromethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-cyano-1-(2-fluoroethyl)-1H-pyrazole-4-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-cyano-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-cyano-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-cyano-1-(2-fluoro-2-methylpropyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-fluoro-2-methylpropyl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2-fluoroethyl)-1H-pyrrole-3-carboxamide, 5-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxamide, 3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxamide, tert-butyl (3R)-3-(4-{[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]carbamoyl}-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-[(3R)-pyrrolidin-3-yl]-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-(difluoromethyl)-1-ethyl-1H-pyrazole-4-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-cyano-1H-pyrazole-4-carboxamide, 6-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-one, 4-amino-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]piperidine-1-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(propan-2-yl)piperazine-1-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyrrolidine-1-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]piperazine-1-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-methylpiperazine-1-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-fluoro-3-methylpyrrolidine-1-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3,3-difluoropiperidine-1-carboxamide, 1-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-methyl-3-[(3R)-oxolan-3-yl]urea, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5-azaspiro[2.3]hexane-5-carboxamide, 1-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-methyl-3-[(3S)-oxolan-3-yl]urea, (3S)-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-fluoropyrrolidine-1-carboxamide, (3R,4R)-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3,4-difluoropyrrolidine-1-carboxamide, (3S)-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-fluoropiperidine-1-carboxamide, 5-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(propan-2-yl)-1H-pyrrole-3-carboxamide, (2R,3R)-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-(hydroxymethyl)-2-methylpyrrolidine-1-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-2-methyl-4H,5H,6H,7H-[1,3]thiazolo[5,4-c]pyridine-5-carboxamide, N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-4-(2-methylpropanoyl)piperazine-1-carboxamide, and N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-3-fluoro-3-methylazetidine-1-carboxamide.

[0114] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of any one of structure (I) or formulas (Ia)-(1f), or a pharma-ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, together with at least one pharma-ceutically acceptable carrier, diluent, or excipient. For example, the active compound is usually mixed with a carrier, diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that serves as a vehicle, excipient, or medium for the active compound. The active compound may be adsorbed onto a particulate solid carrier, for example, contained in a sachet. Some examples of suitable carriers include water, saline, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or cellulose, silicic acid, fatty acids, fatty acid amines, lower alkyl ethers of fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone.Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

[0115] As used herein, the term "pharmaceutical composition" refers to a composition containing one or more of the compounds described herein, or their pharma- ceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, formulated in a pharma- ceutically acceptable carrier, which may also contain other excipients, and which has been manufactured or sold with the approval of a government regulatory agency as part of a therapeutic regimen for the treatment of a disease in a mammal. The pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., tablets, capsules, caplets, gelcaps, or syrups), for topical administration (e.g., as a cream, gel, lotion, or ointment), for intravenous administration (e.g., as a sterile solution free of particulate plugs and in a solvent system suitable for intravenous use), for administration to pediatric subjects (e.g., as solutions, syrups, suspensions, elixirs, powders for reconstitution as suspensions or solutions, dispersible / effervescent tablets, chewable tablets, lollipops, freezer pops, lozenges, oral flakes, orally disintegrating tablets, orally disintegrating flakes, and sprinkle oral powders, or granules), or in any other formulation described herein, including as a spray-dried dispersion (e.g., a single-phase amorphous molecular dispersion of a compound described herein in a polymer matrix). Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005) and The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

[0116] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of structure (I) or any one of formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein the compound, or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, is in amorphous form. In other embodiments, the compound, or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, is micronized. In yet other embodiments, the compound, or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, is crystalline.

[0117] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of structure (I) or any one of formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein the compound, or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, has a particle size distribution. For example, in certain embodiments, the D of a compound of structure (I) or any one of formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, 50 The particle size distribution is in the range of about 500 nm to about 500 μm. In another embodiment, the D of any one of the compounds of structure (I) or formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, 50 The particle size distribution is in the range of about 500 nm to about 1 μm, or about 1 μm to about 50 μm, or about 50 μm to about 100 μm, or about 100 μm to about 150 μm. In yet another embodiment, the D isomer of any one of the compounds of structure (I) or formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, 50 The particle size distribution ranges from about 1 μm to about 10 μm, or from about 2 μm to about 8 μm, or from about 3 μm to about 7 μm.

[0118] In certain embodiments, a compound of any one of structure (I) or formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, D90 The particle size distribution ranges from about 1 μm to about 1000 μm. In another embodiment, the D of any one of the compounds of structure (I) or formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, 90 The particle size distribution is in the range of about 2 μm to about 100 μm, or about 100 μm to about 200 μm, or about 200 μm to about 300 μm, or about 300 μm to about 400 μm, or about 400 μm to about 500 μm, or about 500 μm to about 600 μm, or about 600 μm to about 700 μm, or about 700 μm to about 800 μm, or about 800 μm to about 900 μm, or about 900 μm to about 1000 μm. In yet another embodiment, the D of any one of the compounds of structure (I) or formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, is 90 The particle size distribution ranges from about 5 μm to about 25 μm, or from about 7 μm to about 23 μm, or from about 9 μm to about 21 μm, or from about 11 μm to about 19 μm.

[0119] In some embodiments, the pharmaceutical composition comprising a compound of structure (I) or any one of formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, together with at least one pharma- ceutically acceptable carrier, diluent, or excipient, further comprises a second therapeutic agent.

[0120] In one embodiment, the second therapeutic agent is an antihistamine, such as an H1 receptor antagonist or an H2 receptor antagonist. In one embodiment, the second therapeutic agent is an H1 receptor antagonist antihistamine, such as levocetirizine, loratadine, fexofenadine, cetirizine, desloratadine, olopatadine, diphenhydramine, cyproheptadine, or hydroxyzine pamoate. In one embodiment, the second therapeutic agent is an H2 receptor antagonist, such as cimetidine, nizatidine, ranitidine, or famotidine. In one embodiment, the second therapeutic agent is a leukotriene receptor antagonist or a leukotriene synthesis inhibitor, such as montelukast, zafirlukast, pranlukast, or a 5-lipoxygenase inhibitor (e.g., zileuton, St. John's wort). In one embodiment, the second therapeutic agent is an immunomodulator, such as omalizumab or immunoglobulin therapy. In one embodiment, the second therapeutic agent is a corticosteroid, such as hydrocortisone, cortisone, ethamethasoneb, triamcinolone, prednisone, prednisolone, or fludrocortisone. In one embodiment, the second therapeutic agent is a tricyclic antidepressant that can relieve itch, such as doxepin, amitriptyline, or nortriptyline. In one embodiment, the second therapeutic agent is an anti-inflammatory drug, such as dapsone, sulfasalazine, hydroxychloroquine, or colchicine. In one embodiment, the second therapeutic agent is an immunosuppressant, such as cyclosporine, methotrexate, mycophenolic acid, or tacromilus.

[0121] In one embodiment, the second therapeutic agent is an H1 receptor antagonist antihistamine, such as levocetirizine, loratadine, fexofenadine, cetirizine, desloratadine, olopatadine, diphenhydramine, cyproheptadine, or hydroxyzine pamoate. In one embodiment, the second therapeutic agent is an H2 receptor antagonist, such as cimetidine, nizatidine, ranitidine, or famotidine. In one embodiment, the second therapeutic agent is a leukotriene receptor antagonist or leukotriene synthesis inhibitor, such as montelukast, zafirlukast, pranlukast, or a 5-lipoxygenase inhibitor (e.g., zileuton, St. John's wort). In one embodiment, the second therapeutic agent is an immunomodulatory agent, such as omalizumab or immunoglobulin therapy. In one embodiment, the second therapeutic agent is a corticosteroid, such as hydrocortisone, cortisone, ethamethasoneb, triamcinolone, prednisone, prednisolone, or fludrocortisone. In one embodiment, the second therapeutic agent is a tricyclic antidepressant that can relieve itch, such as doxepin, amitriptyline, or nortriptyline. In one embodiment, the second therapeutic agent is an anti-inflammatory drug, such as dapsone, sulfasalazine, hydroxychloroquine, or colchicine. In one embodiment, the second therapeutic agent is an immunosuppressant, such as cyclosporine, methotrexate, mycophenolic acid, or tacromilus.

[0122] As used herein, the term "pharmaceutical acceptable carrier" refers to any component (e.g., a carrier capable of suspending or dissolving an active compound) other than the disclosed compound or its pharmaceutical acceptable isomer, racemate, hydrate, solvate, isotope, or salt, which has the characteristics of being non-toxic and non-inflammatory to patients. Excipients may include, for example, anti-adhesive agents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film-forming or coating agents, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydration water. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn starch), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0123] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of any one of structure (I) or formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, and at least one polymeric carrier. In some embodiments, the pharmaceutical composition is in the form of an amorphous solid dispersion comprising at least one polymeric carrier.

[0124] In some embodiments, the polymeric carrier comprises at least one selected from the group consisting of an enteric polymer, a hydrophilic polymer, a surfactant, an amphiphilic polymer, and combinations thereof.

[0125] In some embodiments, the pharmaceutical composition comprises a compound of structure (I) or any one of formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, and a methacrylate polymer, a hydroxypropyl methylcellulose phthalate (HPMCP) polymer, a hydroxypropyl methylcellulose acetate-succinate (HPMCAS) polymer, a cellulose acetylate phthalate (CAP) polymer, a starch, a sodium carboxymethylcellulose polymer, a sodium alginate, a polyethylene glycol (PEG), a polyvinylpyrrolidone (PVP), a hydroxypropyl methylcellulose (HPMC) polymer, a polyvinyl a and a polymer carrier comprising at least one selected from the group consisting of polyvinyl alcohol (PVA), beta-cyclodextrin polymers, mannitol polymers, chitosan polymers, carrageenan polymers, hydroxypropyl cellulose (HPC) polymers, polyethylene-polypropylene glycol, lecithin, bile salts, lauroyl polyoxy-32 glycerides, polyethylene oxide (PEO) / polypropylene glycol (PPG) copolymers, PEG modified starch, vinyl acetate / vinylpyrrolidone random copolymers, polyacrylic acid, polyacrylates, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PCL-PVAc-PEG) graft copolymers.

[0126] In some embodiments, the pharmaceutical composition comprises a compound of any one of structure (I) or formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, and a polymeric carrier comprising at least one selected from the group consisting of hydroxylpropylmethylcellulose phthalate (HPMCP) polymer, hydroxypropylmethylcellulose acetate-succinate (HPMCAS) polymer, polyvinylpyrrolidone (PVP), and hydroxypropylcellulose (HPC) polymer. In more specific embodiments, the polymeric carrier comprises hydroxypropylmethylcellulose acetate-succinate (HPMCAS) polymer. For example, in some embodiments, the polymeric carrier comprises HPMCAS-MG.

[0127] In some embodiments, the pharmaceutical composition comprises a compound of structure (I) or any one of formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, and at least one polymeric carrier, such that the mass ratio of the compound to the polymeric carrier ranges from about 1:100 to about 50:1. For example, in some embodiments, the mass ratio of the compound to the polymeric carrier ranges from about 1:100 to about 1:50, or from about 1:50 to about 1:10, or from about 1:10 to about 1:1, or from about 1:1 to about 10:1, or from about 10:1 to about 20:1, or from about 20:1 to about 50:1. In other embodiments, the mass ratio of the compound to the polymeric carrier ranges from about 1:1 to about 1:5.

[0128] In some embodiments, the pharmaceutical composition comprises a compound of any one of structure (I) or formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, and at least one polymeric carrier, such that the weight percentage of the compound ranges from about 2% to about 70% based on the combined weight of the compound and the polymeric carrier. In other embodiments, the weight percentage of the compound ranges from about 2% to about 10%, or from about 10% to about 20%, or from about 15% to about 25%, or from about 20% to about 30%, or from about 30% to about 40%, or from about 40% to about 50%, or from about 50% to about 60%, or from about 60% to about 70% based on the combined weight of the compound and the polymeric carrier.

[0129] In certain embodiments, the present invention provides a pharmaceutical composition further comprising at least one pharma- ceutically acceptable excipient. For example, in some embodiments, the pharmaceutical composition comprises a compound of any one of structure (I) or formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, at least one polymeric carrier as described above, and at least one pharma- ceutically acceptable excipient. The pharma- ceutically acceptable excipient may include, for example, a filler, a binder, a disintegrant, a surfactant, a lubricant, a glidant, a capsule shell, and mixtures thereof. The filler may include, for example, mannitol, microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), and mixtures thereof. The binder may include, for example, hydroxypropyl methylcellulose (HPMC), povidone, and mixtures thereof. The disintegrant may include, for example, sodium starch glycolate (SSG), croscarmellose sodium (CCS), and mixtures thereof. Surfactants may include, for example, sodium lauryl sulfate (SLS), polaxamer, and mixtures thereof. Lubricants may include, for example, magnesium stearate (MS), sodium stearyl fumarate (SSF), and mixtures thereof. Glidants may include, for example, silicon dioxide, talc, and mixtures thereof. Capsule shells may include, for example, HPMC capsules or gelatin capsules. Surfactants may include, for example, sodium lauryl sulfate (SLS).

[0130] In some embodiments, the pharmaceutical composition comprises at least one solvent, which can include, for example, water and organic solvents such as dimethylsulfoxide.

[0131] The preparation can be mixed with auxiliary substances that do not react with the active compound in a manner that adversely affects it. Such additives can include wetting agents, emulsifying and suspending agents, salts for influencing osmotic pressure, buffers and / or coloring substances, preservatives, sweeteners, or flavoring agents. If necessary, the composition can be sterilized.

[0132] The route of administration can be any route that effectively transports the active compound of the present invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subcutaneous, intradermal, transdermal, or parenteral, including intravenous, subcutaneous and / or intramuscular. In one embodiment, the route of administration is oral. In another embodiment, the route of administration is topical.

[0133] The dosage form may be administered once a day, or more than once a day, for example, twice or three times a day. Alternatively, the dosage form may be administered less frequently than daily, such as every other day or every week, if found to be recommended by the prescribing physician or the drug's prescription information. The dosing regimen may include, for example, dose escalation as necessary or useful for the indication being treated, thus allowing the patient's body to adapt to the treatment, minimize or avoid undesirable side effects associated with the treatment, and / or maximize the therapeutic effect of the compound. Other dosage forms include delayed or controlled release forms. Suitable dosing regimes and / or forms include, for example, those described in the latest edition of the Physicians' Desk Reference, which is incorporated herein by reference.

[0134] Appropriate dosages for pediatric patients can be determined using known methods, including body weight, age, body surface area, and models, such as Simcyp® Pediatric Simulation modeling (CERTARA, Princeton, NJ), which can be used to establish a pharmacokinetic approach for dosing that takes into account the patient's age, ontogeny of clearance pathways for eliminating a compound of any one of Formulae (Ia)-(1f), and body surface area (BSA). In one embodiment, the dosage form is formulated to provide a pediatric dose of about 30% to about 100% of the adult dose, or about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the adult dose.

[0135] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a compound of structure (I) or any one of formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, together with at least one pharma- ceutically acceptable oral carrier, diluent, or excipient. In another embodiment, a topical pharmaceutical composition comprising a compound of structure (I) or any one of formulas (Ia)-(1f), or a pharma- ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, together with at least one pharma- ceutically acceptable oral carrier, diluent, or excipient. For example, an oral pharmaceutical composition is provided for treating cholestatic pruritus, and the dosing regimen is, for example, once a day. In one embodiment, a topical pharmaceutical composition is provided for treating atopic dermatitis.

[0136] In another embodiment, a method of making a composition of a compound described herein is provided, comprising formulating a compound of the invention with a pharma- ceutically acceptable carrier or diluent. In some embodiments, the pharma- ceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the method may further comprise formulating the composition into a tablet or capsule. In other embodiments, the pharma- ceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the method further comprises lyophilizing the composition to form a lyophilized preparation. In some embodiments, the composition is formulated into a pediatric dosage form suitable for treating pediatric subjects.

[0137] In certain embodiments, the present invention provides a compound having any one of the structures (I) or formulas (Ia)-(1f), or a pharma-ceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof. Such compounds can be synthesized using standard synthetic techniques known to those skilled in the art. For example, the compounds of the present invention can be synthesized using appropriately modified synthetic procedures described in the following examples and reaction schemes.

[0138] To this end, the reactions, processes, and synthetic methods described herein are not limited to the specific conditions described in the following experimental section, but rather are intended as a guide to those of skill in the art. For example, the reactions can be carried out in any suitable solvent or other reagent to effect the required transformation. In general, suitable solvents are protic or aprotic solvents that are substantially non-reactive with the reactants, intermediates, or products at the temperature at which the reaction is carried out (i.e., temperatures that may range from freezing to boiling). A given reaction can be carried out in a mixture of one or more solvents. Depending on the particular reaction, a suitable solvent can be used for a particular post-reaction work.

[0139] All reagents whose synthesis is not described in the experimental section are commercially available, are known compounds, or can be formed from known compounds by known methods by those skilled in the art. Compounds and intermediates produced according to the methods of the present invention may require purification. Purification of organic compounds is well known to those skilled in the art, and there may be several ways to purify the same compound. In some cases, purification may not be necessary. In some cases, compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, compounds may be purified by chromatography, particularly flash column chromatography, using dedicated or pre-packed silica gel cartridges and eluents such as gradients of solvents such as heptane, ether, ethyl acetate, acetonitrile, ethanol, etc. In some cases, compounds may be purified by preparative HPLC using the methods described.

[0140] The purification method described herein may provide compounds of the present invention having sufficiently basic or acidic functional groups in the form of a salt, for example, trifluoroacetate or formate salts in the case of sufficiently basic compounds of the present invention, or ammonium salts in the case of sufficiently acidic compounds of the present invention. This type of salt may be converted to its free base or free acid form, respectively, by various methods known to those skilled in the art, or may be used as a salt in subsequent biological assays. It should be understood that the specific form of the compound of the present invention isolated and described herein is not necessarily the only form in which the compound can be applied to a biological assay to quantify a specific biological activity.

[0141] Chemical names were generated using ChemDraw naming software (version 17.0.0.206) from PerkinElmer Informatics, Inc. In some cases, generally accepted names of commercially available reagents were used in place of names generated by the naming software. EXAMPLES

[0142] Common methods 1 H NMR (400 MHz) spectra were obtained in solutions of deuterated chloroform (CDCl3), deuterated methanol (CD3OD), or dimethylsulfoxide-D6 (DMSO). HPLC retention times, purity, and mass spectra (LCMS) were obtained using one of the following methods: Method 1: Agilent 1260 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 2.7 μm, 4.6×100 mm column at 30° C. using HO with 0.1% formic acid as mobile phase A and MeCN with 0.1% formic acid as mobile phase B. An ESI detector in positive mode was used. The gradient was 5-95% mobile phase B over 12 min, followed by a hold at 95% for 1.8 min, then back to 10% mobile phase B over 0.2 min. The flow rate was 1 mL / min.

[0143] Method 2: A SHIMADZU LCMS-2020 system equipped with a Kinetex EVO C18 2.1 x 30 mm column (5um particles) using HO containing 0.0375% trifluoroacetic acid as mobile phase A and MeCN containing 0.01875% trifluoroacetic acid as mobile phase B. An ESI detector in positive mode was used. The gradient was 5% B at 0.00 min, 5-90% B at 0.00-0.80 min, 90-95% B at 0.80-0.12 min, then 95-5% B at 0.01 min, held at 5% B for 0.34 min, and the flow rate was 1.5 ml / min.

[0144] Method 3: Agilent 1200 system equipped with a Kinetex C18 50*×2.1 mm column (5 um particles) using HO with 0.037% trifluoroacetic acid as mobile phase A and MeCN with 0.018% trifluoroacetic acid as mobile phase B. ESI detector in positive mode was used. The gradient was 5% B at 0.00 min, 5-90% B from 0.00-0.80 min, 90-95% B from 0.80-0.12 min, then 95-5% B at 0.01 min, hold at 5% B for 0.34 min, flow rate was 1.5 ml / min.

[0145] Method 4: A SHIMADZU LCMS-2020 system equipped with a Kinetex EVO C18 2.1 x 30 mm column (5um particles) using HO containing 0.0375% trifluoroacetic acid as mobile phase A and MeCN containing 0.01875% trifluoroacetic acid as mobile phase B. An ESI detector in positive mode was used. The gradient was 5% B at 0.00 min, 5-90% B from 0.00-0.80 min, 90-95% B from 0.80-0.12 min, then 95-5% B at 0.01 min, held at 5% B for 0.34 min, and the flow rate was 1.5 ml / min.

[0146] Method 5: Agilent 1200 system equipped with Xbridge Shield RP18 2.1*50mm column (5um particles) using H2O with 10mM NH4HCO3 as mobile phase A and MeCN as mobile phase B. ESI detector in positive mode was used. The gradient was 5-95% B in 0.30 min, then 30-95% B in 0.30-0.80 min, hold at 95% B for 0.4 min, then 95-5% B in 0.01 min, and the flow rate was 1.5ml / min.

[0147] Method 6: A SHIMADZU LCMS-2020 system equipped with a Kinetex EVO C18 2.1 x 30 mm column (5um particles) using HO containing 0.0375% trifluoroacetic acid as mobile phase A and MeCN containing 0.01875% trifluoroacetic acid as mobile phase B. An ESI detector in positive mode was used. The gradient was 5% B at 0.00 min, 5-90% B from 0.00-0.80 min, 90-95% B from 0.80-0.12 min, then 95-5% B at 0.01 min, held at 5% B for 0.34 min, and the flow rate was 1.5 ml / min.

[0148] Method 7: A SHIMADZU LCMS-2020 system equipped with a Chromolith® Flash RP-18E 25-2 MM column using HO containing 0.0375% trifluoroacetic acid as mobile phase A and MeCN containing 0.01875% trifluoroacetic acid as mobile phase B. An ESI detector in positive mode was used. The gradient was 5% B at 0.00 min, 5-90% B at 0.00-0.80 min, 90-95% B at 0.80-0.12 min, then 95-5% B at 0.01 min, held at 5% B for 0.34 min, and the flow rate was 1.5 ml / min.

[0149] Method 8: A SHIMADZU LCMS-2020 system equipped with a Kinetex EVO C18 2.1 x 30 mm column (5um particles) using HO containing 0.0375% trifluoroacetic acid as mobile phase A and MeCN containing 0.01875% trifluoroacetic acid as mobile phase B. An ESI detector in positive mode was used. The gradient was 5% B at 0.00 min, 5-90% B from 0.00-0.80 min, 90-95% B from 0.80-0.12 min, then 95-5% B at 0.01 min, held at 5% B for 0.34 min, and the flow rate was 1.5 ml / min.

[0150] Method 9: Agilent 1290 Infinity II system equipped with an Agilent Poroshell 120 EC-18, 2.7 μm, 4.61×100 mm column at 35° C. using HO with 0.1% formic acid as mobile phase A and MeCN with 0.1% formic acid as mobile phase B. An ESI detector in positive mode was used. The gradient was 5-95% mobile phase B over 8.0 min, followed by a hold at 95% for 1.8 min, then back to 20% mobile phase B over 0.2 min. The flow rate was 0.7 mL / min.

[0151] Method 10: Agilent 1260 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 2.7 μm, 4.6×100 mm column at 30° C. using HO with 0.1% formic acid as mobile phase A and MeCN with 0.1% formic acid as mobile phase B. An ESI detector in positive mode was used. The gradient was 5-95% mobile phase B over 5 min, followed by a hold at 95% for 1.8 min, then back to 20% mobile phase B over 0.2 min. The flow rate was 1 mL / min.

[0152] Method 11: Agilent 1290 Infinity II system equipped with an Agilent Poroshell 120 EC-18, 1.9 μm, 2.1×50 mm column at 35° C. using HO with 0.1% formic acid as mobile phase A and MeCN with 0.1% formic acid as mobile phase B. An ESI detector in positive mode was used. The gradient was 20-95% mobile phase B over 0.8 min, followed by a hold at 95% for 0.7 min, then back to 20% mobile phase B over 0.7 min. The flow rate was 0.7 mL / min.

[0153] Method 12: A SHIMADZU LCMS-2020 system equipped with a Kinetex EVO C18 2.1x30mm (2.6um particles) using HO with 0.0375% trifluoroacetic acid as mobile phase A and MeCN with 0.01875% trifluoroacetic acid as mobile phase B. An ESI detector in positive mode was used. The gradient was 5% B at 0.00 min, and 5-95% B from 0.00-0.8 min, 95-95% B from 0.80-1.09 min, then 95-5% B at 0.01 min, hold at 5% B for 0.1 min, and the flow rate was 1.5ml / min.

[0154] Method 13: Agilent 1200￥G1956A equipped with a Kinetex EVO C18 30*2.1mm, 5um column using HO with 0.0375% TFA as mobile phase A and MeCN with 0.01875% TFA as mobile phase B. The gradient was 5-95% mobile phase B over 0.8 min, held at 95% for 0.4 min, then back to 5% mobile phase B for 0.01 min and held at 5% for 0.29 min. The flow rate was 1.5mL / min. An ESI detector in positive mode was used.

[0155] Method 14: SHIMADZU LCMS-2020 equipped with a Kinetex® EVO C18 2.1x30mm 5um column using HO with 0.0375% TFA as mobile phase A and MeCN with 0.01875% TFA as mobile phase B. The gradient was 5-95% mobile phase B over 0.8 min, held at 95% for 0.15 min, then back to 5% mobile phase B for 0.01 min and held at 5% for 0.04 min. The flow rate was 2mL / min. An ESI detector in positive mode was used.

[0156] Method 15: Agilent 1100￥G1956A equipped with a Kinetex® 5um EVO C18 30*2.1mm column using HO with 0.0375% TFA as mobile phase A and MeCN with 0.01875% TFA as mobile phase B. The gradient was 5-95% mobile phase B over 0.8 min, held at 95% for 0.4 min, then back to 5% mobile phase B for 0.01 min and held at 5% for 0.29 min. The flow rate was 1.5mL / min. An ESI detector in positive mode was used.

[0157] Method 16: SHIMADZU LCMS-2020 equipped with a Kinetex EVO C18 2.1X30mm, 5um column using HO with 0.0375% TFA as mobile phase A and MeCN with 0.01875% TFA as mobile phase B. The gradient was 5-95% mobile phase B over 0.8 min, held at 95% for 0.4 min, then back to 5% mobile phase B for 0.01 min and held at 5% for 0.04 min. The flow rate was 1.5mL / min. An ESI detector in positive mode was used.

[0158] Pyridine, dichloromethane (DCM), tetrahydrofuran (THF), and toluene used in the procedures were from Aldrich Sure-Seal bottles kept under nitrogen (N2). Other solvents were used as received. All reactions were magnetically stirred and at external reaction temperatures. Chromatography was typically performed using a Combiflash Rf flash purification system (Teledyne Isco) equipped with a Redisep (Teledyne Isco) Rf Gold normal phase silica gel (SiO2) column or similar system.

[0159] Preparative HPLC purifications were typically performed using one of the following systems: 1) Waters System equipped with a Waters 2489 uv / vis detector, Aquity QDA detector, Waters xBridge Prep C18 5 μm OBD, 30×150 mm column, eluting with a varying gradient of HO / MeCN (0.1% formic acid) at a flow rate of 30 mL / min; 2) Teledyne Isco ACCQPrep® HP150 UV system equipped with a Waters xBridge Prep C18 5 μm OBD, 30×150 mm column, eluting with a varying gradient of HO / MeCN (0.1% formic acid) at a flow rate of 42.5 mL / min; or 3) Column: Phenomenex Synergi C18 150 × 30 mm - 4 μm; mobile phase: [HO (0.225% formic acid)-MeCN]; B%: 55% - 85%, 12 min), typically concentrated using a Genevac EZ-2.

[0160] The following additional abbreviations are used: ethyl acetate (ethyl acetate, EA), triethylamine (TEA), water (HO), sodium chloride (NaCl), hydrochloric acid (HCl), methanol (MeOH), dimethylsulfoxide (DMSO), silica gel (SiO), diisobutylaluminum hydride (DIBAL), trifluoroacetic acid (TFA), 4-dimethylaminopyridine (DMAP), diphenylphosphoryl azide (DPPA), benzoyl peroxide (BPO), 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(pinacolato)diboron (Bpin2), tetrahydrofuran (THF), 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO), azabenzotriazole tetramethyluronium hexafluorophosphate (HATU), hydroxybenzotriazole (hydroxyHOB), t), N-methylmorpholine (NMM), N-bromosuccinimide (NBS), diisopropylethylamine (DIPEA or DIEA), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 2-[2-(dicyclohexylphosphino)phenyl]-N-methylindole (CM-Phos), trifluoromethanesulfonic acid (TfOH), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), isopropanol (IPA), dimethylformamide (DMF), dimethylacetamide (DMA), dichloromethane (DCM), 1,2-dichloroethane (DCE), acetonitrile (MeCN or ACN), 1,1'-thiocarbonyldiimidazole (TCDI), petroleum ether (petroleum ether, PE), polyphosphoric acid (PPA) undetermined (ND), retention time (RT, tr, or t R ), molecular weight (mw), room temperature (rt), time (h), and not applicable (N / A). Scheme 1 [ka] Reagents: Step 1-1. R1COCl, base (DIPEA), solvent (DCM); Step 1-2. HCl, solvent (1,4-dioxane); Step 1-3. R2X, base (DIPEA), solvent (DMSO, NMP), heat

[0161] Example 1 Synthesis of Example 1 [ka] Step 1-1. Synthesis of tert-butyl ((1S,3R)-3-(4-methoxybenzamido)cyclohexyl)carbamate [ka] To a stirred ice-cold solution of (1S,3R)-3-amino-1-(Boc-amino)cyclohexane (1.142 g, 1.0 equiv, 5.329 mmol) in DCM (30 mL) was added DIPEA (1.377 g, 1.9 mL, 2.0 equiv, 10.66 mmol), followed by slow addition of 4-methoxybenzoyl chloride (955 mg, 758 μL, 1.05 equiv, 5.60 mmol). The resulting mixture was stirred at room temperature. After stirring for 18 h, the reaction mixture was filtered and the filter cake was washed with DCM and dried under high vacuum to give tert-butyl ((1S,3R)-3-(4-methoxybenzamido)cyclohexyl)carbamate (1.659 g, 4.761 mmol, 89% yield). LCMS-ESI (m / z) calculated value: 348.44, found value: 349.2 [M+H] + , RT=4.239 minutes (Method 10). 1 H NMR(400MHz,DMSO-d6) δ 8.09(d,J=7.9Hz,1H),7.82(d,J=8.4Hz,2H),6.97(d,J=8.4Hz,2H),6.83(d,J=8.1Hz,1H),3.80(s,3H),3.79-3.71(m, 1H),3.31-3.22(m,1H),1.93(d,J=12.0Hz,1H),1.77-1.68(m,3H),1.38(s,9H),1.31-1.17(m,3H),1.11-1.01(m,1H).

[0162] Step 1-2. Synthesis of N-((1R,3S)-3-aminocyclohexyl)-4-methoxybenzamide [ka] To a stirred suspension of tert-butyl ((1S,3R)-3-(4-methoxybenzamido)cyclohexyl)-carbamate (1.654 g, 1 eq, 4.747 mmol) in EtOH (40 mL) was added 1.25 M hydrogen chloride in 1,4-dioxane (1.731 g, 37.97 mL, 1.25 moles, 10 eq, 47.47 mmol). The reaction mixture was stirred at 50° C. for 17 h. The reaction mixture was directly concentrated to give a white solid which was further dried under high vacuum to give N-((1R,3S)-3-aminocyclohexyl)-4-methoxybenzamide hydrochloride (1.331 g, 4.674 mmol, 98%) which was used in the next step without further purification. LCMS-ESI (m / z) calculated value: 248.44, found value: 249.2 [M+H] + , RT=1.665 minutes (Method 10). 1 H NMR(400MHz,DMSO-d6) δ 8.26(d,J=7.9Hz,1H),8.09(s,3H),7.84(d,J=8.4Hz,2H),6.98(d,J=8.4Hz,2H),3.91-3.81(m,1H),3.80(s,3H) ),3.13-3.05(m,1H),2.12(d,J=11.6Hz,1H),1.91(d,J=12.0Hz,1H),1.78(d,J=12.0Hz,2H),1.44-1.21(m,4H).

[0163] Step 1-3. Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-4-methoxybenzamide (Example 1) [ka] To a pressure vial containing a solution of 4,6-dichloro-2-(trifluoromethyl)quinoline (56 mg, 1.0 equiv., 0.21 mmol) and N-((1R,3S)-3-aminocyclohexyl)-4-methoxybenzamide hydrochloride (60 mg, 1.0 equiv., 0.21 mmol) in DMSO (2 mL) was charged DIPEA (0.11 g, 0.15 mL, 4.0 equiv., 0.84 mmol). The vial was closed and the resulting solution was stirred at 130° C. After stirring at 130° C. for 20 h, the reaction mixture was cooled to room temperature. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (ISCO ACCQPrep 150) to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-4-methoxybenzamide (20 mg, 42 μmol, 20% yield). LCMS-ESI (m / z) calculated value: 477.91, found value: 478.2 [M+H] + , RT=7.477 minutes (Method 9). 1 H NMR(400MHz,DMSO-d6) δ 8.61(s,1H),8.18(d,J=7.9Hz,1H),7.89(d,J=9.0Hz,1H),7.83(d,J=8.5Hz, 2H),7.74(dd,J=9.0,2.1Hz,1H),7.50(d,J=8.0Hz,1H),7.01-6.89(m,3H),4. 07-3.98(m,1H),3.92-3.84(m,1H),3.80(s,3H),2.16(d,J=11.9Hz,1H),1.9 7(d,J=12.3Hz,1H),1.91-1.78(m,2H),1.60-1.47(m,2H),1.44-1.29(m,2H).

[0164] Example 2 Synthesis of Example 2 [ka] Step 1-1. Synthesis of tert-butyl ((1S,3R)-3-benzamidocyclohexyl)carbamate To an ice-cold solution of (1S,3R)-3-amino-1-(Boc-amino)cyclohexane (1.238 g, 1 equiv, 5.777 mmol) in DCM (30 mL) was added DIPEA (1.493 g, 2.0 mL, 2 equiv, 11.55 mmol) followed by benzoyl chloride (853 mg, 704 μL, 1.05 equiv, 6.07 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and the filter cake was washed with DCM and dried under high vacuum to give tert-butyl ((1S,3R)-3-benzamido)cyclohexyl)carbamate (1.575 g, 4.946 mmol, 86% yield). LCMS-ESI (m / z) calculated value: 318.30, observed value: 319.2 [M+H] + , RT=4.237 minutes (Method 10). 1 H NMR(400MHz,DMSO-d6) δ 8.26(d,J=7.9Hz,1H),7.83(d,J=7.5Hz,2H),7.53-7.42(m,3H),6.84(d,J=8.0Hz,1H),3.84-3.74(m,1H),3.3 1-3.23(m,1H),1.95(d,J=12.0Hz,1H),1.79-1.68(m,3H),1.38(s,9H),1.31-1.17(m,3H),1.11-1.02(m,1H).

[0165] Step 1-2. Synthesis of N-((1R,3S)-3-aminocyclohexyl)benzamide hydrochloride To a stirred white suspension of tert-butyl ((1S,3R)-3-benzamidocyclohexyl)-carbamate (1.570 g, 1 eq, 4.931 mmol) in 1,4-dioxane (35 mL) was added 4 M hydrogen chloride in 1,4-dioxane (10 eq, 49.31 mmol). The resulting mixture was heated at 50° C. for 19 h. The reaction mixture was directly concentrated and dried under high vacuum to give N-((1R,3S)-3-aminocyclohexyl)benzamide hydrochloride (1.201 g, 4.714 mmol, 96% yield). LCMS-ESI (m / z) calculated value: 218.30, found value: 219.2 [M+H] + , RT=0.261 min (Method 11). 1 H NMR(400MHz,DMSO-d6) δ 8.42(d,J=7.9Hz,1H),8.11(s,3H),7.85(d,J=7.5Hz,2H),7.55-7.41(m,3H),3.93-3.80(m,1H),3.18- 3.04(m,1H),2.14(d,J=11.8Hz,1H),1.92(d,J=12.0Hz,1H),1.79(d,J=11.4Hz,2H),1.48-1.20(m,4H).

[0166] Step 1-3. Synthesis of N-((1R,3S)-3-((2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)benzamide (Example 2) To a solution of 4-chloro-2-(trifluoromethyl)quinoline (55 mg, 1 equiv, 0.24 mmol) and N-((1R,3S)-3-aminocyclohexyl)benzamide hydrochloride (60 mg, 1 equiv, 0.24 mmol) in DMSO (2 mL) was added DIPEA (0.12 g, 0.16 mL, 4 equiv, 0.94 mmol). The vial was capped and the resulting solution was stirred at 130° C. for 18 h. The reaction mixture was cooled to room temperature, passed through a syringe filter, and the filtrate was purified by preparative HPLC (ISCO ACCQPrep 150) to give N-((1R,3S)-3-((2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)benzamide (13.4 mg, 32.4 μmol, 14% yield). LCMS-ESI (m / z) calculated value: 413.44, found value: 414.3 [M+H] + , RT=5.687 minutes (Method 9). 1H NMR(400MHz,DMSO-d6) δ 8.42(d,J=8.5Hz,1H),8.34(d,J=7.9Hz,1H),7.92-7.80(m,3H),7.73(t,J=7.6Hz,1H),7.58-7.37(m,5H),6.90(s,1H),4. 10-3.99(m,1H),3.93-3.82(m,1H),2.19(d,J=12.0Hz,1H),2.01-1.80(m,3H),1.56(q,J=12.1Hz,2H),1.46-1.29(m,2H).

[0167] Example 3 Synthesis of Example 3 [ka] Step 1-1. Synthesis of tert-butyl N-[(1S,3R)-3-[(4-fluorobenzoyl)amino]cyclohexyl]carbamate To a solution of tert-butyl N-[(1S,3R)-3-aminocyclohexyl]carbamate (0.8 g, 3.7 mmol, 1 equiv) and TEA (567 mg, 5.60 mmol, 779 uL, 1.5 equiv) in DCM (5 mL) was added 4-fluorobenzoyl chloride (592 mg, 3.73 mmol, 448 uL, 1 equiv) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with H2O (50 mL) and EA (50 mL). The mixture was filtered and the resulting cake was concentrated under reduced pressure to give the crude product. The filtrate was extracted with EA (50 mL×2). The combined organic layers were washed with saturated aqueous NaCl (50 mL×3), dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give tert-butyl N-[(1S,3R)-3-[(4-fluorobenzoyl)amino]cyclohexyl]carbamate (1.26 g, crude), which was used in the next step without further purification. LCMS-ESI (m / z) calculated value: 336.40, found value 237.2 [M+H-Boc] + , RT=0.9 min (method 2). 1H NMR(400MHz,DMSO-d6) δ=8.30(d,J=8.0Hz,1H),7.92-7.88(m,2H),7.30-7.24(m,2H),6.85(d,J=8.0Hz,1H),3.81-3.73(m ,1H),3.27-3.28(m,1H),1.95(d,J=11.2Hz,1H),1.78-1.71(m,3H),1.37(s,9H),1.31-1.02(m,4H).

[0168] Step 1-2. Synthesis of N-[(1R,3S)-3-aminocyclohexyl]-4-fluoro-benzamide A sample of tert-butyl N-[(1S,3R)-3-[(4-fluorobenzoyl)amino]cyclohexyl]carbamate (1.16 g, 3.45 mmol, 1 equiv.) was added to HCl / MeOH (4 M, 15 mL, 17.40 equiv.) at 25° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in MeOH (50 mL), then resin (base) was added and filtered to remove insoluble particles. The mother liquor was concentrated under reduced pressure to give the crude product N-[(1R,3S)-3-aminocyclohexyl]-4-fluoro-benzamide (0.81 g, 3.43 mmol, 99.41% yield), which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6) δ=8.52-8.46(m,1H),7.96-7.92(m,2H),7.30-7.25(m,2H),3.85-3.83(m,1H),3.06-3.01(m ,1H),2.14(d,J=10.8Hz,1H),1.93(d,J=11.2Hz,1H),1.78-1.76(m,2H),1.49-1.26(m,4H).

[0169] Step 1-3. Synthesis of 4-fluoro-N-[(1R,3S)-3-[[2-(trifluoromethyl)quinazolin-4-yl]amino]cyclohexyl]benzamide (Example 3) A mixture of 4-chloro-2-(trifluoromethyl)quinazoline (80 mg, 344 umol, 1 eq.), N-[(1R,3S)-3-aminocyclohexyl]-4-fluorobenzamide (163 mg, 688 umol, 2 eq.), and DIEA (222 mg, 1.72 mmol, 300 uL, 5 eq.) in DMSO (2 mL) was stirred at 120° C. for 1 hour. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3um; mobile phase: [water (0.225% FA)-ACN]; B%: 50%-70%, 10 min) and lyophilized to give 4-fluoro-N-[(1R,3S)-3-[[2-(trifluoromethyl)-quinazolin-4-yl]amino]cyclohexyl]benzamide (60mg, 138umol, 40% yield). LCMS-ESI (m / z) calculated value: 432.4, observed value: 433.2 [M+H-Boc] + , RT=0.941 min (method 2). 1 H NMR(400MHz,DMSO-d6) δ=8.54(d,J=8.0Hz,1H),8.45-8.38(m,2H),7.93-7.81(m,4H),7.69-7.65(m,1H),7.31-7.25(m,2H) ,4.34-4.29(m,1H),4.00-3.89(m,1H),2.19(d,J=11.6Hz,1H),1.99-1.85(m,3H),1.62-1.30(m,4H).

[0170] Example 4 Synthesis of Example 4 [ka] Step 1-3. Synthesis of 4-methoxy-N-[(1R,3S)-3-[[5-methyl-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]benzamide A mixture of 4-chloro-5-methyl-2-(trifluoromethyl)quinoline (120 mg, 489 umol, 1 equiv), N-[(1R,3S)-3-aminocyclohexyl]-4-methoxy-benzamide (170 mg, 685 umol, 1.4 equiv), and DIEA (189 mg, 1.47 mmol, 255 uL, 3 equiv) in NMP (1 mL) was stirred for 16 h at 120° C. The mixture was cooled to room temperature, filtered, and concentrated. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 32%~62%, 10min) and lyophilized to give 4-methoxy-N-[(1R,3S)-3-[[5-methyl-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]benzamide (8.7mg, 19umol, yield 4%). LCMS-ESI (m / z) calculated value: 457.5, observed value: 458.1 [M+H] + , RT=0.846 min (method 8). 1 H NMR(400MHz,DMSO-d6) δ=8.44-8.38(m,1H),8.18(br d,J=7.6Hz,1H),7.84(d,J=8.9Hz,2H),7.70(d,J=8.1Hz,1H),7.58-7.51(m, 1H),7.28(d,J=7.0Hz,1H),6.97(d,J=8.9Hz,2H),6.90-6.85(m,1H),6.31(br d,J=7.5Hz,1H),4.06-3.95(m,1H),3.85-3.75(m,4H),2.96-2.90(m,3H),2.32-2.24(m,1H),2.11-2.03(m,1H),1.89(br d,J=10.8Hz,1H),1.81(br d,J=13.1Hz,1H),1.61-1.45(m,2H),1.39-1.26(m,2H).

[0171] Example 5 Synthesis of Example 5 [ka] Synthesis of 4-chloro-7-methyl-2-(trifluoromethyl)quinoline A mixture of 7-methyl-2-(trifluoromethyl)quinolin-4-ol (150 mg, 660 umol, 1 eq.) and POCl3 (2.02 g, 13.2 mmol, 1.23 mL, 20 eq.) in ACN (1 mL) was stirred at 90° C. for 2 h. The mixture was cooled to 20° C., slowly poured into water (20 mL), extracted with EtOAc (20 mL), and the organic layer was collected and concentrated under reduced pressure to give crude 4-chloro-7-methyl-2-(trifluoromethyl)quinoline (150 mg), which was used in the next step without further purification. LCMS-ESI (m / z) calculated value: 245.6, observed value: 246.0 [M+H] + , RT=1.018 min (method 2).

[0172] Step 1-2. Synthesis of 4-methoxy-N-[(1R,3S)-3-[[7-methyl-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]benzamide A mixture of 4-chloro-7-methyl-2-(trifluoromethyl)quinoline (150 mg, 611 umol, 1 equiv), N-[(1R,3S)-3-aminocyclohexyl]-4-methoxy-benzamide (227 mg, 914 umol, 1.5 equiv), and DIEA (237 mg, 1.83 mmol, 319 uL, 3 equiv) in NMP (0.5 mL) was stirred for 16 h at 120° C. The mixture was cooled to room temperature, filtered, and concentrated. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 32%~62%, 10min) and lyophilized to give 4-methoxy-N-[(1R,3S)-3-[[7-methyl-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]benzamide (23.5mg, 51umol, 8%). LCMS-ESI (m / z) calculated value: 457.49, observed value: 458.1 [M+H] + , RT=0.818 min (method 2). 1H NMR (400MHz, DMSO-d6) δ=8.31(d,J=8.8Hz,1H),8.21-8.13(m,1H),7.83(d,J=8.8Hz,2H),7.67(s,1 H),7.39(dd,J=1.3,8.7Hz,1H),7.31(d,J=8.1Hz,1H),6.97(d,J=8.8Hz,2H), 6.82(s,1H),4.07-3.96(m,1H),3.80(s,4H),2.47(s,3H),2.20-2.12(m,1H) ,2.00-1.93(m,1H),1.91-1.78(m,2H),1.61-1.47(m,2H),1.45-1.27(m,2H).

[0173] Example 6 Synthesis of Example 6 [ka] Step 1-1: Synthesis of N-[(1R,3S)-3-[[8-bromo-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-4-methoxy-benzamide To a solution of 8-bromo-4-chloro-2-(trifluoromethyl)quinoline (60 mg, 193 umol, 1 eq) in DMSO (1 mL) was added N[(1R,3S)-3-aminocyclohexyl]-4-methoxy-benzamide (52.8 mg, 213 umol, 1.1 eq) and DIEA (50.0 mg, 386 umol, 67 uL, 2 eq). The mixture was stirred at 125° C. for 12 h. The reaction mixture was added to water (20 mL) and extracted with EA (20 mL×2). The combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO2, PE:EA=2:1) ​​to give N-[(1R,3S)-3-[[8-bromo-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-4-methoxy-benzamide (60 mg, 115 umol, 59% yield). LCMS-ESI (m / z) calculated value: 522.6, observed value: 522.1 / 524.1 [M+H] + , RT=0.977 min (method 2).

[0174] Step 1-2: Synthesis of 4-[[(1S,3R)-3-[(4-methoxybenzoyl)amino]cyclohexyl]amino]-2-(trifluoromethyl)quinoline-8-carboxylate To a solution of N-[(1R,3S)-3-[[8-bromo-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-4-methoxy-benzamide (60 mg, 115 umol, 1 equiv), Et3N (34.9 mg, 345 umol, 48 uL, 3 equiv) in MeOH (10 mL) was added Pd(dppf)Cl2.CH2Cl2 (9.4 mg, 11.5 umol, 0.1 equiv) at 25 °C. The suspension was degassed under vacuum and purged with CO several times. The reaction was heated to 70 °C under an atmosphere of CO (50 psi) and stirred for 16 h. The reaction mixture was cooled to room temperature and Et3N (34.9 mg, 345 umol, 48 uL, 3 equiv) and Pd(dppf)Cl2.CH2Cl2 (28.1 mg, 34.5 umol, 0.3 equiv) were added. The suspension was degassed under vacuum and purged with CO several times, then warmed to 70°C and stirred under CO (50 psi) atmosphere for 16 h. Thiourea (resin) (1 g) was added to the reaction mixture and stirred at 20°C for 2 h. The reaction mixture was filtered and the filter cake was washed with MeOH (10 mL x 3). The filtrate was concentrated in vacuum to give a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 35%~65%, 10min) to give methyl 4-[[(1S,3R)-3-[(4-methoxybenzoyl)amino]cyclohexyl]amino]-2-(trifluoromethyl)quinoline-8-carboxylate (7.4mg, 14.8umol, yield 13%). LCMS-ESI (m / z) calculated value: 501.5, observed value: 502.3 [M+H] + , RT=0.980 min (method 2). 1H NMR(400MHz,DMSO) δ=8.56(d,J=7.6Hz,1H),8.18(d,J=7.8Hz,1H),7.89-7.80(m,3H),7.59(dd,J=7.2,8.4Hz,1H), 7.53(d,J=8.2Hz,1H),7.00-6.94(m,3H),4.09-3.96(m,1H),3.87(s,4H),3.80(s,3H),2.17(br d,J=11.9Hz,1H),1.97(br d,J=11.5Hz,1H),1.92-1.77(m,2H),1.55(q,J=12.0Hz,2H),1.46-1.26(m,2H).

[0175] The compounds listed in Table 1 were made using the procedures in Scheme 1. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] Scheme 2 [ka] Reagents: Bases (t-Bu-ONa, TEA, Cs2CO3...), coupling agents (Pd(OAc)2, 1-BuXPhosPd, Pd(dppf)Cl2), solvents (1,4-dioxane)

[0176] Example 7 Synthesis of Example 7 [ka] Step 2: Synthesis of 4-methoxy-N-[(1R,3S)-3-((2-(trifluoromethyl)quinolin-5-yl)amino)cyclohexyl)benzamide A mixture of 5-bromo-2-(trifluoromethyl)quinoline (97 mg, 1 equiv, 351 μmol), N-((1R,3S)-3-aminocyclohexyl)-4-methoxybenzamide hydrochloride (100 mg, 1 equiv, 351 μmol), cesium carbonate (343 mg, 3 equiv, 1.05 mmol), palladium(II) acetate (3.9 mg, 0.05 equiv, 17.6 μmol), and BINAP (22 mg, 0.10 equiv, 35 μmol) in 1,4-dioxane (3 mL) was degassed with nitrogen for 5 min. The vial was capped and the resulting mixture was heated at 100 °C. After stirring at 100 °C for 20 h, the reaction mixture was cooled to room temperature, passed through a syringe filter, and the filtrate was directly loaded / purified by preparative HPLC (ISCO ACCQPrep 150) to give 4-methoxy-N-[(1R,3S)-3-((2-(trifluoromethyl)quinolin-5-yl)amino)cyclohexyl)benzamide (49 mg, 111 μmol, 32% yield). LCMS-ESI (m / z) calculated value: 443.47, observed value: 444.2 [M+H] + , RT=0.987 min (Method 11). 1 H NMR(400MHz,DMSO-d6) δ 9.02(d,J=8.8Hz,1H),8.16(d,J=7.8Hz,1H),7.81(dd,J=8.7,6.8Hz,3H),7.66( t,J=8.1Hz,1H),7.29(d,J=8.3Hz,1H),6.97(d,J=8.4Hz,2H),6.81(d,J=7.9Hz, 1H),6.43(d,J=7.6Hz,1H),4.02-3.92(m,1H),3.79(s,3H),3.65-3.56(m,1H),2 .27(d,J=12.1Hz,1H),2.09-2.03(m,1H),1.92-1.80(m,2H),1.56-1.27(m,4H).

[0177] Example 8 Synthesis of Example 8 [ka] Step 2: Synthesis of 4-methoxy-N-[(1R,3S)-3-((3-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)benzamide A mixture of 4-bromo-3-(trifluoromethyl)quinoline (97 mg, 1 equiv, 351 μmol), N-((1R,3S)-3-aminocyclohexyl)-4-methoxybenzamide hydrochloride (100 mg, 1 equiv, 351 μmol), cesium carbonate (343 mg, 3 equiv, 1.05 mmol), palladium(II) acetate (3.9 mg, 0.05 equiv, 17.6 μmol), and BINAP (22 mg, 0.10 equiv, 35.1 μmol) in 1,4-dioxane (3 mL) was degassed with nitrogen. The vial was capped and the resulting mixture was heated at 100° C. After stirring for 20 h, the reaction mixture was cooled to room temperature, passed through a syringe filter, and the filtrate was directly loaded / purified by preparative HPLC (ISCO ACCQPrep 150) to give 4-methoxy-N-[(1R,3S)-3-((3-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)benzamide (6.5 mg, 15 μmol, 4% yield). LCMS-ESI (m / z) calculated value: 443.47, observed value: 444.2 [M+H] + , RT=0.488 min (Method 11). 1 H NMR(400MHz,DMSO-d6) δ 8.70(s,1H),8.37(d,J=8.6Hz,1H),8.18(d,J=7.7Hz,1H),7.93(d,J=8.4 Hz,1H),7.80(d,J=8.2Hz,3H),7.61(t,J=7.6Hz,1H),6.96(d,J=8.4Hz,2H ),6.03(d,J=9.9Hz,1H),3.79(s,5H),2.07(d,J=12.0Hz,1H),1.95(d,J= 12.5Hz,1H),1.80(d,J=9.0Hz,2H),1.65-1.47(m,2H),1.37-1.24(m,2H).

[0178] The compounds listed in Table 2 were made using the procedures in Scheme 2. [Table 3]

[0179] Example 9 Synthesis of Example 9 [ka] Synthesis of 2-(difluoromethyl)quinolin-4-ol To PPA (26.9 mmol, 10 mL, 5.00 equiv) was added aniline (0.5 g, 5.37 mmol, 490 uL, 1 equiv) and ethyl 4,4-difluoro-3-oxobutanoate (892 mg, 5.37 mmol, 1 equiv) at 140° C. The reaction mixture was stirred at 140° C. for 12 h. The reaction mixture was cooled to room temperature, poured into water (50 mL) and extracted with ethyl acetate (4×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1:2) to give 2-(difluoromethyl)quinolin-4-ol (0.2 g, 1.02 mmol, 19% yield). LCMS-ESI (m / z) calculated value: 195.17, observed value: 196.4 [M+H] + , RT=0.777 min (method 2).

[0180] Synthesis of 4-chloro-2-(difluoromethyl)quinoline To a solution of 2-(difluoromethyl)quinolin-4-ol (200 mg, 1.02 mmol, 1 equiv) in DCE (3 mL) at 0° C., POCl3 (430 mg, 2.80 mmol, 261 uL, 2.74 equiv) was added dropwise. The reaction mixture was then heated at 80° C. for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a brown oil. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=10:1) to give 4-chloro-2-(difluoromethyl)quinoline (200 mg, 936 umol, 91% yield). LCMS-ESI (m / z) calculated value: 213.61, observed value: 214.0 [M+H] + , RT=0.930 min (method 2).

[0181] Step 2: Synthesis of N-[(1R,3S)-3-[[2-(difluoromethyl)-4-quinolyl]amino]cyclohexyl]-4-methoxy-benzamide A mixture of 4-chloro-2-(difluoromethyl)quinoline (30 mg, 140 umol, 1 equiv), N-[(1R,3S)-3-aminocyclohexyl]-4-methoxybenzamide (35 mg, 140 umol, 1 equiv), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium, ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (22 mg, 28 umol, 0.2 equiv), and t-BuONa (27 mg, 281 umol, 2 equiv) in tert-amyl alcohol (1 mL) was heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, poured into water (10 mL), extracted with ethyl acetate (2×10 mL), and the combined organics were dried and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 32%~62%, 8min) to give N-[(1R,3S)-3-[[2-(difluoromethyl)-4-quinolyl]amino]cyclohexyl]-4-methoxy-benzamide (3mg, 6.7umol, yield 5%). LCMS-ESI (m / z) calculated value: 425.47, observed value: 426.2 [M+H] + , RT=0.797 min (method 2). Scheme 3 [ka] Reagents: Step 3-1. R1X, base (DIPEA), solvent (DMSO, NMP), 130°C; Step 3-2. HCl, solvent (1,4-dioxane); Step 3-3. R2COCl, base (DIPEA), solvent (DMF)

[0182] Example 10 Synthesis of Example 10 [ka] Step 3-1. Synthesis of tert-butyl ((1R,3S)-3-((2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamate To a solution of 4-chloro-2-(trifluoromethyl)quinoline (1.08 g, 1 eq, 4.65 mmol) and tert-butyl ((1R,3S)-3-aminocyclohexyl)carbamate (0.996 g, 1 eq, 4.65 mmol) in DMSO (12 mL) was added DIPEA (2.40 g, 3.2 mL, 4 eq, 18.6 mmol). The vial was capped and the resulting solution was heated at 130° C. After stirring at 130° C. for 3 h, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water and extracted with EtOAc (3×20 mL). The organic phases were combined, washed with brine and concentrated under reduced pressure. The residue was purified by flash column chromatography (ISCO Gold 120 g, 0% to 80% EtOAc / hexanes) to give tert-butyl ((1R,3S)-3-((2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamate (0.584 g, 1.43 mmol, 31% yield). LCMS-ESI (m / z) calculated value: 409.45, found value: 410.3 [M+H] + , RT=4.976 minutes (Method 10). 1 H NMR(400MHz,DMSO-d6) δ 8.40(d,J=8.5Hz,1H),7.87(d,J=8.4Hz,1H),7.72(t,J=7.6Hz,1H),7.54(t,J=7.6Hz,1H),7.35(d,J=8.1Hz,1H),6.94-6.75(m,2H),3.81- 3.70(m,1H),3.52-3.39(m,1H),2.07(d,J=12.0Hz,1H),1.91(d,J=12.2Hz,1H),1.84-1.71(m,2H),1.50-1.28(m,12H),1.17-1.07(m,1H).

[0183] Step 3-2. Synthesis of (1S,3R)-N1-(2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride To a stirred suspension of tert-butyl ((1R,3S)-3-((2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamate (580 mg, 1 equiv, 1.42 mmol) in 1,4-dioxane (10 mL) was added 4 M hydrogen chloride in 1,4-dioxane (3.54 mL, 4.00 moles, 10 equiv, 14.2 mmol). The resulting mixture was stirred at 50° C. for 16 h. The reaction mixture was filtered and the resulting filter cake was washed with diethyl ether and dried under high vacuum to give (1S,3R)-N1-(2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (491 mg, 1.42 mmol, 100%). LCMS-ESI (m / z) calculated value: 309.2, observed value: 310.2 [M+H] + , RT=1.294 minutes (Method 10). 1 H NMR(400MHz,DMSO-d6) δ 8.59(d,J=8.5Hz,1H),8.22(s,4H),7.99(d,J=8.4Hz,1H),7.83(t,J=7.7Hz,1H),7.63(t,J=7.6Hz,1H),7.03(s,1H),4.06-3.94 (m,1H),3.32-3.20(m,1H),2.25(d,J=11.7Hz,1H),2.03-1.81(m,3H),1.68-1.56(m,1H),1.54-1.41(m,2H),1.39-1.27(m,1H).

[0184] Step 3-3. Synthesis of 3-methoxy-N-((1R,3S)-3-((2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)benzamide To a solution of (1S,3R)-N1-(2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (20 mg, 1 equiv., 65 μmol) and DIEA (25 mg, 3 equiv., 0.19 mmol) in DMF (1.5 mL) was added 3-(methoxycarbonyl)benzoyl chloride (12 mg, 1.2 equiv., 78 μmol). The reaction mixture was stirred at 25 °C for 18 h. The crude mixture was purified by Waters preparative HPLC (20-90% 0.1% formic acid in MeCN and 0.1% formic acid in water) to give 3-methoxy-N-((1R,3S)-3-((2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)benzamide (8.4 mg, 19 μmol, 29% yield). LCMS-ESI (m / z) calculated value: 443.47, observed value: 444.20 [M+H] + , RT=7.592 minutes (method 1). 1 H NMR(400MHz,DMSO-d6) δ 8.43(d,J=8.5Hz,1H),8.32(d,J=7.9Hz,1H),7.89(d,J=8.4Hz,1H),7.74(t,J=7.7Hz,1H ),7.56(t,J=7.6Hz,1H),7.52-7.30(m,4H),7.08(d,J=8.2Hz,1H),6.90(s,1H),4.05(d, J=11.8Hz,1H),3.88(d,J=7.9Hz,1H),3.80(d,J=1.8Hz,3H),2.19(d,J=12.1Hz,1H),1.9 9(d,J=12.2Hz,1H),1.87(dd,J=25.2,12.8Hz,2H),1.72-1.53(m,2H),1.51-1.20(m,2H).

[0185] Example 11 Synthesis of Example 11 [ka] Step 3-1. Synthesis of tert-butyl ((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamate To a stirred solution of 4,6-dichloro-2-(trifluoromethyl)quinoline (1.241 g, 1 eq, 4.666 mmol) and tert-butyl ((1R,3S)-3-aminocyclohexyl)carbamate (1.0 g, 1 eq, 4.666 mmol) in DMSO (6 mL) was added DIPEA (2.41 g, 3.30 mL, 4 eq, 18.7 mmol). The vial was capped and heated at 130° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine and concentrated in vacuo. The crude residue was purified by flash silica gel column chromatography (0% to 100% of 10% MeOH in EtOAc and hexanes) to give tert-butyl ((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamate (1.229 g, 2.768 mmol, 59% yield).

[0186] Step 3-2. Synthesis of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride To tert-butyl ((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamate (1.229 g, 1 eq, 2.768 mmol) in 1,4-dioxane (10 mL) was added 4 M hydrogen chloride in 1,4-dioxane (1.51 g, 10.4 mL, 4.00 moles, 15 eq, 41.5 mmol). The vial was capped and heated at 50° C. for 14 h. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with diethyl ether (2×10 mL) and dried under high vacuum to give (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (1.15 g, 3.02 mmol, 100% yield). LCMS-ESI (m / z) calculated value: 343.1, found value: 344.1 [M+H] + , RT=0.66 min (Method 11). 1H NMR(400MHz,DMSO-d6) δ 8.64(s,1H),7.95(d,J=9.0Hz,1H),7.91-7.84(m,1H),7.79(d,J=8.9Hz,1H),6.97(s,1H),3.97-3.85(m,1H) ,3.57(s,3H),3.31-3.19(m,1H),2.30-2.22(m,1H),2.04-1.89(m,2H),1.88-1.79(m,1H),1.64-1.27(m,4H).

[0187] Step 3-3. Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-2-methylbenzamide To a solution of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (60 mg, 1 equiv., 0.16 mmol) in DMF (2 mL) was added DIPEA (0.11 mL, 4 equiv., 0.63 mmol) followed by 2-methylbenzoyl chloride (26 mg, 22 μL, 1.05 equiv., 0.17 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was passed through a syringe filter and the filtrate was directly loaded / purified by preparative HPLC (ISCO ACCQPrep 150) to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-2-methylbenzamide (20 mg, 43 μmol, 27% yield). LCMS-ESI (m / z) calculated value: 461.91, found value: 462.2 [M+H] + , RT=1.025 min (Method 11). 1H NMR(400MHz,DMSO-d6) δ 8.60(s,1H),8.24(d,J=8.1Hz,1H),7.89(d,J=9.0Hz,1H),7.74(d,J=8.9Hz,1H),7.50(d,J=8.1Hz,1H),7.32-7.19(m,4H),6.96(s,1H), 4.05-3.86(m,2H),2.32(s,3H),2.17(d,J=12.1Hz,1H),1.98-1.87(m,2H),1.81(d,J=13.3Hz,1H),1.60-1.45(m,2H),1.39-1.22(m,2H).

[0188] Example 12 Synthesis of Example 12 [ka] Step 3-1. Synthesis of tert-butyl ((1R,3S)-3-((6-methyl-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamate To a solution of tert-butyl ((1R,3S)-3-aminocyclohexyl)carbamate (1.0 g, 1 eq, 4.7 mmol) and 4-chloro-6-methyl-2-(trifluoromethyl)quinoline (1.1 g, 1 eq, 4.7 mmol) in DMSO (12 mL) was added DIPEA (1.2 g, 1.6 mL, 2 eq, 9.3 mmol). The vial was capped and the resulting solution was heated at 130° C. After stirring at 130° C. for 3 h, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The organic phases were combined, washed with brine and concentrated under reduced pressure. The residue was dissolved in DCM and purified by flash column chromatography (ISCO Gold 120 g, 0% to 80% EtOAc / Hexanes, 11 CV gradient) to give tert-butyl ((1R,3S)-3-((6-methyl-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamate (1.3 g, 3.1 mmol, 66% yield). LCMS-ESI (m / z) calculated value: 423.48, observed value: 424.2 [M+H] + , RT=5.092 minutes (method 10).

[0189] Step 3-2. Synthesis of (1S,3R)-N1-(6-methyl-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride To tert-butyl ((1R,3S)-3-((6-methyl-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamate (1.3 g, 1 eq, 3.1 mmol) in 1,4-dioxane (10 mL) was added 4 M hydrogen chloride in 1,4-dioxane (7.7 mL, 4.00 moles, 10 eq, 31 mmol). The reaction mixture was stirred at 50° C. for 18 h, cooled to room temperature, filtered, and the filter cake was washed with diethyl ether and dried under high vacuum to give (1S,3R)-N1-(6-methyl-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (1.1 g, 3.1 mmol, 100% yield). LCMS-ESI (m / z) calculated value: 323.82, found value: 324.2 [M+H] + , RT=2.28 minutes (Method 10).

[0190] Step 3-3. Synthesis of N-((1R,3S)-3-((6-methyl-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)benzamide To a solution of (1S,3R)-N1-(6-methyl-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (75 mg, 1 equiv., 0.21 mmol) in DMF (1.5 mL) was added DIPEA (0.15 mL, 4 equiv., 0.83 mmol) followed by benzoyl chloride (31 mg, 1.05 equiv., 0.22 mmol). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was passed through a syringe filter and the filtrate was directly loaded / purified by preparative HPLC (ISCO ACCQPrep 150) to give N-((1R,3S)-3-((6-methyl-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)benzamide (9.1 mg, 21 μmol, 10% yield). LCMS-ESI (m / z) calculated value: 427.47, observed value: 428.3 [M+H]+ , RT=0.848 min (Method 11). 1 H NMR(400MHz,DMSO-d6) δ 8.33(d,J=7.9Hz,1H),8.21(s,1H),7.89-7.71(m,3H),7.60-7.40(m,4H),7.24(d,J=8.0Hz,1H),6.84(s,1H),4.09-3.98 (m,1H),3.89-3.79(m,1H),2.49(s,3H),2.19(d,J=12.0Hz,1H),2.01-1.79(m,3H),1.62-1.48(m,2H),1.45-1.30(m,2H).

[0191] Example 13 Synthesis of Example 13 [ka] Step 3-3. Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)benzamide To a solution of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (45 mg, 1 equiv, 0.12 mmol) in DMF (1.5 mL) was added DIPEA (83 μL, 4 equiv, 0.47 mmol) followed by benzoyl chloride (17 mg, 1.05 equiv, 0.12 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was passed through a syringe filter and the filtrate was directly loaded / purified by preparative HPLC (ISCO ACCQPrep 150) to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)benzamide (5 mg, 0.01 mmol, 9% yield). LCMS-ESI (m / z) calculated value: 447.89, observed value: 448.2 [M+H] + , RT=1.000 min (method 11). 1H NMR(400MHz,DMSO-d6) δ 8.61(s,1H),8.34(d,J=7.9Hz,1H),7.89(d,J=9.0Hz,1H),7.83(d,J=7.6Hz,2H),7.74(d,J=9.0Hz,1H),7.53-7.42(m,4H),6.95(s,1H),4.0 9-4.01(m,1H),3.93-3.84(m,1H),2.17(d,J=12.0Hz,1H),1.97(d,J=12.2Hz,1H),1.92-1.80(m,2H),1.60-1.50(m,2H),1.43-1.30(m,2H).

[0192] The compounds listed in Table 3 were made using the procedures in Scheme 3. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] Scheme 4 [ka] Reagents: Steps 2-4. R2COOH, peptide coupling reaction (HATU), base (DIPEA), solvent (DMF)

[0193] Example 14 Synthesis of Example 14 [ka] Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-3-(methylsulfonamido)benzamide To a stirred solution of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (90 mg, 1 eq, 0.24 mmol) in DMF (2 mL) was added 3-(methylsulfonamido)benzoic acid (51 mg, 1 eq, 0.24 mmol), HATU (0.10 g, 1.1 eq, 0.26 mmol), and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (92 mg, 0.12 mL, 3 eq, 0.71 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and purified by reverse-phase preparative HPLC (35→55% 0.1% formic acid in MeCN and 0.1% formic acid in HO) to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-3-(methylsulfonamido)benzamide (66 mg, 123 μmol, 52% yield). LCMS-ESI (m / z) calculated: 540.99, found 541.2 [M+H]+, RT = 0.906 min (Method 11).

[0194] Example 15 Synthesis of Example 15 [ka] Synthesis of 2-amino-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyrimidine-5-carboxamide To a solution of 2-aminopyrimidine-5-carboxylic acid (12 mg, 1 equiv., 87 μmol) in DMF (2 mL) was added HATU (50 mg, 1.5 equiv., 0.13 mmol). The resulting solution was stirred at room temperature for 10 min. To the mixture was added (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (30 mg, 1 equiv., 87 μmol). The resulting mixture was stirred at room temperature for 19 h. The crude mixture was directly purified by preparative HPLC to give 2-amino-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]pyrimidine-5-carboxamide (33 mg, 71 μmol, 82% yield). LCMS-ESI (m / z) calculated value: 464.88, observed value: 465.2 [M+H] + , RT=7.332 minutes (method 1). 1 H NMR(400MHz,DMSO) δ 8.67(d,J=1.6Hz,2H),8.61(d,J=2.4Hz,1H),8.14(d,J=7.8Hz,1H),7.90(d,J=9 .0Hz,1H),7.74(dd,J=9.1,2.2Hz,1H),7.50(d,J=7.9Hz,1H),7.18(s,2H),6.94( s,1H),4.12-3.76(m,2H),2.18(d,J=12.0Hz,1H),1.98(d,J=12.1Hz,1H),1.86( dd,J=26.2,13.0Hz,2H),1.53(dq,J=23.5,12.6,11.9Hz,2H),1.45-1.18(m,2H).

[0195] Example 16 Synthesis of Example 16 [ka] Synthesis of N-[(1R,3S)-3-[[2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]propanamide To a mixture of propionic acid (5 mg, 64 umol, 5 uL, 1 equiv) in DMF (2 mL) was added DIPEA (8 mg, 64 umol, 11.10 uL, 1 equiv), (1S,3R)-N1-[2-(trifluoromethyl)-4-quinolyl]cyclohexane-1,3-diamine (25 mg, 70 umol, 1.1 equiv, HCl), and HATU (24 mg, 64 umol, 1 equiv). The reaction mixture was stirred at 30° C. for 12 hours. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3um; mobile phase: [water (0.225% FA)-ACN]; B%: 30%~50%, 10 min) to give N-[(1R,3S)-3-[[2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]propanamide (3mg, 7umol, yield 12%). LCMS-ESI (m / z) calculated value: 365.4, observed value: 366.1 [M+H] + , RT=0.731 min (method 6).

[0196] Example 17 Synthesis of Example 17 [ka] N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-2-methoxy-1-methyl-1H-imidazole-5-carboxamide To a stirred solution of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (120 mg, 1 eq, 316 μmol) in DMF (5 mL) was added 2-chloro-1-methyl-1H-imidazole-5-carboxylic acid (50.7 mg, 1 eq, 316 μmol), HATU (120 mg, 1 eq, 316 μmol), and DIPEA (163 mg, 0.22 mL, 4 eq, 1.26 mmol). The resulting mixture was stirred at room temperature. After stirring for 1 h, the reaction mixture was filtered and the filtrate was directly loaded / purified by preparative HPLC (ISCO ACCQPrep 150) to give 2-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-5-carboxamide (83.9 mg, 173 μmol, 54.7%). LCMS-ESI (m / z) calculated value: 485.1, observed value: 486.2 [M+H] + , RT=9.057 minutes (method 1).

[0197] To a solution of 2-chloro-N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-methyl-imidazole-4-carboxamide (20 mg, 1 eq, 41.13 umol) in 2-methylbutan-2-ol (2 mL) was added CHONa (5.4 M, 3 eq, 22.85 uL). The resulting solution was heated at 70° C. for 23 hours. The reaction mixture was cooled to room temperature and purified directly by preparative HPLC to give N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]-cyclohexyl]-2-methoxy-3-methyl-imidazole-4-carboxamide (3.0 mg, 5.67 umol, 14% yield). LCMS-ESI (m / z) calculated value: 481.9, observed value: 482.3 [M+H] + , RT=0.472 min (method 2). 1H NMR(400MHz,DMSO-d6) δ 8.62-8.58(m,1H),8.37-8.29(m,1H),7.94(d,J=8.0Hz,1H),7.89(d,J=9.0Hz,1H),7.76 -7.71(m,1H),7.48(d,J=8.0Hz,1H),7.28(s,1H),6.92(s,1H),3.95(s,4H),3.88-3.80.

[0198] Example 18 Synthesis of Example 18 [ka] Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-6-((2-fluoroethyl)amino)nicotinamide To a solution of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-6-fluoronicotinamide 4-411 (50 mg, 1 equiv., 0.11 mmol) in NMP (4 mL) was charged 2-fluoroethan-1-amine (6.8 mg, 1 equiv., 0.11 mmol) and DIPEA (42 mg, 56 μL, 3 equiv., 0.32 mmol). The resulting yellow solution was stirred at 75° C. for 18 h. The reaction mixture was cooled to room temperature and directly purified by preparative HPLC to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-6-((2-fluoroethyl)amino)nicotinamide (9.0 mg, 18 μmol, 16% yield). LCMS-ESI (m / z) calculated value: 509.93, found value: 510.2 [M+H] + , tR=7.013 minutes (method 1).

[0199] Example 19 Synthesis of Example 19 [ka] Synthesis of tert-butyl 4-(4-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-5-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate To a stirred solution of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (80 mg, 1 eq., 0.21 mmol) and DIPEA (0.15 mL, 4 eq., 0.84 mmol) in DMF (4 mL) was charged HATU (80 mg, 1 eq., 0.21 mmol) and 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-methyl-1H-pyrazole-4-carboxylic acid (65 mg, 1 eq., 0.21 mmol). The resulting solution was stirred at room temperature for 1 h. The crude mixture was directly purified by preparative HPLC to give tert-butyl 4-(4-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-5-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (83.4 mg, 131 μmol, 62% yield). LCMS-ESI (m / z) calculated value: 634.26, observed value: 635.3 [M+H] + , tR=10.514 minutes (method 1). 1 H NMR(400MHz,DMSO-d6) δ 8.60(s,1H),7.89(d,J=9.3Hz,2H),7.80-7.70(m,2H),7.48(d,J=7.8Hz,1H),6.92(d,J=2.8Hz,1H),4.37(t,J=7.8Hz,1H),4.08-3.92(m,3H) ),3.85(d,J=10.0Hz,1H),3.41(s,4H),2.90(s,2H),2.12(d,J=11.7Hz,1H),1.96(d,J=12.4Hz,1H),1.89-1.73(m,6H),1.54-1.25(m,13H).

[0200] Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-5-methyl-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide To a solution of tert-butyl 4-(4-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-5-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (78.9 mg, 1 eq, 0.12 mmol) in 1,4-dioxane (5 mL) was charged a solution of hydrogen chloride in 1,4-dioxane (4.0 M, 311 μL, 10 eq, 1.24 mmol). The resulting suspension was heated at 50° C. for 3 h. The reaction mixture was then cooled to room temperature, filtered, and the filter cake was washed with diethyl ether and dried to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-5-methyl-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide (57.8 mg, 108 μmol, 87.0%). LCMS-ESI (m / z) calculated value: 534.21, observed value: 535.3 [M+H] + , tR=5.987 minutes (method 1). 1 H NMR(400MHz,DMSO-d6) δ 9.09(d,J=10.9Hz,1H),8.81(d,J=11.1Hz,1H),8.66(s,1H),7.97-7.88(m,2H),7.84(d,J=8. 1Hz,1H),7.73(dd,J=23.2,8.4Hz,2H),6.97(s,1H),4.57-4.47(m,1H),4.02-3.85(m,2H),3.3 7(d,J=12.3Hz,2H),3.06(q,J=12.9,12.1Hz,2H),2.51(s,3H),2.24-2.08(m,3H),1.96(d,J= 13.3Hz,3H),1.82(t,J=12.6Hz,2H),1.60-1.46(m,2H),1.44-1.35(m,1H),1.34-1.23(m,1H).

[0201] The compounds listed in Table 4 were made using the procedures in Scheme 4. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11] [Table 5-12] [Table 5-13] [Table 5-14] [Table 5-15] [Table 5-16] [Table 5-17]

Table 5-18

Table 5-19

Table 5-20

Table 5-21

Table 5-22

Table 5-23

Table 5-24

Table 5-25

Table 5-26

Table 5-27

Table 5-28

Table 5-29

Table 5-30

Table 5-31

Table 5-32

Table 5-33

Table 5-34

Table 5-35

Table 5-36

Table 5-37

Table 5-38

Table 5-39

Table 5-40

Table 5-41

Table 5-42

Table 5-43

Table 5-44

Table 5-45

Table 5-46

Table 5-47

Table 5-48

Table 5-49

Table 5-50

Table 5-51

Table 5-52

Table 5-53

Table 5-54

Table 5-55

Table 5-56

Table 5-57

Table 5-58

Table 5-59

Table 5-60

Table 5-61

Table 5-62

Table 5-63

Table 5-64

Table 5-65

Table 5-66

Table 5-67

Table 5-68

[0202] Example 21 Synthesis of Example 21 [ka] Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-3-cyano-1-(difluoromethyl)-1H-pyrazole-4-carboxamide To a solution of N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-cyano-1H-pyrazole-4-carboxamide (60 mg, 1 equiv, 130 umol), (2-chloro-2,2-difluoro-acetyl)oxysodium (39.5 mg, 2 equiv, 259 umol), and Cs2CO3 (85 mg, 2 equiv, 259 umol) in DMF (1 mL). The resulting solution was heated at 100 °C for 1 h. The reaction mixture was cooled to room temperature and directly purified by preparative HPLC to give N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-cyano-1-(difluoromethyl)pyrazole-4-carboxamide (2.3 mg, 4.45 umol, 3.44% yield). LCMS-ESI (m / z) calculated value: 512.87, observed value: 513.2 [M+H] + , RT=0.575 min (method 2). 1 H NMR(400MHz,chloroform-d) δ 8.46(s,1H) 8.03(br d,J=8.88Hz,1H) 7.71(s,1H) 7.65(br d,J=8.76Hz,1H) 7.04-7.26(m,1H) 6.78(s,1H) 6.24(br d,J=6.88Hz,1H) 5.01(br d,J=6.88Hz,1H) 4.16-4.25(m,1H) 3.73(br d,J=7.00Hz,1H) 2.63(br d,J=11.13Hz,1H) 2.18-2.31(m,2H) 2.01-2.06(m,1H) 1.29-1.45(m,4H).

[0203] Example 22 Synthesis of Example 22 [ka] Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-3-(difluoromethyl)-1-(fluoromethyl)-1H-pyrazole-4-carboxamide To a solution of N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-(difluoromethyl)-1H-pyrazole-4-carboxamide (100 mg, 1 equiv, 188.58 umol) in MeCN (2 mL) was added fluoro(iodo)methane (33.18 mg, 1.1 equiv, 207.44 umol) and KCO (52.13 mg, 2 equiv, 377 umol). After heating at 50° C. for 2 hours, the reaction mixture was cooled to room temperature and purified directly by preparative HPLC to give N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]-cyclohexyl]-5-(difluoromethyl)-1-(fluoromethyl)pyrazole-4-carboxamide (11.7 mg, 22.2 umol, 12% yield). LCMS-ESI (m / z) calculated value: 519.2, observed value: 520.2 [M+H] + , RT=0.517 min (method 2). 1 H NMR(400MHz,DMSO-d6) δ=8.60(d,J=2.1Hz,1H),8.49(d,J=7.9Hz,1H),8.27(s,1H),7.90(d,J=9.0Hz,1H),7.88-7.60(m,2H),7.50(br d,J=8.0Hz,1H),6.95(s,1H),6.33(s,1H),6.20(s,1H),4.11-3.83.

[0204] Example 23 Synthesis of Example 23 [ka] Synthesis of 5-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-methyl-1H-pyrrole-3-carboxamide To a solution of 5-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1H-pyrrole-3-carboxamide (50 mg, 1 equiv, 0.11 mmol) in DMF (2 mL) at 0° C. was added sodium hydride (5.1 mg, 60 wt%, 1.2 equiv, 0.13 mmol). After stirring for 30 min, iodomethane (23 mg, 9.9 μL, 1.5 equiv, 0.16 mmol) was added and the resulting mixture was stirred at room temperature for 18 h. The crude mixture was directly purified by preparative HPLC to give 5-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-methyl-1H-pyrrole-3-carboxamide (23.8 mg, 49.0 μmol, 46%). LCMS-ESI (m / z) calculated value: 485.33, observed value: 485.2 [M+H] + , RT=9.522 minutes (method 1). 1 H NMR(400MHz,DMSO-d6) δ 8.60(s,1H),7.89(d,J=8.9Hz,1H),7.73(d,J=9.2Hz,1H),7.66(d,J=8.1Hz,1H),7.48(d,J=7.9Hz,1H),7.36(s,1H),6.92(s,1H),6.54(s,1 H),3.99-3.80(m,2H),3.56(s,3H),2.12(d,J=12.1Hz,1H),1.95(d,J=12.4Hz,1H),1.87-1.76(m,2H),1.59-1.42(m,2H),1.39-1.23(m,2H).

[0205] Example 24 Synthesis of Example 24 [ka] Synthesis of 5-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(2,2-difluoroethyl)-1H-pyrrole-3-carboxamide To a solution of 5-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1H-pyrrole-3-carboxamide (88 mg, 1 equiv, 0.19 mmol) in DMF (2 mL) at 0° C. was added sodium hydride (9.0 mg, 60 wt%, 1.2 equiv, 0.22 mmol). After stirring for 30 min, 2,2-difluoroethyl trifluoromethanesulfonate (60 mg, 37 μL, 1.5 equiv, 0.28 mmol) was added and the resulting mixture was stirred at room temperature for 18 h. The crude mixture was directly purified by preparative HPLC to give 5-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(2,2-difluoroethyl)-1H-pyrrole-3-carboxamide (53.7 mg, 100 μmol, 54%). LCMS-ESI (m / z) calculated value: 535.34, observed value: 535.2 [M+H] + , RT=9.755 minutes (method 1). 1 H NMR(400MHz,DMSO-d6) δ 8.60(s,1H),7.89(d,J=9.1Hz,1H),7.75(dd,J=14.6,8.8Hz,2H),7.52-7.41(m,2H),6.92(s,1H),6.62(s,1H),6.31(t,J=54.6Hz,1H),4.45( t,J=15.6Hz,2H),4.02-3.81(m,2H),2.12(d,J=11.9Hz,1H),1.96(d,J =12.4Hz,1H),1.88-1.77(m,2H),1.60-1.43(m,2H),1.40-1.23(m,2H).

[0206] Example 25 Synthesis of Example 25 [ka] Synthesis of 3-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(methylsulfonyl)-1H-pyrazole-4-carboxamide To a suspension of 3-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide (100 mg, 1 eq, 212 μmol) in DCM (3 mL) was added triethylamine (85.7 mg, 118 μL, 4 eq, 847 μmol), followed by DMAP (5.17 mg, 0.2 eq, 42.3 μmol) and methanesulfonic anhydride (73.8 mg, 2 eq, 423 μmol). The resulting mixture was stirred at room temperature for 1 min and then heated at 50° C. for 1 h. The reaction mixture was cooled to room temperature and directly purified by preparative HPLC to give 3-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(methylsulfonyl)-1H-pyrazole-4-carboxamide (19.4 mg, 35.2 μmol, 17% yield). LCMS-ESI (m / z) calculated value: 550.38, observed value: 550.1 [M+H] + , RT=9.645 minutes (method 1). 1 H NMR(400MHz,DMSO-d6) δ 8.88(s,1H),8.59(s,1H),8.29(d,J=7.7Hz,1H),7.90(d,J=9.0Hz,1H),7.74(d,J=9.1Hz,1H),7.48(d,J=8.0Hz,1H),6.95 (s,1H),4.01-3.83(m,2H),3.68(s,3H),2.17(d,J=11.8Hz,1H),2.01-1.78(m,3H),1.60-1.34(m,3H),1.29-1.19(m,1H).

[0207] Example 26 Synthesis of Example 26 [ka] Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazole-4-carboxamide To a solution of 3-methyl-1H-pyrazole-4-carboxylic acid (33 mg, 263 umol, 1 equiv.) and (1S,3R)-N1-[6-chloro-2-(trifluoromethyl)-4-quinolyl]cyclohexane-1,3-diamine hydrochloride (100 mg, 263 umol, 1 equiv.) in DMF (4 mL), DIEA (102 mg, 789 umol, 137 uL, 3 equiv.) and HATU (120 mg, 316 umol, 1.2 equiv.) were added. After stirring at room temperature for 2 h, the solvent was removed in vacuo. To the crude residue was added water (20 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (3×20 mL), washed with water (3×25 mL), dried over sodium sulfate, filtered through Celite, and concentrated in vacuo to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-3-methyl-1H-pyrazole-4-carboxamide (109 mg, 241 umol), which was used without further purification.

[0208] To a solution of N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-methyl-1H-pyrazole-4-carboxamide (109 mg, 241 umol, 1 equiv.) in DMF (2 mL) was added 2,2-dimethyloxirane (61 mg, 844 umol, 74.97 uL, 3.5 equiv.) and K2CO3 (67 mg, 482 umol, 2 equiv.). The reaction mixture was heated at 100° C. for 12 hours, then the reaction mixture was cooled to room temperature and concentrated in vacuo to give a crude solid. The crude solid was purified by preparative HPLC [(FA): column: Phenomenex luna C18 150×25 mm 10 um; mobile phase: [water (0.225% FA)-ACN], B%: 38%-68%, 10 min] and lyophilized to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazole-4-carboxamide (2.5 mg, 4.6 umol, 2% yield). LCMS-ESI (m / z) calculated value: 523.2, observed value: 524.2 [M+H]+ , RT=0.461 min (Method 11). 1 H NMR(400MHZ,DMSO-D6) δ=8.60(D,J=2.0HZ,1H),8.10(S,1H),7.89(D,J=9.0HZ,1H),7.79-7.69(M,2H),7.48(BR D,J=7.9HZ,1H),6.92(S,1H),6.96-6.89(M,1H),4.00-3.79(M,1H),2.30(S,1H),2.32-2.24(M,1H),2.19-2.09(M,1H),1.96(BR D,J=11.6HZ,1H),1.91-1.74(M,2H),1.59-1.43(M,2H),1.39-1.19(M,2H),1.10-1.00(M,6H)

[0209] Example 27 Synthesis of Example 27 [ka] Synthesis of 3-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide To a stirred solution of 3-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide (50 mg, 1 eq, 0.11 mmol) was added tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (44 mg, 1.5 eq, 0.16 mmol) and cesium carbonate (86 mg, 2.5 eq, 0.26 mmol). The resulting suspension was heated and stirred at 90° C. for 18 h. The crude mixture was directly purified by preparative HPLC to give tert-butyl 4-(3-chloro-4-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (35.7 mg, 54.5 μmol, 51% yield). LCMS-ESI (m / z) calculated value: 654.21, observed value: 655.1 [M+H] + , RT=1.140 min (Method 11). 1 H NMR(400MHz,DMSO-d6) δ 8.60(s,1H),8.31(s,1H),7.89(d,J=8.2Hz,1H),7.81-7.70(m,2H),7.48(d,J=7.9Hz,1H),6.93(s,1H),4.39-4.28(m,1H),4. 10-3.81(m,4H),2.91(s,2H),2.19-2.11(m,1H),2.04-1.93(m,2H),1.93-1.74(m,4H),1.73-1.63(m,1H),1.55-1.22(m,13H).

[0210] To a stirred solution of tert-butyl 4-(3-chloro-4-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (32.2 mg, 1 eq, 49.1 μmol) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (123 μL, 10 eq, 491 μmol). The resulting suspension was heated at 50° C. for 18 h. The reaction mixture was cooled to room temperature, dissolved in MeOH, and purified directly by preparative HPLC to give 3-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide (8.9 mg, 16 μmol, 33%) as a solid. LCMS-ESI (m / z) calculated: 554.16, found 554.9 [M+H]+, RT = 6.170 min (Method 1). 1H NMR(400MHz,DMSO-d6) δ 8.60(d,J=2.3Hz,1H),8.31(s,1H),8.23(s,1H),7.89(d,J=9.0Hz,1H),7.84(d,J=7.8Hz, 1H),7.74(dd,J=9.0,2.2Hz,1H),7.49(d,J=8.0Hz,1H),6.93(s,1H),4.38-4.24(m,1H),3 .99-3.83(m,2H),3.27-3.15(m,3H),2.82-2.74(m,2H),2.16(d,J=11.9Hz,1H),2.09-2.0 1(m,2H),1.96(d,J=11.3Hz,1H),1.92-1.78(m,4H),1.59-1.42(m,2H),1.40-1.22(m,2H).

[0211] Example 28 Synthesis of Example 28 [ka] Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-3-cyano-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxamide To a solution of N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-5-cyano-1H-pyrazole-4-carboxamide (50 mg, 1 eq., 108 umol) in DMF (3 mL), K2CO3 (44.8 mg, 3 eq., 324 umol) and 2,2-difluoroethyl trifluoromethanesulfonate (30.0 mg, 1.3 eq., 140 umol) were added. The resulting mixture was heated at 60° C. for 1 h. The mixture was cooled to room temperature, filtered directly, and the filtrate was collected. The residue was purified by preparative HPLC to give -(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-cyano-1-(2,2-difluoroethyl)pyrazole-4-carboxamide (11 mg, 21 umol, 19% yield). LCMS-ESI (m / z) calculated value: 526.2, observed value: 527.3 [M+H] + , RT=0.594 min (Method 11). 1 H NMR (400MHz, methanol-d4) δ=8.37(d,J=2.3Hz,1H),8.32(s,1H),7.91(d,J=9.0Hz,1H),7.69(dd,J=2.3,9.0Hz,1H),6.91(s,1H),6.42-6.12(m,1H),4.72(dt,J =3.5,14.6Hz,2H),4.09-4.00(m,1H),3.87-3.77(m,1H),2.43-2.36(m,1H),2.17-1.92(m,3H),1.70-1.58(m,1H),1.55-1.36(m,3H).

[0212] Example 29 Synthesis of Example 29 [ka] Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-5-(difluoromethyl)-1-(fluoromethyl)-1H-pyrazole-4-carboxamide To a solution of N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-(difluoromethyl)-1H-pyrazole-4-carboxamide (100 mg, 189 umol, 92% purity, 1 equiv.) in MeCN (2 mL) was added fluoro(iodo)methane (33 mg, 207 umol, 1.1 equiv.) and K2CO3 (52 mg, 377 umol, 2 equiv.). The resulting mixture was heated at 50° C. for 2 h. The mixture was cooled to room temperature, filtered, and the crude product was purified by reverse phase HPLC: column (Phenomenex luna C18 150*25mm*10um) conditioned water ((0.225% FA)-ACN) to obtain N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-(difluoromethyl)-1-(fluoromethyl)pyrazole-4-carboxamide (yield 33%). LCMS-ESI (m / z) calculated value: 519.1, observed value: 520.1 [M+H] +, RT=0.517 min (Method 11). 1 H NMR(400MHz,DMSO-d6) δ=8.60(d,J=2.1Hz,1H),8.49(d,J=7.9Hz,1H),8.27(s,1H),7.90(d,J=9.0Hz,1H),7.88-7.60(m,2H),7.50(br d,J=8.0Hz,1H),6.95(s,1H),6.33(s,1H),6.20(s,1H),4.11-3.83(m,2H),2.18(br d,J=12.0Hz,1H),2.03-1.88(m,2H),1.84(br d,J=13.1Hz,1H),1.59-1.49(m,2H),1.44-1.27(m,2H).

[0213] The compounds listed in Table 5 were made using the procedures in Scheme 5. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] Scheme 6 [ka] Reagents: i. R2-mesylate or R2-triflate, base (K2CO3), ii. NaOH or LiOH aqueous solution / THF, iii. peptide coupling conditions (HATU), base (DIPEA), solvent (DMF), iv. R2 deprotection or further modification

[0214] Example 30 Synthesis of Example 30 [ka] Synthesis of 3-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide To a stirred solution of ethyl 3-chloro-1H-pyrazole-4-carboxylate (200 mg, 1 eq, 1.15 mmol) in DMF (5 mL) at room temperature was added cesium carbonate (1.12 g, 3 eq, 3.44 mmol) dropwise over 2 min. After stirring for 30 min, 2,2,2-trifluoroethyl trifluoromethanesulfonate (798 mg, 3 eq, 3.44 mmol) was added dropwise over 2 min. The reaction mixture was stirred for 14 h. Water (5 mL) was added and the mixture was extracted with EtOAc (3×5 mL), dried over sodium sulfate, filtered through Celite, and concentrated in vacuo to give an 87:13 mixture of ethyl 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate and ethyl 5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate, which was used without further purification.

[0215] To a stirred solution of a mixture of crude ethyl 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate and 5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate (294 mg, 1 eq, 1.15 mmol) in THF (6 mL) was added 1 M aqueous sodium hydroxide (5.7 mL, 5 eq, 5.73 mmol). The reaction mixture was heated at 50° C. for 14 h. 10 mL of 3 M HCl was added. The aqueous layer was extracted with EtOAc (3×10 mL), dried over sodium sulfate, filtered through Celite, and concentrated in vacuo to give a mixture of 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid and 5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (276 mg, 1.21 mmol, 105%), which was used without further purification.

[0216] To a stirred solution of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (100 mg, 1 equiv., 0.264 mmol) in DMF (1.5 mL) was added a mixture of 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid and 5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (60 mg, 1 equiv., 0.264 mmol), N-ethyl-N-isopropylpropan-2-amine (DIPEA) (0.138 mL, 3 equiv., 0.793 mmol), and HATU (111 mg, 1.1 equiv., 0.291 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude residue was analyzed by reverse phase HPLC (35 [ka] Purification by 55% MeCN with 0.1% formic acid and 0.1% formic acid in HO) gave 3-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (69 mg, 47% yield). LCMS-ESI (m / z) calculated value: 553.09, observed value: 553.8 [M+H] + , RT=10.114 minutes (method 1). 1 H NMR(400MHz,DMSO-d6) δ 8.60(d,J=10.9Hz,1H),8.35(s,1H),8.06(d,J=7.9Hz,1H),7.90(d,J=9.0Hz,1H),7.74(dd,J=9.0,2.3Hz,1H),7.48(d ,J=7.9Hz,1H),5.21(q,J=9.0Hz,1H),4.01-3.83(m,2H),2.17(d,J=12.0Hz,1H),2.00-1.78(m,3H),1.61-1.21(m,4H).

[0217] Example 31 Synthesis of Example 31 [ka] Synthesis of 3-chloro-N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-1-(2-hydroxy-2-methylpropyl)pyrazole-4-carboxamide To a solution of ethyl 3-chloro-1H-pyrazole-4-carboxylate (9.0 g, 52 mmol, 1 equiv.) and 2,2-dimethyloxirane (11.2 g, 155 mmol, 13.7 mL, 3 equiv.) in DMF (100 mL) was added K2CO3 (14.3 g, 103 mmol, 2 equiv.) and the resulting mixture was heated at 60° C. for 2 h. The reaction was cooled to room temperature, diluted with water, and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate in petroleum ether (25%) to give 3-chloro-1-(2-hydroxy-2-methyl-propyl)pyrazole-4-carboxylate (60% yield) as an oil. LCMS-ESI (m / z) calculated value: 246.1, observed value 247 [M+H] +, RT=0.478 min (Method 14). 1 H NMR(400MHz,DMSO-d6) δ=8.22(s,1H),4.77(s,1H),4.22(q,J=7.1Hz,2H),4.01(s,2H),1.27(t,J=7.1Hz,3H),1.07(s,6H).

[0218] To a solution of ethyl 3-chloro-1-(2-hydroxy-2-methyl-propyl)pyrazole-4-carboxylate (6.6 g, 27 mmol, 1 equiv.) in MeOH (25 mL) and H2O (25 mL), LiOH.H2O (3.37 g, 80.3 mmol, 3 equiv.) was added and the resulting mixture was stirred at 25 °C for 1.5 h. The pH of the reaction mixture was adjusted to pH 5-6 using 1 M HCl. The mixture was concentrated in vacuo to give a crude residue. The residue was purified by reverse phase flash (conditions 0.1% FA in H2O / CH3CN, 0%). The crude product was obtained by lyophilization. The crude product was diluted with 20 mL of H2O and adjusted to pH 1-2 with 6 mL of HCl. The reaction solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-chloro-1-(2-hydroxy-2-methyl-propyl)pyrazole-4-carboxylic acid (74% yield). LCMS (m / z) calculated value: 218.1, found value: 201.2 [M18+H]+, t R =0.272 minutes (method 14). 1 H NMR(400MHz,DMSOd6) δ=12.62(s,1H),8.16(s,1H),4.77(s,1H),4.00(s,2H),1.07(s,6H)

[0219] To a solution of 3-chloro-1-(2-hydroxy-2-methyl-propyl)pyrazole-4-carboxylic acid (3.7 g, 16.92 mmol, 1 equiv.) in DCM (40 mL) was added TEA (5.14 g, 50.8 mmol, 7.07 mL, 3 equiv.), HOBt (2.29 g, 16.9 mmol, 1 equiv.), EDCI (3.89 g, 20.3 mmol, 1.2 equiv.) and (1S,3R)-N1-[6-chloro-2-(trifluoromethyl)-4-quinolyl]cyclohexane-1,3-diamine (5.53 g, 16.08 mmol, 0.95 equiv.). The reaction was stirred at 25° C. for 12 h. The reaction solution was diluted with water (200 mL) and then extracted with DCM (2×200 mL). The combined organic layers were washed with brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. The residue was triturated with CH3CN (40 mL). The mixture was filtered, and the filter cake was collected and concentrated in vacuo to give a crude residue. The crude residue was purified by reverse-phase flash column chromatography ([water (NH4HCO3)-ACN], B%: 38%-68%) to give 3-chloro-N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-1-(2-hydroxy-2-methylpropyl)pyrazole-4-carboxamide as a solid. LCMS (m / z) calculated: 543.1; found: 544.2 [M+H] + , t R =0.529 minutes (method 14). 1 H NMR(400MHz,DMSO-d6) δ=8.59(s,1H),8.19(s,1H),7.91-7.84(m,2H),7.72(br d,J=8.5Hz,1H),7.48(br d,J=7.9Hz,1H),6.93(s,1H),4.80(s,1H),3.96(s,2H),3.95-3.79(m,2H),2.16(br d,J=11.1Hz,1H),2.07(s,1H),2.00-1.77(m,3H),1.58-1.44(m,2H),1.40-1.22(m,2H),1.07(s,6H).

[0220] Example 32 Synthesis of Example 32 [ka] Synthesis of N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-cyano-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide To a solution of ethyl 1H-pyrazole-4-carboxylate (10 g, 71.36 mmol, 1 equiv) in THF (50 mL) was added NaH (3.42 g, 85.6 mmol, 60% purity, 1.2 equiv) and stirred at 0° C. for 1 h under N2. SEM-Cl (14.3 g, 85.6 mmol, 15.2 mL, 1.2 equiv) was added and the mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3×25 mL). The combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude material. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 80 / 20) to give ethyl 1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (15.8 g, 58.4 mmol, 82% yield) as an oil.

[0221] To a solution of ethyl 1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (15.5 g, 57.3 mmol, 1 equiv) in THF (200 mL) was added LDA (2 M, 43.0 mL, 1.5 equiv) dropwise over 10 min at -70 °C. After stirring for 30 min, DMF (25.1 g, 344 mmol, 26.5 mL, 6 equiv) was added. The resulting mixture was stirred at -70 °C for an additional 20 min. The reaction was quenched with saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 85 / 15) to give ethyl 5-formyl-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (6.1 g, 20.4 mmol, 36% yield) as an oil.

[0222] To a solution of ethyl 5-formyl-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (6.0 g, 20.1 mmol, 1 equiv.) in EtOH (20 mL) was added NaOAc (4.95 g, 60.3 mmol, 3 equiv.) and NH s OH.HCl (1.68 g, 24.1 mmol, 1.2 equiv.) was added. After stirring at 70° C. for 3 h, the reaction mixture was cooled to room temperature and partitioned between EtOAc (50 mL) and water (50 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organics were dried over MgSO4 and concentrated in vacuo to give ethyl 5-(hydroxyiminomethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (8.1 g, crude) as a solid, which was used without further purification.

[0223] Ethyl 5-(hydroxyiminomethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (7.5 g, 23.9 mmol, 1 equiv.) was dissolved in Ac2O (20 mL) and heated at 145° C. for 12 h. TLC indicated 70% of the starting material remained. To the reaction mixture, additional Ac2O (20 mL) was added and the mixture was heated at 145° C. for an additional 12 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (25 mL) and water (25 mL). The aqueous phase was extracted with EtOAc (2×10 mL). The combined organics were dried over MgSO4 and concentrated in vacuo to give ethyl 5-cyano-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate.

[0224] To a solution of ethyl 5-cyano-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (350 mg, 1.18 mmol, 1 equiv.) in MeOH (2 mL) and HO (2 mL) was added LiOH.HO (149 mg, 3.55 mmol, 3 equiv.). After stirring at 25° C. for 1 h, the reaction mixture was concentrated in vacuo to give 5-cyano-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylic acid (300 mg, 1.12 mmol, 95% yield) as a solid.

[0225] To a solution of 5-cyano-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylic acid (300 mg, 1.12 mmol, 1 equiv.) (1S,3R)-N1-[6-chloro-2-(trifluoromethyl)-4-quinolyl]cyclohexane-1,3-diamine (427 mg, 1.12 mmol, 1 equiv., HCl) in DMF (6 mL) was added DIPEA (435 mg, 3.37 mmol, 586 uL, 3 equiv.) and HATU (640 mg, 1.68 mmol, 1.5 equiv.). The resulting mixture was stirred at 25° C. for 12 h. The mixture was partitioned between EtOAc (25 mL) and water (25 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organics were dried over MgSO4 and concentrated in vacuo to give a crude residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 63 / 37) to give N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-5-cyano-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxamide (500 mg, 843 umol, yield 75%) as a solid.

[0226] N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-5-cyano-1-(2-trimethylsilylethoxymethyl)pyrazole 4-carboxamide (500 mg, 843 umol, 1 equiv) was dissolved in TBAF (1.0 M, 10 mL, 11.9 equiv) in THF and heated at 50° C. for 2 h. The mixture was filtered and the residue was purified by preparative TLC (SiO2, PE:EtOAc=1:1, TLC, PE:EtOAc=1:1, Rf=0) and concentrated in vacuo to give N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-5-cyano-1H-pyrazole-4-carboxamide (170 mg, 367 umol, 44% yield) as a solid.

[0227] To a solution of N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-cyano-1H-pyrazole-4-carboxamide (100 mg, 216 umol, 1 eq.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (100 mg, 432 umol, 2 eq.) in MeCN (3 mL) was added Cs2CO3 (211 mg, 648 umol, 3 eq.). The reaction mixture was heated at 60° C. for 12 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a residue. The crude product was purified by reverse phase HPLC: column (Phenomenex luna C18 150*25mm*10um) conditioned water ((0.225% FA)-ACN) start B(50) end B(80) gradient time (min) (10) to give N-[(1R,3S)-3-[[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-cyano-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide (19.5mg, 35.8umol, yield 16%, purity 100%). C 23 H 19 LCMS (m / z) calculated for ClF6N6O: 544.1; found 545.1 [M+H] + , t R =0.602 minutes (method 11). 1 H NMR(400MHz,DMSO-d6) δ=8.60-8.56(m,2H),8.46(d,J=7.6Hz,1H),7.90(d,J=9.0Hz,1H),7.74(dd,J=2.3,9.0Hz, 1H),7.47(d,J=8.0Hz,1H),6.95(s,1H),5.43(q,J=9.1Hz,2H),4.02-3.85(m,2H),2.18(br d,J=11.6Hz,1H),2.00-1.89(m,2H),1.87-1.78(m,1H),1.57-1.22(m,4H).

[0228] Example 33 Synthesis of Example 33 [ka] N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-cyano-1-(2-hydroxy-2-methylpropyl)pyrazole-4-carboxamide To a solution of N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-5-cyano-1H-pyrazole-4-carboxamide (45 mg, 97 umol, 1 eq.) and 2,2-dimethyloxirane (10.5 mg, 146 umol, 13 uL, 1.5 eq.) in DMF (2 mL) was added K2CO3 (27 mg, 194.45 umol, 2 eq.). The mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC: column (Welch Xtimate C18 150*25mm*5um) conditioned water ((0.05% HCl)-ACN) to give N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-cyano-1-(2-hydroxy-2-methylpropyl)pyrazole-4-carboxamide (30% yield) as a solid. LCMS-ESI (m / z) calculated value: 534.2, observed value: 535.2 [M+H] + , RT=0.582 min (method 14). 1 H NMR(400MHz,DMSO-d6) δ=8.49(s,1H),8.04-7.95(m,1H),7.71(d,J=8.5Hz,1H),7.17-7.09(m,2H), 6.91-6.84(m,1H),3.92-3.76(m,1H),3.65-3.51(m,1H),1.77-1.64(m,8H).

[0229] Example 34 Synthesis of Example 34 [ka] N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-3-cyano-1-(2-fluoro-2-methylpropyl)-1H-pyrazole-4-carboxamide To a solution of N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-cyano-1-(2-hydroxy-2-methylpropyl)pyrazole-4-carboxamide (140 mg, 1 equiv, 262 umol) in DCM (2 mL) was added DAST (127 mg, 1 equiv, 785 umol, 104 uL). The reaction mixture was stirred at 25° C. for 1 h. The solvent was filtered and the filtrate was collected. The crude product was purified by preparative HPLC to give N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-cyano-1-(2-fluoro-2-methylpropyl)pyrazole-4-carboxamide (23 mg, 42 umol, 15% yield) as a solid. LCMS-ESI (m / z) calculated value: 536.95, observed value: 537.3 [M+H] + , RT=0.479 min (method 11). 1 H NMR (400MHz, methanol-d4) δ=8.37(d,J=2.1Hz,1H),8.27(d,J=1.3Hz,1H),7.91(d,J=9.0Hz,1H),7.69(dd,J=2.3,9 .0Hz,1H),6.91(s,1H),4.52-4.34(m,2H),4.10-3.99(m,1H),3.86-3.76(m,1H),2.39(br d,J=12.0Hz,1H),2.16-1.93(m,3H),1.71-1.38(m,4H),1.37-1.28(m,6H).

[0230] Example 35 Synthesis of Example 35 [ka] Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide To a stirred suspension of tert-butyl 4-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-1H-pyrazole-1-carboxylate (1.014 g, 1 equiv, 1.885 mmol) in 1,4-dioxane (15 mL) was added HCl in 1,4-dioxane (687.2 mg, 4.712 mL, 4.00 mol, 10 equiv, 18.85 mmol). The resulting mixture was heated at 50° C. for 2 h and then concentrated under reduced pressure to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide hydrochloride (1128 mg, 2.378 mmol, 126%) as a solid. The product was used in the next step without further purification. LCMS-ESI (m / z) calculated value: 437.12, observed value: 438.0 [M+H] + , RT=0.825 min (Method 11).

[0231] To a stirred solution of 1-(tert-butoxycarbonyl)-1H-pyrazole-4-carboxylic acid (960 mg, 1 eq, 4.52 mmol) and DIPEA (2.34 g, 3.2 mL, 4 eq, 18.1 mmol) in DMF (10 mL) was added HATU (1.72 g, 1 eq, 4.52 mmol). After stirring at room temperature for 10 min, (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (1.72 g, 1 eq, 4.52 mmol) was added in one portion. The resulting mixture (brown solution) was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc and washed with H2O. The organic layer was collected and the aqueous layer was back-extracted twice with EtOAc. The organic layers were combined, washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL) and purified by reverse-phase flash column chromatography to give tert-butyl 4-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-1H-pyrazole-1-carboxylate (1.042 g, 1.937 mmol, 43%) as a solid. LCMS-ESI (m / z) calculated value: 537.17, observed value: 538.0 [M+H] + , RT=5.264 minutes (Method 10).

[0232] To a stirred solution of 1-bromo-2-fluoro-2-methylpropane (64 mg, 3 eq, 0.41 mmol) in DMF (2 mL) was then added N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide hydrochloride (60 mg, 1 eq, 0.14 mmol) and potassium carbonate (28 mg, 1.5 eq, 0.21 mmol). The resulting white suspension was heated and stirred at 80° C. for 2 days. The reaction mixture was cooled to room temperature and directly purified by preparative HPLC to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(2-fluoro-2-methylpropyl)-1H-pyrazole-4-carboxamide (12 mg, 23 μmol, 17%) as a solid. LCMS-ESI (m / z) calculated value: 511.18, observed value: 512.3 [M+H] + , RT=8.865 minutes (method 1). 1 H NMR(400MHz,DMSO-d6) δ 8.59(s,1H),8.13(s,1H),7.97(d,J=8.0Hz,1H),7.92-7.85(m,2H),7.76-7. 71(m,1H),7.48(d,J=7.9Hz,1H),6.93(s,1H),4.33(d,J=19.9Hz,2H),4.03-3 .94(m,1H),3.91-3.83(m,1H),2.15(d,J=11.9Hz,1H),2.00-1.93(m,1H),1.9 0-1.78(m,2H),1.60-1.44(m,2H),1.42-1.34(m,1H),1.27(d,J=21.5Hz,7H).

[0233] Example 36 Synthesis of Example 36 [ka] Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide To a stirred solution of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (40 mg, 1 eq, 0.11 mmol) in DMF (2 mL) was added 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazole-4-carboxylic acid (31 mg, 1 eq, 0.11 mmol), HATU (40 mg, 1 eq, 0.11 mmol) and DIPEA (54 mg, 73 μL, 4 eq, 0.42 mmol). The resulting mixture was stirred at room temperature for 20 h. The reaction mixture was directly purified by preparative HPLC to give tert-butyl 4-(4-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (36.6 mg, 58.9 μmol, 56%) as a solid. LCMS-ESI (m / z) calculated value: 620.25, found value: 621.3 [M+H] + , RT=9.935 minutes (method 1). 1 H NMR(400MHz,DMSO-d6) δ 8.59(s,1H),8.23(s,1H),7.94-7.82(m,3H),7.74(d,J=8.5Hz,1H),7.48(d ,J=7.9Hz,1H),6.93(s,1H),4.36(t,J=11.8Hz,1H),4.00(s,3H),3.87(d,J =9.5Hz,1H),2.90(s,2H),2.15(d,J=11.9Hz,1H),2.00(d,J=12.9Hz,3H),1 .89-1.69(m,4H),1.60-1.44(m,2H),1.44-1.34(m,10H),1.29-1.22(m,1H).

[0234] To a stirred solution of tert-butyl 4-(4-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (30.4 mg, 1 eq, 48.9 μmol) in 1,4-dioxane (1.5 mL) was added 4M HCl in 1,4-dioxane (122 μL, 10 eq, 489 μmol). The resulting cloudy suspension was stirred at 50° C. for 2 h. The reaction mixture was then purified by preparative HPLC to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide (11.7 mg, 22.5 μmol, 46%) as a solid. LCMS-ESI (m / z) calculated value: 520.20, observed value: 521.2 [M+H] + , RT=5.861 minutes (method 1). 1 H NMR(400MHz,DMSO-d6) δ 8.59(s,1H),8.20(s,1H),7.95-7.80(m,3H),7.74(d,J=9.0Hz,1H),7.48(d,J= 7.9Hz,1H),6.93(s,1H),4.25(t,J=11.9Hz,1H),4.02-3.94(m,1H),3.91-3.82( m,1H),3.10(d,J=12.5Hz,2H),2.68(t,J=12.2Hz,2H),2.15(d,J=11.9Hz,1H),1 .99(d,J=12.6Hz,3H),1.90-1.76(m,4H),1.57-1.35(m,3H),1.29-1.22(m,1H).

[0235] Example 37 Synthesis of Example 37 [ka] Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(2-fluoroethyl)-1H-pyrrole-3-carboxamide To a stirred solution of methyl 1H-pyrrole-3-carboxylate (250 mg, 1 equiv, 2.00 mmol) in DMF (4 mL) at 0° C. was added sodium hydride (95.9 mg, 60 wt%, 1.2 equiv, 2.40 mmol). The reaction mixture was stirred for 10 min. 1-Bromo-2-fluoroethane (380 mg, 1.5 equiv, 3.00 mmol) was added and the reaction mixture was allowed to warm to room temperature. After stirring overnight at room temperature, H2O (5 mL) was added. The aqueous layer was extracted with EtOAc (3×5 mL), washed with H2O (3×5 mL), dried over sodium sulfate, filtered through Celite, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography (0→50% EtOAc and hexanes) to afford methyl 1-(2-fluoroethyl)-1H-pyrrole-3-carboxylate (205.3 mg, 1.199 mmol, 60.0% yield). LCMS-ESI (m / z) calculated value: 171.07, found value: 172.0 [M+H] + , RT=0.660 min (method 11).

[0236] To a stirred solution of methyl 1-(2-fluoroethyl)-1H-pyrrole-3-carboxylate (205 mg, 1 equiv, 1.19 mmol) in THF (6 mL) was added sodium hydroxide (240 mg, 5.99 mL, 1 mole, 5 equiv, 5.99 mmol). The reaction mixture was heated at 50° C. for 12 h. Additional sodium hydroxide (240 mg, 5.99 mL, 1 mole, 5 equiv, 5.99 mmol) was added and heated at 70° C. overnight. The reaction mixture was cooled to room temperature, 3 M HCl was added (10 mL), extracted with EtOAc (3×10 mL), dried over sodium sulfate, filtered through Celite, and concentrated in vacuo to give 1-(2-fluoroethyl)-1H-pyrrole-3-carboxylic acid (169 mg, 1.08 mmol, 90% yield). LCMS-ESI (m / z) calculated value: 157.05, observed value: 158.0 [M+H] + , RT=0.487 min (Method 11).

[0237] Using Scheme 4, N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(2-fluoroethyl)-1H-pyrrole-3-carboxamide was synthesized starting from 1-(2-fluoroethyl)-1H-pyrrole-3-carboxylic acid and (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride. LCMS-ESI (m / z) calculated value: 482.15, observed value: 483.2 [M+H] + , RT=9.764 minutes (method 1). 1 H NMR(400MHz,DMSO) δ 8.61(s,1H),7.93-7.88(m,1H),7.77-7.14(m,1H),7.64-7.59(m,1H),7.52-7.47(m,1 H),7.35(s,1H),6.93(s,1H),6.79-6.75(m,1H),6.51-6.47(m,1H),4.75-4.69(m,1H) ,4.62-4.58(m,1H),4.28-4.21(m,1H),4.20-4.14(m,1H),4.04-3.93(m,1H),3.91-3. 79(m,1H),2.17-2.09(m,1H),2.01-1.91(m,1H),1.90-1.78(m,2H),1.58-1.23(m,5H).

[0238] Examples 38 and 39 Synthesis of Examples 38 and 39 [ka] Synthesis of 3-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxamide and 5-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxamide To a stirred solution of ethyl 3-chloro-1H-pyrazole-4-carboxylate (200 mg, 1 equiv, 1.15 mmol) in MeCN (15 mL) was added cesium carbonate (1.49 g, 4 equiv, 4.58 mmol) and 2-bromo-1,1-difluoroethane (498 mg, 3 equiv, 3.44 mmol). The vial was capped and heated at 60° C. overnight and concentrated in vacuo. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with EtOAc (2×20 mL), dried over sodium sulfate, filtered through Celite, and concentrated in vacuo to give a mixture of ethyl 3-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylate and ethyl 5-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylate (335.3 mg, 1.405 mmol, 123%), which was used without further purification.

[0239] To a stirred solution of crude ethyl 3-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylate and ethyl 5-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylate (273 mg, 1 eq, 1.14 mmol) in THF (8 mL) was added sodium hydroxide (229 mg, 5.72 mL, 1 mol, 5 eq, 5.72 mmol). The reaction mixture was heated at 50° C. for 4 h. The reaction mixture was concentrated in vacuo, 3M HCl was added (10 mL), and the mixture was extracted with EtOAc (3×10 mL), dried over sodium sulfate, filtered through Celite, and concentrated in vacuo to give 3-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylic acid and 5-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylic acid (289 mg, 1.37 mmol, 120%) as a crude mixture which was used without further purification.

[0240] To a stirred solution of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (100 mg, 1 eq, 264 μmol) in DMF (1.5 mL) was added crude 3 / 5-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylic acid (55.7 mg, 1 eq, 264 μmol), N-ethyl-N-isopropylpropan-2-amine (DIPEA) (103 mg, 138 μL, 3 eq, 793 μmol) and HATU (111 mg, 1.1 eq, 291 μmol). The reaction mixture was stirred at room temperature for 2 h. The crude mixture was purified by reverse-phase HPLC (35-55% 0.1% formic acid in MeCN and 0.1% formic acid in HO) to give 3-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxamide (70 mg, 131 μmol, 50%) and 5-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxamide (26 mg, 48 μmol, 18%).

[0241] Example 38: LCMS-ESI (m / z) calculated: 535.1, found: 536.1 [M+H] + , RT=9.368 minutes (method 1).

[0242] Example 39: LCMS-ESI (m / z) calculated: 535.1, found: 536.1 [M+H] + , RT=9.622 minutes (method 1).

[0243] Example 40 Synthesis of Example 40 [ka] Synthesis of tert-butyl (R)-3-(4-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate To a solution of (S)-tert-butyl 3-bromopyrrolidine-1-carboxylate (500 mg, 1.2 eq, 2.00 mmol) in DMF (5 mL) was charged ethyl 4-pyrazolecarboxylate (233 mg, 1 eq, 1.67 mmol) and cesium carbonate (1.36 g, 2.5 eq, 4.16 mmol). The resulting suspension was heated and stirred at 90° C. After stirring for 19 h, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with cold water and extracted with EtOAc (3×100 mL). The organic phases were combined, washed with brine and concentrated under reduced pressure to give the expected product. The crude product was used without further purification or characterization.

[0244] To a solution of ethyl (R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxylate (515 mg, 1 equiv, 1.66 mmol) in THF (20 mL) was added 1 M sodium hydroxide (666 mg, 16.6 mL, 1.00 mol, 10 equiv, 16.6 mmol). The resulting solution was heated and stirred at 50° C. overnight. The reaction mixture was stirred at 50° C. for 18 h. The aqueous residue was acidified to pH 3-4 using 3 N HCl. The mixture was extracted with EtOAc (3×30 mL) and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give (R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxylic acid (351 mg, 1.25 mmol, 75%).

[0245] To a solution of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (40 mg, 1 eq, 0.11 mmol) in DMF (2 mL) was added HATU (40 mg, 1 eq, 0.11 mmol), (R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxylic acid (30 mg, 1 eq, 0.11 mmol), and DIPEA (73 μL, 4 eq, 0.42 mmol). The resulting solution was stirred at room temperature for 18 h. The crude material was directly purified by preparative HPLC to give tert-butyl (R)-3-(4-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (13.5 mg, 22.2 μmol, 21%). LCMS-ESI (m / z) calculated value: 606.23, found value: 607.3 [M+H] + , RT=9.718 minutes (method 1). 1 H NMR(400MHz,DMSO-d6) δ 8.59(s,1H),8.23(s,1H),7.96-7.83(m,3H),7.74(d,J=9.0Hz,1H),7.48(d,J=7.9H z,1H),6.93(s,1H),5.00-4.92(m,1H),4.02-3.83(m,2H),3.74-3.67(m,1H),3.52( d,J=11.3Hz,1H),3.46-3.35(m,2H),2.29(d,J=25.7Hz,2H),2.15(d,J=11.8Hz,1H) ,1.96(d,J=12.3Hz,1H),1.90-1.78(m,2H),1.59-1.44(m,2H),1.42-1.24(m,11H).

[0246] Example 41 Synthesis of Example 41 [ka] Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-((R)-pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide To a solution of tert-butyl (R)-3-(4-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (9.2 mg, 1 eq, 15 μmol) in 1,4-dioxane (1.5 mL) was added hydrogen chloride in 1,4-dioxane (5.5 mg, 38 μL, 4.00 mol, 10 eq, 0.15 mmol). The resulting mixture was heated at 50° C. for 2 h. The reaction mixture was diluted in MeOH and purified directly by preparative HPLC to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-((R)-pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide (2.2 mg, 4.3 μmol, 29% yield). LCMS-ESI (m / z) calculated value: 506.18, observed value: 507.2 [M+H] + , RT=5.834 minutes (method 1).

[0247] Example 42 Synthesis of Example 42 [ka] Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-5-(difluoromethyl)-1-ethyl-1H-pyrazole-4-carboxamide To a solution of ethyl 5-(difluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (200 mg, 624 umol, 1 equiv.) in THF (1.5 mL) and HO (1.5 mL) was added LiOH.HO (79 mg, 1.9 mmol, 3 equiv.) and heated at 50° C. for 2 h. The reaction mixture was cooled to room temperature and neutralized to pH 7 with 5% HCl. The reaction mixture was concentrated in vacuo to give 5-(difluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylic acid (180 mg, 617 umol, 99% yield) as a solid, which was used without further purification.

[0248] To a solution of 5-(difluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylic acid (175 mg, 599 umol, 1 eq.) and (1S,3R)-N1-[6-chloro-2-(trifluoromethyl)-4-quinolyl]cyclohexane-1,3-diamine (206 mg, 599 umol, 1 eq.) in DMF (4 mL) was added HATU (341 mg, 898 umol, 1.5 eq.) and DIEA (232 mg, 1.80 mmol, 313 uL, 3 eq.). The mixture was stirred for 12 h at 25° C. The mixture was partitioned between EtOAc (15 mL) and water (15 mL). The aqueous phase was back-extracted with EtOAc (2×10 mL). The combined organic phase was dried over MgSO4 and concentrated in vacuo to give the crude material. The crude residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0-0 / 1) to give N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-5-(difluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxamide (280 mg, 453 umol, 76% yield) as an oil.

[0249] To a solution of N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-5-(difluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxamide (280 mg, 453 umol, 1 eq) in DCM (3 mL) was added TFA (924 mg, 8.10 mmol, 600 uL, 17.9 eq). The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. MeOH (3 mL) and K2CO3 (313 mg, 2.26 mmol, 5 eq) were added and heated at 50° C. for 1 h. The mixture was cooled to room temperature and partitioned between EtOAc (10 mL) and water (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL). The combined organics were dried over MgSO4 and concentrated in vacuo to give N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-(difluoromethyl)-1H-pyrazole-4-carboxamide (210 mg, 396 umol, 87% yield, 92% purity) as an oil which was used without further purification.

[0250] To a solution of N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-3-(difluoromethyl)-1H-pyrazole-4-carboxamide (60 mg, 113 umol, 92% purity, 1 eq.) and iodoethane (53 mg, 340 umol, 27 uL, 3 eq.) in MeCN (1.5 mL), K2CO3 (47 mg, 340 umol, 3 eq.) was added and the mixture was heated at 50° C. for 14 hours. The mixture was cooled to room temperature and filtered to remove insoluble material. The crude product was purified by reverse phase HPLC: column (Phenomenex luna C18 150*25mm*10um) conditioned water ((0.225% FA)-ACN) start B(46) end B(76) gradient time (min) (10.5) to give N-[(1R,3S)-3-[[[6-chloro-2-(trifluoromethyl)-4-quinolyl]amino]cyclohexyl]-5-(difluoromethyl)-1-ethyl-pyrazole-4-carboxamide (9.3mg, 17.4umol, 15% yield, 97% purity) as a solid. LCMS-ESI (m / z) calculated value: 515.1, observed value: 516.1 [M+H] + , RT=0.625 min (Method 14). 1 H NMR(400MHz,DMSO-d6) δ=8.59(d,J=2.0Hz,1H),8.30-8.30(m,1H),8.29(d,J=8.0Hz,1H),8.09(s,1H),7.89(d,J=9.0Hz,1H),7.87-7.58(m,2H),7.48(br d,J=8.0Hz,1H),6.93(s,1H),4.29(q,J=7.1Hz,2H),4.06-3.81(m,2H),2.15(br d,J=12.1Hz,1H),1.97(br d,J=11.3Hz,1H),1.92-1.78(m,2H),1.59-1.46(m,2H),1.37(t,J=7.2Hz,3H),1.34-1.20(m,2H).

[0251] The compounds listed in Table 6 were made using the procedures in Scheme 6. [Table 7] Scheme 7 [ka] Reagents: X is independently C or N. Step 6-1 Base (DIPEA), Solvent (DMF); Step 6-2 NaOH aqueous solution / THF; Step 5-3 Peptide coupling conditions (HATU), Base (DIPEA), Solvent (DMF)

[0252] Example 43 Synthesis of Example 43 [ka] Synthesis of 6-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-one To a stirred solution of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (50 mg, 1 equiv, 0.13 mmol) in DMF (1.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (DIPEA) (85 mg, 0.12 mL, 5 equiv, 0.66 mmol) and methyl 3-(bromomethyl)picolinate (46 mg, 1.5 equiv, 0.20 mmol). The vial was capped and heated at 40° C. overnight. The crude product was purified by reverse-phase HPLC (35→55% 0.1% formic acid in HO and 0.1% formic acid in MeCN) to give 6-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (37.1 mg, 80.5 μmol, 61% yield). LCMS-ESI (m / z) calculated value: 460.13, found value: 461.2 [M+H] + , RT=8.116 minutes (method 1). 1 H NMR(400MHz,DMSO) δ 8.72(s,1H),8.61(s,1H),8.07(d,J=7.9Hz,1H),7.91(d,J=8.7Hz,1H),7.75(d,J=9.6Hz,1H),7.60-7.51(m,2H),7.00(s,1H),4.52(app q,J=13.0Hz,2H),4.43-4.29(m,1H),4.09-3.98(m,1H),2.20-2.12(m,1H), 2.04-1.98(m,1H),1.94-1.76(m,3H),1.69-1.56(m,2H),1.52-1.40(m,1H). Scheme 8 [ka] Reagents: R2R3NH, di(1H-imidazol-1-yl)methanone or triphosgene, base (TEA), solvent (DCM)

[0253] Example 44 Synthesis of Example 44 [ka] Step 7. N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-4-isobutyrylpiperazine-1-carboxamide To a stirred solution of di(1H-imidazol-1-yl)methanone (2.14 g, 5 eq, 13.2 mmol) and triethylamine (348 mg, 479 μL, 1.3 eq, 3.44 mmol) in DCM (20 mL) at 0° C., (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (1.00 g, 1 eq, 2.64 mmol) was added in two portions 10 min apart. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 30 min. The reaction mixture was concentrated in vacuo to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1H-imidazole-1-carboxamide, which was dried under high vacuum and used without further purification.

[0254] To a stirred solution of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1H-imidazole-1-carboxamide (100 mg, 50 wt%, 1 equiv, 114 μmol) in DCM (1.5 mL) was added 2-methyl-1-(piperazin-1-yl)propan-1-one (89.2 mg, 5 equiv, 571 μmol) and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (73.8 mg, 99.5 μL, 5 equiv, 571 μmol). The reaction mixture was stirred at room temperature overnight. The crude mixture was purified by reverse-phase preparative HPLC to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-4-isobutyrylpiperazine-1-carboxamide (29.1 mg, 55.3 μmol). LCMS-ESI (m / z) calculated value: 526, observed value: 526.3 [M+H] + , RT=8.141 minutes (method 1).

[0255] Example 45 Synthesis of Example 45 [ka] Step 5. Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-3-fluoro-3-methylazetidine-1-carboxamide To a stirred solution of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-3-hydroxy-3-methylazetidine-1-carboxamide (40 mg, 1.0 equiv, 0.088 mmol) in DCM (0.5 mL) at room temperature was added a solution of Deoxo-Fluor (29 mg, 1.5 equiv, 0.13 mmol). The reaction mixture was stirred at room temperature for 5 min. Saturated ammonium chloride solution (2 mL) was added dropwise. The aqueous layer was extracted with EtOAc / MeOH (5:1) (2×5 mL), dried over sodium sulfate, filtered through Celite, and concentrated in vacuo. The crude mixture was purified by preparative HPLC to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-3-fluoro-3-methylazetidine-1-carboxamide (23.5 mg, 51.2 μmol, 58%). LCMS-ESI (m / z) calculated: 458.15, found 459.2 [M+H]+, RT = 8.638 min (Method 1).

[0256] Example 46 Synthesis of Example 46 [ka] Synthesis of N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-2-methyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide To an ice-cold solution of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine 60 mg, 1 equiv., 0.16 mmol) and DIPEA (0.10 g, 0.14 mL, 5 equiv., 0.79 mmol) in MeCN (2 mL) was added triphosgene 47 mg, 1 equiv., 0.16 mmol) in one portion. The resulting mixture was stirred at 0° C. for 10 min. Then, 4,5,6,7-tetrahydro-2-methylthiazolo[5,4-c]pyridine (61 mg, 2.5 equiv., 0.39 mmol) was added to the mixture followed by DIPEA (50 mg, 70 μL, 2.5 equiv.). The reaction mixture was stirred at 50° C. for 18 h. The crude mixture was directly purified by preparative HPLC to give N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-2-methyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide (52.6 mg, 100 μmol, 64% yield). LCMS-ESI (m / z) calculated: 524.00, found 524.2 [M+H]+, RT = 8.534 min (Method 1). 1 H NMR(400MHz,DMSO-d6) δ 8.60(s,1H),7.89(d,J=9.1Hz,1H),7.73(d,J=9.1Hz,1H),7.45(d,J=7.8Hz,1H),6.88(s,1H),6.51(d,J=7.6Hz,1H),4.51(s,2H),3.82-3.60( m,4H),2.67(s,2H),2.58(s,3H),2.11(d,J=11.7Hz,1H),1.94(d,J=12. 2Hz,1H),1.79(t,J=15.3Hz,2H),1.53-1.37(m,2H),1.35-1.19(m,2H).

[0257] The compounds listed in Table 8 were made using the procedures in Scheme 8. [Table 8-1] [Table 8-2] [Table 8-3]

[0258] Example 47 MRGPRX2 activity CHO cells stably transfected to express human MRGPRX2 were maintained in a 37°C incubator with 5% CO2 and grown in F12 (HAM) medium with 10% fetal bovine serum (FBS), 1% Glutamax, 1% penicillin / streptomycin, 800 μg / mL Geneticin (G418), and 300 μg / mL Hygromycin B.

[0259] Cells were plated in 384-well assay plates at 20,000 cells per well in 12 μL of Opti-MEM and kept in the incubator overnight. On the day of the assay, compounds solubilized at 10 mM in DMSO were added as a 10-point curve (1:3 serial dilutions to a final top concentration of 30 uM) using a Tecan D300E digital dispenser. Agonists were diluted in assay buffer (final concentration 5.7 mM Tris-HCl, 43 mM NaCl, 50 mM LiCl, pH=8) and 2 μL of the appropriate agonist, cortistatin 14 (CPC Scientific, catalog CORT-002) was added to each well. The final concentration of agonist was 0.3 μM cortistatin. The final concentration of DMSO was kept constant across the plate. Plates were incubated in the dark at 37° C. for 1 hour, then at room temperature for 1 minute. IP-1 standards and HTRF detection reagents were added according to the IP-One-Gq kit purchased from Cisbio (part number 62IPAPEJ) and incubated for 1 hour at room temperature in the dark. Plates were read on a Molecular Devices SpectraMax iD5 plate reader. HTRF ratios were calculated from the raw data and graphed using GraphPad Prism, and IC50 values ​​for each compound were calculated.

[0260] Activity data for selected MRGPRX2 antagonists (vs. 0.3 uM cortistatin-14 agonist) are shown in Table 9. Activity ranges are indicated as follows: "+++++" indicates antagonist activity less than 100 nM, "++++" indicates antagonist activity between 100-500 nM, "+++" indicates activity between 501-1000 nM, "++" indicates activity between 1001-2500 nM, and "+" indicates activity greater than 2500 nM. [Table 9-1] [Table 9-2] [Table 9-3]

[0261] Example 48 Mast cell beta-hexosaminidase release assay Human LAD2 cells (NIH) were maintained in an incubator at 37 °C with 5% CO2 and cultured at 2–5 × 10 cells / well in StemPro-34 serum-free medium (Gibco 10639011) supplemented with 2 mM L-glutamine, 100 U / ml penicillin, 50 mg / ml streptomycin, and 100 ng / ml SCF (Invitrogen PEP0860). 5 The cells were cultured at a concentration of 10 cells / mL and semi-depleted every 1-2 weeks.

[0262] 2.5 x 10 cells 5The cells were transferred to SCF-free medium at 1000 cells / mL and kept in an incubator overnight. On the day of the assay, the cells were washed twice with assay buffer (final concentrations 10 mM HEPES, 137 mM NaCl, 5.6 mM D-glucose, 2.7 mM KCl, 1 mM MgCl, 1.8 mM CalCl2, 0.4 mM Na2HPO4.7H2O, 0.04% BSA, pH=7.4) and seeded in 96-well v-bottom plates at 20,000 cells / well in 80 μL of assay buffer. Antagonist compounds solubilized at 10 mM in DMSO were diluted 10× the final desired concentration in assay buffer as a 10-point curve (10 μM final top concentration in a 1:3 serial dilution) and 10 μL was added per well. The plates were then incubated at 37° C. for 1 hour. Agonists were diluted 10x to the desired concentration in assay buffer and 10 μL of the appropriate agonist was added to each well. The final concentration of cortistatin-14 (Tocris 3374) used in the antagonist assay was 500 nM. The final concentration of DMSO was kept constant across the plate. The plate was then incubated at 37°C for 30 minutes in a hot air oven, followed by centrifugation at 450xg for 5 minutes at 4°C. 50 μL of supernatant from each well was then transferred to a 96-well flat-bottom plate containing 100 μL of substrate solution (3.5 mg / mL p-nitrophenyl-N-acetyl-β-D-glucosaminide (Sigma 487052) in citrate buffer containing a final concentration of 40 mM citric acid, 20 mM Na2HPO4.7H2O, pH=4.5) per well. The cell pellets, remaining in the remaining assay buffer, were then resuspended by adding 150 μL of 0.1% Triton-X-100 to each well and pipetting up and down, and 50 μL of cell lysate was transferred to a second 96-well flat-bottom plate containing 100 μL of substrate solution per well. The plate containing the transferred supernatant and cell lysate was then incubated in a warm air oven at 37° C. for 90 minutes.After incubation, 50 μL of 400 mM glycine buffer (pH 10.7) was added to each well and the plate was read on a Molecular Devices SpectraMax iD5 plate reader (absorbance at 405 nm, reference filter at 620 nm). After background subtraction, degranulation rate (beta-hexosaminidase release rate) was calculated as 100×(supernatant value) / (supernatant+lysate value) and subsequently analyzed using GraphPad Prism software to determine the IC of each compound. 50 values ​​were calculated.

[0263] Activity data for selected MRGPRX2 antagonists in the mast cell beta-hexosaminidase release assay is shown in Table 10. Activity ranges are indicated as follows: "+++++" indicates antagonist activity less than 100 nM, "++++" indicates antagonist activity between 100-500 nM, "+++" indicates activity between 501-1000 nM, "++" indicates activity between 1001-2500 nM, and "+" indicates activity greater than 2500 nM. [Table 10]

[0264] Example 49 Pharmacokinetic studies in mice Compounds were formulated at a concentration of 5 mg / mL in 5% DMSO, 5% Solutol, and 90% PBS (pH 7.4) without Ca and Mg. Male C57BL / 6 mice (n=3 / compound) were administered a 50 mg / kg dose of each compound by oral gavage under non-fasted conditions. Blood samples were collected onto K2-EDTA via the saphenous vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-dose, and plasma was prepared and stored at or below -80°C until analysis. Plasma sample preparation for analysis was performed by protein precipitation using acetonitrile (with verapamil as an internal standard) followed by centrifugation. Compound concentrations were measured in extracted plasma using LC-MS / MS against a 12-point calibration curve covering the range 1-4000 nM. Pharmacokinetic parameters such as area under the curve, clearance, and half-life were estimated using non-compartmental analysis using Phoenix WinNonlin. The doses were confirmed by analysis of residual dose material by UPLC-UV compared to single point calibration samples. The results of these studies are shown in Table 11. [Table 11]

[0265] Example 50 Evans Blue Vascular Permeability Assay Eight- to ten-week-old C57BL / 6J (strain 000664, Jackson Laboratories) or MrgprX2 knock-in (Mrgb2KI, Escient Pharmaceuticals Inc.) mice were anesthetized with isoflurane and had their backs shaved 5 to 6 days before the start of the study. On the day of the study, mice were administered vehicle or EP8615 at 100, 30, 20, 10, or 3 mg / kg 3 h prior to Evans blue injection. Animals were restrained and placed under isoflurane with 200 mg of EP8615 in 0.9% saline. [ka] 1 of 1% Evans Blue (catalog no. 314-13-6, Fisher Chemical) was injected intravenously (IV). Ten minutes after the IV injection, the animals were kept under anesthesia and then incubated for 25 min. [ka] l of vehicle PBS, cortistatin-14 (C-14, 300 nM, Cat. No. 3374, Tocris Bioscience), icatibant (HOE-140, 38 [ka] M, Cat. No. 3014, Tocris Bioscience), or goat anti-mouse IgE (50 [ka] The animals were intradermally injected with 100 mg / ml of 1000 mg ... [ka] 1 of extracted dye in formamide was placed in duplicate in a 96-well plate along with a standard curve of known Evans Blue concentration standards. The plate was read on a plate reader at 620 nM and the results expressed as 1 / 2 μg of dye per mg of tissue. [ka] The mean and standard error of the mean were expressed as mean and standard error of the mean. Statistical differences between groups were compared using unpaired t-test.

[0266] The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and / or non-patent publications mentioned in this application and / or listed in the application data sheets are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified, as necessary, to use concepts from the various patents, applications, and publications to provide still further embodiments.

[0267] These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and claims, but should be construed to include all possible embodiments, along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by this disclosure.

Claims

1. A compound having one of the following structures: or a pharma- ceutically acceptable salt, hydrate, solvate or isotope thereof. 【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】

2. 20. The compound of claim 1 having the structure of Example 19, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

3. 2. The compound of claim 1 having one of the following structures: or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof: 【Table 2-1】 【Table 2-2】 【Table 2-3】 【Table 2-4】 【Table 2-5】 【Table 2-6】 【Table 2-7】 【Table 2-8】

4. 20. The compound of claim 1 having the structure of Example 26, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

5. 20. The compound of claim 1 having the structure of Example 27, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

6. 20. The compound of claim 1 having the structure of Example 28, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

7. 20. The compound of claim 1 having the structure of Example 29, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

8. 2. The compound of claim 1 having one of the following structures: or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof: 【Table 3-1】 【Table 3-2】 【Table 3-3】

9. 3. The compound of claim 1 having the structure of Example 30, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

10. 3. The compound of claim 1 having the structure of Example 31, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

11. 33. The compound of claim 1 having the structure of Example 32, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

12. 2. The compound of claim 1 having the structure of Example 33, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

13. 3. The compound of claim 1 having the structure of Example 34, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

14. 36. The compound of claim 1 having the structure of Example 35, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

15. 36. The compound of claim 1 having the structure of Example 36, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

16. 20. The compound of claim 1 having the structure of Example 37, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

17. 37. The compound of claim 1 having the structure of Example 38, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

18. 39. The compound of claim 1 having the structure of Example 39, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

19. 2. The compound of claim 1 having the structure of Example 40, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

20. 2. The compound of claim 1 having the structure of Example 41, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

21. 2. The compound of claim 1 having the structure of Example 42.

22. 13. The compound of claim 1 having the structure of compound 6-1, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

23. 2. The compound of claim 1 having the structure of Compound 8-16, or a pharma- ceutically acceptable salt, hydrate, solvate, or isotope thereof.

24. The compound of claim 1 having the structure of Example 30, or a pharma- ceutically acceptable salt thereof.

25. The compound of claim 1 having the structure of Example 30.

26. The compound of claim 1 having the structure of Example 32, or a pharma- ceutically acceptable salt thereof.

27. The compound of claim 1 having the structure of Example 32.

28. 28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, or a pharma- ceutically acceptable salt, hydrate, solvate or isotope thereof, and at least one pharma- ceutically acceptable excipient.

29. A pharmaceutical composition comprising the pharmaceutical composition of claim 28 and for use in a method of modulating Mas-related G protein receptor (MRGPR) X2 or an MRGPRX2 ortholog, the method being carried out by contacting MRGPRX2 or an MRGPRX2 ortholog with an effective amount of the pharmaceutical composition of claim 28.

30. A pharmaceutical composition comprising the pharmaceutical composition of claim 28 and for use in a method for treating an MRGPRX2 or MRGPRX2 ortholog dependent condition, said method being carried out by administering to a subject in need of such treatment an effective amount of the pharmaceutical composition of claim 28.

31. A pharmaceutical composition comprising the pharmaceutical composition of claim 28 and for use in a method for treating a pseudoallergic reaction, an itch-related condition, a pain-related condition, a cancer-related condition, an inflammatory or autoimmune disorder, said method being effected by administering to a subject in need of such treatment an effective amount of the pharmaceutical composition of claim 28.

32. The pseudo-allergic reaction is induced by a secretagogue, a cationic peptidergic drug, an anionic peptidergic drug, a neutral peptidergic drug, a nonsteroidal antagonist drug, a neuropeptide, an antimicrobial peptide, an MCD peptide, substance P, VIP, PACAP, dynorphin, somatostatin, compound 48 / 80, cortistatin-14, mastoparan, meletin, cathelicidin peptide, ciprofloxacin, vancomycin, leuprolide, goserelin, histrelin , triptorelin, cetrorelix, ganirelix, degarelix, octreotide, lanreotide, pasireotide, sermorelin, tesamorelin, icatibant, glatiramer acetate, teriparatide, pramlintide, bleomycin, exenatide, glucagon, liraglutide, enfuvirtide, colistimethate, succinylcholine, tubocurarine, atracurium, mivacurium, and rocuronium.

33. The itch-related condition is selected from the group consisting of chronic itch, contact dermatitis, allergic blepharitis, anemia, atopic dermatitis, bullous pemphigoid, candidiasis, chickenpox, end stage renal failure, hemodialysis, chronic urticaria, contact dermatitis, atopic dermatitis, dermatitis herpetiformis, diabetes, drug allergies, dry skin, dyshidrotic dermatitis, ectopic eczema, eosinophilic fasciitis, epidermolysis bullosa, erythrasma, food allergies, folliculitis, fungal skin infections, hemorrhoids, herpes, HIV infection, Hodgkin's disease, hyperthyroidism, allergies to iodine-containing contrast dyes, iron deficiency anemia, 32. The pharmaceutical composition of claim 31, wherein the treatment is selected from the group consisting of blood, kidney disease, leukemia, porphyria, lymphoma, malignant tumor, mastocytosis, multiple myeloma, neurodermatitis, onchocerciasis, Paget's disease, lice infestation, polycythemia vera, prurigo nodularis, lichen planus, lichen sclerosus, perianal pruritus, pseudorabies, psoriasis, rectal prolapse, sarcoidosis granuloma, scabies, schistosomiasis, scleroderma, severe stress, stasis dermatitis, swimmer's prurigo, thyroid disease, tinea cruris, rosacea, cutaneous amyloidosis, scleroderma, acne, wound healing, burn healing, itchy eyes, and urticaria.

34. 32. The pharmaceutical composition of claim 31, wherein the itch-related condition is urticaria, pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema.

35. The pain-related condition may be acute pain, advanced prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, arthrofibrosis, ataxic cerebral palsy, autoimmune atrophic gastritis, avascular necrosis, back pain, Behcet's disease (syndrome), burning mouth syndrome, bursitis, cancer pain, carpal tunnel, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical stenosis, Charcot-Marie-Tooth (CMT) disease, chronic fatigue syndrome (CFS), chronic functional abdominal pain (CFAP), chronic pain, chronic pancreatitis, chronic pelvic pain syndrome, collapsed lung (pulmonary embolism), chronic pulmonary edema, ... chest), complex regional pain syndrome (RSD), corneal neuropathic pain, Crohn's disease, degenerative disc disease, toothache, Dercum's disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dystonia, Ehlers-Danlos syndrome (EDS), endometriosis, eosinophilia-myalgia syndrome (EMS), erythromelalgia, fibromyalgia, gout, headache, herniated disc, hydrocephalus, intercostal neuralgia, interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatitis (dermatomyositis), knee injury, leg pain, lower back pain hematuria syndrome, lupus, Lyme disease, sponge kidney (M SK), dysesthesias, mesothelioma, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, osteoarthritis, Paget's disease, Parsonage-Turner syndrome, pelvic pain, periodontitis pain, peripheral neuropathy, phantom limb pain, compressed nerve, polycystic kidney disease, polymyalgia rheumatica, polymyositis, porphyria, postherniorrhaphy pain syndrome, postmastectomy, postoperative pain, pain syndrome, poststroke pain, postthoracotomy pain syndrome, postherpetic neuralgia (shingles), postpolio syndrome, primary lateral sclerosis, 32. The pharmaceutical composition of claim 31, wherein the condition is psoriatic arthritis, pudendal neuralgia, radiculopathy, Raynaud's disease, rheumatoid arthritis (RA), sacroiliac joint dysfunction, sarcoidosis, Scheuermann's kyphosis, sciatica, scoliosis, shingles (herpes zoster), Sjogren's syndrome, spasmodic torticollis, sphincter of Oddi dysfunction, spinocerebellar ataxia (SCA ataxia), spinal cord injury, lumbar spinal stenosis, syringomyelia, Tarlov's cyst, transverse myelitis, trigeminal neuralgia, neuropathic pain, ulcerative colitis, vascular pain, or vulvodynia.

36. The inflammatory or autoimmune disorder is selected from the group consisting of chronic inflammation, mast cell activation syndrome, multiple sclerosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, appendicitis, bursitis, cutaneous lupus, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (rsd / crps), rhinitis, tendinitis, tonsillitis, acne vulgaris, sinusitis, rosacea, psoriasis, graft-versus-host disease, reactive airway disorder, asthma, respiratory tract infections, allergic rhinitis, autoinflammatory diseases, celiac disease, Chronic prostatitis, diverticulitis, glomerulonephritis, sweat gland abscess, hypersensitivity, intestinal disorders, epithelial intestinal disorders, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, lupus erythematosus, interstitial cystitis, otitis, pelvic inflammatory disease, endometrial pain, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, psoriasis, pneumonia, chronic obstructive pulmonary disease, persistent sputum eosinophilia, eosinophilic leukemia, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic duodenitis, eosinophilic gastroenteritis, mast cell gastrointestinal disease , hypereosinophilic syndrome, aspirin-exacerbated respiratory disease, nasal polyposis, chronic rhinosinusitis, antibody-dependent cell-mediated cytotoxicity, neurofibromatosis, swannamatosis, tubulointerstitial nephritis, glomerulonephritis, diabetic nephropathy, allograft rejection, amyloidosis, renal vascular ischemia, reflux nephropathy, polycystic kidney disease, hepatic fibrosis / cirrhosis, autoimmune liver disease, biliary atresia, acute and chronic hepatitis B and C viruses, liver tumors and cancer, alcoholic liver disease, polycystic liver 32. The pharmaceutical composition of claim 31, wherein the therapeutic agent is selected from the group consisting of chronic myelitis, hepatobiliary cancer, neuromyelitis optica spectrum disorder, cardiovascular disease, inflammation induced by bacterial or viral infection, inflammation associated with SARS-CoV-2 infection or variants thereof and coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome, pneumonia, prolonged / prolonged / chronic COVID, post-acute COVID-19 sequelae (PASC), myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS "brain fog") and vasculitis.

37. The cancer-related condition is selected from the group consisting of adenoid cystic carcinoma, adrenal tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia telangiectasia, Beckwith-Wiedemann syndrome, cholangiocarcinoma, Birt-Hogg-Dube syndrome, bone cancer, brain stem glioma, brain tumor, breast cancer (inflammatory, metastatic, male), prostate, basal cell, melanoma, colon cancer, colorectal cancer, bladder cancer, kidney cancer, lacrimal gland cancer, laryngeal and hypopharyngeal cancer, lung cancer (non-small cell lung cancer, non ... leukemia (acute lymphoblastic, acute lymphocytic, acute myeloid, B-cell prolymphocytic, chronic lymphocytic, chronic myeloid, chronic T-cell lymphocytic, eosinophilic), liver cancer, Li-Fraumeni syndrome, lymphoma (Hodgkin and non-Hodgkin), Lynch syndrome, mastocytosis, medulloblastoma, meningioma, mesothelioma, multiple endocrine neoplasia, multiple myeloma, MUTYH-associated polyposis, myelodysplastic syndrome, nasal and paranasal cancer, neuroblastoma tumors, neuroendocrine tumors, neurofibromatosis, penile cancer, parathyroid carcinoma, ovarian fallopian tube and peritoneal cancer, osteosarcoma, pituitary tumors, pleuropulmonary blastoma, oral and oropharynx, thyroid, uterine, pancreatic, Carney complex, brain and spinal cord cancer, cervical cancer, Cowden syndrome, craniopharyngioma, desmoid tumor, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial pancreatic 32. The pharmaceutical composition of claim 31, wherein the cancer is selected from the group consisting of cancers including cancer of the gallbladder, gastrointestinal stromal tumor, germ cell tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyomatosis, and renal cell cancer, hereditary pancreatitis, hereditary papillary renal cell carcinoma, hereditary mixed polyposis syndrome, HIV / AIDS-related cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Kaposi's sarcoma, small intestine cancer, gastric cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, vaginal cancer, Culver cancer, Werner's syndrome, and xeroderma pigmentosum.

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