Phenyleoxyamide kinase inhibitors

Abstract

Compounds having activity as kinase inhibitors are provided. The compounds have the structure (I) or a stereoisomer, tautomer, or salt thereof, wherein R 1 , R 3 and m are as defined herein. Also provided are methods related to the preparation and use of such compounds, pharmaceutical compositions containing such compounds, and methods of their use for the treatment of diseases and disorders.

Description

[Technical Field]

[0001] Representation of Government Interests This invention was made with government support under Grant No. W81XWH-18-1-0617 awarded by the Department of Defense, Congressionally Directed Medical Research Program, Breast Cancer Research Program. The government has certain rights in this invention. [Background technology]

[0002] Technical Field FIELD OF THE DISCLOSURE Embodiments of the present disclosure relate generally to compounds and methods for their preparation and use as therapeutic or prophylactic agents, such as for the treatment of cancer or osteoporosis.

[0003] 2. Description of Related Art The RON (Recepteur d'origine nantais) receptor tyrosine kinase (RTK) and its ligand, serum macrophage-stimulating protein (MSP), are well-established oncogenic promoters of tumorigenesis and metastasis. RON frequently undergoes alternative splicing, resulting in various constitutively active isoforms. Therefore, RON is an attractive target for cancer therapeutics, such as small-molecule inhibitors and monoclonal antibodies. Anti-RON monoclonal antibody therapy has been developed and studied in clinical trials, but with limited success.

[0004] Therefore, there is a need to develop small molecule inhibitors that target the RON pathway and thereby effectively treat several pathological diseases such as cancer and osteoporosis. Embodiments of the present disclosure fulfill this need and further provide related advantages.

[0005] summary Briefly, embodiments of the present disclosure provide compounds, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, as stereoisomers, enantiomers, or tautomers thereof, or mixtures thereof, that are capable of modulating the RON pathway.

[0006] One embodiment is a compound of structure (I): [ka] or a stereoisomer, tautomer, or salt thereof, wherein: [ka] R 1 , R 3 and m are as defined herein. In another embodiment, pharmaceutical compositions comprising the disclosed compounds and methods of use thereof for the treatment of diseases and disorders are also provided.

[0007] Detailed Description In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the present disclosure. However, it will be understood by those skilled in the art that the present disclosure may be practiced without these details.

[0008] Unless the context otherwise requires, throughout this specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," are to be interpreted in their open and inclusive sense, i.e., "including but not limited to."

[0009] As used herein, unless otherwise specified, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the stated range, and fractions thereof (e.g., tenths or hundredths of an integer), where appropriate. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the stated range, value, or composition, unless otherwise specified. As used herein, the terms "a" and "an" refer to "one or more" of the listed components. The use of alternative terms (e.g., "or") should be understood to mean one, both, or any combination of the alternative terms.

[0010] Throughout this specification, references to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrase "in one embodiment" or "an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0011] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used in the specification and claims, the singular forms "a," "an," and "the" also include the plural forms unless the context clearly dictates otherwise.

[0012] "Amino" refers to the -NH2 radical. "Carboxy" or "carboxyl" refers to the -CO2H radical. "Cyano" refers to the -CN radical. "Hydroxy" or "hydroxyl" refers to the --OH radical. "Nitro" refers to the -NO2 radical. "Oxo" refers to the =O substituent. "Thiol" refers to an --SH substituent. "Thioxo" refers to the =S substituent.

[0013] "Alkyl" refers to an alkyl group having 1 to 12 carbon atoms (e.g., C1 to C 12"(C-C alkyl)" refers to a saturated, straight- or branched-chain hydrocarbon radical consisting solely of carbon and hydrogen atoms having 1 to 8 carbon atoms (C-C alkyl), 1 to 8 carbon atoms (C-C alkyl), or 1 to 6 carbon atoms (C-C alkyl), or any value within these ranges (e.g., C-C alkyl), which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1 dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. The carbon numbers referenced relate to the carbon backbone and carbon branches, but do not include carbon atoms belonging to substituents. Unless otherwise specified in the specification, alkyl groups are optionally substituted.

[0014] "Alkenyl" refers to an alkyl group containing one or more carbon-carbon double bonds and having 2 to 12 carbon atoms (C2-C 12 "Alkenyl" refers to an unsaturated, straight- or branched-chain hydrocarbon radical consisting solely of carbon and hydrogen atoms, having 2 to 8 carbon atoms (C2-C8 alkenyl), 2 to 6 carbon atoms (C2-C6 alkenyl), or any value within these ranges, which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. The carbon numbers referenced relate to the carbon backbone and carbon branches, but do not include carbon atoms belonging to substituents. Unless stated otherwise specifically in the specification, alkenyl groups are optionally substituted.

[0015] The term "alkynyl" refers to an alkynyl group having 2 to 12 carbon atoms (C 12"Alkynyl" refers to an unsaturated, straight- or branched-chain hydrocarbon radical having 2 to 9 carbon atoms (C2-C9 alkynyl), or 2 to 6 carbon atoms (C2-C6 alkynyl), or any value within these ranges, and having at least one carbon-carbon triple bond. Examples of alkynyl groups can be selected from the group consisting of ethynyl, propargyl, but-1-ynyl, but-2-ynyl, and the like. The number of carbons referred to refers to the carbon backbone and carbon branches, but does not include carbon atoms belonging to substituents. Unless stated otherwise specifically in the specification, alkynyl groups are optionally substituted.

[0016] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing no unsaturation, and having 1 to 12 carbon atoms, with the remainder of the molecule connecting to a radical group, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless otherwise specified in the specification, an alkylene chain may be optionally joined by one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR, -O, -O- ... 20 , -OC(O)-R 20 , -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)OR 22 , -N(R 20 )C(O)R 22 , -N(R 20 )S(O) t R 22 (where t is 1 to 2), S(O) t OR 22 (where t is 1 to 2), S(O) p R 22 (where p is 0 to 2), and S(O)t N(R 20 )2 (where t is 1 to 2)], where each R 20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0017] "Alkoxy" means a group of the formula -OR a where R a is a group of 1 to 12 carbon atoms (C1 to C 12 an alkyl radical as defined above containing 1 to 8 carbon atoms (C1-C8 alkoxy), 1 to 8 carbon atoms (C1-C8 alkoxy), or 1 to 6 carbon atoms (C1-C6 alkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[0018] "Haloalkoxy" refers to a group of the formula -OR a where R a is a group of 1 to 12 carbon atoms (C1 to C 12 haloalkoxy), 1 to 8 carbon atoms (C1-C8 haloalkoxy), or 1 to 6 carbon atoms (C1-C6 haloalkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, a haloalkoxy group is optionally substituted.

[0019] "Aminyl" is a group of the formula -NR a R b where R a and R b are each independently H or C1-C6 alkyl as defined above. a and R bWhen both are H, the "aminyl" group is the same as the "amino" group defined above. The C1-C6 alkyl portion of the aminyl group is optionally substituted unless otherwise specified.

[0020] An "aromatic ring" refers to a cyclic, planar molecule or portion of a molecule (i.e., radical) having a resonance-bonded ring that provides increased stability relative to other bonding arrangements with the same set of atoms. Generally, an aromatic ring comprises a set of covalently bonded, coplanar atoms and is composed of an even, but not a multiple of four, number of π electrons (e.g., alternating double and single bonds) (i.e., 4n+2 π electrons, where n=0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, or pyrimidonyl. Unless otherwise specified herein, "aromatic ring" includes all optionally substituted radicals.

[0021] "Aryl" refers to an alkyl group having 6 to 18 carbon atoms, e.g., 6 to 10 carbon atoms (C6-C 10 "aryl" refers to a carbocyclic ring system radical containing at least one carbocyclic aromatic ring. For purposes of embodiments of the present disclosure, an aryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified in the specification, an aryl group is optionally substituted.

[0022] "Arylalkyl" refers to a group of the formula -R b R c where R b is an alkylene chain as defined above, and R cis one or more aryl radicals as defined above, e.g., benzyl, diphenylmethyl, etc. The alkylene chain part of the aralkyl radical may be optionally substituted as described above for an alkylene chain. The aryl part of the arylalkyl radical may be optionally substituted as described above for an aryl group.

[0023] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic carbocyclic radical, consisting solely of carbon and hydrogen atoms, having 3 to 15 ring carbon atoms (C3 to C4). 15 Cycloalkyl), 3 to 10 ring carbon atoms (C3 to C 10 Cycloalkyl radicals may include fused or bridged ring systems having 3 to 8 ring carbon atoms (C-C cycloalkyl), or 3 to 8 ring carbon atoms (C-C cycloalkyl), or any value within these ranges, e.g., 3 to 4 carbon atoms (C-C cycloalkyl), which may be saturated or partially unsaturated and are attached to the remainder of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless stated otherwise specifically in the specification, cycloalkyl groups are optionally substituted.

[0024] "Halo" refers to bromine, chlorine, fluorine, or iodine.

[0025] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

[0026] "Hydroxylalkyl" or "hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more hydroxyl radicals. The hydroxyalkyl radical is attached to the backbone through an alkyl carbon atom. Unless otherwise specified specifically in the specification, a hydroxyalkyl group is optionally substituted.

[0027] "Heterocyclyl" refers to a 3- to 18-membered, e.g., 3- to 10-membered, or 3- to 8-membered, non-aromatic ring radical having 1 to 10 ring carbon atoms (e.g., 2 to 10) and 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. Unless stated otherwise specifically in the specification, a heterocyclyl radical is partially or fully saturated and is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spiro, and / or bridged ring systems. The nitrogen, carbon, phosphorus, and sulfur atoms in the heterocyclyl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Examples of such heterocyclyl radicals include, but are not limited to, phosphinane-1-oxide, 1,4-oxaphosphinane-4-oxide, 1,4-azaphosphinane-4-oxide, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro- Examples include 1H-pyrrolidine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, heterocyclyl groups are optionally substituted.

[0028] "Heterocyclylalkyl" refers to a group of the formula -R b R hwhere R b is an alkylene chain as defined above, and R h is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at a nitrogen atom. The alkylene chain of the heterocyclylalkyl radical may be optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkyl radical may be optionally substituted as defined above for a heterocyclyl group.

[0029] "Heteroaryl" refers to a 5- to 18-membered, e.g., 5- or 6-membered, ring system radical containing 1 to 13 ring carbon atoms, 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized and the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl , indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted.

[0030] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen. The N-heteroaryl radical may be optionally substituted as described above for heteroaryl radicals.

[0031] The terms "pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, and / or pyridinonyl" refer to rings having the following respective structures: [ka]

[0032] Each ring can be connected to the remainder of the molecule or to a portion of the molecule through a single bond, where the connection is made by replacing a hydrogen with a single bond. For example, in some embodiments of structure (I), [ka] is pyrazolyl and R 2 When is methyl, the pyrazolyl has one of the following structures: [ka]

[0033] In some embodiments, the pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, and / or pyridinonyl are optionally substituted with one or more (e.g., 1, 2, or 3) additional substituents. In certain embodiments, the pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, and / or pyridinonyl do not include additional substituents.

[0034] The term "-NH-aryl-alkyl-heterocyclyl-alkenyl" refers to a heterocyclyl group of the formula NH-R a -R b -R c -R d where R ais an aryl group as defined above, and R b is an alkylene chain as defined above, and R c is a heterocyclyl group as defined above, and R d is an alkenyl radical as defined above. Each portion of the radical (i.e., aryl, alkyl, or alkylene, heterocyclyl, and alkenyl) may be optionally substituted as defined above for each group. An example of -NH-aryl-alkyl-heterocyclyl-alkenyl is a radical having one of the following structures: [ka] wherein each of the above structures may be optionally substituted with one or more additional substituents (e.g., oxo in the alkyl or heterocyclyl portion of the radical).

[0035]

[0023] As used herein, the term "substituted" refers to any of the above groups (e.g., alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminylalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclene, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and / or hydroxylalkyl) in which at least one hydrogen atom (e.g., 1, 2, 3, or all hydrogen atoms) has been replaced with a bond to a non-hydrogen substituent. Examples of non-hydrogen substituents include, but are not limited to, amino, carboxyl, cyano, hydroxyl, halo, nitro, oxo, thiol, thioxo, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and / or hydroxylalkyl substituents, each of which may be optionally substituted with one or more of the above substituents.

[0036] In some particular embodiments, the optional substituents are halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C 10 In some embodiments, the optional substituents are independently selected from the group consisting of aryl, 5- or 6-membered heteroaryl, C1-C6 alkoxy, and 3- to 8-membered heterocyclyl. In some embodiments, the optional substituents are independently selected from the group consisting of halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkoxy, and optionally substituted C3-C8 cycloalkyl. In some embodiments, the optional substituents are independently selected from the group consisting of halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkoxy, or optionally substituted C3-C8 cycloalkyl, optionally substituted 5- to 10-membered heterocyclylalkyl, optionally substituted 5- to 10-membered heterocyclyloxy, and optionally substituted C6-C8 cycloalkyl. 10 aryl.

[0037] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to affect its intended use, including, but not limited to, disease treatment, as defined below. A therapeutically effective amount will vary depending on the intended therapeutic use (in vivo) or the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, the method of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that induces a specific response in target cells (e.g., decreased platelet adhesion and / or cell migration). The specific dose will vary depending on the compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.

[0038] As used herein, "treatment" or "treating" refers to an approach to achieving beneficial or desired results with respect to a disease, disorder, or condition, including, but not limited to, a therapeutic effect and / or a preventative effect. A therapeutic effect refers to the eradication or amelioration of the underlying disease being treated. A therapeutic effect is also achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, resulting in an observed improvement in the subject, even though the subject may still be suffering from the underlying disease. A preventative effect includes delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. In certain embodiments, for a preventative effect, a composition is administered to a subject at risk of developing a particular disease, or to a subject who may not have been diagnosed with the disease but who reports one or more physiological symptoms of the disease.

[0039] As used herein, the terms "co-administration," "co-administration," and their grammatical equivalents include the administration of two or more agents to an animal, including a human, such that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration of separate compositions, administration of separate compositions at different times, or administration of a composition in which both agents are present.

[0040] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0041] A "pharmaceutically acceptable acid addition salt" refers to a salt that retains the biological effectiveness of the free base and is biologically acceptable or biologically suitable for administration to a subject. See generally SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Suitable pharmaceutically acceptable acid addition salts are salts that are pharmacologically effective and suitable for contact with a patient's tissues without causing undue toxicity, irritation, or allergic reaction. Pharmaceutically acceptable acid addition salts include those formed with inorganic acids and those formed with organic acids. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, and the like. Acids that are often used as amines include nicotinic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0042] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness of the free acid and is biologically tolerable or biologically suitable for administration to a subject. See generally SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Suitable pharmaceutically acceptable base addition salts are salts that are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation, or allergic reaction. Pharmaceutically acceptable base addition salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Suitable inorganic salts include ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins (e.g., ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like). Particularly suitable organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0043] In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts, such as quaternary amine alkyl halide salts (eg, methyl bromide).

[0044] "Subject" refers to an animal, e.g., a mammal such as a human. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human.

[0045] "Mammal" includes humans and both domestic animals, such as laboratory animals and household pets (eg, cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife.

[0046] The term "prodrug" is intended to refer to a compound that can be converted under physiological conditions or by solvation to a biologically active compound described herein (e.g., a compound of structure (I)). Accordingly, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. In some embodiments, a prodrug is inactive when administered to a subject, but is converted to an active compound in vivo, e.g., by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammals (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 79, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties. The term "prodrug" is also meant to include any covalently bonded carriers that release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the active compounds described herein are typically prepared by modifying functional groups present in the active compound such that the modifications become the parent active compound upon cleavage, either by routine manipulation or in vivo. Prodrugs include compounds in which a hydroxy group, an amino group, or a thiol group is bonded to any group that is cleaved to form a free hydroxy group, a free amino group, or a free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject.Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of hydroxy functional groups or acetamide, formamide and benzamide derivatives of amine functional groups in the active compounds.

[0047] The term "in vivo" refers to events that occur inside a subject's body. The embodiments disclosed herein are also intended to include all pharmaceutically acceptable compounds of structure (I), including its stereoisomers, enantiomers, or tautomers, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0048] Certain embodiments are also intended to include in vivo metabolic products of the disclosed compounds. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily through enzymatic processes. Accordingly, embodiments include compounds produced by a process comprising administering a compound of the present disclosure to a mammal for a period of time sufficient to produce a metabolic product thereof. Such products are typically identified by administering a detectable dose of a radiolabeled compound of the present disclosure to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological sample.

[0049] "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.

[0050] In many cases, crystallization produces solvates of the compounds disclosed herein.The term "solvate" used herein refers to an aggregate comprising one or more compounds of the present disclosure and one or more solvent molecules.In some embodiments, the solvent is water, and in this case, the solvate is a hydrate.Alternatively, in other embodiments, the solvent is an organic solvent.Therefore, the compounds of the present disclosure can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as corresponding solvate forms.In some embodiments, the compounds of the present disclosure are true solvates, while in other cases, the compounds of the present disclosure simply retain incidental water or are a mixture of water and some incidental solvent.

[0051] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both cases where said event or circumstance occurs and cases where said event or circumstance does not occur. For example, "optionally substituted aryl" means that the aryl group may be substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups ("unsubstituted"). If a functional group is described as "optionally substituted," and then a substituent on the functional group is also described as "optionally substituted," etc., for purposes of this disclosure, such repetitions are limited to 5, 4, or 3 times. In some embodiments, such repetitions are limited to 2 times. In some embodiments, such repetitions are limited to 1 time. In some embodiments, if a functional group is described as "optionally substituted," the substituent on the functional group is not substituted.

[0052] A "pharmaceutical composition" refers to a formulation of a compound of the present disclosure and a vehicle generally accepted in the art for delivering the compound of the present disclosure to a mammal, such as a human, including any pharmaceutically acceptable carrier, diluent, or excipient therefor.

[0053] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, an adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier.

[0054] "Stereoisomers" refer to compounds composed of the same atoms joined by the same bonds, but with different, incompatible three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0055] The compounds of the present disclosure (i.e., compounds of structure (I)) or pharmaceutically acceptable salts thereof can contain one or more centers of geometric asymmetry and can therefore give rise to stereoisomers, such as enantiomers, diastereoisomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- of amino acids. Accordingly, 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 conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When a compound described herein contains an olefinic double bond or other center of geometric asymmetry, and unless otherwise specified, the compound is intended to include both the E and Z geometric isomers, as well as all tautomeric forms.

[0056] Embodiments of the present disclosure include all types of rotamers and conformationally restricted states of the disclosed compounds. Also included are atropisomers, which are stereoisomers that arise due to hindered rotation around a single bond, where the energy difference due to steric strain or other factors creates a rotational barrier sufficient to allow isolation of individual conformers. As an example, certain compounds of the present disclosure may exist as a mixture of atropisomers, or may be purified or enriched for the presence of a single atropisomer.

[0057] In some embodiments, the compound of structure (I) is a mixture of enantiomers or diastereomers. In other embodiments, the compound of structure (I) is substantially one enantiomer or diastereomer.

[0058] "Tautomer" refers to the shifting of a proton from one atom of a molecule to another atom of the same molecule. Thus, embodiments include tautomers of the disclosed compounds.

[0059] The chemical naming protocols and structural diagrams used herein are a modification of the IUPAC naming system using the ACD / Name version 9.07 software program and / or the ChemDraw Professional version 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names used herein, substituents are typically named before the group to which they are attached. For example, cyclopropylethyl consists of an ethyl backbone with a cyclopropyl substituent, and cyanoalkyl consists of an alkyl backbone with a cyano substituent. Except as noted below, all bonds identified in the chemical structural diagrams herein are assumed to be identified, except for all bonds on some carbon atoms, which are assumed to be connected to sufficient hydrogen atoms to complete valence.

[0060] compound The present disclosure relates to a compound having the following structure (I): [ka] [In the formula, R 1 has the following structure: [ka] and During the ceremony, R 1a is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted 5-membered heteroaryl, or -P(=O)R a R b where R a and R b are each independently alkyl; R 1b is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; R 1c is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, or -P(=O)R c R d where R c and R d are each independently alkyl; R 1d is halo, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or -P(=O)R e R f where R e and R f are each independently alkyl; R 1e each occurrence is independently alkyl, halo, haloalkyl, cycloalkyl, hydroxyl, amino, or cyano; R 2 is alkyl, haloalkyl, or -P(=O)Rg R h where R g and R h are each independently alkyl; R 3 each occurrence is independently alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, hydroxyl, amino, or cyano; [ka] is pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, or pyridinonyl; n is 0, 1, 2, or 3; and m is 0, 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0061] One embodiment is a compound having the following structure (I): [ka] [In the formula, R 1 has the following structure: [ka] and During the ceremony, R 1a is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted 5-membered heteroaryl, or -P(=O)R a R b where R a and R b are each independently alkyl, or R a and R b together with the P atom to which they are attached form an optionally substituted heterocyclyl; R1b is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, unsubstituted arylalkyl, or optionally substituted heterocyclylalkyl; R 1c is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, or -P(=O)R c R d where R c and R d are each independently alkyl; R 1d is halo, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or -P(=O)R e R f where R e and R f are each independently alkyl; R 1e each occurrence is independently alkyl, halo, haloalkyl, cycloalkyl, hydroxyl, amino, or cyano; R 1f is -P(=O)R e R f where R e and R f are each independently alkyl; R 1g is hydrogen or amino; R 3 each occurrence is independently alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, hydroxyl, amino, or cyano; [ka] has the following structure: [ka] have one of; n is 0, 1, 2, or 3, and m is 0, 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0062] In some embodiments, R 1 has the following structure: [ka] It has.

[0063] In some embodiments, R 1a is an optionally substituted 5-membered heteroaryl. In certain embodiments, R 1a is an optionally substituted 5-membered N-heteroaryl. In some embodiments, R 1a is optionally substituted imidazolyl or optionally substituted pyrazolyl. In some embodiments, R 1a has the following structure: [ka] It has one of the following.

[0064] In some embodiments, R 1a is -P(=O)R a R b In some embodiments, R a is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R b is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 1a has the following structure: [ka] It has.

[0065] In some embodiments, R 1a has the following structure: [ka] [In the formula, X is -CH2-, -N(R a ')- or -O-, and R a ' is hydrogen or C1-C6 alkyl.

[0066] In certain embodiments, R 1a is optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted aryl. In some embodiments, R 1a is optionally substituted with alkyl, halo, haloalkyl, cycloalkyl, hydroxyl, amino, or cyano. 1a is not replaced.

[0067] In some embodiments, R 1 has the following structure: [ka] It has.

[0068] In certain embodiments, R 1b is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, unsubstituted arylalkyl, or optionally substituted heterocyclylalkyl. In some embodiments, R 1b is optionally substituted cyclohexyl, optionally substituted piperidinyl, optionally substituted phenyl, unsubstituted benzyl, or optionally substituted —(CH)-morpholino. In certain embodiments, R 1bis cyclohexyl, piperidinyl, or phenyl substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkoxy, halo, -P(=O)-(CH3), -NH-C(=O)-alkenyl, -NH-C(=O)-alkenyl-N(CH3), -NH-C(=O)-alkyl-N(CH3)-C(=O)alkenyl-N(CH3), optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl.

[0069] In some embodiments, R 1b is optionally substituted aryl. In certain embodiments, R 1b is optionally substituted phenyl. In some embodiments, R 1b is substituted phenyl. In some embodiments, R 1b is phenyl substituted with heterocyclyl.

[0070] In certain embodiments, R 1b has one of the following structures: [ka] [ka]

[0071] In some embodiments, R 1b has one of the following structures: [ka]

[0072] In certain embodiments, R 1b is optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R 1b is optionally substituted with alkyl, halo, haloalkyl, cycloalkyl, hydroxyl, amino, or cyano.

[0073] In some embodiments, R 1 has the following structure: [ka]

[0074] In certain embodiments, R 1c is an optionally substituted 5-membered heteroaryl. In some embodiments, R 1c is an optionally substituted 5-membered N-heteroaryl. In certain embodiments, R 1c is optionally substituted imidazolyl or optionally substituted pyrazolyl. In some embodiments, R 1c has one of the following structures: [ka]

[0075] In some embodiments, R 1c is -P(=O)R c R d In some embodiments, R c is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R d is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 1c has the following structure: [ka]

[0076] In some embodiments, R 1c has one of the following structures: [ka] [In the formula, X is -CH2-, -N(R c ')- or -O-; and R c ' is hydrogen or C1-C6 alkyl.

[0077] In some embodiments, R 1 has the following structure: [ka]

[0078] In certain embodiments, R 1d is an optionally substituted 5-membered heteroaryl. In some embodiments, R 1d is an optionally substituted 5-membered N-heteroaryl. In certain embodiments, R 1d is optionally substituted imidazolyl or optionally substituted pyrazolyl. In some embodiments, R 1d has the following structure: [ka]

[0079] In some embodiments, R 1c is -P(=O)R e R f In some embodiments, R e is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R f is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 1d has the following structure: [ka]

[0080] In some embodiments, R 1d has one of the following structures: [ka] [In the formula, X is -CH2-, -N(R d ')- or -O-; and R d ' is hydrogen or C1-C6 alkyl.

[0081] In certain embodiments, R 1d is fluoro, chloro, bromo, or iodo. In some embodiments, R 1d is chloro or fluoro. In some embodiments, R 1d is bromo.

[0082] In some embodiments, n is 0. In certain embodiments, n is 1, 2, 3, and R 1e Each occurrence of is independently halo, hydroxyl, or amino. In some embodiments, n is 1 and R 1e is amino. In some embodiments, n is 0. In certain embodiments, n is 1, 2, 3, and R 1e is independently halo, hydroxyl, amino, or -NH-aryl-alkyl-heterocyclyl-alkenyl. In some embodiments, n is 1 and R 1e is an amino or has the structure: [ka]

[0083] In certain embodiments, R 1 has the following structure: [ka]

[0084] In some embodiments, R 1f has the following structure: [ka]

[0085] In some embodiments, R 1f has one of the following structures: [ka] [In the formula, X is -CH2-, -N(R f ')- or -O-; and R f ' is hydrogen or C1-C6 alkyl.

[0086] In some embodiments, R 1g is amino. In some embodiments, R 1g is hydrogen.

[0087] In certain embodiments, R 1 has one of the following structures: [ka] [ka] [ka] [ka]

[0088] In some embodiments, R 1 has one of the following structures: [ka]

[0089] In some embodiments, R 1 has one of the following structures: [ka] [ka] [ka]

[0090] In some embodiments, R 1 has one of the following structures: [ka]

[0091] In certain embodiments, R 1 has one of the following structures: [ka]

[0092] In certain embodiments, R 1 has one of the following structures: [ka]

[0093] In some embodiments, R 1 has one of the following structures: [ka]

[0094] In certain embodiments, R 1 has one of the following structures: [ka]

[0095] In some embodiments, R 1 has one of the following structures: [ka]

[0096] In some embodiments, R2 is haloalkyl. In certain embodiments, R 2 is trifluoromethyl. In some embodiments, R 2 is alkyl. In certain embodiments, R 2 is methyl. In some embodiments, R 2 has the following structure: [ka]

[0097] In some embodiments, R 2 has one of the following structures: [ka] [In the formula, X is -CH2-, -N(R 2 ')- or -O-, and R 2a ' is hydrogen or C1-C6 alkyl.

[0098] In certain embodiments, [ka] has one of the following structures: [ka]

[0099] In some embodiments, [ka] has one of the following structures: [ka]

[0100] In certain embodiments, [ka] has one of the following structures: [ka]

[0101] In some embodiments, m is 0. In certain embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, R 3 Each occurrence of is independently halo or haloalkyl. In some embodiments, R 3 In certain embodiments, m is 1 and R 3 is fluoro.

[0102] In some embodiments, the compound of structure (I) [ka] The moiety has the following structure: [ka]

[0103] One embodiment provides a compound having one of the structures set forth in Table 1, as a stereoisomer, enantiomer, or tautomer thereof, or as a pharmaceutically acceptable salt, solvate, or prodrug thereof. The compounds of Table 1 were prepared as described in the Examples or by methods known in the art, and analyzed by mass spectrometry (MS) and / or nuclear magnetic resonance spectroscopy (NMR). [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]

[0104] It is understood that, in the present description, combinations of substituents and / or variables of the depicted formulae are permissible only if such combinations result in stable compounds.

[0105] In additional embodiments, various compounds of the present disclosure that exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of compounds of the present disclosure can be converted to their free base or acid form by standard techniques.

[0106] Pharmaceutical Composition Another embodiment relates to a pharmaceutical composition. The pharmaceutical composition comprises any one (or more) of the aforementioned compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In even more embodiments, the pharmaceutical composition comprises a compound disclosed herein and an additional therapeutic agent (e.g., an anti-cancer agent). Non-limiting examples of such therapeutic agents are described below.

[0107] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Further, by way of example only, parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as epidural, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0108] In certain embodiments, the compounds described herein are administered by local administration rather than systemic administration, for example, by direct injection of the compound into an organ, often as a depot or sustained-release formulation.In a specific embodiment, long-acting formulations are administered by implantation (for example, subcutaneous or intramuscular) or intramuscular injection.In addition, in another embodiment, the compounds are delivered in targeted drug delivery systems, for example, liposomes coated with organ-specific antibodies.In such embodiments, the liposomes target and are selectively taken up by the organ.In yet another embodiment, the compounds described herein are provided in the form of a fast-release formulation, a sustained-release formulation, or an intermediate-release formulation.In yet another embodiment, the compounds described herein are administered locally.

[0109] In methods of treatment according to embodiments of the present disclosure, an effective amount of at least one compound of structure (I) is administered to a subject suffering from or diagnosed with such a disease, disorder, or medical condition. Effective amounts or dosages can be ascertained by methods such as modeling, dose escalation studies, or clinical trials, taking into account, for example, the mode or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the disease, disorder, or condition, previous or current treatments of the subject, the subject's health status and response to the drug, and the judgment of the treating physician.

[0110] The compounds of the present disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages of 10-5000 mg, 100-5000 mg, 1000-4000 mg, and 1000-3000 mg per day are exemplary dosages used in some embodiments. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the weight of the subject being treated, and the preference and experience of the attending physician.

[0111] In some embodiments, the compound of the present disclosure is administered in a single dose.Usually, this administration is carried out by injection, for example, intravenous injection, in order to rapidly introduce the drug.However, other administration routes can also be used if necessary.A single dose of the compound of the present disclosure can also be used to treat acute symptoms.

[0112] In some embodiments, the compound of the present disclosure is administered multiple times. In some embodiments, administration is about once, twice, three times, four times, five times, six times, or six or more times per day. In another embodiment, administration is about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compound of the present disclosure and another agent (e.g., an anticancer agent) are administered together about once to about six times per day. In another embodiment, administration of the compound of the present disclosure and another agent continues for less than about 7 days. In yet another embodiment, administration continues for about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year or more. In some cases, continuous administration is performed and continued as long as necessary.

[0113] Administration of the disclosed compound can be continued as long as necessary. In some embodiments, the disclosed compound is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the disclosed compound is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the disclosed compound is administered chronically, for example, to treat chronic effects.

[0114] In some embodiments, the compounds of the present disclosure are administered in individual dosage forms. It is known in the art that optimal treatment requires individualized dosing regimens due to subject-to-subject variability in the pharmacokinetics of compounds.

[0115] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In a specific embodiment, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of the compounds of the present disclosure into pharmaceutical preparations. Appropriate formulations vary depending on the selected route of administration. Any pharmaceutically acceptable technology, carrier, and excipient can be used appropriately to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999).

[0116] Provided herein are pharmaceutical compositions comprising one or more compounds of structure (I) and a pharmaceutically acceptable carrier.

[0117] Provided herein is a pharmaceutical composition comprising one or more compounds selected from the compounds of structure (I) and pharmaceutically acceptable diluents, excipients, and carriers.In certain embodiments, the described compounds are administered as pharmaceutical compositions, in which one or more compounds selected from the compounds of structure (I) are mixed with other active ingredients, as in the case of combination therapy.Included herein are all combinations of active substances described in the following combination therapy section and throughout this disclosure.In specific embodiments, the pharmaceutical composition comprises one or more compounds of structure (I).

[0118] As used herein, a pharmaceutical composition refers to a mixture of one or more compounds selected from the compounds of structure (I) with other chemical components (e.g., carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients). In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, a therapeutically effective amount of one or more compounds selected from the compounds of structure (I) provided herein is administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. In certain embodiments, the mammal is a human. In certain embodiments, the therapeutically effective amount will vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds described herein are used alone or in combination with one or more therapeutic agents as components of a mixture.

[0119] In one embodiment, one or more compounds selected from the compounds of structure (I) are formulated in an aqueous solution. In a specific embodiment, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In another embodiment, one or more compounds selected from the compounds of structure (I) are formulated for transmucosal administration. In a specific embodiment, the transmucosal formulation includes a penetrant appropriate for the barrier to be permeated. In yet another embodiment, where the compounds described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In a specific embodiment, such solutions include physiologically compatible buffers and / or excipients.

[0120] In another embodiment, the compounds described herein are formulated for oral administration.The compounds described herein are formulated by combining active compounds with, for example, pharmaceutically acceptable carriers or excipients.In various embodiments, the compounds described herein are formulated in oral dosage forms, including, but not limited to, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, etc.

[0121] In certain embodiments, pharmaceutical preparations for oral use are prepared by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and then adding suitable auxiliary agents as needed, and then processing the granular mixture as desired to obtain tablets or dragee cores.Suitable excipients are fillers, such as sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.In certain embodiments, disintegrants are optionally added.Disintegrants include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salt (such as sodium alginate).

[0122] In one embodiment, dosage forms such as dragee cores and tablets are coated with one or more suitable coatings.In a specific embodiment, concentrated sugar solutions are used to coat dosage forms.The sugar solutions optionally contain additional components, such as, but not limited to, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.For identification purposes, dyes and / or pigments are also optionally added to the coating.Furthermore, dyes and / or pigments are optionally used to distinguish different combinations of active compound doses.

[0123] In certain embodiments, at least one therapeutically effective amount of the compounds described herein is incorporated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer (e.g., glycerol or sorbitol). In a specific embodiment, the push-fit capsules contain the active ingredient mixed with one or more fillers. Fillers include, by way of example only, lactose, binders (e.g., starch), and / or lubricants (e.g., talc or magnesium stearate), and optionally, stabilizers. In another embodiment, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, optionally, stabilizers are added.

[0124] In yet another embodiment, the compounds described herein are formulated for parenteral injection, including formulations suitable for, for example, bolus injection or continuous infusion. In a specific embodiment, the injectable formulation is provided in unit dosage form (e.g., in ampoules) or in multi-dose containers. Optionally, a preservative is added to the injectable formulation. In yet another embodiment, the pharmaceutical composition is formulated in a form suitable for parenteral injection, for example, as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. Optionally, the parenteral injection formulation includes formulating agents such as suspending agents, stabilizers, and / or dispersing agents. In a specific embodiment, the pharmaceutical formulation for parenteral administration includes an aqueous solution of the active compound in water-soluble form. In an additional embodiment, a suspension of one or more compounds selected from the compounds of structure (I) is suitably prepared as an oily injection suspension. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in another embodiment, the active ingredient is in powder form for reconstitution with a suitable vehicle, such as sterile, pyrogen-free water, before use.

[0125] Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient and, as an active ingredient, one or more compounds selected from the compounds of structure (I) described herein. The active ingredient may be in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also called polymorphs), and active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Furthermore, the compounds described herein include unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents, such as water and ethanol. Solvated forms of the compounds presented herein are also considered to be disclosed herein. Additionally, pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants (e.g., preservatives, stabilizers, wetting agents, or emulsifiers), solubility enhancers, salts for regulating osmotic pressure, buffers, and / or other therapeutically useful substances.

[0126] Methods for preparing compositions containing the compounds described herein include combining the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form solid, semi-solid, or liquid forms. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions containing the compounds, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The pharmaceutical compositions described herein may take the form of liquid solutions or suspensions, solid forms suitable for dissolution or suspension in liquid prior to use, or emulsions. These compositions also optionally contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like.

[0127] In some embodiments, pharmaceutical compositions comprising one or more compounds selected from the compounds of structure (I) are illustratively in the form of a liquid, where the drug is present in solution, suspension, or both. Typically, when the composition is administered as a suspension, a first portion of the drug is present in solution, and a second portion of the drug is present in granular form as a suspension in a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In another embodiment, the liquid composition is aqueous.

[0128] In certain embodiments, aqueous suspensions contain one or more polymers as suspending agents.Polymers include water-soluble polymers, such as cellulose polymers (e.g., hydroxypropylmethylcellulose), and water-insoluble polymers, such as cross-linked carboxyl-containing polymers.Specific pharmaceutical compositions described herein include mucoadhesive polymers selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0129] The pharmaceutical compositions also optionally include a solubilizing agent to aid in the dissolution of one or more compounds selected from the compounds of structure (I). The term "solubilizing agent" generally includes agents that result in the formation of a micellar or true solution of the drug. Certain acceptable nonionic surfactants, such as polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers.

[0130] In addition, the pharmaceutical compositions optionally contain one or more pH adjusting or buffering agents, including, for example, acids (e.g., acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid); bases (e.g., sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trishydroxymethylaminomethane); and buffers (e.g., citric acid / dextrose, sodium bicarbonate, and ammonium chloride). Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0131] The composition also optionally contains one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range, including salts containing sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0132] Other pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances, such as merfen and thiomersal, and stabilized chlorine dioxide, as well as quaternary ammonium compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0133] The composition may contain one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil, and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as Octoxynol 10 and Octoxynol 40.

[0134] The compositions may optionally include one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0135] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case the compositions typically contain a preservative.

[0136] In alternative embodiments, other delivery systems are used for hydrophobic pharmaceutical compounds. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also used. In further embodiments, the compounds described herein are delivered using sustained-release systems, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. A variety of sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compound for several weeks to over 100 days. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies for protein stabilization are used.

[0137] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizers. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium or zinc, or (n) combinations thereof.

[0138] In some embodiments, the concentration of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical composition of the present disclosure is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 16% ,15.75%,15.50%,15.25%,15%,14.75%,14.50%,14.25%,14%,13.75%,13.50%,13.25%,13%,12.75%,12.50%,12.25%12%,11.75%,11.50%,11.25%,11%,10.75%,10.50%,10.25%,10%,9.75%,9.50%,9.25%,9%,8.75%,8.50%,8.25%,8%, ,7.75%,7.50%,7.25%,7%,6.75%,6.50%,6.25%,6%,5.75%,5.50%,5.25%,5%,4.75%,4.50%,4.25%,4%,3.75%,3.50%,3.25%,3%,2.75%,2.50%,2.25%,2%,1.75%,1.50%,1.25%,1%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.07% , 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or greater than 0.0001% w / w, w / v, or v / v.

[0139] In some embodiments, the concentration of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical compositions of the present disclosure is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 10%, from about 0.08% to about 12%, from about 0.09% to about 26%, from about 0.10% to about 12%, from about 0.11% to about 13%, from about 0.12% to about 14%, from about 0.13% to about 15%, from about 0.14% to about 16%, from about 0.15% to about 17%, from about 0.16% to about 18%, from about 0.17% to about 19%, from about 0.18% to about 20%, from about 0.19% to about 21%, from about 0.20% to about 22%, from about 0.21% to about 23%, from about 0.22% to about 24%, from about 0.23% to about 25%, from about 0.24% to about 26%, from about 0.25% to about 27%, from about 0.26% to about 28%, from about 0.27% to about 29%, from about 0.28% to about 29%, from about 0.29% to about 30%, from about 0.30% to about 31%, from about 0.31% to about 31%, from about 0.32% to about 32%, from about The range is from about 0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, or from about 1% to about 10% w / w, w / v, or v / v.

[0140] In some embodiments, the amount of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical composition of the present disclosure is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g , 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g or less.

[0141] In some embodiments, the amount of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical composition of the present disclosure ranges from 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0142] Packaging materials used to package the pharmaceutical compositions described herein include, for example, those described in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material appropriate for the selected formulation and intended administration and mode of treatment. For example, a container contains one or more compounds described herein, optionally in a composition or in combination with another agent disclosed herein. The container optionally has a sterile access port (e.g., the container is an intravenous solution bag or a vial with a stopper pierceable by a hypodermic injection needle). Such kits optionally include the compound with an identifying description or label or instructions for use in the methods described herein.

[0143] For example, kits typically include one or more additional containers, each containing one or more of various materials (e.g., reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use with the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; labels and / or instructions for use on carriers, containers, vials, and / or tubes describing the contents, and package inserts containing the instructions. A set of instructions is also typically included. A label is optionally on or associated with a container. For example, a label is on a container when letters, numbers, or other characters comprising the label are attached, molded, or etched onto the container itself; a label is associated with a container when the label is present in a receptacle or carrier that holds the container (e.g., as a package insert). Additionally, labels are used to indicate that the contents are to be used for a particular therapeutic application. Furthermore, labels indicate how to use the contents, for example, in the methods described herein. In certain embodiments, the pharmaceutical compositions are provided in a pack or dispenser device containing one or more unit dosage forms comprising a compound provided herein. The pack may comprise, for example, metal or plastic foil, such as a blister pack. Alternatively, the pack or dispenser device may be accompanied by instructions for administration. Alternatively, the pack or dispenser may have associated therewith a notice on the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, the notice reflecting approval by the agency of the drug form for human or veterinary administration. Such notice may be, for example, labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. In some embodiments, a composition comprising a compound provided herein formulated in a compatible pharmaceutical carrier is prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0144] method RON belongs to the receptor tyrosine kinase subfamily. RON is encoded by the MST1R gene. RON is also known as the macrophage-stimulating protein receptor. RON is activated by the serum-derived growth factor macrophage-stimulating protein (MSP). RON gene transcription is essential for embryonic development and is crucial for regulating certain physiological processes. Activation of RON leads to activation of common receptor tyrosine kinase downstream signaling pathways, such as MAPK, PI3K, RAS-ERK, and beta-catenin. Furthermore, RON is involved in crosstalk with other signaling pathways, such as insulin-like growth factor 1 (IGF1R) and EGF receptor (EGFR), which are common tumorigenesis mechanisms. Certain embodiments provide methods or compositions for use in modulating these signaling pathways.

[0145] Embodiments of the present disclosure are useful as modulators of the RON pathway in a host species. RON inhibitors can also inhibit the activity of the RON pathway, which includes MSP, MBD4, SRC, and PI3K. Thus, compounds of structure (I) are useful for treating conditions mediated by these kinases.

[0146] The host or patient may belong to any mammalian species, such as a primate species, particularly humans, rodents (including mice, rats, and hamsters), rabbits, horses, cows, dogs, cats, etc. Animal models are valuable for experimental investigations to provide a model for the treatment of human disease.

[0147] Methods of treating a disease or disorder include administering to a subject in need thereof a compound of the present disclosure, as its stereoisomer, enantiomer, or tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of the present disclosure.

[0148] In some embodiments, the disease is cancer. In certain embodiments, the cancer is skin cancer, breast cancer, prostate cancer, lung cancer, pancreatic cancer, colon cancer, bone cancer, bladder cancer, rectal cancer, stomach cancer, esophageal cancer, tracheal cancer, pharyngeal cancer, cervical cancer, liver cancer, kidney cancer, brain cancer, thyroid cancer, testicular cancer, ovarian cancer, and cervical cancer. In some embodiments, the cancer is carcinoma, sarcoma, lymphoma, leukemia, blastoma, or germ cell tumor. In some embodiments, the cancer is bone cancer. In certain embodiments, the cancer includes bone tumors.

[0149] In certain embodiments, the disease is osteolysis or osteoporosis. Suppressing or treating osteolysis can include reducing bone metabolism, reducing the progression of bone loss, inhibiting osteoclasts, or a combination thereof. In some embodiments, the subject is diagnosed with a condition selected from inflammation, cyst, cancer, cancer with bone metastasis, and cancer-mediated bone destruction. Provided herein is a method for treating osteoporosis in a subject in need of treatment. Treating osteoporosis can include preventing osteoporosis, reducing the progression of osteoporosis, or a combination thereof.

[0150] In some embodiments, the inhibitor may act independently of the RANKL and / or TGFβ pathway. In certain embodiments, the compound may not affect the function of RANKL and / or TGFβ. In some embodiments, the compound may be selective or specific for RON. As used herein, a RON-selective inhibitor inhibits the activity of RON more strongly than it inhibits the activity of another protein, such as another receptor tyrosine kinase, under physiological conditions. Receptor tyrosine kinases other than RON include, for example, Met and Axl. For example, a RON-selective inhibitor may inhibit RON more strongly than it inhibits Met under physiological conditions. For example, a RON-selective inhibitor may inhibit RON more strongly than it inhibits Axl under physiological conditions.

[0151] In some embodiments, compounds of the present disclosure can inhibit the activity of RON at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 50-fold, or at least 100-fold more potently than they inhibit the activity of other receptor tyrosine kinases (e.g., Met or Axl).

[0152] In some embodiments, compounds of the present disclosure inhibit IC50 activity against other receptor tyrosine kinases. 50 However, IC for RON 50 It may be at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 50-fold, or at least 100-fold greater than

[0153] Embodiments of the present disclosure also relate to the use of compounds of structure (I) and / or physiologically acceptable salts thereof for the prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or modulated by RON pathway activity. Furthermore, embodiments of the present disclosure relate to the use of compounds of structure (I) and / or physiologically acceptable salts thereof for the manufacture of a medicament for the prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or modulated by RON pathway activity. In certain embodiments, the present disclosure provides the use of compounds of structure (I) or physiologically acceptable salts thereof for the manufacture of a medicament for the prophylactic or therapeutic treatment of RON-mediated disorders.

[0154] Therapeutic agents include agents for analgesia and inflammation, such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances produced by the biotransformation of selective hydrolysis products of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory drugs, analgesics and antipyretics, agents that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of inducible cyclooxygenase, selective inhibitors of inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, β-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers, and leukotriene inhibitors.

[0155] Another embodiment of the present disclosure relates to combinations in which at least one anti-inflammatory compound is an anti-monoclonal antibody (e.g., eculizumab or pexelizumab), a TNF antagonist (e.g., entanercept), or infliximab (which is an anti-TNF alpha monoclonal antibody).

[0156] The disclosed compounds of structure (I) can be administered in combination with other known therapeutic agents, including anti-cancer agents. As used herein, the term "anti-cancer agent" refers to any agent administered to a cancer patient for the purpose of treating the cancer.

[0157] In some embodiments, the anti-cancer agent belongs to the following categories:

[0158] Alkylating agents: such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosylate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechlorethamine, carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH-3024, VAL-0834;

[0159] Platinum compounds: e.g., carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;

[0160] DNA modifying agents: such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine, brostallicin, pixantrone, laromustine;

[0161] Topoisomerase inhibitors: e.g. etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan, amonafide, belotecan, elliptinium acetate, voreloxine;

[0162] Microtubule modulating agents: for example, cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabine, tesetaxel;

[0163] Antimetabolites: for example, asparaginase 3, azacitidine, levofolinate calcium, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacitarabine, raltitrexed, sapacitabine, tegafur, trimetrexate;

[0164] Anticancer antibiotics: for example, bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunulobicin, plicamycin; aclarubicin, peplomycin, pirarubicin;

[0165] Hormones / antagonists: e.g., abarelix, abiraterone, bicalutamide, buserelin, calstalon, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotrophin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epithiostanol, orteronel, enzalutamide;

[0166] Aromatase inhibitors: e.g., aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane;

[0167] Small molecule kinase inhibitors: e.g., crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinascik Rib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifamib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib.

[0168] In some embodiments, the agent administered in combination with a compound described herein includes any suitable agent usefully delivered by inhalation, such as an analgesic, e.g., codeine, dihydromorphine, ergotamine, fentanyl, or morphine; an antianginal agent, e.g., diltiazem; an antiallergic, e.g., cromoglycate, ketotifen, or nedocromil; an anti-infective, e.g., cephalosporin, penicillin, streptomycin, sulfonamide, tetracycline, or pentamidine; an antihistamine, e.g., methapyrilene; an anti-inflammatory, e.g., beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide, or fluticasone; an antitussive, e.g., noscapine; a bronchodilator, e.g., ephedrine, adrenaline, fenoterol, formoterol, or the like. anticholinergics such as ipratropium, atropine, or oxitropium; hormones such as cortisone, hydrocortisone, or prednisolone; xanthines such as aminophylline, choline theophyllinate, lysine theophyllinate, or theophylline; and therapeutic proteins and peptides such as insulin or glucagon. It will be apparent to those skilled in the art that, where appropriate, drugs may be used in the form of a salt (e.g., as an alkali metal salt or amine salt, or as an acid addition salt), or as an ester (e.g., a lower alkyl ester), or as a solvate (e.g., a hydrate) to optimize the activity and / or stability of the drug.

[0169] The drugs disclosed herein or other suitable drugs are administered according to the symptoms to be treated. Thus, in some embodiments, one or more of the disclosed compounds are co-administered with other drugs as described above. When used in combination therapy, the compounds described herein are administered simultaneously or separately with the second drug. This co-administration includes simultaneous administration of the two drugs in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the above drugs can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds disclosed herein and any of the above drugs can be administered simultaneously, where both drugs are in separate formulations. In another alternative, the compounds disclosed herein can be administered immediately after any of the above drugs, or vice versa. In some embodiments of the separate administration protocol, the compounds disclosed herein and any of the above drugs are administered within minutes, hours, or days.

[0170] In some embodiments, the compound of structure (I) is administered as a monotherapy. To identify signal transduction pathways or mechanistic pathways and to detect interactions between various signal transduction pathways, various scientists have developed appropriate models or model systems, such as cell culture models and transgenic animal models. Interacting compounds can be used to modulate signals to determine specific steps in the signal transduction cascade. Compounds of embodiments of the present disclosure can also be used as reagents to study kinase-dependent signal transduction pathways in animal and / or cell culture models or in clinical diseases mentioned in this application.

[0171] The methods of the disclosed embodiments can be carried out either in vitro or in vivo. The susceptibility of a particular cell to treatment with a compound of structure (I), whether during research or clinical application, can be particularly determined by in vitro testing. Typically, a culture of cells is combined with various concentrations of the compound for a period of time sufficient for the active agent to inhibit kinase activity, usually from about one hour to one week. In vitro treatment can be carried out using cells cultured from a biopsy sample or a cell line.

[0172] In some embodiments, the IC of a compound of structure (I) that inhibits kinase activity 50 was determined by the concentration of compound required to inhibit 50% of the kinase activity. Compounds of structure (I) have an IC50 of less than about 5 mM, preferably less than about 1 mM, and more preferably less than about 0.100 mM, as described in more detail in the Examples. 50 demonstrated its strength and worth.

[0173] The examples and preparations provided below further describe and illustrate the compounds of the present disclosure and methods for preparing and testing such compounds. It should be understood that the scope of the present disclosure is in no way limited by the scope of the following examples and preparations. In the following examples and throughout the specification and claims, molecules with a single stereocenter exist as a racemic mixture unless otherwise specified. Molecules with two or more stereocenters exist as a racemic mixture of diastereomers unless otherwise specified. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0174] Methods for making the compounds described herein are set forth below: Generally, the starting components can be obtained from commercial sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)), or prepared as described herein. [Example]

[0175] The following examples are provided for illustrative purposes.

[0176] Abbreviation ℃(degrees Celsius); 1 H NMR (proton nuclear magnetic resonance); ACN (acetonitrile); Boc (tert-butyloxycarbonyl); (Boc)O (di-tert-butyl dicarbonate); DCM (dichloromethane); DIPEA (N,N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); DMF (N,N-dimethylformamide); DMSO-d (deuterated dimethyl sulfoxide); eq (equivalent); EtOAc (ethyl acetate); EtOH (ethanol); g (gram); h (hour); HCl (hydrochloric acid); HPLC (high performance liquid chromatography); LCMS (liquid chromatography mass spectrometry); MeOH (methanol); mg (milligram); min (minute); mL (milliliter); μL (microliter); mmol (millimol); Pd(PPh) or "tetrakis" (tetrakis(triphenylphosphine)palladium(0)); SM (starting material); TEA (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TLC (thin layer chromatography); UPLC (ultra performance liquid chromatography).

[0177] Intermediate example 1 Synthesis of N-(4-((2-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka]

[0178] Step 1: Synthesis of ethyl 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate: [ka] To a stirred solution of ethyl (2E)-2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate (7.39 g, 30.8 mmol, 1.0 equiv.) and 4-fluorophenylhydrazine hydrochloride (5 g, 30.8 mmol, 1.0 equiv.) in toluene (25 mL), 10% aqueous sodium hydroxide (25 mL) was added dropwise at 0 °C. The mixture was then stirred at the same temperature for 10 min. The progress of the reaction was monitored by TLC. After the SM was consumed by TLC, the reaction solution was acidified with concentrated hydrochloric acid and diluted with water (100 mL). The mixture was then extracted with ethyl acetate (300 mL × 3), and the combined organic layers were dried over NaSO and concentrated under reduced pressure to give the title compound 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (9.2 g, yield 98.99%) as a brown oil. LCMS: 303.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1H), 7.66 - 7.62 (m, 2H), 7.44 (t, J=8.80 Hz, 2H), 4.31 (q, J=7.20 Hz, 2H), 1.29 (t, J=7.20 Hz, 3H).

[0179] Step 2: Synthesis of 2-methyl-5-[(3-phenyloxetan-3-yl)amino]pyridine-4-carboxylic acid: [ka] To a stirred solution of ethyl 2-methyl-5-[(3-phenyloxetan-3-yl)amino]pyridine-4-carboxylate (9 g, 29.8 mmol, 1.0 equiv.) in THF:MeOH (1:1) (90 mL) was added sodium hydroxide (5.96 g, 149 mmol, 5.0 equiv.) dissolved in water (50 mL). The reaction mixture was then stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and then diluted with water (200 mL). The reaction mixture was acidified with concentrated HCl under cooling and extracted with ethyl acetate (300 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the title compound 2-methyl-5-[(3-phenyloxetan-3-yl)amino]pyridine-4-carboxylic acid (6 g, 73.49% yield) as an off-white solid. LCMS: 273.1 (MH) + . 1 H NMR (400 MHz, DMSO-d6): δ 13.37 (brs, 1H), 8.24 (s, 1H), 7.65-7.62 (m, 2H), 7.43 (t, J=8.40 Hz, 2H).

[0180] Step 3: Synthesis of N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a stirred solution of 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (5.5 g, 20.1 mmol, 1.0 equiv.), 4-amino-2-fluorophenol (3.83 g, 30.1 mmol, 1.5 equiv.), and DIPEA (7.16 mL, 40.1 mmol, 2 equiv.) in DCM (100 mL) was added T3P (50% in ethyl acetate) (7.72 mL, 30.1 mmol, 3 equiv.) at room temperature. The reaction mixture was then stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water (200 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (350 mL × 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a brown, gummy liquid crude product. The crude compound was purified by flash column (100-200 silica mesh) using 30% ethyl acetate in hexane as the eluent to give the title compound N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (4 g, 52% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.45 (s, 1H), 9.72 (s, 1H), 8.28 (s, 1H), 7.63 - 7.57 (m, 3H), 7.47 - 7.43 (m, 2H), 7.24 (d, J =8.4 Hz, 1H), 6.93 (t, J=9.2 Hz, 1H). LCMS: 384.25 (M+H) + . .

[0181] Step 4: Synthesis of N-{4-[(2-chloropyrimidin-4-yl)oxy]-3-fluorophenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a solution of N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (2 g, 5.22 mmol, 1 equiv.) and 2,4-dichloropyrimidine (777 mg, 5.22 mmol, 1 equiv.) in DMF (20 mL) was added K2CO3 (517 mg, 5.22 mmol, 1 equiv.). The reaction mixture was then stirred at 80 °C for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, water (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 150 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a brown, gummy liquid crude product. The crude compound was purified by flash column (100-200 silica mesh) using 50% ethyl acetate in hexane as eluent to give the title compound N-{4-[(2-chloropyrimidin-4-yl)oxy]-3-fluorophenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (1.5 g, 57.98% yield) as a brownish solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 8.70 (d, J=5.60 Hz, 1H), 8.35 (s, 1H), 7.88 (d, J=12.40 Hz, 1H), 7.66 - 7.63 (m, 2H), 7.54 (d, J=8.80 Hz, 1H), 7.47 (t, J=8.80 Hz, 3H), 7.36 (d, J=5.60 Hz, 1H). LCMS: 496.53 (M+H) + .

[0182] Intermediate example 2 Synthesis of N-(4-((2-((3-aminocyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a stirred solution of N-(4-((2-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (1 g, 2.02 mmol, 1 equiv.) in DMF (10 mL) was added (1S)-(+)-10-camphorsulfonic acid (1.41 g, 6.05 mmol, 3 equiv.), followed by 1,3-cyclohexanediamine (461 mg, 4.03 mmol, 2 equiv.). The reaction mixture was stirred at 90° C. for 3 h. The progress of the reaction was followed by LCMS. After completion of the reaction, the reaction mixture was cooled to room temperature, ice-cold water (50 mL) was added, and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (30 mL), then dried over Na2SO4, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC using 0.1% FA in acetonitrile to give N-(4-((2-((3-aminocyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (200 mg, 17.29% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 8.35 (s, 2H), 8.21 - 8.18 (m, 1H), 7.83 - 7.80 (m, 1H), 7.65 - 7.61 (m, 2H), 7.49 - 7.44 (m, 3H), 7.34 (t, J=7.2 Hz, 1H), 7.15 (m, 1H), 6.28 (m, 1H), 3.77 - 3.74 (m, 2H), 1.97 - 1.70 (m, 3H), 1.59 - 1.47 (m, 2H), 1.37 - 1.31 (m, 1H), 1.16 - 1.07 (m, 1H), LCMS: 574.51 (M+H) + .

[0183] Intermediate example 3 Synthesis of N-(4-((2-((3-aminophenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka]

[0184] Step 1: Synthesis of N-(3-fluoro-4-((2-((3-nitrophenyl)amino)pyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a stirred solution of m-nitroaniline (418 mg, 3.03 mmol, 1.5 equiv.) and N-{4-[(2-chloropyrimidin-4-yl)oxy]-3-fluorophenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (1 g, 40.3 μmol, 1 equiv.), 4-methylbenzene-1-sulfonic acid hydrate (1.53 g, 8.07 μmol, 4 equiv.) was added at room temperature. The reaction mixture was then stirred at 90 °C for 10 h. The reaction progress was followed by TLC and LCMS. After completion of the reaction, the RM was cooled to room temperature, ice-cold water (50 mL) was added, and then extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude compound. The resulting crude residue was purified by column chromatography to give the title compound N-{3-fluoro-4-[2-(m-nitrophenylamino)-4-pyrimidinyloxy]phenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (630 mg, yield 52.28%). 1H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 10.12 (s, 1H), 8.50 (d, J=5.6 Hz, 2H), 8.35 (s, 1H), 8.01 - 7.78 (m, 2H), 7.71 (d, J=8.1 Hz, 1H), 7.72 - 7.59 (m, 2H), 7.59 - 7.10 (m,5H), 6.70 (d, J=5.6 Hz, 1H). LCMS: 598.1 (M+H) + .

[0185] Step 2: Synthesis of N-(4-((2-((3-aminophenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a stirred solution of N-(3-fluoro-4-((2-((3-nitrophenyl)amino)pyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (0.26 g, 435 μmol, 1 equiv.) in ethanol (4 mL), water (2 mL), and DMF (1 mL) at 0° C., iron (243 mg, 4.35 mmol, 10 equiv.) and ammonium chloride (466 mg, 8.7 mmol, 20 equiv.) were added. The reaction mixture was then stirred at 80° C. for 1 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOH and then filtered over a pad of diatomaceous earth (i.e., Celite®) and washed with water:DMF (2:1). The filtrate was added with water (10 mL) and sodium bicarbonate solution (3 mL) and extracted with 10% MeOH in DCM (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude compound. The resulting crude residue was purified by column chromatography to give the title compound N-(4-((2-((3-aminophenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (200 mg, 83.33% yield) as a green gummy solid. 1 H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 9.34 (s, 1H), 8.35 (d, J=5.6 Hz, 2H), 7.87 (d, J=12.8 Hz, 1H), 7.64 (dd, J=8.8, 4.8 Hz, 2H), 7.59 - 7.33 (m, 4H), 6.81 - 6.59 (m, 3H), 6.50 (d, J=5.6 Hz, 1H), 6.11 (d, J=8.4 Hz, 1H), 4.73 (s, 2H). LCMS: 568.2 (M+H) + .

[0186] Synthesis Example 1 Synthesis of N-(3-fluoro-4-((2-((3-morpholinophenyl)amino)pyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka]

[0187] Step 1: Synthesis of ethyl 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate: [ka] To a stirred solution of ethyl (2E)-2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate (7.39 g, 30.8 mmol, 1 equiv.) and 4-fluorophenylhydrazine hydrochloride (5 g, 30.8 mmol, 1 equiv.) in ice-cooled toluene (25 mL), 10% aqueous sodium hydroxide solution (2.5 g sodium hydroxide in 25 mL water) was added dropwise. The mixture was then stirred at the same temperature for 10 minutes. After the reaction solution was acidified with concentrated hydrochloric acid, water (100 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layers were then combined. After drying over Na2SO4, the solvent was removed under reduced pressure to give ethyl 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate as a brown oil (10 g, crude product). LCMS: 303.1 (M+H). + . 1 H NMR (400 MHz, DMSO-d6): δ=8.29 (s, 1H), 7.65 - 7.62 (m, 2H), 7.45 - 7.41 (m, 2H), 4.31 (q, J =14 Hz, 7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 2H).

[0188] Step 2: Synthesis of 2-methyl-5-[(3-phenyloxetan-3-yl)amino]pyridine-4-carboxylic acid: [ka] To a stirred solution of ethyl 2-methyl-5-[(3-phenyloxetan-3-yl)amino]pyridine-4-carboxylate (10 g, 33.1 mmol, 1.0 equiv.) in THF:MeOH (50 mL:50 mL) was added sodium hydroxide (6.62 g, 165 mmol, 5.0 equiv.) dissolved in water (50 mL), and the reaction mixture was stirred at room temperature for 2 hours. After complete conversion was confirmed by TLC, the reaction mixture was concentrated under reduced pressure and diluted with water. The reaction mixture was acidified with concentrated HCl under cooling and extracted with ethyl acetate. The organic layer was separated and concentrated under reduced pressure to give the title compound, 2-methyl-5-[(3-phenyloxetan-3-yl)amino]pyridine-4-carboxylic acid, as an off-white solid (6 g, 66.14%). 1 H NMR (400 MHz, DMSO-d6): δ=13.39 (br.s, 1H), 8.24 (s, 1H), 7.65 - 7.62 (m, 2H), 7.45 - 7.41 (m, 2H).

[0189] Step 3: Synthesis of N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a mixture of 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (260 mg, 948 μmol, 1 equiv), 4-amino-2-fluorophenol (181 mg, 1.42 mmol, 1.5 equiv), and diisopropylethylamine (339 μL, 1.9 mmol, 2 equiv) in DCM (2.6 mL) was added tripropyl-1,3,5,2λ 5 ,4λ 5 ,6λ 5N-trioxatriphosphinane-2,4,6-trione (365 μL, 1.42 mmol, 1.5 equiv.) was added at room temperature. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was then quenched with water (25 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with 0.5 M HCl (25 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product as a brown gummy liquid. The crude product was purified by flash column chromatography using 100-200 silica mesh with 30% ethyl acetate in n-hexane as the mobile phase to give N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide as an off-white solid (200 mg, 35.77%). LCMS: 384.29 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=10.44 (s, 1H), 9.71 (s, 1H), 8.27 (s, 1H), 7.63 - 7.57 (m, 3H), 7.47 - 7.43 (m, 2H), 7.23 (d, J =10 Hz, 1H), 6.93 (t, J=9.6 Hz, 1H).

[0190] Step 4: Synthesis of N-{4-[(2-chloropyrimidin-4-yl)oxy]-3-fluorophenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a solution of N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (300 mg, 783 μmol, 1 equiv.) and 2,4-dichloropyrimidine (233 mg, 1.57 mmol, 2 equiv.) in acetonitrile (20 mL) was added KCO (85.3 mg, 861 μmol, 1.1 equiv.) at room temperature. The reaction mixture was then stirred at 80° C. for 2 h. After 2 h, the reaction mixture was cooled to room temperature, and ice water (30 mL) was added, followed by extraction with ethyl acetate (3×50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude compound as a brown gum. The crude product was purified by flash column using 100-200 silica mesh with 30% ethyl acetate in hexane as the mobile phase to give N-{4-[(2-chloropyrimidin-4-yl)oxy]-3-fluorophenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (300 mg, 77.31%). LCMS: 496.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=10.85 (s, 1H), 8.70 (d, J=6 Hz, 1H), 8.35 (s, 1H), 7.87 (m, 1H), 7.66 - 7.63 (m, 2H), 7.54 (m, 1H), 7.49 - 7.44 (m, 3H), 7.36 (d, J=5.6 Hz, 1H).

[0191] Step 5: Synthesis of N-(3-fluoro-4-((2-((3-morpholinophenyl)amino)pyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a mixture of N-{4-[(2-chloropyrimidin-4-yl)oxy]-3-fluorophenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (150 mg, 303 μmol, 1 equiv.) and 3-(morpholin-4-yl)aniline (53.9 mg, 303 μmol, 1 equiv.) in DMF (5 mL) was added 4-methylbenzene-1-sulfonic acid hydrate (230 mg, 1.21 mmol, 4 equiv.) at room temperature. The reaction mixture was then stirred at 90 °C for 16 h. The reaction was cooled to room temperature, quenched with water (25 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure to give a light brown gum crude compound. The crude compound was purified by flash column using 100-200 silica mesh with 50% ethyl acetate in n-hexane as the mobile phase to give N-{3-fluoro-4-[(2-{[3-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)oxy]phenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (40 mg, 20.74%). LCMS: 638.71 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=10.84 (s, 1H), 9.44 (s, 1H), 8.38 (d, J=5.6 Hz, 1H), 8.34 (s, 1H), 7.86 (dd, J=12.4 Hz, 2 Hz, 1H), 7.66 - 7.63 (m, 2H), 7.53 - 7.40 (m, 4H), 7.08 (br.s, 1H), 7.02 - 7.00 (m, 1H), 6.93 (t, J=8 Hz, 1H), 6.54 (d, J=5.6 Hz, 1H), 6.48 (d, J=7.6 Hz, 1H), 3.69 (t, J=4.4 Hz, 4H), 2.93 (t, J=4.8 Hz, 4H). HPLC: 95.73 %.

[0192] Synthesis Example 2 Synthesis of N-(3-fluoro-4-{[6-(1-methyl-1H-imidazol-4-yl)thieno[3,2-D]pyrimidin-4-yl]oxy}phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka]

[0193] Step 1: Synthesis of N-[4-({6-bromothieno[3,2-d]pyrimidin-4-yl}oxy)-3-fluorophenyl]-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a stirred solution of N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (307 mg, 802 μmol, 1 equiv.) in DMF (5 mL), dipotassium carbonate (522 mg, 1.6 mmol, 2 equiv.) was added and stirred at room temperature for 0.5 h. After that, 6-bromo-4-chlorothieno[3,2-d]pyrimidine (0.2 g, 802 μmol, 1 equiv.) was added. The reaction mixture was stirred at room temperature for 2 h. After 2 hours, the reaction mixture was quenched with ice water (30 mL) to form a solid precipitate, which was filtered and dried under reduced pressure to give N-[4-({6-bromothieno[3,2-d]pyrimidin-4-yl}oxy)-3-fluorophenyl]-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide as an off-white solid (400 mg, 83.68%). LCMS: 596.59 (M). + , 598.59 (M+2) + . 1 H NMR (400 MHz, DMSO-d6): δ=8.72 (s, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 7.93 - 7.87 (m, 1H), 7.64 - 7.60 (m, 2H), 7.47 - 7.41 (m, 5H).

[0194] Step 2: Synthesis of 1-methyl-4-(tributylstannyl)-1H-imidazole: Scheme. [ka] To a stirred solution of 4-iodo-1-methylimidazole (2 g, 9.62 mmol, 1 equiv.) in DCM (5 mL) was added dropwise 3 M ethylmagnesium bromide (2.66 mL, 7.69 mmol, 0.8 equiv.) at room temperature under nitrogen protection. After 30 min, tributyl(chloro)stannane (3.29 mL, 11.5 mmol, 1.2 equiv.) was added and stirred at room temperature for 16 h. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution (50 mL), diluted with water (30 mL), and then extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to give 1-methyl-4-(tributylstannyl)-1H-imidazole (3.3 g, 92.47%), which was used directly in the next step. LCMS: 373.2 (M+H). + .

[0195] Step 3: Synthesis of N-(3-fluoro-4-{[6-(1-methyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-yl]oxy}phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] A stirred solution of N-[4-({6-bromothieno[3,2-d]pyrimidin-4-yl}oxy)-3-fluorophenyl]-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (0.2 g, 335 μmol, 1 equiv.) and 1-methyl-4-(tributylstannyl)-1H-imidazole (187 mg, 503 μmol, 1.5 equiv.) in DMF (3 mL) was degassed with nitrogen for 10 minutes. Tetrakis(triphenylphosphane)palladium (38 mg, 33.5 μmol, 0.1 equiv.) was then added and again degassed with nitrogen for 3 minutes. The reaction was then stirred at 130 °C for 16 hours. The reaction mixture was then cooled to room temperature, quenched with water (20 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column using 100-200 silica mesh with a 10% MeOH mobile phase in DCM to give N-(3-fluoro-4-{[6-(1-methyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-yl]oxy}phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide as an off-white solid (79 mg, 39.42%). LCMS: 598.5 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=10.85 (s, 1H), 8.64 (s, 1H), 8.37 (s, 1H), 8.02 (s, 1H), 7.90 - 7.87 (m, 1H), 7.81 - 7.80 (m, 2H), 7.67 - 7.63 (m, 2H), 7.55 - 7.51 (m, 2H), 7.49 - 7.45 (m, 2H), 3.76 (s, 3H). HPLC: 98.81 %

[0196] Synthesis Example 3 Synthesis of N-(4-{[2-amino-3-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl]oxy}-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka]

[0197] Step 1: Synthesis of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine: [ka] A mixture of 4-chloro-3-iodopyridin-2-amine (1.5 g, 5.89 mmol, 1 equiv.), 2-fluoro-4-nitrophenol (1.85 g, 11.8 mmol, 2 equiv.), and DIPEA (1.54 mL, 8.84 mmol, 1.5 equiv.) in NMP (5 mL) was placed in a glass pressure vessel and rapidly heated to 170 °C. Heating was continued for 18 h. The volatile components were removed under reduced pressure, and the viscous residue was poured into ice-water (300 mL). The mixture was adjusted to pH 7.5 with saturated aqueous NaHCO3 and extracted with ethyl acetate (3 × 100 mL). The combined ethyl acetate layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by Combiflash (40 g) with gradient elution from 10 to 15% ethyl acetate in n-hexane to give 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine as a yellow solid (1.1 g, 49.7%). LCMS: 376.23 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=8.40 (dd, J=10.8 Hz, 2.4 Hz, 1H), 8.14 - 8.12 (m, 1H), 7.88 (d, J=5.6 Hz, 1H), 7.33 (t, J=8.4 Hz, 1H), 6.41 (br.s, 2H), 6.20 (d, J=5.6 Hz, 1H).

[0198] Step 2: Synthesis of 4-(2-fluoro-4-nitrophenoxy)-3-(1-methyl-1H-imidazol-4-yl)pyridin-2-amine: [ka] A stirred solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (600 mg, 1.6 mmol, 1 equiv.) and 1-methyl-4-(tributylstannyl)-1H-imidazole (891 mg, 2.4 mmol, 1.5 equiv.) in DMF (5 mL) was degassed under nitrogen for 15 minutes. After 15 minutes, tetrakis(triphenylphosphine)palladium(0) (185 mg, 160 μmol, 0.1 equiv.) was added to the reaction mixture and heated at 130 °C for 16 hours. The reaction mixture was then cooled to room temperature, quenched with water (20 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column using 100-200 silica mesh with 50% ethyl acetate in hexane as the mobile phase to give 4-(2-fluoro-4-nitrophenoxy)-3-(1-methyl-1H-imidazol-4-yl)pyridin-2-amine as a light brown solid (160 mg, 30.38%). LCMS: 330.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=13.38 (s, 1H), 11.23 (s, 1H), 9.12 (t, J=8.8 Hz, 1H), 8.14 - 8.09 (m, 2H), 7.96 (t, J=5.6 Hz, 2H), 7.85 (s, 1H), 6.68 (d, J=5.6 Hz, 1H), 3.78 (s, 3H).

[0199] Step 3: Synthesis of 4-(4-amino-2-fluorophenoxy)-3-(1-methyl-1H-imidazol-4-yl)pyridin-2-amine: [ka] To a stirred solution of 4-(2-fluoro-4-nitrophenoxy)-3-(1-methyl-1H-imidazol-4-yl)pyridin-2-amine (0.1 g, 304 μmol, 1 equiv.) in a mixture of ethanol (1 mL) and DMF (1 mL) was added iron powder (170 mg, 3.04 mmol, 10 equiv.) and NHCl (325 mg, 6.07 mmol, 20 equiv.) at 0° C. The reaction was then stirred at 80° C. for 3 h. The reaction mixture was then cooled to room temperature, diluted with ethanol, and filtered through a pad of diatomaceous earth (i.e., Celite®). The filtrate was concentrated, diluted with water (20 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to provide the crude compound. The crude compound was purified by flash column using 100-200 silica mesh with 50% ethyl acetate in hexane as the mobile phase to give 4-(4-amino-2-fluorophenoxy)-3-(1-methyl-1H-imidazol-4-yl)pyridin-2-amine as a light brown solid (30 mg, 22%). LCMS: 300.39 (M+H) + .

[0200] Step 4: Synthesis of N-(4-{[2-amino-3-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl]oxy}-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a mixture of 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (27.5 mg, 0.1 mmol, 1 equiv.) and 4-(4-amino-2-fluorophenoxy)-3-(1-methyl-1H-imidazol-4-yl)pyridin-2-amine (30 mg, 0.1 mmol, 1 equiv.) in DMF (3 mL), DIPEA (0.035 mL, 0.2 mmol, 2 equiv.) and HATU (47.2 mg, 0.2 mmol, 2 equiv.) were added at room temperature. The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was then quenched with ice water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column using 100-200 silica mesh with 10% MeOH in DCM as the mobile phase to give N-(4-{[2-amino-3-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl]oxy}-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (20 mg, 35.92%). LCMS: 556.65 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=12.19 (s, 1H), 10.88 (s, 1H), 10.55 (s, 1H), 8.62 (t, J=9.2 Hz, 1H), 8.31 (s, 1H), 7.88 (s, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.78 (s, 1H), 7.73 (dd, J=13.6 Hz, 2 Hz, 1H), 7.64 - 7.61 (m, 2H), 7.45 (t, J=8.8 Hz, 2H), 7.31 (d, J=10.4 Hz, 1H), 6.48 (d, J=5.6 Hz, 1H), 3.77 (s, 3H). HPLC: 99.23%.

[0201] Synthesis Example 4 Synthesis of N-(4-((2-bromopyrazolo[1,5-a]pyrimidin-7-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka]

[0202] Step 1: Synthesis of N-(4-((2-bromopyrazolo[1,5-a]pyrimidin-7-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a stirred solution of N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (330 mg, 860 μmol, 1 equiv.) in DMF (5 mL) was added cesium carbonate (561 mg, 1.72 mmol, 2 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 0.5 h. Next, 2-bromo-7-chloropyrazolo[1,5-a]pyrimidine (200 mg, 860 μmol, 1 equiv.) was added to the reaction mixture and stirred at room temperature for 2 h. After 2 h, the reaction mixture was quenched with ice-water (3 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column using 100-200 silica mesh with 50% ethyl acetate in hexane as the mobile phase to give N-(4-((2-bromopyrazolo[1,5-a]pyrimidin-7-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide as an off-white solid (200 mg, 40.13%). LCMS: 579.62 (M) + . 1H NMR (400 MHz, DMSO-d6): δ=10.95 (s, 1H), 8.44 (d, J=4.8 Hz, 1H), 8.36 (s, 1H), 8.02 (dd, J=12.8 Hz, 2 Hz, 1H), 7.70 - 7.62 (m, 4H), 7.47 (t, J=8.8 Hz, 2H), 7.01 (s, 1H), 6.35 (d, J=4.8 Hz, 1H). HPLC: 98.31 %.

[0203] Synthesis Example 5 Synthesis of N-(4-{[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]oxy}-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka]

[0204] Step 1: Synthesis of 4-(4-amino-2-fluorophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine: [ka] To a stirred solution of 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine (170 mg, 493 μmol, 1 equiv.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (154 mg, 739 μmol, 1.5 equiv.) in 1,4-dioxane (5 mL) and water (2 mL), potassium carbonate (204 mg, 1.48 mmol, 3 equiv.) was added and the mixture was degassed with nitrogen gas for 5 minutes. Next, tetrakis(triphenylphosphane)palladium (57 mg, 49.3 μmol, 0.1 equiv.) was added at room temperature and the mixture was again degassed with nitrogen gas. The reaction mixture was then stirred at 90 °C for 16 hours. The reaction progress was monitored by TLC / LCMS. After completion of the reaction, the reaction mixture was concentrated, diluted with ethyl acetate (20 mL), and washed with saturated NaHCO3 solution (3 mL) and water (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column using 100-200 silica mesh with 5% MeOH in DCM as the mobile phase to give 4-(4-amino-2-fluorophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (65 mg, 44.09%). LCMS: 300.28 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=7.87 (s, 1H), 7.70 (d, J=5.6 Hz, 1H), 7.60 (s, 1H), 6.89 (t, J=9.2 Hz, 1H), 6.47 (dd, J=13.2 Hz, 2.4 Hz, 1H), 6.37 (dd, J=8.8 Hz, 2 Hz, 1H), 5.84 (d, J=5.6 Hz, 1H), 5.75 (s, 2H), 5.37 (s, 2H), 3.88 (s, 3H).

[0205] Step 2: Synthesis of N-(4-{[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]oxy}-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a solution of 4-(4-amino-2-fluorophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (65 mg, 217 μmol, 1 equiv.) and 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (59.5 mg, 217 μmol, 1 equiv.) in DMF (2 mL), DIPEA (77.5 μL, 434 μmol, 2 equiv.) and HATU (102 mg, 434 μmol, 2 equiv.) were added at room temperature. The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was then quenched with ice water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column using 100-200 silica mesh with 10% MeOH in DCM as the mobile phase to give N-(4-{[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]oxy}-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (25 mg, 20.72%). LCMS: 556.56 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=10.79 (s, 1H), 8.33 (s, 1H), 7.90 (s, 1H), 7.85 (dd, J=12.8 Hz, 2 Hz, 1H), 7.75 (d, J=5.6 Hz, 1H), 7.65 - 7.61 (m, 3H), 7.49 - 7.44 (m, 3H), 7.27 (t, J=8.8 Hz, 1H), 5.93 (d, J=5.6 Hz, 1H),5.69 (s, 2H), 3.89 (s, 3H). HPLC: 99.65 %.

[0206] Synthesis Example 6 Synthesis of N-(4-((2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxamide [ka]

[0207] Step 1: Synthesis of 1-azido-4-fluorobenzene: [ka] To a stirred solution of 4-fluoroaniline (1 g, 9 mmol, 1 equiv.) in 10 mL of 15% HCl (5 mL water: 5 mL concentrated HCl), a solution of NaNO (745 mg, 10.8 mmol, 1.2 equiv.) in water (30 mL) was added dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at this temperature for 30 minutes. Next, sodium azide (1.17 g, 18 mmol, 2 equiv.) in water (5 mL) was added dropwise to the above reaction mixture at 0 °C. After the addition, the reaction was stirred at 0 °C for 1 hour. The progress of the reaction was monitored by TLC. After the reaction was complete, the product was extracted with ethyl acetate (50 mL) and subsequently washed with water to a neutral pH. The organic layer was then dried over anhydrous sodium sulfate and concentrated by distillation at room temperature to give 1-azido-4-fluorobenzene as a crude product (1 g, crude), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ=7.10 - 7.04 (m, 2H), 7.03 - 6.99 (m, 2H).

[0208] Step 2: Synthesis of ethyl 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylate: [ka] To a stirred solution of the appropriate 1-azido-4-fluorobenzene (1 g, 7.29 mmol, 1 equiv.) was added ethyl 4,4,4-trifluoro-3-oxobutanoate (1.09 mL, 7.29 mmol, 1 equiv.) and diethylamine (377 μL, 3.65 mmol, 0.5 equiv.) in DMSO (10 mL) and heated at 80° C. for 4 h. After 4 h, the reaction mixture was poured into ice water and extracted with dichloromethane (50 mL). The organic phase was separated, washed with brine, dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash column using 100-200 silica mesh with 20% ethyl acetate in hexane as the mobile phase to give ethyl 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylate as a break red oil (1.4 g, 63.31%). LCMS: 304.36 (M+H). + . 1 H NMR (400 MHz, CDCl3): δ=7.51 - 7.48 (m, 2H), 7.32 - 7.28 (m, 2H), 4.53 (q, J=14.4 Hz, 7.2 Hz, 2H), 1.47 (t, J=7.2 Hz, 3H)

[0209] Step 3: Synthesis of 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylic acid: [ka] To a stirred solution of ethyl 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylate (1.4 g, 4.62 mmol, 1.0 equiv) in EtOH:HO (10 mL:10 mL) was added sodium hydroxide (369 mg, 9.23 mmol, 2.0 equiv) at room temperature and stirred at 50 °C for 4 h. After complete conversion was confirmed by TLC, the reaction mixture was concentrated under reduced pressure to give a crude residue, which was diluted with water and washed with DCM. The aqueous layer was acidified with 10% HCl solution under cooling to give a precipitate. The precipitate was collected by filtration and dried under reduced pressure to give 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylic acid as an off-white solid (1.15 g, 90.52%). LCMS: 274.0 (MH). + . 1 H NMR (400 MHz, DMSO-d6): δ=14.14 (br, 1H), 7.82 - 7.79 (m, 2H), 7.54 - 7.49 (m, 2H).

[0210] Step 4: Synthesis of N-(4-((2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxamide: [ka] To a mixture of 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylic acid (91.9 mg, 334 μmol, 1 equiv.) and 4-(4-amino-2-fluorophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (100 mg, 334 μmol, 1.2 equiv.) in DMF (5 mL) was added DIPEA (119 μL, 668 μmol, 2 equiv.) and HATU (157 mg, 668 μmol, 2 equiv.) at room temperature. The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was then quenched with ice water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column using 100-200 silica mesh with 10% MeOH in DCM as the mobile phase to give N-(4-((2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxamide as an off-white solid (85 mg, 45%). LCMS: 557.46 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=11.25 (s, 1H), 7.95 (dd, J=12.8 Hz, 2.4 Hz, 1H), 7.91 (s, 1H), 7.85 - 7.82 (m, 2H), 7.76 (d, J=5.6 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.62 (s, 1H), 7.55 (t, J=8.8 Hz, 2H), 7.29 (t, J=8.8 Hz, 1H), 5.95 (d, J=6 Hz, 1H), 5.70 (s, 2H), 3.89 (s, 3H). HPLC: 99.39%.

[0211] Synthesis Example 7 Synthesis of N-(3-fluoro-4-{[2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-A]pyrimidin-7-yl]oxy}phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka]

[0212] Step 1: Synthesis of 3-(1-methyl-1H-imidazol-4-yl)-1H-pyrazol-5-amine: [ka] To a stirred solution of 3-bromo-1H-pyrazol-5-amine (1 g, 6.17 mmol, 1 equiv.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.28 g, 6.17 mmol, 1 equiv.) in 1,4-dioxane (20 mL) and water (5 mL), dipotassium carbonate (1.71 g, 12.3 mmol, 2 equiv.) was added. The reaction mixture was then degassed with nitrogen for 5 minutes, and tetrakis(triphenylphosphane)palladium (357 mg, 309 μmol, 0.05 equiv.) was added and degassed again for 3 minutes. After degassing, the reaction mixture was stirred at 100 °C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of diatomaceous earth (i.e., Celite®), and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column using 100-200 silica mesh with 10-20% MeOH in DCM as the mobile phase to give 3-(1-methyl-1H-imidazol-4-yl)-1H-pyrazol-5-amine as an off-white solid (290 mg, 28.79%). LCMS: 164.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=11.48 (br.s, 1H), 7.87 (s, 1H), 7.63 (s, 1H), 5.49 (s, 1H), 4.59 (br.s, 2H), 3.83 (s, 3H).

[0213] Step 2: Synthesis of ethyl 2-(1-methyl-1H-imidazol-4-yl)-7-oxo-4H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylate: [ka] To a suspension of 3-(1-methyl-1H-imidazol-4-yl)-1H-pyrazol-5-amine (140 mg, 858 μmol, 1 equiv.) in acetic acid (3 mL) was added 1-ethyl 3-propyl(2Z)-2-(ethoxymethylidene)propanedioate (269 μL, 1.29 mmol, 1.5 equiv.) at room temperature, and the resulting suspension was heated at 120 °C for 4 h. The suspension was cooled to room temperature and concentrated in vacuo to give the crude product. The crude product was triturated with cold ethanol, and the solid precipitate was filtered, washed with cold ethanol, and dried in vacuo to give ethyl 2-(1-methyl-1H-imidazol-4-yl)-7-oxo-4H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylate as an off-white solid (100 mg, 40.57%). 1 H NMR (400 MHz, DMSO-d6): δ=13.09 (s, 1H), 8.55 (s, 1H), 8.26 (s, 1H), 7.92 (s, 1H), 6.50 (s, 1H), 4.23 (q, J=14.4 Hz, 6.8 Hz, 2H), 3.89 (s, 3H), 1.29 (t, J=6.8 Hz, 3H).

[0214] Step 3: Synthesis of 2-(1-methyl-1H-imidazol-4-yl)-7-oxo-4H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid: [ka] To a suspension of ethyl 2-(1-methyl-1H-imidazol-4-yl)-7-oxo-4H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylate (210 mg, 731 μmol, 1 equiv.) in EtOH (3 mL) at room temperature was added NaOH (73.1 mg, 1.83 mmol, 2.5 equiv.) dissolved in 2 mL of water. The resulting suspension was heated at 100° C. for 3.5 h. The suspension was cooled to room temperature, the EtOH was concentrated in vacuo, diluted with water (10 mL), and acidified using 5% citric acid solution (5 mL) to form a white suspension. The suspension was stirred for another 30 minutes, filtered, washed with water, and the solid compound was dried to give 2-(1-methyl-1H-imidazol-4-yl)-7-oxo-4H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (190 mg, 100%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ=12.85 (br, 1H), 8.66 (s, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 6.60 (s, 1H), 3.89 (s, 3H).

[0215] Step 4: Synthesis of 2-(1-methyl-1H-imidazol-4-yl)-4H,7H-pyrazolo[1,5-a]pyrimidin-7-one: [ka] A mixture of 2-(1-methyl-1H-imidazol-4-yl)-7-oxo-4H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (3.1 g, 12 mmol) in Dowtherm (2 mL) was heated at 240° C. for 2.5 hours. At that time, the mixture was cooled to room temperature and diluted with hexanes (100 mL). The tan precipitate was filtered, resuspended in hexanes (100 mL), stirred, filtered, and washed with hexanes (100 mL) to afford 2-(1-methyl-1H-imidazol-4-yl)-4H,7H-pyrazolo[1,5-a]pyrimidin-7-one as an off-white solid (110 mg, 69.73%). LCMS: 216.1 (M+H). + . 1H NMR (400 MHz, DMSO-d6): δ=12.30 (s, 1H), 8.20 (s, 1H), 7.87 (s, 1H), 7.81 (t, J=5.6 Hz, 1H), 6.35 (s, 1H), 5.65 (d, J=7.2 Hz, 1H), 3.88 (s, 3H).

[0216] Step 5: Synthesis of 2-bromo-7-chloropyrazolo[1,5-a]pyrimidine: [ka] To 2-(1-methyl-1H-imidazol-4-yl)-4H,7H-pyrazolo[1,5-a]pyrimidin-7-one (110 mg, 511 μmol, 1 equiv.) was slowly added POCl3 (5 mL) and N,N-diisopropylethylamine (196 μL, 1.12 mmol, 2.2 equiv.) at room temperature. The reaction mixture was heated to reflux for 16 h. The mixture was cooled to room temperature, and most of the solvent was evaporated. The resulting residue was diluted with ethyl acetate (100 mL), poured slowly into water (100 mL), and the pH was adjusted to 7.5 with saturated NaHCO3 solution, then stirred for 15 min. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated to give the crude compound. The crude compound was purified by flash column using 100-200 silica mesh with 5% MeOH in DCM as the mobile phase to give 2-bromo-7-chloropyrazolo[1,5-a]pyrimidine (50 mg, 41.87%) as an off-white solid. LCMS: 234.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=8.45 (d, J=4.8 Hz, 1H), 8.32 (s, 1H), 7.98 (s, 1H), 7.33 (d, J=4.8 Hz, 1H), 7.09 (s, 1H), 3.92 (s, 3H).

[0217] Step 6: Synthesis of N-(3-fluoro-4-{[2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]oxy}phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a stirred solution of N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (65.6 mg, 171 μmol, 1 equiv.) in DMF (5 mL), cesium carbonate (112 mg, 342 μmol, 2 equiv.) was added at room temperature and stirred for 0.5 h. Next, 4-{7-chloropyrazolo[1,5-a]pyrimidin-2-yl}-1-methyl-1H-pyrazole (40 mg, 171 μmol, 1 equiv.) was added to the reaction mixture at room temperature. Again, the reaction mixture was stirred at room temperature for 2 h. Next, ice water (10 mL) was added to the reaction mixture, which was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by Combiflash (12 g) using a gradient elution of 60% ethyl acetate in hexane to give N-(3-fluoro-4-{[2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]oxy}phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide as a white solid (30 mg, 30.19%). LCMS: 581.53 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=10.94 (s, 1H), 8.36 - 8.32 (m, 3H), 8.02 - 7.99 (m, 2H), 7.71 - 7.61 (m, 4H), 7.47 (t, J=8.8 Hz, 2H), 6.96 (s, 1H), 6.18 (d, J=5.2 Hz, 1H), 3.91 (s, 3H). HPLC: 99.90%.

[0218] Synthesis Examples 8-10 The following compounds were prepared in a manner similar to that described herein, using appropriately substituted starting materials and intermediates: [Table A]

[0219] Synthesis Example 11 Synthesis of N-(3-fluoro-4-((2-((2-morpholinoethyl)amino)pyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 28) [ka] To a mixture of N-{4-[(2-chloropyrimidin-4-yl)oxy]-3-fluorophenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (0.2 g, 403 μmol, 1 equiv.) and 2-(morpholin-4-yl)ethan-1-amine (52.5 mg, 403 μmol, 1 equiv.) in DMF (5 mL) was added ethylbis(propan-2-yl)amine (215 μL, 1.21 mmol, 3 equiv.) at room temperature. The reaction mixture was then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, ice water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude residue was purified by preparative HPLC to afford the title compound N-{3-fluoro-4-[(2-{[2-(morpholin-4-yl)ethyl]amino}pyrimidin-4-yl)oxy]phenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (35 mg, 14.72% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 8.32 (s, 1H), 8.17 (s, 1H), 7.84-7.81 (m, 1H), 7.65 - 7.62 (m, 2H), 7.46 (t, J=8.80 Hz, 3H), 7.34 (t, J=8.80 Hz, 1H), 6.27 (d, J=5.60 Hz, 1H), 3.47 (m, 5H), 3.04 (m, 2H), 2.15 (m, 4H). LCMS: 590.2 (M+H) + .

[0220] Synthesis Example 12 Synthesis of N-(3-fluoro-4-((2-((1-methylpiperidin-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 27) [ka] To a mixture of N-{4-[(2-chloropyrimidin-4-yl)oxy]-3-fluorophenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (0.2 g, 403 μmol, 1 equiv.) and 1-methylpiperidin-4-amine (46.1 mg, 403 μmol, 1 equiv.) in DMF (5 mL) was added ethylbis(propan-2-yl)amine (215 μL, 1.21 mmol, 3 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, ice water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 25 mL). The combined organic phase was dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give the title compound N-[3-fluoro-4-({2-[(1-methylpiperidin-4-yl)amino]pyrimidin-4-yl}oxy)phenyl]-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (45 mg, 19.45% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.79 (s, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 7.81 (d, J=10.80 Hz, 1H), 7.65 - 7.62 (m, 2H), 7.49-7.44 (m, 3H), 7.34 (t, J=8.80 Hz, 1H), 7.24-7.01 (m, 1H), 6.25 (brs, 1H), 3.68-3.66 (m, 1H), 2.76-2.67 (m, 2H), 2.21-2.09 (m, 3H), 2.01-1.97 (m, 1H), 1.79-1.62 (m, 3H), 1.47-1.45 (m, 1H), 1.39-1.34 (m, 1H). LCMS: 574.2 (M+H) + .

[0221] Synthesis Example 13 In a similar manner as above, using appropriately substituted starting materials and intermediates, the following compounds were prepared: [Table B]

[0222] Synthesis Example 14 Synthesis of N-(4-((2-((3-(dimethylphosphoryl)phenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 26) [ka]

[0223] Step 1: Synthesis of N-(4-((2-((3-(dimethylphosphoryl)phenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a stirred solution of N-{4-[(2-chloropyrimidin-4-yl)oxy]-3-fluorophenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (200 mg, 403 μmol, 1 equiv.) and 3-iodoaniline (88.4 mg, 403 μmol, 1 equiv.) in DMF (20 mL) was added 4-methylbenzene-1-sulfonic acid hydrate (307 mg, 1.61 mmol, 4 equiv.) at room temperature. The reaction mixture was stirred at 90 °C for 10 h. The progress of the reaction was followed by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to room temperature, ice-cold water (50 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by Combiflash using 20-25% ethyl acetate in n-hexane as the eluent to give the title compound N-[3-fluoro-4-({2-[(3-iodophenyl)amino]pyrimidin-4-yl}oxy)phenyl]-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (150 mg, 54.81% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 9.77 (s, 1H), 8.43 (d, J=5.60 Hz, 1H), 8.34 (s, 1H), 7.94 9s, 1H), 7.89 (dd, J=2.00 Hz, 12.80 Hz, 1H), 7.66 - 7.63 (m, 2H), 7.55 - 7.53 (m, 1H), 7.49 - 7.41 (m, 4H), 7.20 (d, J=8.00 Hz, 1H), 6.89 (t, J=8.0 Hz, 1H), 6.63 (d, J=5.6 Hz, 1H).

[0224] Step 2: Synthesis of N-(4-((2-((3-(dimethylphosphoryl)phenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a stirred solution of N-[3-fluoro-4-({2-[(3-iodophenyl)amino]pyrimidin-4-yl}oxy)phenyl]-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (100 mg, 14.7 μmol, 1 equiv.) in 1,4-dioxane (3 mL), tripotassium phosphate (34.4 mg, 162 μmol, 1.1 equiv.) was added and the mixture was purged with N gas for 10 min. Then, [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (8.53 mg, 14.7 μmol, 0.1 equiv.) and dimethyl(oxo)-λ 5 N-phosphanylium (28.4 mg, 369 μmol, 2.5 equiv.) was added. The reaction mixture was purged with N gas for 3 minutes, and then Pd(dba) (6.75 mg, 7.37 μmol, 0.05 equiv.) was added. The reaction mixture was microwaved at 110° C. for 2 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through a pad of diatomaceous earth (i.e., Celite®). The filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by preparative HPLC to obtain the title compound N-{4-[(2-{[3-(dimethylphosphoryl)phenyl]amino}pyrimidin-4-yl)oxy]-3-fluorophenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (45 mg, 48.57% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 9.76 (s, 1H), 8.42 (d, J=5.60 Hz, 1H), 8.36 (s, 1H), 7.89 - 7.81 (m, 2H), 7.72 - 7.63 (m, 3H), 7.54 - 7.42 (m, 4H), 7.26 - 7.21 (m, 2H), 6.61 (d, J=5.60 Hz, 1H), 1.56 (d, J=13.20 Hz, 6H), LCMS: 629.3 (M+H) + .

[0225] Synthesis Example 15 Synthesis of N-[3-fluoro-4-({2-[(4-fluorophenyl)amino]pyrimidin-4-yl}oxy)phenyl]-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 25) [ka] To a stirred solution of N-{4-[(2-chloropyrimidin-4-yl)oxy]-3-fluorophenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (200 mg, 403 μmol, 1 equiv.) and 4-fluoroaniline (44.8 mg, 403 μmol, 1 equiv.) in DMF (8 mL) was added 4-methylbenzene-1-sulfonic acid hydrate (307 mg, 1.61 mmol, 4 equiv.) at room temperature. The reaction mixture was stirred at 90 °C for 10 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, water (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 75 mL). The combined organic phase was dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give the title compound N-[3-fluoro-4-({2-[(4-fluorophenyl)amino]pyrimidin-4-yl}oxy)phenyl]-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (20 mg, 8.69% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 9.69 (s, 1H), 8.39 (d, J=5.20 Hz, 1H), 8.36 (s, 1H), 7.86 (dd, J=2.40 Hz, 12.60 Hz, 1H), 7.66 - 7.63 (m, 2H), 7.53-7.39 (m, 6H), 6.90 (t, J=8.80 Hz, 1H), 6.58 (d, J=5.60 Hz, 1H), LCMS: 571.2 (M+H) + .

[0226] Synthesis Examples 16-26 The following compounds were prepared in a manner similar to that described herein, using appropriately substituted starting materials and intermediates: [Table C-1] [Table C-2] [Table C-3] [Table C-4]

[0227] Synthesis Example 27 Synthesis scheme of N-(4-((2-amino-3-(dimethylphosphoryl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (compound 17) [ka]

[0228] Step 1: Synthesis of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine: [ka] To a mixture of 4-chloro-3-iodopyridin-2-amine (80 g, 314 mmol) and 2-fluoro-4-nitrophenol (98.8 g, 2 equiv., 629 mmol) in N-methyl-2-pyrrolidone (240 mL), ethylbis(propan-2-yl)amine (82.1 mL, 1.5 equiv., 472 mmol) was added. The reaction mixture was placed in a glass pressure vessel (sealed tube) and rapidly heated at 170 °C for 18 h. The reaction progress was monitored by TLC. After completion of the reaction, the volatile components were removed under reduced pressure, and the viscous residue was poured into ice water (500 mL). The pH of the mixture was then adjusted to 7.5 with saturated aqueous NaHCO3. The aqueous layer was extracted with ethyl acetate (3 × 600 mL). The ethyl acetate phase was separated, washed with brine (100 mL), and then dried over Na2SO4. The organic layer was concentrated under reduced pressure to give the crude product residue. The crude compound was purified by column chromatography using silica 60-120 (eluted with 10-15% ethyl acetate in n-hexane) to give the title compound 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (40 g, 33.92% yield) as a pale yellow solid. LCMS: 376.00 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=8.39 (dd, J=10.8 Hz, 2.4 Hz, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.87 (d, J=5.2 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 6.41 (s, 2H), 6.19 (d, J=5.6 Hz, 1H).

[0229] Step 2: Synthesis of 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine: [ka] To a stirred solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (40 g, 10.7 mmol, 1 equiv.) in ethanol (400 mL), water (40 mL), and DMF (40 mL) was added iron powder (59.6 g, 107 mmol, 10 equiv.) and ammonium chloride (2.28 g, 214 mmol, 20 equiv.) at 0° C. The reaction mixture was then stirred at 80° C. for 1 hour. The hot reaction mixture was filtered through a pad of diatomaceous earth (i.e., Celite®), and the filter cake was washed with DMF and MeOH. The filtrate was concentrated, then diluted with water (300 mL) and sodium bicarbonate solution (100 mL), and extracted with 10% MeOH in DCM (3×100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to provide the crude compound. The crude compound was purified by flash column using 100-200 silica mesh with 30% ethyl acetate in hexane as eluent to give 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine (22 g, 59.76% yield). LCMS: 346.00 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=7.70 (d, J=5.6 Hz, 1H), 6.94 (t, J=9.2 Hz, 1H), 6.49 (dd, J=13.2 Hz, 2.4 Hz, 1H), 6.40 (dd, J=8.8 Hz, 2.0 Hz, 1H), 6.13 (s, 2H), 5.71 (d, J=5.6 Hz, 1H), 5.45 (s, 2H).

[0230] Step 3: Synthesis of (2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)dimethylphosphine oxide: [ka] To a stirred solution of 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine (22 g, 63.7 mmol) in 1,4-dioxane (220 mL), potassium phosphate tripotassium (21.6 g, 1.6 equiv., 102 mmol) was added. Then, [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (5.53 mg, 0.15 equiv., 9.56 mmol) was added to the above reaction mixture, which was then purged with N gas for 30 minutes. After 30 minutes, dimethyl(oxo)-λ 5 -Phosphanilium (14.7 g, 3 equiv., 191 mmol) and palladium(2+) diacetate (2.15 g, 0.15 equiv., 9.56 mmol) were added to the reaction mixture at room temperature and purged again with N2 gas for 30 minutes. The reaction mixture was stirred at 130 °C for 3 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated to give the crude residue. The crude compound was purified by Combiflash using 3% MeOH in DCM as the eluent to give the title compound 4-(4-amino-2-fluorophenoxy)-3-(dimethylphosphoryl)pyridin-2-amine (9 g, 47.82% yield) as a pale green liquid. LCMS: 296.23 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=7.87 (d, J=5.6 Hz, 1H), 6.97 (t, J=8.8 Hz, 1H), 6.49 (d, J=13.2 Hz, 1H), 6.40 (d, J=8.0 Hz, 1H), 5.77-5.71 (s, 1H), 5.48 (s, 2H), 1.77 (d, J=18.8 Hz, 6H).

[0231] Step 4: Synthesis of N-(4-((2-amino-3-(dimethylphosphoryl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a stirred solution of [2-amino-4-(4-amino-2-fluorophenoxy)-3-pyridyl]dimethylphosphine oxide (9 g, 30.5 mmol) and 1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxylic acid (10 g, 1.2 equiv., 36.6 mmol) in tetrahydrofuran (100 mL, 10 vol.), chloro(dimethylamino)methylenebis(methyl)azanium hexafluoride phosphate(1-) (25.7 g, 3 equiv., 91.4 mmol) and N-ethylbis(isopropyl)amine (27.2 mL, 5 equiv., 152 mmol) were added at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, water (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 150 mL). The ethyl acetate layer was separated, washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude residue. The crude compound was purified by column chromatography on silica 60-120 (eluting with 2-3% MeOH in DCM) to give the desired compound (60% pure by LCMS). The compound was again purified by reverse-phase chromatography (using 0.1% TFA in water and acetonitrile as eluent) to give N-{4-[2-amino-3-(dimethylphosphoryl)-4-pyridyloxy]-3-fluorophenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide-methane (1 / 1) (1.2 g, 2.11 mmol) as a white solid. LCMS: 552.58 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ=10.92 (s, 1H), 8.35 (s, 1H), 8.04 (d, J=6.8 Hz, 1H), 7.94 (dd, J=12.4 Hz, 2.4 Hz, 1H), 7.65-7.57 (m, 3H), 7.53-7.44 (m, 3H), 6.25-6.23 (m, 1H), 1.91 (d, J=14.0 Hz, 6H).

[0232] Synthesis Example 28 Synthesis of N-(4-((2-((3-(1-acryloylpiperidin-3-yl)phenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (compound 38) [ka]

[0233] Step 1: Synthesis of tert-butyl 5-(m-nitrophenyl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate: [ka] To a stirred solution of m-bromonitrobenzene (1 g, 4.95 mmol, 1 equiv.) in 1,4-dioxane (6 mL, 70.3 mmol) and water (4 mL, 222 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate (1.84 g, 1.2 equiv., 5.94 mmol) and dipotassium carbonate (205 mg, 3 equiv., 1.49 mmol) were added, and the reaction mixture was purged with argon gas for 5 minutes. Then, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (362 mg, 0.1 equiv., 495 μmol) was added. The reaction mixture was again degassed with argon for 3 minutes and stirred at 80 °C for 4 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by Combiflash on a silica column using 0 to 50% ethyl acetate in hexane to give the title compound tert-butyl 5-(m-nitrophenyl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate (1.1 g, 3.61 mmol, 73.01% yield) as a solid. 1H NMR (400 MHz, DMSO) δ 8.23 ​​(s, 1H), 8.50 (d, J=8.0 Hz, 2H), 7.67 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 6.37 - 6.35 (m, 1H), 4.30 (s, 2H), 3.57 (t, J=5.6 Hz, 2H), 2.36 (s, 1H), 1.50 (s, 9H).

[0234] Step 2: Synthesis of tert-butyl 3-(m-aminophenyl)-1-piperidinecarboxylate: [ka] To a stirred solution of tert-butyl 5-(m-nitrophenyl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate (1.2 g, 3.94 mmol) in ethanol (10 mL, 171 mmol) was added platinum dioxide (0.4 g, 1.76 mmol) under inert conditions at 0 °C. The reaction temperature was raised to room temperature and stirred overnight under H2 gas. The progress of the reaction was followed by TLC and crude LCMS. The reaction was concentrated in vacuo. It was then dissolved in ethyl acetate (100 mL) and washed with brine (100 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the crude product. This compound was purified by flash chromatography using 5-50% EA in hexane to give the desired compound tert-butyl 3-(m-aminophenyl)-1-piperidinecarboxylate (0.8 g, 73.41%). 1 H NMR (400 MHz, DMSO) δ 6.93 (t, J=7.6 Hz, 1H), 6.42 - 6.37 (m, 3H), 4.98 (s, 2H), 3.97 - 3.95 (m, 2H), 2.71 - 2.66 (m, 2H), 2.42 - 2.32 (s, 1H), 1.85 - 1.82 (m, 1H) 1.70 - 1.60 (m, 1H), 1.59 - 1.45 (m, 2H), 1.40 (s, 9H).

[0235] Step 3: Synthesis of N-(4-{2-[m-(1-acryloyl-3-piperidyl)phenylamino]-4-pyrimidinyloxy}-3-fluorophenyl)-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide: [ka] To a stirred solution of N-[4-(2-chloro-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (0.5 g, 1.01 mmol) and tert-butyl 3-(m-aminophenyl)-1-piperidinecarboxylate (362 mg, 1.3 equiv., 1.31 mmol) in dimethylformamide (10 mL, 129 mmol) was added 4-methylbenzene-1-sulfonic acid hydrate (767 mg, 4 equiv., 4.03 mmol). The reaction mixture was then stirred at 90 °C for 10 h. The reaction was then monitored by TLC and LCMS. Ice water (40 mL) was then added to the reaction mixture, which was then extracted with ethyl acetate (3 × 75 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography using 30% ethyl acetate in hexane to give the title compound N-(3-fluoro-4-{2-[m-(3-piperidyl)phenylamino]-4-pyrimidinyloxy}phenyl)-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (180 mg, 28.08% yield). 1H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 9.62 (s, 1H), 8.41 - 8.38 (m, 2H), 7.88 (d, J=13.2 Hz, 1H), 7.66 - 7.62 (m, 2H), 7.54 (d, J=7.2 Hz, 1H), 7.50 - 7.40 (m, 6H), 7.35 (s, 1H), 7.11 (d, J=8.0 Ha, 2H), 7.07 - 7.05 (m, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.58 (d, J=5.2 Hz, 1H), 3.26 (s, 2H), 2.92 - 2.77 (m, 2H), 2.28 (s, 2H), 2.42 - 2.32 (s, 1H), 1.87 - 1.69 (m, 2H) 1.64 - 1.56 (m, 1H), LCMS: 636.56 (M+H + ).

[0236] Step 4: Synthesis of N-(4-{2-[m-(1-acryloyl-3-piperidyl)phenylamino]-4-pyrimidinyloxy}-3-fluorophenyl)-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide: [ka] To a stirred solution of N-(3-fluoro-4-{2-[m-(3-piperidyl)phenylamino]-4-pyrimidinyloxy}phenyl)-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (150 mg, 236 μmol) in dichloromethane (15 mL, 234 mmol), triethylamine (98.7 μL, 3 equiv., 708 μmol) was added dropwise at 0° C. After 5 minutes, acryloyl chloride (17.2 μL, 0.9 equiv., 212 μmol) was added dropwise under inert conditions. The reaction mixture was stirred for 6 hours. The progress of the reaction was followed by LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a crude residue. The crude compound was purified by preparative HPLC to give the title compound N-(4-{2-[m-(1-acryloyl-3-piperidyl)phenylamino]-4-pyrimidinyloxy}-3-fluorophenyl)-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (12 mg, 7.37% yield). 1 H NMR (400 MHz, DMSO) δ 10.16 (s, 1H), 8.30 - 8.27 (m, 2H), 7.62 (d, J=9.2 Hz, 1H), 7.54 - 7.49 (m, 2H), 7.46 - 7.42 (m, 2H), 7.22 - 7.16 (m, 4H), 7.09 (s, 1H), 6.85 - 6.83 (m, 2H), 6.74 - 6.66 (m, 1H), 6.48 (d, J=5.6 Hz, 1H), 5.76 (dd, J=1.6 Hz, 10.6 Hz, 1H), 4.75 - 4.65 (m, 1H), 4.12 - 3.90 (m, 1H), 3.16 - 2.99 (m, 1H), 2.79 (t, J=8.0 Hz, 1H), 2.64 - 2.58 (m, 1H), 2.02 - 1.96 (m, 1H) 1.90 - 1.86 (m, 1H), 1.55 (m, 2H), LCMS: 690.72 (M+H + ).

[0237] Synthesis Example 29 Synthesis of (E)-N-(4-((2-((3-(4-(dimethylamino)but-2-enamido)phenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 40) [ka] N-{4-[2-(m-aminophenylamino)-4-pyrimidinyloxy]-3-fluorophenyl}-2-(p-fluorophenyl)-3-(trifluoromethyl)-1,2λ in DMF (5 mL) 5 To a stirred solution of (E)-diazole-4-carboxamide (100 mg, 176 μmol, 1 equiv.) and (E)-4-(dimethylamino-2-butenoic acid) (27.3 mg, 211 μmol, 1.2 equiv.), 2-methyl-2,6,8-triaza-6,7-decadiene-hydrogen chloride (1 / 1) (50.7 mg, 264 μmol, 1.5 equiv.) and 1H-1,2,3-benzotriazol-1-ol:water (1:1) (40.5 mg, 264 μmol, 1.5 equiv.) were added, followed by N-ethylbis(isopropyl)amine (92.1 μL, 529 μmol, 3 equiv.) at room temperature. The reaction was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give the title compound N-[4-(2-{m-[(E)-3-(dimethylamino)-1-propenylcarbonylamino]phenylamino}-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (20 mg, 16.72% yield) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 10.13 (s, 1H), 9.66 (s, 1H), 8.46 - 8.35 (m, 2H), 7.86 (d, J=12.7 Hz, 1H), 7.74 (s, 1H), 7.65 (dd, J=8.7, 4.9 Hz, 2H), 7.58 - 7.33 (m, 4H), 7.25 (d, J=7.8 Hz, 2H), 6.99 (t, J=8.1 Hz, 1H), 6.72 (dd, J=15.3, 6.8 Hz, 1H), 6.56 (d, J=5.6 Hz, 1H), 6.39 (d, J=15.7 Hz, 1H), 3.57 (s, 2H), LCMS: 679.68. (M+H) + .

[0238] Synthesis Example 30 Synthesis of N-(4-((2-((3-acrylamidophenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 42) [ka] N-{4-[2-(m-aminophenylamino)-4-pyrimidinyloxy]-3-fluorophenyl}-2-(p-fluorophenyl)-3-(trifluoromethyl)-1,2λ in DCM (7.5 mL) 5To a stirred solution of 4-diazole-1-carboxamide (150 mg, 264 μmol, 1 equiv.) was added trimethylamine (110 μL, 792 μmol, 3 equiv.). After stirring for 5 minutes, acryloyl chloride (1.71 μL, 21.1 μmol, 1.2 equiv.) was added at room temperature. The reaction mixture was stirred at room temperature for 10 minutes. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction was quenched with water (15 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give the title compound N-(3-fluoro-4-{2-[m-(vinylcarbonylamino)phenylamino]-4-pyrimidinyloxy}phenyl)-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (40 mg, 24.35% yield) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 10.03 (s, 1H), 9.66 (s, 1H), 8.40 - 8.35 (m, 2H), 7.86 (dd, J=12.6, 2.4 Hz, 1H), 7.73 (s, 1H), 7.66 - 7.63 (m, 2H), 7.52 - 7.39 (m, 4H), 7.26 - 7.23 (m, 2H), 6.99 (t, J=8.0 Hz, 1H), 6.56 (d, J=5.6 Hz, 1H), 6.47 - 6.40 (m, 1H), 6.22 (dd, J=17.0, 2.0 Hz, 1H), 5.71 (dd, J=10.0, 2.0 Hz, 1H), LCMS: 622.59 (M+H) + .

[0239] Synthesis Example 31 Synthesis of N-(4-((2-((3-((S)-2-((E)-4-(dimethylamino)-N-methylbut-2-enamido)propanamido)cyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 41) [ka]

[0240] Step 1: Synthesis of tert-butyl (E)-N-(4-(dimethylamino)but-2-enoyl)-N-methyl-L-alaninate: [ka] To a stirred solution of (E)-4-(dimethylamino)but-2-enoic acid (100 mg, 0.774 mmol, 1 equiv.) in DCM (5 mL) was added oxalyl chloride (0.1 mL, 1.16 mmol, 1.5 equiv.), followed by DMF (cat.) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After the starting material was consumed by TLC, this solution was added to a stirred solution of tert-butyl methyl-L-alaninate (123 mg, 0.774 mmol, 1 equiv.) and trimethylamine (0.32 mL, 2.32 mmol, 3 equiv.) in DCM (5 mL) at 0 °C. The reaction mixture was stirred for 2 h until the starting material was completely consumed. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using 2-3% MeOH in DCM to give the title compound (E)-N-(4-(dimethylamino)but-2-enoyl)-N-methyl-L-alaninate tert-butyl ester (70 mg, 33% yield) as a pale yellow syrup. 1 H NMR (400 MHz, DMSO) δ 6.66 - 6.53 (m, 2H), 4.85 - 4.74 (m, 1H), 3.08 - 3.03 (m, 2H), 2.95 (s, 2H), 2.72 (s, 1H), 2.17 (s, 6H), 1.38 (s, 9H), 1.33 - 1.26 (m, 3H), LCMS: 271.2 (M+H) + .

[0241] Step 2: Synthesis of (E)-N-(4-(dimethylamino)but-2-enoyl)-N-methyl-L-alanine: [ka] To a stirred solution of tert-butyl (E)-N-(4-(dimethylamino)but-2-enoyl)-N-methyl-L-alaninate (50 mg, 0.185 mmol, 1 equiv.) in 1,4-dioxane (2 mL) was added 4 M HCl in dioxane (0.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 4 h. The volatiles were evaporated under reduced pressure to give the crude residue as a brown solid, (E)-N-(4-(dimethylamino)but-2-enoyl)-N-methyl-L-alaninate HCl salt (50 mg). 1 H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 6.86 (d, J=14.8 Hz, 1H), 6.66 - 6.50 (m, 1H), 4.96 - 4.78 (m, 1H), 3.91 - 3.83 (m, 2H), 2.99 (s, 2H), 2.78 (s, 6H), 1.39 - 1.30 (m, 3H), LCMS: 215.2 (M+H) + .

[0242] Step 3: Synthesis of N-(4-((2-((3-((S)-2-((E)-4-(dimethylamino)-N-methylbut-2-enamido)propanamido)cyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a stirred solution of N-(4-((2-((3-aminocyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (90 mg, 0.157 mmol, 1 equiv.) in DCM (3 mL), triethylamine (47.6 mg, 0.471 mmol, 3 equiv.) and HATU (119 mg, 0.314 mmol, 2 equiv.) were added, and the reaction mixture was stirred for 5 minutes. After that, (E)-N-(4-(dimethylamino)but-2-enoyl)-N-methyl-L-alanine (33.6 mg, 0.157 mmol, 1 equiv.) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was followed by TLC. After completion of the reaction, the reaction mixture was quenched with water (15 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated under reduced pressure to give a crude residue. The crude compound was purified by preparative HPLC using 0.1% FA in acetonitrile ACN to give a white solid of N-(4-((2-((3-((S)-2-((E)-4-(dimethylamino)-N-methylbut-2-enamido)propanamido)cyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (35 mg, 28.97% yield). 1H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 8.33 - 8.30 (m, 1H), 8.18 (d, J=5.2 Hz, 1H), 7.92 - 7.72 (m, 2H), 7.65 - 7.61 (m, 2H), 7.46 (t, J=8.8 Hz, 3H), 7.33 (t, J=8.8 Hz, 3H), 7.06 (m, 1H), 6.59 - 6.49 (m, 2H), 6.24 (m, 1H), 4.99 - 4.52 (m, 1H), 4.04 - 3.93 (m, 1H), 3.75 - 3.58 (m, 1H), 3.01 - 2.90 (m, 5H), 2.14 (s, 6H), 1.90 - 1.46 (m, 5H), 1.25 - 1.09 (m, 6H), LCMS: 768.83 (MH) + .

[0243] Synthesis Example 32 Synthesis of (E)-N-(4-((2-((3-(4-(dimethylamino)but-2-enamido)cyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 39) [ka] To a stirred solution of N-(4-((2-((3-aminocyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (90 mg, 0.157 mmol, 1 equiv) in DCM (3 mL) was added triethylamine (47.6 mg, 0.471 mmol, 3 equiv), followed by HATU (119 mg, 0.314 mmol, 2 equiv), and the reaction mixture was stirred for 5 min, followed by the addition of (E)-4-(dimethylamino)but-2-enoic acid (31.1 mg, 0.188 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (15 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (20 mL), then dried over NaSO and concentrated under reduced pressure. The crude compound was purified by preparative HPLC using 0.1% FA in acetonitrile to give (E)-N-(4-((2-((3-(4-(dimethylamino)but-2-enamido)cyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (50 mg, 46.54% yield) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 8.34 (s, 1H), 8.18 (d, J=5.6 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.81 - 7.76 (m, 1H), 7.65 - 7.61 (m, 2H), 7.48 - 7.44 (m, 3H), 7.37 - 7.32 (m, 1H), 7.05 - 6.99 (m, 1H), 6.54 - 6.47 (m, 2H), 6.24 - 6.13 (m, 1H), 5.98 (d, J=15.2 Hz, 1H), 4.06 - 4.05 (m, 1H), 3.78 - 3.57 (m, 1H), 2.97 - 2.94 (m, 2H), 2.12 (d, J=4.0 Hz, 6H), 1.95 - 1.90 (m, 1H), 1.87 - 1.49 (m, 4H), 1.35 - 1.28 (m, 1H), 1.23 - 1.16 (m, 1H), 1.10 - 0.99 (m, 1H), LCMS: 685.85 (M+H) + .

[0244] Synthesis Example 33 Synthesis of N-(4-((2-((3-acrylamidocyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 44) [ka] To a stirred solution of N-(4-((2-((3-aminocyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (200 mg, 0.349 mmol, 1 equiv.) in DMF (5 mL) was added DIPEA (135 mg, 1.05 mmol, 3 equiv.), EDCI (100 mg, 0.523 mmol, 1.5 equiv.), and HOBt (70.7 mg, 0.523 mmol, 1.5 equiv.), and acrylic acid (27.6 mg, 0.384 mmol, 1.1 equiv.). The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The crude compound was purified by preparative HPLC using 0.1% TFA in acetonitrile and water to give the title compound N-(4-((2-((3-acrylamidocyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (peak 1 and peak 2) as a white solid.

[0245] Conclusion: Preparative HPLC separated two peaks: Peak 1 (10 mg) and Peak 2 (15 mg).

[0246] Analysis of Peak 1: 1 H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.82 (d, J=11.6 Hz, 2H), 7.65 - 7.61 (m, 2H), 7.49 - 7.44 (m, 3H), 7.37 (t, J=8.8 Hz, 1H), 6.34 (m, 2H), 6.07 - 6.02 (m, 1H), 5.54 (d, J=10.0 Hz, 1H), 4.06 (m, 2H), 1.75 (s, 1H), 1.64 - 1.47 (m, 7H), LCMS: 628.60 (M+H)+ .

[0247] Analysis of Peak 2: 1 H NMR (400 MHz, DMSO) δ 10.80 (s, 1H), 8.35 (s, 1H), 8.21 (d, J=5.6 Hz, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.80 (d, J=12.4 Hz, 1H), 7.65 - 7.61 (m, 2H), 7.48 - 7.44 (m, 3H), 7.37 (t, J=8.8 Hz, 1H), 6.34 (m, 1H), 6.21 - 6.14 (m, 1H), 6.07 - 6.02 (m, 1H), 5.54 (dd, J=2.4, 9.6 Hz, 1H), 3.74 (m, 2H), 3.24 - 3.16 (m, 1H), 1.98 - 1.90 (m, 2H), 1.75 - 1.71 (m, 3H), 1.28 - 1.23 (m, 2H), 1.20 - 1.13 (m, 2H), 1.11 - 0.99 (m, 2H), LCMS: 628.64 (M+H) + .

[0248] Synthesis Example 34 Synthesis scheme of N-(4-((3-(dimethylphosphoryl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 52) and N-(4-((3-(dimethylphosphoryl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 53) [ka]

[0249] Step 1: Synthesis of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine: [ka] A mixture of 4-chloro-3-iodopyridine (1 g, 4.18 mmol) and 2-fluoro-4-nitrophenol (984 mg, 1.5 equiv., 6.26 mmol) in N-methyl-2-pyrrolidone (15 mL) was added to N,N-ethylbis(propan-2-yl)amine (2.18 mL, 3 equiv., 12.5 mmol) in a glass pressure vessel (sealed tube). The reaction mixture was heated at 170 °C for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the volatile components were removed under reduced pressure, and the viscous residue was poured into ice water (500 mL). The pH of the mixture was adjusted to approximately 7.5 with saturated aqueous NaHCO3 solution, followed by extraction with ethyl acetate (100 mL). The ethyl acetate layer was separated, washed with brine (30 mL), and dried over Na2SO4. The organic layer was concentrated under reduced pressure to give the crude residue. The crude compound was purified by column chromatography using silica 60-120 (10-15% ethyl acetate in n-hexane as eluent) to give the title compound 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine (0.6 g, 1.67 mmol) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ=8.97 (s, 1H), 8.48-8.43 (m, 2H), 8.17 (d, J=8.80 Hz, 1H), 7.50 (t, J=8.40 Hz, 1H), 7.07 (d, J=5.60 Hz, 1H), LCMS: 361.0 (M+H) + .

[0250] Step 2: Synthesis of 3-fluoro-4-((3-iodopyridin-4-yl)oxy)aniline: [ka] To a stirred solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine (0.4 g, 1.11 mmol) in ethanol (4 mL, 68.5 mmol), water (0.5 mL, 27.8 mmol), and dimethylformamide (0.5 mL, 6.46 mmol) at 0° C., iron (620 mg, 10 equiv., 11.1 mmol) and ammonium chloride (1.19 g, 20 equiv., 22.2 mmol) were added. The reaction mixture was then stirred at 80° C. for 1 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOH (10 mL), filtered through a pad of diatomaceous earth (i.e., Celite®), and washed with water and DMF (2:1). The filtrate was concentrated, and then the aqueous layer was quenched with aqueous sodium bicarbonate (50 mL) and extracted with 10% MeOH in DCM (3 × 200 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography using 10% MeOH in DCM as the eluent to give the title compound 3-fluoro-4-(3-iodo-4-pyridyloxy)aniline (250 mg, 757 μmol) as a colorless semi-solid. 1 H NMR (400 MHz, DMSO-d6): δ=8.79 (s, 1H), 8.31 (d, J=5.20 Hz, 1H), 7.01 (t, J=8.80 Hz, 1H), 6.56 (d, J=5.60 Hz, 1H), 6.53-6.49 (m, 1H), 6.42 (d, J=8.40 Hz, 1H), 5.52 (s, 2H), LCMS: 331.0 (M+H) + .

[0251] Step 3: Synthesis of (4-(4-amino-2-fluorophenoxy)pyridin-3-yl)dimethylphosphine oxide: [ka] To a stirred solution of 3-fluoro-4-(3-iodo-4-pyridyloxy)aniline (0.4 g, 1.21 mmol) in 1,4-dioxane (8.36 mL, 98.1 mmol) was added potassium phosphate tripotassium (772 mg, 3 equiv., 3.64 mmol). The reaction mixture was purged with N gas for 20 minutes. Then, dimethyl(oxo)-λ 5 To the mixture was added 4-phosphanylium (280 mg, 3 equiv., 3.64 mmol) and palladium(2+) diacetate (136 mg, 0.5 equiv., 606 μmol). The reaction mixture was again purged with N2 gas for 10 minutes. The reaction mixture was then stirred at 120 °C for 6 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, excess dioxane was evaporated under reduced pressure to give the crude residue. The crude compound was purified by column chromatography on silica gel (100-200 mesh) using 10% MeOH in DCM as the eluent to give the title compound [4-(4-amino-2-fluorophenoxy)-3-pyridyl]dimethylphosphine oxide (250 mg, 892 μmol) as a semisolid. 1 H NMR (400 MHz, DMSO-d6): δ=8.75 (d, J=7.60 Hz, 1H), 8.57 (d, J=5.60 Hz, 1H), 7.04 (t, J=8.80 Hz, 1H), 6.65-6.64 (m, 1H), 6.52 (d, 6.45-6.39 (m, 1H), 5.54 (s, 2H), 1.77 (d, J=13.6 Hz, 6H), LCMS: 281.1 (M+H) + .

[0252] Step 4: Synthesis of N-(4-((3-(dimethylphosphoryl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide and N-(4-((3-(dimethylphosphoryl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a stirred solution of [4-(4-amino-2-fluorophenoxy)-3-pyridyl]dimethylphosphine oxide (0.3 g, 1.07 mmol) and 1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxylic acid (352 mg, 1.2 equiv., 1.28 mmol) in tetrahydrofuran (135 mL, 1.66 mol), chloro(dimethylamino)methylenebis(methyl)azanium hexafluoride phosphate(1-) (601 mg, 2 equiv., 2.14 mmol) and N-ethylbis(isopropyl)amine (956 μL, 5 equiv., 5.35 mmol) were added at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give the crude residue. The crude compound was purified on silica gel (100-200 mesh) using 15% MeOH in DCM as the eluent to give fraction 1 (70 mg, 62% pure by LCMS) and fraction 2 (170 mg, 42% pure by LCMS). Fraction 1 was purified again by preparative HPLC with 0.1% FA in water and acetonitrile to give N-{4-[3-(dimethylphosphoryl)-4-pyridyloxy]-3-fluorophenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (7 mg, 13.1 μmol) as a white solid, and fraction 2 was purified again by preparative HPLC with 0.1% FA in water and acetonitrile to give N-(4-((3-(dimethylphosphoryl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (41 mg, 13.1 μmol) as a white solid.

[0253] Analysis of compound 52: 1H NMR (400 MHz, DMSO-d6): δ=10.89 (s, 1H), 8.81 (d, J=7.20 Hz, 1H), 8.60 (d, J=6.00 Hz, 1H), 8.35 (s, 1H), 7.94 (dd, J=2.00 Hz, 12.80 Hz, 1H), 7.66-7.57 (m, 3H), 7.52-7.44 (m, 3H), 7.76 (t, J=4.80 Hz, 1H), 1.81 (d, J=14.00 Hz, 6H), LCMS: 537.2 (M+H) + .

[0254] Analysis of compound 53: 1 H NMR (400 MHz, DMSO-d6): δ=10.32 (s, 1H), 8.60 (s, 1H), 8.48 (d, J=7.60 Hz, 1H), 8.30 (d, J=6.80 Hz, 1H), 7.73-7.69 (m, 2H), 7.49-7.42 (m, 3H), 7.39-7.36 (m, 1H), 7.14-7.11 (m, 1H), 1.86 (d, J=13.60 Hz, 6H), LCMS: 537.1 (M+H) + .

[0255] Synthesis Example 35 Synthesis of N-{4-[5-(dimethylphosphoryl)-4-pyrimidinyloxy]-3-fluorophenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (compound 54) [ka]

[0256] Step 1: Synthesis of 3-fluoro-4-(5-iodo-4-pyrimidinyloxy)aniline: [ka] To a mixture of 4-chloro-5-iodopyrimidine (1 g, 4.16 mmol, 1 equiv.) and 4-amino-2-fluorophenol (793 mg, 1.5 equiv., 6.24 mmol) in dimethylformamide (20 mL), dicesium carbonate (2.03 g, 1.5 equiv., 6.24 mmol) was added and placed in a glass pressure vessel (sealed tube) and rapidly heated to 150 °C. Heating was continued for 3 h. The progress of the reaction was followed by TLC. After completion of the reaction, the reaction mixture was quenched with ice-cold water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated under reduced pressure to give the crude residue. The crude compound was purified by flash column using 100-200 silica mesh with 2-3% MeOH in DCM as eluent to give the title compound 3-fluoro-4-(5-iodo-4-pyrimidinyloxy)aniline (0.4 g, 29.05% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ=9.01 (s, 1H), 8.64 (s, 1H), 6.97 (t, J=8.80 Hz, 1H), 6.46 (dd, J=2.40 Hz, 13.20 Hz, 1H), 6.38 (dd, J=1.20 Hz, 8.60 Hz, 1H), 5.42 (s, 2H), LCMS: 332.0 (M+H) + .

[0257] Step 2: Synthesis of [4-(4-amino-2-fluorophenoxy)-5-pyrimidinyl]dimethylphosphine oxide: [ka] To a stirred solution of 3-fluoro-4-(5-iodo-4-pyrimidinyloxy)aniline (0.4 g, 1.21 mmol, 1 equiv.) in 1,4-dioxane (7.69 mL) was added potassium phosphate tripotassium (410 mg, 1.6 equiv., 1.93 mmol). The reaction mixture was degassed with argon gas for 20 minutes. Next, [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (105 mg, 0.15 equiv., 0.181 mmol) and dimethyl(oxo)-λ 5 -phosphanylium (0.244 mL, 3 equiv., 3.62 mmol) was added. The reaction mixture was then degassed again with argon gas for 10 minutes. Palladium(2+) diacetate (13.6 mg, 0.05 equiv., 0.060 mmol) was then added at room temperature under an argon atmosphere. The reaction mixture was stirred at 130 °C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by Combiflash using 3% MeOH in DCM as the eluent to obtain the title compound [4-(4-amino-2-fluorophenoxy)-5-pyrimidinyl]dimethylphosphine oxide (150 mg, 44.15% yield) as a pale green solid. 1 H NMR (400 MHz, DMSO-d6): δ=8.90-8.87 (m, 2H), 6.02 (t, J=8.80 Hz, 1H), 6.48 (dd, J=2.40 Hz, 13.20 Hz, 1H), 6.40 (dd, J=2.40 Hz, 8.60 Hz, 1H), 5.44 (s, 2H), 1.81 (d, J=14.00 Hz, 6H), LCMS: 282.1 (M+H) + .

[0258] Step 3: Synthesis of N-{4-[5-(dimethylphosphoryl)-4-pyrimidinyloxy]-3-fluorophenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide: [ka] To a stirred solution of 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (97.5 mg, 0.356 mmol, 1 equiv.) in dimethylformamide (5 mL) was added N,N-ethylbis(propan-2-yl)amine (0.191 mL, 3 equiv., 1.07 mmol) and [bis(dimethylamino)methylidene]({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl})oxidanium (167 mg, 2 equiv., 0.711 mmol). The reaction mixture was stirred for 5 minutes, followed by the addition of [4-(4-amino-2-fluorophenoxy)-5-pyrimidinyl]dimethylphosphine oxide (0.1 g, 0.356 mmol, 1 equiv.). The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phase was washed with brine (10 mL), dried over NaSO, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by preparative HPLC using 0.1% TFA in acetonitrile and water to obtain the title compound N-{4-[5-(dimethylphosphoryl)-4-pyrimidinyloxy]-3-fluorophenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (8 mg, yield 4.19%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ=10.84 (s, 1H), 8.96-8.92 (m, 2H), 8.35 (s, 1H), 7.86 (dd, J=2.40 Hz, 12.60 Hz, 1H), 7.65-7.62 (m, 2H), 7.54 (dd, J=2.00 Hz, 9.00 Hz, 1H), 7.50-7.44 (m, 3H), 1.85 (d, J=14.00 Hz, 6H), LCMS: 538.54 (M+H) + .

[0259] Synthesis Example 36 Synthesis of N-{4-[6-amino-5-(dimethylphosphoryl)-4-pyrimidinyloxy]-3-fluorophenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 55) [ka]

[0260] Step 1: Synthesis of 6-(4-amino-2-fluorophenoxy)-5-iodo-4-pyrimidineamine: [ka] To a stirred mixture of 6-chloro-5-iodo-4-pyrimidinylamine (1 g, 3.91 mmol, 1 equiv.) and 4-amino-2-fluorophenol (746 mg, 1.5 equiv., 5.87 mmol) in dimethylformamide (40 mL) was added dicesium carbonate (1.91 g, 1.5 equiv., 5.87 mmol) in a glass pressure vessel (sealed tube) and rapidly heated to 150 °C. Heating was continued for 3 h. The progress of the reaction was followed by TLC. After completion of the reaction, the reaction mixture was quenched with ice-cold water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column using 100-200 silica mesh with 2-3% MeOH in DCM as eluent to give the title compound 6-(4-amino-2-fluorophenoxy)-5-iodo-4-pyrimidinamine (0.7 g, 51.66% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ=7.87 (s, 1H), 6.87 (t, J=8.80 Hz, 1H), 6.42 (dd, J=2.40 Hz, 12.80 Hz, 1H), 6.34 (dd, J=1.60 Hz, 8.60 Hz, 1H), 5.32 (s, 2H), LCMS: 347.0 (M+H) + .

[0261] Step 2: Synthesis of [6-amino-4-(4-amino-2-fluorophenoxy)-5-pyrimidinyl]dimethylphosphine oxide: [ka] To a stirred solution of 6-(4-amino-2-fluorophenoxy)-5-iodo-4-pyrimidinamine (0.7 g, 2.02 mmol, 1 equiv.) in 1,4-dioxane (6.98 mL), tripotassium phosphate (687 mg, 1.6 equiv., 3.24 mmol) was added and degassed with argon gas for 20 minutes. Next, [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (176 mg, 0.15 equiv., 0.303 mmol) and dimethyl(oxo)-λ 5 -Phosphanilium (0.408 mL, 3 equiv., 6.07 mmol) was added, and the reaction mixture was again degassed with argon gas for 10 minutes. Palladium(2+) diacetate (22.7 mg, 0.05 equiv., 0.101 mmol) was then added to the reaction mixture at room temperature under an argon atmosphere. The reaction mixture was stirred at 130 °C for 3 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude residue. The crude compound was then purified by Combiflash, eluting the spot with 3% MeOH in DCM to give the title compound [6-amino-4-(4-amino-2-fluorophenoxy)-5-pyrimidinyl]dimethylphosphine oxide (0.4 g, 66.76%) as a pale green solid. 1 H NMR (400 MHz, DMSO-d6): δ=8.61 (s, 1H), 8.06 (d, J=2.00 Hz, 1H), 7.38 (brs, 1H), 6.91 (t, J=8.80 Hz, 1H), 6.42 (dd, J=2.40 Hz, 13.20 Hz, 1H), 6.34 (dd, J=1.60 Hz, 8.80 Hz, 1H), 5.35 (s, 2H), LCMS: 297.1 (M+H) + .

[0262] Step 3: Synthesis of N-{4-[6-amino-5-(dimethylphosphoryl)-4-pyrimidinyloxy]-3-fluorophenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide: [ka] To a stirred solution of 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (185 mg, 0.675 mmol) in dimethylformamide (6.67 mL) was added N,N-ethylbis(propan-2-yl)amine (0.362 mL, 3 equiv., 2.03 mmol) and [bis(dimethylamino)methylidene]({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl})oxidanium (318 mg, 2 equiv., 1.35 mmol). The reaction mixture was stirred at room temperature for 5 minutes, followed by the addition of [6-amino-4-(4-amino-2-fluorophenoxy)-5-pyrimidinyl]dimethylphosphine oxide (0.2 g, 0.675 mmol, 1 equiv.). The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice-cold water (15 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over NaSO, and then concentrated under reduced pressure to give a crude residue. The crude compound was purified by preparative HPLC using 0.1% TFA in acetonitrile and water to give the title compound N-{4-[6-amino-5-(dimethylphosphoryl)-4-pyrimidinyloxy]-3-fluorophenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (40 mg, 10.73% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ=10.77 (s, 1H), 8.67 (d, J=3.2 Hz, 1H), 8.34 (s, 1H), 8.08 (d, J=2.00 Hz, 1H), 7.79 (dd, J=2.40 Hz, 12.60 Hz, 1H), 7.65-7.61 (m, 2H), 7.53-7.44 (m, 4H), 7.37 (t, J=8.80 Hz, 1H), 1.83 (d, J=13.60 Hz, 6H), LCMS: 553.55 (M+H) + .

[0263] Synthesis Example 37 Synthesis of N-{4-[6-amino-5-(dimethylphosphoryl)-4-pyrimidinyloxy]-3-fluorophenyl}-4-ethoxy-1-(p-fluorophenyl)-2-oxo-1,2-dihydronicotinamide (Compound 56) [ka]

[0264] Step 1: Synthesis of ethyl (E)-2-cyano-3-ethoxybut-2-enoate: [ka] To a stirred solution of 1,1,1-triethoxyethane (14.7 mL, 80.1 mmol, 1 equiv.) and acetic acid (1.11 mL, 18.4 mmol, 0.23 equiv.), ethyl cyanoacetate (4.53 mL, 40.1 mmol, 0.5 equiv.) was added sequentially, and the reaction mixture was stirred at 120 °C for 16 h. After stirring at 120 °C for 16 h, the reaction mixture was cooled to room temperature and concentrated in vacuo to give crude (E)-ethyl 2-cyano-3-ethoxybut-2-enoate (14 g, crude product). The crude residue was carried forward without further purification (as reported in US 2022 / 0288043 A1).

[0265] Step 2: Synthesis of ethyl (2E,4E)-2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate: [ka] A mixture of ethyl (E)-2-cyano-3-ethoxybut-2-enoate (14 g, 76.4 mmol, 1 equivalent, theoretically crude) and N,N-dimethyl(dimethoxymethyl)amine (8 mL) was heated at 70 °C for 3 h. After stirring at 70 °C for 3 h, the reaction mixture was concentrated under high vacuum to give crude ethyl (2E,4E)-2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate (16 g, crude product). The residue was carried on to the next step without further purification (as reported in U.S. Publication No. 2022 / 0288043).

[0266] Step 3: Synthesis of ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate: [ka] A mixture of ethyl (2E,4E)-2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate (16 g, 67.1 mmol, 0.89 equiv.) and acetic acid (35 mL) was refluxed for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated to dryness under high vacuum, treated with water (50 mL), and washed with ethyl acetate (30 mL) to remove impurities. The pH of the aqueous layer was adjusted to pH 9–10 with aqueous NaHCO3. The mixture was extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude residue. The residue was purified by silica gel chromatography to give the desired compound, ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (2.5 g, 15.67% yield), as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ=11.65 (s, 1H), 7.48 (d, J=7.60 Hz, 1H), 6.23 (d, J=7.20 Hz, 1H), 4.19-4.11 (m, 4H), 1.27-1.21 (m, 6H), LCMS: 212.1 (M+H) + .

[0267] Step 4: Synthesis of ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate: [ka] To a stirred solution of ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (2 g, 9.47 mmol, 1 equiv.), (p-fluorophenyl)boranediol (3.97 g, 28.4 mmol, 3 equiv.), and copper(II) acetate (3.44 g, 18.9 mmol, 2 equiv.) in DCM (20 mL) was added pyridine (3.06 mL, 37.9 mmol, 4 equiv.). The reaction mixture was stirred at room temperature in the presence of air for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with DCM (100 mL), filtered through a pad of diatomaceous earth (i.e., Celite®), and washed with DCM (50 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), then dried over Na2SO4 and concentrated under reduced pressure to give a crude residue. The crude compound was purified by flash column chromatography using 50-100% ethyl acetate in hexane to give the title compound ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (1.5 g, 51.89% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ=7.81 (d, J=7.60 Hz, 1H), 7.46-7,42 (m, 2H), 7.34 (t, J=8.80 Hz, 2H), 6.44 (d, J=8.00 Hz, 1H), 4.24-4.15 (m, 4H), 1.28 (t, J=7.2 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H), LCMS: 306.1 (M+H) + .

[0268] Step 5: Synthesis of 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid: [ka] To a stirred suspension of ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (1 g, 3.28 mmol, 1 equiv.) in ethanol (15 mL) and water (7.5 mL) was added lithium hydroxide monohydrate (550 mg, 13.1 mmol, 4 equiv.). The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, all solvents were evaporated under reduced pressure, and the residue was diluted with water (20 mL), cooled to 0°C, acidified with 1N HCl, and stirred for 10 minutes. The resulting solid was filtered and washed with water (20 mL) and diethyl ether (30 mL). It was then dried under vacuum to give the title compound, 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (650 mg, 71.58% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ=13.81 (s, 1H), 7.98 (d, J=8.00 Hz, 1H), 7.53-7.49 (m, 2H), 7.38 (t, J=8.40 Hz, 2H), 6.61 (d, J=8.00 Hz, 1H), 4.31 (q, J=6.8 Hz, 2H), 1.35 (t, J=6.8 Hz, 3H), LCMS: 278.1 (M+H) + .

[0269] Step 6: Synthesis of N-{4-[6-amino-5-(dimethylphosphoryl)-4-pyrimidinyloxy]-3-fluorophenyl}-4-ethoxy-1-(p-fluorophenyl)-2-oxo-1,2-dihydronicotinamide: [ka] To a stirred solution of 4-ethoxy-1-(p-fluorophenyl)-2-oxo-1,2-dihydronicotinic acid (187 mg, 0.675 mmol) in dimethylformamide (6.67 mL) was added N,N-ethylbis(propan-2-yl)amine (0.362 mL, 3 equiv., 2.03 mmol) and [bis(dimethylamino)methylidene]({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl})oxidanium (318 mg, 2 equiv., 1.35 mmol). The reaction mixture was stirred for 5 minutes, after which [6-amino-4-(4-amino-2-fluorophenoxy)-5-pyrimidinyl]dimethylphosphine oxide (0.2 g, 0.675 mmol, 1 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice-cold water (15 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over NaSO, and concentrated under reduced pressure to give a crude residue. The crude compound was purified by preparative HPLC using 0.1% TFA in water and acetonitrile to give the title compound N-{4-[6-amino-5-(dimethylphosphoryl)-4-pyrimidinyloxy]-3-fluorophenyl}-4-ethoxy-1-(p-fluorophenyl)-2-oxo-1,2-dihydronicotinamide (80 mg, 21.33% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.52 (s, 1H), 8.66 (d, J=3.2 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 7.85 (d, J=8.00 Hz, 1H), 7.79 (dd, J=2.0 Hz, 12.80 Hz, 2H), 7.51-7.43 (m, 3H), 7.39-7.34 (m, 3H), 7.29 (t, J=8.80 Hz, 1H), 6.50 (d, J=8.00 Hz, 1H), 4.24 (q, J=6.8 Hz, 2H), 1.82 (d, J=13.60 Hz, 6H), 1.29 (t, J=6.8 Hz, 3H), LCMS: 556.36 (M+H) + .

[0270] Synthesis Example 38 Synthesis scheme of N-(4-((2-((3-(2-(4-acryloylpiperazin-1-yl)-2-oxoethyl)phenyl)amino)-3-(dimethylphosphoryl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (compound 57) [ka]

[0271] Step 1: Synthesis of tert-butyl 4-(2-(3-bromophenyl)acetyl)piperazine-1-carboxylate: [ka] To a stirred solution of (m-bromophenyl)acetic acid (1 g, 4.65 mmol) and tert-butyl 1-piperazinecarboxylate (1.04 g, 1.2 equiv., 5.58 mmol) in DMF (5 mL) was added 1H-1,2,3-benzotriazol-1-ol-water (1 / 1) (855 mg, 1.2 equiv., 5.58 mmol) and N-ethylbis(isopropyl)amine (1.62 mL, 2 equiv., 9.3 mmol). After stirring for 5 minutes, 2-methyl-2,6,8-triaza-6,7-decadiene:hydrogen chloride (1:1) (1.07 g, 1.2 equiv., 5.58 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give crude compound tert-butyl 4-[2-(m-bromophenyl)acetyl]-1-piperazinecarboxylate (1.4 g, 3.65 mmol) as a colorless gummy solid, which was carried on to the next step as is. 1H NMR (400 MHz, DMSO-d6): δ=7.44 (s, 1H), 7.42 (m, 1H), 7.29-7.21 (m, 2H), 3.75 (s, 2H), 3.50-3.42 (m, 4H), 3.29 (m, 4H), 1.40 (s, 9H).

[0272] Step 2: Synthesis of 2-(3-bromophenyl)-1-(piperazin-1-yl)ethan-1-one (4): [ka] To a stirred solution of tert-butyl 4-[2-(m-bromophenyl)acetyl]-1-piperazinecarboxylate (1.4 g, 3.65 mmol) in dichloromethane (15.7 mL, 245 mmol), trifluoroacetic acid (5 mL, 10 equivalents, 36.5 mmol) was added at 0 °C, and the temperature was allowed to rise to room temperature. The reaction mixture was then stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude compound, which was washed with diethyl ether (2 × 20 mL) to give the title compound 2-(m-bromophenyl)-1-(1-piperazinyl)-1-ethanone (1 g, 3.53 mmol, 96.68% yield) as a colorless gum. The crude compound was carried on to the next step as is. 1 H NMR (400 MHz, DMSO-d6): δ=10.63 (brs, 1H), 9.06 (s, 2H), 7.44-7.42 (m, 2H), 7.27 (t, J=8.00 Hz, 1H), 7.21 (d, J=7.60 Hz, 1H), 3.78 (s, 2H), 3.72-3.65 (m, 4H), 3.16-3.05 (m, 4H).

[0273] Step 3: Synthesis of 1-(4-(2-(3-bromophenyl)acetyl)piperazin-1-yl)prop-2-en-1-one: [ka] To a stirred solution of 2-(m-bromophenyl)-1-(1-piperazinyl)-1-ethanone (1 g, 3.53 mmol) in dichloromethane (10 mL, 156 mmol) at 10 °C, triethylamine (1.07 g, 3 equiv., 10.6 mmol) was added dropwise. After 10 min, acryloyl chloride (320 mg, 3.53 mmol) was added dropwise, and the reaction was stirred at room temperature for 10 min. The progress of the reaction was followed by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold NaHCO3 solution (3 × 20 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were collected, dried over Na2SO4, and concentrated in vacuo to give the crude residue. The crude compound was purified by Combiflash to give the title compound 1-(4-acryloyl-1-piperazinyl)-2-(m-bromophenyl)-1-ethanone (450 mg, 1.33 mmol, 37.79% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ=7.44-7.42 (m, 2H), 7.29-7.22 (m, 2H), 6.84-6.77 (m, 1H), 6.13 (dd, J=2.00 Hz, 16.60 Hz, 1H), 5.70 (dd, J=2.40 Hz, 10.40 Hz, 1H), 3.77 (s, 2H), 3.53-3.49 (m, 8H).

[0274] Step 4: Synthesis of N-(4-((2-((3-(2-(4-acryloylpiperazin-1-yl)-2-oxoethyl)phenyl)amino)-3-(dimethylphosphoryl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] A stirred solution of N-{4-[2-amino-3-(dimethylphosphoryl)-4-pyridyloxy]-3-fluorophenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (0.1 g, 181 μmol), 1-(1-acryloyl-4-piperidyl)-2-(m-bromophenyl)-1-ethanone (85.4 mg, 1.4 equivalents, 254 μmol), and dicesium carbonate (118 mg, 2 equivalents, 363 μmol) in isopropanol (10 mL, 131 mmol) was purged with argon gas for 20 minutes. Next, bis(tert-butyl)[2',4',6'-tris(isopropyl)-2-biphenylyl]phosphine (7.7 mg, 0.1 equivalent, 18.1 μmol) and (1E,4E)-1,5-diphenyl-1,4-pentadien-3-one-1,5-diphenyl-1,4-pentadien-3-one-palladium (1 / 2 / 2) (8.3 mg, 0.05 equivalent, 9.07 μmol) were added to the reaction mixture at room temperature, and the reaction mixture was again purged with argon gas for 15 minutes. The reaction mixture was stirred at 80 °C for 12 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to room temperature and then diluted with acetone (15 mL). The reaction mixture was stirred for 10 minutes and then filtered through a pad of diatomaceous earth (i.e., Celite®). The filtrate was concentrated in vacuo to provide the crude compound. The crude compound was purified by preparative HPLC to afford the title compound N-(4-((2-((3-(2-(4-acryloylpiperazin-1-yl)-2-oxoethyl)phenyl)amino)-3-(dimethylphosphoryl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (45 mg, 55.8 μmol, 30.76% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ=11.48 (s, 1H), 10.86 (s, 1H), 8.35 (s, 1H), 8.14 (d, J=6.00 Hz, 1H), 7.92 (dd, J=2.00 Hz, 12.80 Hz, 1H), 7.65-7.55 (m, 4H), 7.46 (d, J=8.80 Hz, 3H), 7.40 (s, 1H), 7.22 (t, J=7.60 Hz, 1H), 6.83-6.75 (m, 2H), 6.13-6.08 (m, 2H), 5.68 (d, J=10.00 Hz, 1H), 3.73 (s, 2H), 3.53-3.47 (m, 8H), 1.92 (d, J=14.40 Hz, 6H), LCMS: 808.75 (M+H) + .

[0275] Synthesis Example 40 Synthesis of N-(4-((2-amino-3-(dimethylphosphoryl)pyridin-4-yl)oxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (compound 58) [ka] To a stirred solution of [2-amino-4-(4-amino-2-fluorophenoxy)-3-pyridyl]dimethylphosphine oxide (0.2 g, 677 μmol, 1 equiv.) and 2-ethoxy-5-(p-fluorophenyl)-6-oxo-1,3-cyclohexadiene-1-carboxylic acid (187 mg, 677 μmol, 1 equiv.) in tetrahydrofuran (85.5 mL, 1.05 mol), chloro(dimethylamino)methylenebis(methyl)azanium hexafluoride phosphate(1-) (570 mg, 3 equiv., 2.03 mmol) and N-ethylbis(isopropyl)amine (605 μL, 5 equiv., 3.39 mmol) were added at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 60 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by Combiflash using 3% MeOH in DCM as the eluent to obtain the title compound (59% purity by LCMS). The compound was then purified again by preparative HPLC to obtain the pure title compound N-{4-[2-amino-3-(dimethylphosphoryl)-4-pyridyloxy]-3-fluorophenyl}-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydronicotinamide (45 mg, 11.98% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ=10.57 (s, 1H), 7.90-7.85 (m, 3H), 7.48-7.43 (m, 3H), 7.39-7.31 (m, 3H), 6.51 (d, J=8.00 Hz, 3H),4.25 (q, J=6.80 Hz, 2H), 1.79 (d, J=14.00 Hz, 6H), LCMS: 555.51 (M+H) + .

[0276] Synthesis example 39A Synthesis of N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 43) [ka]

[0277] Step 1: Synthesis of 1-(mesyloxy)-2-(m-nitrophenyl)ethane: [ka] To a stirred solution of 2-(m-nitrophenyl)ethanol (1 g, 5.98 mmol) in DCM (15 mL) was added triethylamine (1.08 mL, 1.3 equiv., 7.78 mmol) at 0 °C under a nitrogen atmosphere. Next, (chlorosulfonyl)methane (926 μL, 2 equiv., 12 mmol) was added dropwise, and the reaction temperature was raised to room temperature and stirred for an additional 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed, and the residue was dissolved in DCM (100 mL), washed with water (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the title compound, 1-(mesyloxy)-2-(m-nitrophenyl)ethane, as a colorless liquid (1.2 g, 81.79% yield). 1 H NMR (400 MHz, DMSO-d6): δ=8.14 (d, J=8.8 Hz, 2H), 7.61 (d, J=7.6 Hz, 1H), 7.53 (t, J=8.0 Hz 1H), 4.48 (t, J=6.8 Hz, 2H), 3.19 (t, J=6.8 Hz, 2H), 2.96 (s, 3H).

[0278] Step 2: Synthesis of tert-butyl 4-[2-(m-nitrophenyl)ethyl]-1-piperazinecarboxylate: [ka] To a stirred solution of 1-(mesyloxy)-2-(m-nitrophenyl)ethane (1.5 g, 6.12 mmol) in dimethylformamide (15 mL, 194 mmol) was added dicesium carbonate (4.98 g, 2.5 equiv., 15.3 mmol) at room temperature. After some time, tert-butyl 1-piperazinecarboxylate (1.37 g, 1.2 equiv., 7.34 mmol) was added, and the reaction mixture was heated to 100 °C and continued for an additional 4 h. The reaction progress was followed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash chromatography using 30% EA in hexane to give the title compound tert-butyl 4-[2-(m-nitrophenyl)ethyl]-1-piperazinecarboxylate (460 mg, 22.42% yield). 1 H NMR (400 MHz, DMSO-d6): δ=8.13 (s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 3.42 - 3.40 (m, 2H), 3.34 - 3.30 (m, 2H), 3.08 - 3.05 (m, 2H), 2.88 (m, 2H), 2.60 - 2.56 (m, 2H), 2.39 (m, 2H), 1.40 (s, 9H). LCMS: 336.2 (M+H) + .

[0279] Step 3: tert-Butyl 4-[2-(m-aminophenyl)ethyl]-1-piperazinecarboxylate: [ka] To a stirred solution of tert-butyl 4-[2-(m-nitrophenyl)ethyl]-1-piperazinecarboxylate (360 mg, 1.07 mmol) in ethanol (7 mL, 120 mmol) and water (5.5 mL, 305 mmol), iron (599 mg, 10 equiv., 10.7 mmol) and ammonium chloride (1.15 g, 20 equiv., 21.5 mmol) were added at 0 °C. The temperature was then raised to room temperature, dimethylformamide (2.5 mL, 32.3 mmol) was added, and the reaction was refluxed for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled and dried under vacuum. The reaction mixture was then dissolved in ethyl acetate (30 mL) and washed with water (40 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude product. The crude product was purified by flash chromatography using 30% ethyl acetate in hexane to give the title compound tert-butyl 4-[2-(m-aminophenyl)ethyl]-1-piperazinecarboxylate (150 mg, 45.8% yield). 1 H NMR (400 MHz, DMSO-d6): δ=6.89 (t, J=7.6 Hz, 1H), 6.39 - 6.32 (m, 3H), 3.30 (m, 4H), 2.58 - 2.54 (m, 2H), 2.47 - 2.43 (m, 2H), 2.37 - 2.34 (m, 4H), 1.39 (s, 9H). LCMS: 306.15 (M+H) + .

[0280] Step 4: Synthesis of N-[3-fluoro-4-(2-{m-[2-(1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide: [ka] To a stirred solution of N-[4-(2-chloro-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (0.1 g, 202 μmol) and tert-butyl 4-[2-(m-aminophenyl)ethyl]-1-piperazinecarboxylate (73.9 mg, 1.2 equiv., 242 μmol) in dimethylformamide (4 mL, 51.7 mmol) was added 4-methylbenzene-1-sulfonic acid hydrate (153 mg, 4 equiv., 807 μmol). The reaction mixture was stirred at 90 °C for 10 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was dissolved in ethyl acetate (30 mL) and washed with water (20 mL × 3). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude compound. The crude compound was purified by flash chromatography using 5% MeOH in DCM as the eluent to give the title compound N-[3-fluoro-4-(2-{m-[2-(1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (80 mg, 59% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d6): δ=11.79 (brs, 1H), 8.43 (s, 1H), 8.40 (d, J=6.0 Hz, 1H), 7.91 (dd, J=2.4, 12.6 Hz, 1H), 7.66 - 7.58 (m, 3H), 7.49 - 7.36 (m, 5H), 7.06 (t, J=8.0 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 6.59 (d, J=5.6 Hz, 1H), 3.77 - 3.58 (m, 2H), 3.56 - 3.50 (m, 2H), 3.42 - 3.40 (m, 2H), 3.39 - 3.17 (m, 4H), 2.97 - 2.93 (m, 2H).

[0281] Step 5: Synthesis of N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide: [ka] To a stirred solution of N-[3-fluoro-4-(2-{m-[2-(1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (40 mg, 60.2 μmol, 1 equiv.) was added triethylamine (25.2 μL, 181 μmol, 3 equiv.) at 0° C., followed by stirring for 2 minutes. Acryloyl chloride (4.38 μL, 54.2 μmol, 0.9 equiv.) was then added to the reaction mixture at 0° C., and the reaction mixture was stirred for 5 minutes. The progress of the reaction was followed by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with ice-cold water (20 mL). The organic layer was separated, and the aqueous layer was extracted again with dichloromethane (2×10 mL). The combined organic layers were washed with NaHCO, dried over NaSO, and concentrated under reduced pressure to give the crude residue. The crude compound was purified by preparative HPLC to give the desired product N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (12 mg, 27.9% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ=10.82 (s, 1H), 9.58 (s, 1H), 8.39 (d, J=5.60 Hz, 1H), 8.35 (s, 1H), 7.90 - 7.85 (m, 1H), 7.66 - 7.62 (m, 2H), 7.54 - 7.52 (m, 1H), 7.49 - 7.40 (m, 3H), 7.32 (s, 1H), 7.26 (d, J=5.6 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H), 6.80 - 6.72 (m, 2H), 6.57 (d, J=5.60 Hz, 1H), 6.08 (dd, J=2.40, 16.8 Hz, 1H), 5.65 (dd, J=2.0, 10.6 Hz, 1H), 3.51 - 3.47 (m, 4H), 2.56 - 2.54 (m, 2H), 2.44 - 2.40 (m, 2H), 2,36 - 2.33 (m, 4H). LCMS: 719.92 (M+H) + .

[0282] Synthesis example 39B An alternative synthetic route to N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (compound 43) [ka]

[0283] Step 1: tert-Butyl 4-[2-(m-nitrophenyl)acetyl]-1-piperazinecarboxylate: [ka] To a stirred solution of (m-nitrophenyl)acetic acid (10.0 g, 55.2 mmol, 1.0 equiv.) and tert-butyl 1-piperazinecarboxylate (11.3 g, 60.7 mmol, 1.1 equiv.) in DMF (100 mL) was added 1H-1,2,3-benzotriazol-1-ol:water (1:1) (10.1 g, 66.2 mmol, 1.2 equiv.), followed by N-ethylbis(isopropyl)amine (19.2 mL, 110 mmol, 2 equiv.). EDC-HCl (12.7 g, 66.2 mmol, 1.2 equiv.) was then added to the above reaction mixture at 0 °C. The reaction was then stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water (250 mL) was added to the reaction mixture, and the solid thus formed was filtered. The solid compound was dissolved in DCM (150 mL) and washed with NaHCO solution (60 mL) and brine (40 mL). The organic layer was dried over NaSO and concentrated under reduced pressure to give pure compound tert-butyl 4-[2-(m-nitrophenyl)acetyl]-1-piperazinecarboxylate as an off-white solid (10.0 g, 51.85% yield). 1 H NMR (400 MHz, DMSO-d6): δ=8.10 (d, J=7.2 Hz, 2H), 7.68 (d, J=7.6 Hz, 1H), 7.60 (t, J=7.6 Hz 1H), 3.92 (s, 2H), 3.54 - 3.51 (m, 2H), 3.47 - 3.44 (m, 2H), 3.35 - 3.29 (m, 4H), 1.41 (s, 9H).

[0284] Step 2: tert-Butyl 4-[2-(m-nitrophenyl)ethyl]-1-piperazinecarboxylate: [ka] To a stirred solution of tert-butyl 4-[2-(m-nitrophenyl)acetyl]-1-piperazinecarboxylate (10.0 g, 28.6 mmol, 1 equiv.) in THF (100 mL) was added 1 M borane-tetrahydrofuran (60 mL, 57.2 mmol, 2 equiv.) dropwise at 0 °C. The reaction was refluxed for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 0 °C and quenched with methanol. The reaction mixture was then concentrated under reduced pressure to obtain the crude compound. The resulting crude product was purified by Combiflash using 50% ethyl acetate in hexane as the eluent to obtain the title compound tert-butyl 4-[2-(m-nitrophenyl)ethyl]-1-piperazinecarboxylate as an off-white solid (6.3 g, 65.63% yield). 1 H NMR (400 MHz, DMSO-d6): δ=8.17 (d, J=1.60 Hz, 1H), 8.10 (dt, J=0.80, 8.13 Hz, 1H), 7.75 (d, J=7.60 Hz, 1H), 7.62 (t, J=7.60 Hz, 1H), 3.54-3.58 (m, 4H), 3.18-3.22 (m, 2H), 3.01-3.05 (m, 2H), 2.88 (s, 4H), 1.41 (s, 9H), LCMS: 336.2 (M+H) + .

[0285] Step 3: 1-[2-(m-nitrophenyl)ethyl]piperazine TFA salt: [ka] A stirred solution of tert-butyl 4-[2-(m-nitrophenyl)ethyl]-1-piperazinecarboxylate (6.3 g, 18.8 mmol, 1 equiv.) in trifluoroacetic acid / dichloromethane (1:1) (20 mL) was stirred at room temperature for 8 hours. After TLC showed the reaction was complete, the reaction mixture was concentrated in vacuo, and the resulting residue was triturated with diethyl ether and pentane to give the title compound, 1-[2-(m-nitrophenyl)ethyl]piperazine-TFA salt (6 g crude product), as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ=8.18 (s, 1H), 8.11 (dd, J=1.60, Hz, 1H), 7.74 (d, J=7.60 Hz, 1H), 7.63 (t, J=8.00 Hz, 1H), 3.23-3.29 (m, 10H), 3.04-3.07 (m, 2H), Mass: 236.2 (M+H) + .

[0286] Step 4: 1-{4-[2-(m-nitrophenyl)ethyl]-1-piperazinyl}-2-propen-1-one: [ka] To a stirred solution of 1-[2-(m-nitrophenyl)ethyl]piperazine (1 g, 4.25 mmol, 1 equiv.) in DCM (10 mL) was added triethylamine (2.96 mL, 5 equiv., 21.3 mmol) at 0 °C. After stirring for 20 min, acryloyl chloride (343 μL, 4.25 mmol, 1 equiv.) was added at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (3 × 50 mL), and washed with saturated NaHCO solution (50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash chromatography using 0-5% MeOH in DCM to give 1-{4-[2-(m-nitrophenyl)ethyl]-1-piperazinyl}-2-propen-1-one as a colorless gummy solid (400 mg, 32.53% yield). 1H NMR (400 MHz, DMSO-d6): δ=8.14 (s, 1H), 8.06 (dd, J=1.60, 8.20 Hz, 1H), 7.73 (d, J=7.60 Hz, 1H), 7.58 (t, J=7.60 Hz, 1H), 6.80 (dd, J=10.40, 16.80 Hz, 1H), 6.10 (dd, J=2.40, 16.80 Hz, 1H), 5.67 (dd, J=2.40, 10.60 Hz, 1H), 3.51-3.54 (m, 4H), 2.90 (t, J=7.60 Hz, 2H), 2.59 (t, J=7.20 Hz, 2H), 2.44 (s, 4H).

[0287] Step 5: 1-{4-[2-(m-aminophenyl)ethyl]-1-piperazinyl}-2-propen-1-one: [ka] To a stirred solution of 1-{4-[2-(m-nitrophenyl)ethyl]-1-piperazinyl}-2-propen-1-one (0.4 g, 1.38 mmol, 1 equiv.) in dimethyl sulfoxide (4 mL) at 0 °C was added 4,4'-bipyridyl (32.4 mg, 0.15 equiv., 207 μmol). After stirring for 5 min, 1,1,2,2-diborane tetrol (4) (496 mg, 4 equiv., 5.53 mmol) was added portionwise and the reaction was allowed to proceed at room temperature. The reaction was complete within 10 min as determined by TLC. The reaction mixture was poured into ice-cold water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were collected, dried over Na2SO4, and concentrated in vacuo to give the crude compound. The resulting crude compound was purified using column chromatography (gradient elution of 0 to 6% MeOH in DCM) to give the title compound 1-{4-[2-(m-aminophenyl)ethyl]-1-piperazinyl}-2-propen-1-one (350 mg, yield 97.62%) as a gummy solid. 1H NMR (400 MHz, DMSO-d6): δ=6.90 (t, J=7.60 Hz, 1H), 6.73 (dd, J=10.40, 16.60 Hz, 1H), 6.36-6.41 (m, 3H), 6.08 (dd, J=2.40, 16.60 Hz, 1H), 5.68 (dd, J=2.00, 10.40 Hz, 1H), 3.52 (t, J=5.60 Hz, 4H), 2.50-2.56 (m, 6H), 2.39-2.43 (m, 4H), Mass: 260.2 (M+H) + .

[0288] Step 6: N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide; [ka] To a stirred solution of N-[4-(2-chloro-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (0.5 g, 1.01 mmol, 1 equiv.) and 1-{4-[2-(m-aminophenyl)ethyl]-1-piperazinyl}-2-propen-1-one (314 mg, 1.2 equiv., 1.21 mmol) in DMF (10 mL) was added 4-methylbenzene-1-sulfonic acid hydrate (767 mg, 4 equiv., 4.03 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give the title compound N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (52 mg, 72.4 μmol) as a white solid (52 mg, 7.17% yield). 1 H NMR (400 MHz, DMSO-d6): δ=10.81 (s, 1H), 9.57 (s, 1H), 8.39 (d, J=5.60 Hz, 1H), 8.35 (s, 1H), 7.89 - 7.85 (m, 1H), 7.66 - 7.62 (m, 2H), 7.53 (d, J=8.0 Hz, 1H), 7.54 - 7.41 (m, 3H), 7.32 (s, 1H), 7.26 (d, J=6.8 Hz, 1H), 6.98 (t, J=7.6 Hz, 1H), 6.80 - 6.72 (m, 2H), 6.56 (d, J=5.60 Hz, 1H), 6.08 (dd, J=2.40, 16.8 Hz, 1H), 5.65 (dd, J=2.40, 10.4 Hz, 1H), 3.51 - 3.47 (m, 4H), 2.44-2.40 (m, 4H), 2.36-2.31 (m, 4H), LCMS: 719.3 (M+H) + .

[0289] Synthesis Example 40 Synthesis of N-[3-fluoro-4-(2-{m-[2-(4-propionyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 59) [ka]

[0290] Step 1: 1-{4-[2-(m-nitrophenyl)ethyl]-1-piperazinyl}-1-propanone: [ka] To a stirred solution of 1-[2-(m-nitrophenyl)ethyl]piperazine (1 g, 4.25 mmol, 1 equiv.) in DCM (10 mL) was added triethylamine (2.96 mL, 5 equiv., 21.3 mmol) at 0 °C. After stirring for 20 min, propionyl chloride (443 μL, 1.2 equiv., 5.1 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (3 × 50 mL), and the organic layer was washed with saturated NaHCO . The combined organic layers were dried over Na SO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash chromatography using 0-5% MeOH in DCM to give the desired compound 1-{4-[2-(m-nitrophenyl)ethyl]-1-piperazinyl}-1-propanone (630 mg, 50.88% yield) as a colorless gummy solid. 1H NMR (400 MHz, DMSO-d6): δ=8.10 (s, 1H), 8.04 (dd, J=1.20, 7.60 Hz, 1H), 7.70 (d, J=7.60 Hz, 1H), 7.56 (t, J=7.60 Hz, 1H), 3.39 (s, 4H), 2.88 (t, J=7.20 Hz, 2H), 2.54 (t, J=7.60 Hz, 2H), 2.43 - 2.41 (m, 4H), 2.31 - 2.25 (m, 2H), 0.99 - 0.94 (m, 3H), LCMS: 292.1 (M+H) + .

[0291] Step 2: 1-{4-[2-(m-aminophenyl)ethyl]-1-piperazinyl}-1-propanone: [ka] To a stirred solution of 1-{4-[2-(m-nitrophenyl)ethyl]-1-piperazinyl}-1-propanone (530 mg, 1.82 mmol, 1 equiv.) in dimethyl sulfoxide (5 mL) at 0 °C was added 4,4'-bipyridyl (42.6 mg, 0.15 equiv., 273 μmol). After stirring for 5 min, 1,1,2,2-diborane tetrol (4) (652 mg, 4 equiv., 7.28 mmol) was added portionwise, and the reaction was stirred at room temperature. The reaction was complete within 10 min as determined by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were collected, dried over Na2SO4, and concentrated in vacuo. The resulting crude product was purified by column chromatography (gradient elution of 0–6% MeOH in DCM) to afford the title compound 1-{4-[2-(m-aminophenyl)ethyl]-1-piperazinyl}-1-propanone (250 mg, 52.58% yield) as a gummy solid. 1H NMR (400 MHz, DMSO-d6): δ=6.90 (t, J=7.60 Hz, 1H), 6.41 - 6.35 (m, 3H), 3.41 (d, J=4.0 Hz, 4H), 2.57 - 2.48 (m, 4H), 2.40 - 2.36 (m, 4H), 2.34 - 2.27 (m, 2H), 0.95 (t, J=7.2 Hz, 3H), Mass: 262.1 (M+H) + .

[0292] Step 3: N-[3-fluoro-4-(2-{m-[2-(4-propionyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide: [ka] To a stirred solution of N-[4-(2-chloro-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (250 mg, 504 μmol, 1 equiv.) and 1-{4-[2-(m-aminophenyl)ethyl]-1-piperazinyl}-1-propanone (198 mg, 1.5 equiv., 756 μmol) in DMF (4 mL), 4-methylbenzene-1-sulfonic acid hydrate (384 mg, 4 equiv., 2.02 mmol) was added at room temperature, and the reaction mixture was stirred at 90 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give the title compound N-[3-fluoro-4-(2-{m-[2-(4-propionyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (60 mg, 16.51% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ=8.37 (d, J=5.60 Hz, 1H), 8.31 (s, 1H), 7.86 (dd, J=2.40, 12.60 Hz, 1H), 7.60-7.64 (m, 1H), 7.53 (d, J=8.40 Hz, 1H), 7.39-7.48 (m, 3H), 7.26 (s, 1H), 7.20 (d, J=8.40 Hz, 1H), 6.98 (t, J=7.60 Hz, 1H), 6.72 (d, J=7.60 Hz, 1H), 6.57 (d, J=5.60 Hz, 1H), 3.37 (s, 4H), 2.41 (d, J=8.00 Hz, 2H), 2.34-2.38 (m, 2H), 2.27-2.31 (m, 2H), 2.23-2.25 (m, 2H), LCMS: 721.3 (M+H) + .

[0293] Synthesis Example 41 Synthesis of N-[3-fluoro-4-(2-{m-[2-(1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 60) and N-[3-fluoro-4-(2-{m-[2-(4-methyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 45) [ka]

[0294] Step 1: tert-Butyl 4-[2-(m-aminophenyl)ethyl]-1-piperazinecarboxylate: [ka] To a stirred solution of tert-butyl 4-[2-(m-nitrophenyl)ethyl]-1-piperazinecarboxylate (0.8 g, 2.39 mmol, 1 equiv.) in dimethyl sulfoxide (8 mL, 112 mmol) at 0 °C was added 4,4'-bipyridyl (55.9 mg, 0.15 equiv., 358 μmol). After stirring for 5 min, 1,1,2,2-diboranetetrol (4) (855 mg, 4 equiv., 9.54 mmol) was added portionwise, and the reaction was stirred at room temperature. The reaction was complete within 10 min as determined by TLC. The reaction mixture was then poured into ice-cold water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were collected, dried over Na2SO4, and concentrated in vacuo. The resulting crude compound was purified by column chromatography (gradient elution of 0-6% MeOH in DCM) to give the title compound tert-butyl 4-[2-(m-aminophenyl)ethyl]-1-piperazinecarboxylate (0.6 g, 82.36% yield) as a gummy solid. 1 H NMR (400 MHz, DMSO-d6): δ=6.89 (t, J=7.60 Hz, 1H), 6.39 - 6.33 (m, 3H), 4.92 (s, 2H), 3.30 (s, 4H), 2.56-2.54 (m, 2H), 2.47-2.45 (m, 2H), 2.36 (s, 4H), 1.39 (s, 9H).

[0295] Step 2: N-[3-fluoro-4-(2-{m-[2-(1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide: [ka] To a stirred solution of N-[4-(2-chloro-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (350 mg, 706 μmol, 1 equiv.), 4-fluoroaniline (44.8 mg, 403 μmol, 1 equiv.) in DMF (5 mL) was added 4-methylbenzene-1-sulfonic acid hydrate (537 mg, 4 equiv., 2.82 mmol) at room temperature, and the reaction mixture was then stirred at 90 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give the title compound N-[3-fluoro-4-(2-{m-[2-(1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (70 mg, 14.92% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ=8.29 (d, J=5.60 Hz, 1H), 8.06 (s, 1H), 7.69-7.75 (m, 1H), 7.44-7.47 (m, 2H), 7.37 (m, 1H), 7.30 (s, 1H), 7.20 (q, J=8.00 Hz, 3H), 7.10 (t, J=8.00 Hz, 1H), 6.98-7.00 (m, 1H), 6.75 (d, J=8.00 Hz, 1H), 6.46 (d, J=5.60 Hz, 1H), 2.83 (s, 4H), 2.48-2.52 (m, 8H), LCMS: 665.0 (M+H) + .

[0296] Step 3: N-[3-fluoro-4-(2-{m-[2-(4-methyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide: [ka] To a stirred solution of N-[3-fluoro-4-(2-{m-[2-(1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (60 mg, 90.3 μmol, 1 equiv.) in methanol (2 mL) was added formaldehyde (44.9 μL, 5 equiv., 451 μmol) and acetic acid (2.01 mL, 35.1 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. After stirring for 30 min, sodium bis(acetyloxy)boranudyl acetate (57.4 mg, 3 equiv., 271 μmol) was added to the reaction mixture at room temperature. The reaction mixture was then stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was directly concentrated under reduced pressure, and the resulting crude product was diluted with ethyl acetate (10 mL) and washed with saturated NaHCO solution (10 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give the title compound N-[3-fluoro-4-(2-{m-[2-(4-methyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (12 mg, 19.59% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ=8.29 (d, J=5.60 Hz, 1H), 8.17 (s, 1H), 7.85 (d, J=12.0 Hz, 1H), 7.59-7.56 (m, 2H), 7.47 (d, J=8.4 Hz, 1H), 7.37 - 7.22 (m, 5H), 7.04 (t, J=8.00 Hz, 1H), 6.78 (d, J=7.60 Hz, 1H), 6.49 (d, J=5.60 Hz, 1H), 3.47 - 3.42 (m, 1H), 3.24 - 3.14 (m, 1H), 2.79 - 2.69 (m, 10H), 2.51 (m, 3H), LCMS: 679.3 (M+H) + .

[0297] Synthesis Example 42 Synthesis of N-(4-((2-((3-(2-(4-ethylpiperazin-1-yl)ethyl)phenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 46) [ka]

[0298] Step 1: Synthesis of 1-ethyl-4-(3-nitrophenethyl)piperazine: [ka] To a stirred solution of 1-[2-(m-nitrophenyl)ethyl]piperazine (1 g, 4.25 mmol) in acetonitrile, K2CO3 (1.76 g, 4.25 mmol) was added and stirred at 10 °C for 15 min. Next, 1-iodoethane (683 μL, 4.25 mmol) was added dropwise to the solution and stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (3 × 10 mL). The combined organic phases were collected, dried over Na2SO4, and concentrated in vacuo to give the crude compound. The resulting residue was purified by flash chromatography (3% MeOH in DCM) to give 1-ethyl-4-(3-nitrophenethyl)piperazine (2) (0.56 g, 50% yield) as a liquid. 1 H NMR (400 MHz, CDCl3): δ 8.08-8.05 (m, 2H), 7.54-7.52 (m, 1H), 7.46-7.42 (m, 1H), 2.92-2.88 (m, 2H), 2.66-2.60 (m, 6H), 2.48-2.42 (m, 2H), 1.28 (s, 2H), 1.12-1.09 (m, 3H).

[0299] Step 2: Synthesis of 3-(2-(4-ethylpiperazin-1-yl)ethyl)aniline: [ka] To a stirred solution of 4-ethyl-1-[2-(m-nitrophenyl)ethyl]piperazine (0.56 g, 2.13 mmol) in DMSO under a nitrogen atmosphere, 4,4'-bipyridine (49.8 mg, 2.13 mmol) was added. After 5 min, B2(OH)4 (763 mg, 2.13 mmol) was slowly added and stirred for 5–10 min until the reaction was complete (the reaction progress was monitored by TLC). Next, after completion of the reaction, ice water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 20 mL). The organic layer was collected, dried over Na2SO4, and concentrated under reduced pressure to give the crude residue. The crude residue was washed with pentane to give 3-(2-(4-ethylpiperazin-1-yl)ethyl)aniline (120 mg, 24.1% yield) as a sticky solid. 1 H NMR (400 MHz, DMSO-d6): δ 6.91-6.87 (m, 1H), 6.38-6.33 (m, 1H), 4.93 (s, 2H), 1.90 (s, 1H), 1.23 (s, 1H), 1.01 (s, 3H).

[0300] Step 3: Synthesis of N-(4-((2-((3-(2-(4-ethylpiperazin-1-yl)ethyl)phenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] In a sealed tube, (N-[4-(2-chloro-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide) (0.2 g, 403 μmol) was dissolved in DMF (5 mL). To the above solution, pTSA (278 mg, 1.61 mmol) and 3-(2-(4-ethylpiperazin-1-yl)ethyl)aniline (3) (120 mg, 444 μmol) were added sequentially. After the reagent addition was complete, the reaction was heated to 90 °C and stirred overnight until the starting material was completely consumed (the reaction progress was monitored by TLC). Then, after the reaction was complete, ice water (10 mL) was added to the reaction mixture, which was extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over NaSO and concentrated in vacuo to give the crude compound. The crude compound was purified by preparative HPLC to give the desired product (14 mg, 14.11% yield) as a white fluffy solid. 1 H NMR (400 MHz, CD3OD); δ 8.28 (d, J=5.6 Hz, 1H), 8.16 (s, 1H), 7.84 (dd, J=2.4, 12.4 Hz, 1H), 7.58-7.55 (m, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.36-7.21 (m, 5H), 7.02 (t, J=8.0 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 6.48 (d, J=5.6 Hz, 1H), 2.68-2.63 (m, 12H), 1.15 (t, J=7.2 Hz, 3H).LCMS: 693.3 [M+H] + .

[0301] Synthesis Example 43 Synthesis of N-(3-fluoro-4-((2-((3-(2-(4-propylpiperazin-1-yl)ethyl)phenyl)amino)pyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 47) [ka]

[0302] Step 1: Synthesis of 1-(3-nitrophenethyl)-4-propylpiperazine: [ka] To a stirred solution of 1-[2-(m-nitrophenyl)ethyl]piperazine TFA salt (0.5 g, 2.13 mmol) in acetonitrile, K2CO3 (0.88 g, 2.13 mmol) was added and stirred at 10 °C for 10 minutes. Next, 1-iodopropane (206 μL, 2.13 mmol) was added dropwise to the solution, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (3 × 15 mL). The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to give the crude compound. The resulting residue was purified by flash chromatography (5% MeOH in DCM) to give the title compound 1-(3-nitrophenethyl)-4-propylpiperazine (3) (0.53 g, 44.96% yield) as a sticky mass. 1 H NMR (400 MHz, DMSO-d6): δ 8.09-8.05 (m, 2H), 7.55-7.53 (m, 1H), 7.46-7.43 (m, 1H), 2.93-2.89 (m, 2H), 2.66-2.59 (m, 8H), 2.47-2.41 (m, 2H), 1.82 (s, 2H), 1.25 (s, 1H), 1.12-1.08 (m, 3H) ppm.

[0303] Step 2: Synthesis of 3-(2-(4-propylpiperazin-1-yl)ethyl)aniline: [ka] To a stirred solution of 1-(3-nitrophenethyl)-4-propylpiperazine (3) (0.7 g, 2.52 mmol) in DMSO (5 mL) under a nitrogen atmosphere, 4,4'-bipyridine (59.1 mg, 379 μmol) was added. After 5 min, B2(OH)4 (905 mg, 10.1 mmol) was slowly added and stirred for 5–10 min until the reaction was complete (reaction progress was monitored by TLC). Next, ice water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 20 mL). The organic phase was collected, dried over Na2SO4, and concentrated under reduced pressure to give the crude compound. The crude residue was washed with pentane (10–15 mL) to give m-[2-(4-propyl-1-piperazinyl)ethyl]aniline (340 mg, 54.46% yield) as a sticky solid. 1 H NMR (400 MHz, CDCl3): δ 7.08-7.04 (m, 1H), 6.59 (d, J=8.0 Hz, 1H), 6.53-6.51 (m, 2H), 3.58 (s, 1H), 2.74-2.70 (m, 2H), 2.62-2.58 (m, 9H), 2.37-2.33 (m, 2H), 2.01 (s, 1H), 1.56-1.51 (m, 2H), 1.28 (s, 1H), 0.92-0.87 (m, 3H), LCMS: 248.3 [M+H] + .

[0304] Step 3: Synthesis of N-(3-fluoro-4-((2-((3-(2-(4-propylpiperazin-1-yl)ethyl)phenyl)amino)pyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] In a sealed tube, N-[4-(2-chloro-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (0.5 g, 1.01 mmol) was dissolved in DMF (5 mL). To this solution, pTSA (695 mg, 4.03 mmol) and 3-(2-(4-propylpiperazin-1-yl)ethyl)aniline (299 mg, 1.21 mmol) were added sequentially. After the reagent addition was complete, the reaction was heated to 90 °C and stirred overnight until the starting material was completely consumed (reaction progress was monitored by TLC). Next, ice water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 30 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude residue. The crude compound was purified by preparative HPLC to give the title compound N-(3-fluoro-4-((2-((3-(2-(4-propylpiperazin-1-yl)ethyl)phenyl)amino)pyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (80 mg, 11.22% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6); δ 10.86 (s, 1H), 9.62 (s, 1H), 8.40 (d, J=5.6 Hz, 1H), 8.36 (s, 1H), 7.88 (dd, J=2.4, 12.4 Hz, 1H), 7.66-7.62 (m, 2H), 7.53-7.40 (m, 4H), 7.36 (m, 2H), 7.03 (t, J =7.6 Hz, 1H), 6.78 (d, J=7.2 Hz, 1H), 6.58 (d, J=5.6 Hz, 1H), 3.55 - 3.48 (m, 14H), 3.25 - 2.7 (m, 10H), 1.61 - 1.58 (m, 2H), 0.89 (t, J=7.6 Hz, 3H). LCMS: 707.3 [M+H] + .

[0305] Synthesis Example 44 Synthesis of N-[3-fluoro-4-(2-{m-[2-(4-isopropyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 48) [ka]

[0306] Step 1: Synthesis of 1-isopropyl-4-(3-nitrophenethyl)piperazine: [ka] To a stirred solution of 1-[2-(m-nitrophenyl)ethyl]piperazine-TFA salt (0.5 g, 2.13 mmol) in acetonitrile, cesium carbonate (4.15 g, 3 equiv., 12.8 mmol) and 2-iodopropane (509 μL, 5.1 mmol) were added at room temperature. The reaction was then refluxed for 4 hours. The reaction progress was monitored by TLC. After TLC showed the reaction was complete, the reaction mixture was cooled to room temperature and filtered through a pad of diatomaceous earth (i.e., Celite®), washing with ethyl acetate (20 mL). The collected filtrate was evaporated under reduced pressure to give the crude residue. The crude compound was purified by flash chromatography using 0 to 50% ethyl acetate in hexane as the eluent to give 1-isopropyl-4-(3-nitrophenethyl)piperazine (2) (520 mg, 44.11% yield) as a gummy solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 8.05 (dd, J=1.6 Hz, 8.4 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 2.86 (t, J=7.2 Hz, 2H), 2.55 (t, J=6.8 Hz, 3H), 2.50-2.44 (m, 5H), 0.97 (bs, 6H), LCMS: 278.38 [M+H] + .

[0307] Step 2: Synthesis of 3-(2-(4-isopropylpiperazin-1-yl)ethyl)aniline: [ka] Under a nitrogen atmosphere, 4,4'-bipyridine (43.9 mg, 281 μmol) was added to a stirred solution of 1-isopropyl-4-(3-nitrophenethyl)piperazine (520 mg, 1.87 mmol) in DMSO (5 mL). After stirring for 5 min, B2(OH)4 (672 mg, 7.5 mmol) was slowly added and stirred for 5–10 min until the reaction was complete (the reaction progress was monitored by TLC). After completion of the reaction, ice water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 20 mL). The combined organic layers were collected, dried over Na2SO4, and concentrated under reduced pressure to give the crude residue. The crude compound was purified by flash chromatography using 10% MeOH in DCM to give the title compound, 3-(2-(4-isopropylpiperazin-1-yl)ethyl)aniline (360 mg, 77.62% yield), as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 6.89 (t, J=7.6 Hz, 1H), 6.39-6.32 (m, 3H), 4.92 (s, 2H), 2.61-2.54 (m, 4H), 2.50-2.33 (m, 8H), 1.90 (s, 1H), 0.96 (d, J=6.8 Hz, 6H) ppm, Mass: 248.2 [M+H] + .

[0308] Step 3: Synthesis of N-[3-fluoro-4-(2-{m-[2-(4-isopropyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide: [ka] In a sealed tube, RT-001 (N-[4-(2-chloro-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide) (460 mg, 928 μmol) was dissolved in DMF (5 mL). To the above stirred solution, camphorsulfonic acid (862 mg, 3.71 mmol) and 3-(2-(4-isopropylpiperazin-1-yl)ethyl)aniline (298 mg, 1.21 mmol) were added sequentially. After the addition of the reagents was complete, the reaction mixture was heated to 100 °C and stirred overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, ice water (10 mL) was added and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phase was dried over anhydrous NaSO and concentrated in vacuo to give the crude residue. The crude residue was purified by preparative HPLC to afford the title compound N-[3-fluoro-4-(2-{m-[2-(4-isopropyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (50 mg, 7.63% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6); δ 10.82 (s, 1H), 9.57 (s, 1H), 8.39 (d, J=5.6 Hz, 1H), 8.36 (s, 1H), 7.85 (dd, J=2.0 Hz, 9.6 Hz, 1H), 7.65-7.62 (m, 2H), 7.54-7.41 (m, 4H), 7.29-7.24 (m, 2H), 6.98 (t, J=7.6 Hz, 1H), 6.72 (d, J=7.2 Hz, 1H), 6.57 (d, J=5.6 Hz, 1H), 2.54-2.50 (m, 3H), 2.38-2.34 (m, 10H), 0.92 (d, J=6.4 Hz, 6H), LCMS: 707.3 [M+H] + .

[0309] Synthesis Example 45 Synthesis of N-(4-((2-((3-(2-(4-cyclopropylpiperazin-1-yl)ethyl)phenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 49) [ka]

[0310] Step 1: Synthesis of 1-cyclopropyl-4-(3-nitrophenethyl)piperazine: [ka] To a stirred solution of 1-[2-(m-nitrophenyl)ethyl]piperazine-trifluoroacetic acid (1 / 1) (1.0 g, 2.86 mmol) in a solvent mixture of tetrahydrofuran (15 mL) and MeOH (15 mL), (1-ethoxycyclopropoxy)tris(methyl)silane (1.16 mL, 2 equiv., 5.73 mmol) and sodium cyanoborohydride (270 mg, 1.5 equiv., 4.29 mmol) were added, followed by acetic acid (258 μL, 1.5 equiv., 4.29 mmol). The reaction mixture was stirred at 60 °C for 6 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, water (10 mL) was added, and then neutralized with 1N NaOH and extracted with DCM (3 × 10 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The crude compound was purified by flash silica gel column chromatography using 3-5% MeOH in DCM to give 4-cyclopropyl-1-[2-(m-nitrophenyl)ethyl]piperazine (450 mg, 57.09% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6); δ 8.09-8.06 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 2.93-2.89 (m, 2H), 2.68 (bs, 3H), 2.63-2.60 (m, 2H), 2.59-2.54 (m, 4H), 1.63-1.60 (m, 1H), 0.48-0.39 (m, 4H), LCMS: 276.35 [M+H] + .

[0311] Step 2: Synthesis of 3-(2-(4-cyclopropylpiperazin-1-yl)ethyl)aniline: [ka] To a stirred solution of 1-cyclopropyl-4-(3-nitrophenethyl)piperazine (0.45 g, 1.66 mmol, 1 equiv.) in dimethyl sulfoxide (10 mL) was added 4,4'-bipyridyl (38.6 mg, 0.15 equiv., 0.245 mmol). After stirring for 5 minutes, 1,1,2,2-diboranetetraol (591 mg, 4 equiv., 6.54 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 10 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude residue. The crude residue was purified by flash column chromatography (gradient elution of 5-10% MeOH in DCM) to afford the title compound 3-(2-(4-cyclopropylpiperazin-1-yl)ethyl)aniline (180 mg, 45.0% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6); δ 6.89 (t, J=7.6 Hz, 1H), 6.39- 6.33 (m, 3H), 4.92 (s, 1H), 2.55-2.50 (m, 6H), 2.42-2.33 (m, 6H), 1.58 (m, 1H), 0.40-0.37 (m, 2H), 0.28-0.26 (m, 2H).

[0312] Step 3: Synthesis of N-(4-((2-((3-(2-(4-cyclopropylpiperazin-1-yl)ethyl)phenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide: [ka] To a stirred solution of N-[4-(2-chloro-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (242 mg, 0.489 mmol) and 3-(2-(4-cyclopropylpiperazin-1-yl)ethyl)aniline (180 mg, 1.5 equiv., 0.734 mmol) in dimethylformamide (6 mL) was added 4-methylbenzene-1-sulfonic acid hydrate (334 mg, 4 equiv., 1.96 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 15 mL). The combined organic phase was dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC using 0.1% FA in acetonitrile to give the title compound N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)-2-oxoethyl]phenylamino}-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (100 mg, 19.34% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6); δ 10.85 (s, 1H), 9.64 (s, 1H), 8.40 (d, J=5.6 Hz, 1H), 8.36 (s, 1H), 7.87 (dd, J=2.0 Hz, 12.8 Hz, 1H), 7.66-7.62 (m, 2H), 7.53-7.36 (m, 6H), 7.05 (t, J=7.6 Hz, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.58 (d, J=5.6 Hz, 1H), 3.44 (m, 2H), 3.21-3.09 (m, 4H), 2.95-2.93 (m, 2H), 2.85-2.81 (m, 2H), 2.62-2.59 (m, 2H), LCMS: 705.76 [M+H] + .

[0313] Synthesis Example 46 Synthesis of N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)-2-oxoethyl]phenylamino}-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 50) [ka]

[0314] Step 1: 1-(4-Acryloyl-1-piperazinyl)-2-(m-nitrophenyl)-1-ethanone [ka] To a stirred solution of 2-(m-nitrophenyl)-1-(1-piperazinyl)-1-ethanone:trifluoroacetic acid (1:1) (0.5 g, 1.38 mmol, 1 equiv.) in dichloromethane (25 mL) at 10 °C, triethylamine (0.959 mL, 5 equiv., 6.88 mmol) was added dropwise to the reaction mixture while maintaining the reaction temperature. After 10 min, acryloyl chloride (0.133 mL, 1.2 equiv., 1.65 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature. The reaction was stirred for 1 h, and the progress of the reaction was followed by TLC. The reaction mixture was poured into ice-cold NaHCO3 solution (3 × 30 mL) and extracted with DCM (3 × 40 mL). The combined organic layers were collected, dried over NaSO, and concentrated in vacuo to give crude compound 1-(4-acryloyl-1-piperazinyl)-2-(m-nitrophenyl)-1-ethanone (500 mg), which was used directly in the next step. 1 H NMR (400 MHz, DMSO-d6); δ 8.12 (s, 1H), 8.10 (s, 1H), 7.68 (d, J=7.2 Hz, 1H), 7.6t (t, J=7.6 Hz, 1H), 6.85-6.81 (m, 1H), 6.13 (dd, J=2.4 Hz, 16.4 Hz, 1H), 5.76 - 5.69 (m, 1H), 3.95 (s, 2H), 3.57-3.33 (m, 8H).

[0315] Step 2: 1-(4-acryloyl-1-piperazinyl)-2-(m-aminophenyl)-1-ethanone [ka] To a stirred solution of 1-(4-acryloyl-1-piperazinyl)-2-(m-nitrophenyl)-1-ethanone (0.5 g, 1.65 mmol, 1 equiv.) in dimethyl sulfoxide (10 mL), 4,4'-bipyridyl (38.6 mg, 0.15 equiv., 0.247 mmol) was added and stirred for 5 min, followed by the addition of 1,1,2,2-diboranetetrol (591 mg, 4 equiv., 6.59 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 10 min. The progress of the reaction was followed by TLC. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude residue. The crude residue was purified by flash column chromatography (gradient elution of 5 to 10% MeOH in DCM) to afford the title compound 1-(4-acryloyl-1-piperazinyl)-2-(m-aminophenyl)-1-ethanone (160 mg, 35.51% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6); δ 6.93 (t, J=7.6 Hz, 1H), 6.81- 6.74 (m, 1H), 6.42- 6.35 (m, 3H), 6.00 (dd, J=2.0 Hz, 16.4 Hz, 1H), 5.68 (d, J=10.0 Hz, 1H), 5.03 (m, 2H), 3.57 (s, 2H), 3.48- 3.41 (m, 8H) Mass: 274.2 [M+H] + .

[0316] Step 3: N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)-2-oxoethyl]phenylamino}-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide [ka] To a stirred solution of N-[4-(2-chloro-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (150 mg, 0.303 mmol) and 1-(4-acryloyl-1-piperazinyl)-2-(m-aminophenyl)-1-ethanone (124 mg, 1.5 equiv., 0.454 mmol) in dimethylformamide (6 mL) was added 4-methylbenzene-1-sulfonic acid hydrate (230 mg, 4 equiv., 1.21 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 15 mL). The combined organic phase was dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC using 0.1% FA in acetonitrile to give the title compound N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)-2-oxoethyl]phenylamino}-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (45 mg, 20.3% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6); δ 10.87 (s, 1H), 9.65 (s, 1H), 8.39 (d, J=5.6 Hz, 1H), 8.34 (s, 1H), 7.88 (d, J=12.8 Hz, 1H), 7.66-7.63 (m, 2H), 7.54 (d, J=8.8 Hz, 1H), 7.50-7.42 (m, 3H), 7.34-7.31 (m, 2H), 7.02 (t, J=7.6 Hz, 1H), 6.78-6.70 (m, 2H), 6.58 (d, J=5.6 Hz, 1H), 6.10 (d, J=16.8 Hz, 1H),5.67 (s, 1H), 3.56 (s, 2H), 3.51-3.34 (m, 8H), LCMS: 733.2 [M+H] + .

[0317] Synthesis Example 47 Synthesis of N-[4-(2-{m-[2-(4-acryloyl-2-oxo-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 51) [ka]

[0318] Step 1: Synthesis of 2-(m-nitrophenyl)ethanol: [ka] To a stirred solution of (m-nitrophenyl)acetic acid (5 g, 27.6 mmol) in THF (50 mL) was added 1 M tetrahydrofuran-boron (1 / 1) in THF (55 mL, 2 equiv., 55.2 mmol) at 0 °C, and the reaction was refluxed for 2 h. The progress of the reaction was followed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with methanol at 0 °C. It was then concentrated under reduced pressure to give the crude product. The crude compound was purified by Combiflash using 50% ethyl acetate in hexane as the eluent to give the title compound 2-(m-nitrophenyl)ethanol (4.5 g, 97.53% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ=8.13 - 8.10 (m, 2H), 7.59 (d, J=7.6 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 3.94 (t, J=6.0 Hz, 2H), 2.99 (t, J=6.4 Hz, 2H), 1.47 (s, 1H).

[0319] Step 2: 1-(mesyloxy)-2-(m-nitrophenyl)ethane: [ka] To a solution of 2-(m-nitrophenyl)ethanol (3.8 g, 22.7 mmol, 1 equiv.) in dichloromethane (38 mL) was added triethylamine (4.12 mL, 1.3 equiv., 29.6 mmol) at 0 °C under a nitrogen atmosphere. After stirring at 0 °C for 30 min, (chlorosulfonyl)methane (3.52 mL, 2 equiv., 45.5 mmol) was added dropwise to the above reaction mixture. After the addition was complete, the reaction was allowed to warm to room temperature, where it was stirred for an additional 2 h. After TLC showed the reaction was complete, the solvent was removed and the residue was dissolved in DCM (100 mL). The organic layer was washed with water (40 mL), dried over Na2SO4, and concentrated to give 1-(mesyloxy)-2-(m-nitrophenyl)ethane (6 g crude product, 24.5 mmol) without further purification. 1 H NMR (400 MHz, DMSO-d6): δ=8.16 - 8.13 (m, 2H), 7.60 (d, J=7.6 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H), 4.48 (t, J=6.4 Hz, 2H), 3.19 (t, J=6.4 Hz, 2H), 2.97 (s, 3H).

[0320] Step 3: Synthesis of 2-(m-nitrophenyl)ethanamine: [ka] The compound 1-(mesyloxy)-2-(m-nitrophenyl)ethane (5 g, 20.4 mmol) was taken with 25% ammonium hydroxide (50 mL) and stirred at 80 °C for 1 h. The progress of the reaction was followed by TLC. After TLC showed the reaction was complete, the solvent was removed and the crude residue was dissolved in DCM (100 mL). The organic layer was washed with water (50 mL), dried over NaSO, and concentrated to give crude 2-(m-nitrophenyl)ethanamine (2.6 g crude product, 76.74% yield) as a gummy solid, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ=8.07 - 8.05 (m, 2H), 7.68 (d, J=7.2 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 2.82 - 2.78 (m, 4H), LCMS: 167.1 (M+H) + .

[0321] Step 4: Synthesis of tert-butyl-2-[2-(m-nitrophenyl)ethylamino]ethylaminoformate: [ka] To a stirred solution of 2-(m-nitrophenyl)ethanamine (2 g, 12 mmol, 1 equiv.) in DMF (10 mL) was added dipotassium carbonate (4.99 g, 3 equiv., 36.1 mmol) at room temperature. 2-Bromoethylamino-tert-butyl formirate (3.24 g, 1.2 equiv., 14.4 mmol) was then added to the reaction mixture, which was stirred at 60 °C for 4 h. The reaction progress was monitored by TLC and LCMS. After TLC showed completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography using a gradient elution of 0-5% MeOH in DCM to afford the title compound tert-butyl-2-[2-(m-nitrophenyl)ethylamino]ethylaminoformylate (900 mg, 24.17% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d6): δ=8.37 (d, J=8.0 Hz, 2H), 7.66 (d, J=7.6 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 6.70 (s, 1H), 2.97 (t, J=6.4 Hz, 2H), 2.82 (d, J=6.4 Hz, 2H), 2.75 - 2.72 (m, 2H), 2.53 (d, J=6.4 Hz, 2H), 1.37 (s, 9H), LCMS: 310.2 (M+H) + .

[0322] Step 5: Synthesis of 2-{[2-(m-nitrophenyl)ethyl](bromomethyl)carbonylamino}ethyl 2-methyl-2-propanecarbamate: [ka] To a stirred solution of 2-[2-(m-nitrophenyl)ethylamino]ethyl 2-methyl-2-propanecarbamate (0.9 g, 2.91 mmol, 1 equiv.) in DCM (10 mL) was added triethylamine (1.22 mL, 3 equiv., 8.73 mmol) at 0 °C, followed by stirring for 20 min. Bromoacetyl bromide (304 μL, 1.2 equiv., 3.49 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was followed by TLC and LCMS. After TLC showed the reaction was complete, the reaction mixture was diluted with water (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The resulting crude compound was purified by column chromatography using a gradient elution of 25 to 75% ethyl acetate in hexane to afford the title compound 2-{[2-(m-nitrophenyl)ethyl](bromomethyl)carbonylamino}ethyl 2-methyl-2-propanecarbamate (600 mg, 47.93% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ=8.24 - 8.07 (m, 2H), 7.78 - 7.69 (m, 1H), 7.65 - 7.57 (m, 1H), 6.99 - 6.85 (m, 1H), 4.07 (s, 2H), 3.58 - 3.47 (m, 2H), 3.27 - 3.25 (m, 2H), 3.10 - 3.05 (m, 2H), 2.97 - 2.90 (m, 2H), 1.35 (s, 9H), LCMS: 332.1 (M+H-Boc) + .

[0323] Step 6: Synthesis of N-2-aminoethyl-N-[2-(m-nitrophenyl)ethyl]bromoacetamide: [ka] The compound 2-{[2-(m-nitrophenyl)ethyl](bromomethyl)carbonylamino}ethyl-2-methyl-2-propanecarbamate (0.6 g, 1.39 mmol, 1 equiv.) was taken up in trifluoroacetic acid:dichloromethane (1:1) (12 mL) and stirred at room temperature for 2 h. After TLC showed the reaction was complete, the reaction was concentrated in vacuo, and the resulting residue was triturated with diethyl ether (10 mL) and pentane (15 mL) to give the title compound N-2-aminoethyl-N-[2-(m-nitrophenyl)ethyl]bromoacetamide-TFA salt (0.5 g, 95% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ=8.17 (t, J=7.6 Hz, 1H), 7.81 - 7.79 (m, 1H), 7.73 - 7.68 (m, 1H), 7.66 - 7.61 (m, 1H), 4.26 (s, 2H), 3.61 - 3.37 (m, 5H), 3.07 - 2.90 (m, 3H), LCMS: 332.1 (M+H) + .

[0324] Step 7: Synthesis of 1-[2-(m-nitrophenyl)ethyl]-2-piperazinone: [ka] To a stirred solution of N-2-aminoethyl-N-[2-(m-nitrophenyl)ethyl]bromoacetamide (0.5 g, 1.51 mmol) in ethanol (5 mL) was added dipotassium carbonate (1.05 g, 5 equiv., 7.57 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 20 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (3 × 25 mL), dried over NaSO, and concentrated under reduced pressure. The resulting crude compound was purified by column chromatography using a gradient elution of 0–5% MeOH in DCM to afford the title compound 1-[2-(m-nitrophenyl)ethyl]-2-piperazinone (350 mg, 92.72% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ=8.10 - 8.07 (m, 2H), 7.70 (d, J=7.6 Hz, 1H), 7.59 (t, J=8.0 Hz, 1H), 3.51 (t, J=7.2 Hz, 2H), 3.19 (t, J=5.2 Hz, 2H), 3.15 (s, 2H), 2.93 (t, J=7.2 Hz, 2H), 2.79 (t, J=5.2 Hz, 2H), LCMS: 250.15 (M+H) + .

[0325] Step 8: Synthesis of 4-acryloyl-1-[2-(m-nitrophenyl)ethyl]-2-piperazinone: [ka] To a stirred solution of 1-[2-(m-nitrophenyl)ethyl]-2-piperazinone (350 mg, 1.4 mmol) in dichloromethane (4 mL) at 0 °C, triethylamine (587 μL, 3 equiv., 4.21 mmol) was added. The reaction mixture was stirred for 20 min, and then acryloyl chloride (136 μL, 1.2 equiv., 1.68 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with DCM (2 × 25 mL). The combined organic layers were washed with NaHCO solution, and the combined organic layers were dried over NaSO and concentrated in vacuo to give the crude product. The crude compound was purified by Combiflash using 1-6% MeOH in DCM as the eluent to give the desired product 4-acryloyl-1-[2-(m-nitrophenyl)ethyl]-2-piperazinone (0.2 g, 46.96% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=8.12 - 8.07 (m, 2H), 7.70 (d, J=7.6 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 6.84 - 6.70 (m, 1H), 6.15 (d, J=16.8 Hz, 1H), 5.76 - 5.71 (m, 1H), 4.16 - 4.02 (m, 2H), 3.77 (s, 1H), 3.67 (s, 1H), 3.59 (t, J=7.2 Hz, 2H), 3.32 (s, 2H), 2.96 (t, J=7.2 Hz, 2H), 3.15 (s, 2H), 2.93 (t, J=7.2 Hz, 2H), 2.79 (t, J=5.2 Hz, 2H).

[0326] Step 9: Synthesis of 4-acryloyl-1-[2-(m-aminophenyl)ethyl]-2-piperazinone: [ka] To a stirred solution of 4-acryloyl-1-[2-(m-nitrophenyl)ethyl]-2-piperazinone (0.2 g, 659 μmol, 1 equiv.) in dimethyl sulfoxide (2 mL) at 0 °C was added 4,4'-bipyridyl (15.4 mg, 0.15 equiv., 98.9 μmol). After stirring for 5 min, 1,1,2,2-diboranetetrol (4) (236 mg, 4 equiv., 2.64 mmol) was added portionwise, and the reaction was stirred at room temperature. TLC confirmed the reaction was complete within 10 min. The reaction mixture was then poured into ice-cold water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting crude compound was purified using a gradient elution of 0-6% MeOH in DCM to afford the title compound 4-acryloyl-1-[2-(m-aminophenyl)ethyl]-2-piperazinone (90 mg, 49.94% yield) as a gummy solid. 1H NMR (400 MHz, DMSO-d6): δ=6.91 (t, J=7.6 Hz, 1H), 6.77 - 6.73 (m, 1H), 6.41 - 6.39 (m, 2H), 6.35 (d, J=7.6 Hz, 1H), 6.14 (d, J=16.0 Hz, 1H), 5.72 (dd, J=2.0, 10.4 Hz, 1H), 4.18 - 4.05 (m, 2H), 3.73 - 3.65 (m, 2H), 3.44 (t, J=7.6 Hz, 2H), 3.25 (s, 2H), 2.64 - 2.58 (m, 2H), LCMS: 274.26 (M+H) + .

[0327] Step 10: N-[4-(2-{m-[2-(4-acryloyl-2-oxo-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide: [ka] To a stirred solution of N-[4-(2-chloro-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (90 mg, 182 μmol) in dimethylformamide (2 mL) was added 4-acryloyl-1-[2-(m-aminophenyl)ethyl]-2-piperazinone (74.4 mg, 1.5 equiv., 272 μmol) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC using 0.1% formic acid buffer in water and acetonitrile to give the title compound N-[4-(2-{m-[2-(4-acryloyl-2-oxo-1-piperazinyl)ethyl]phenylamino}-4-pyrimidinyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (5 mg, 3.76% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ=10.88 (s, 1H), 9.61 (s, 1H), 8.39 (d, J=5.6 Hz, 1H), 8.36 (s, 1H), 7.88 (dd, J=2.0, 12.6 Hz, 1H), 7.66 - 7.63 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 7.49 - 7.41 (m, 4H), 7.34 - 7.28 (m, 2H), 7.00 (t, J=8.0 Hz, 1H), 6.78 - 6.69 (m, 2H), 6.57 (d, J=5.6 Hz, 1H), 6.11 (d, J=16.8 Hz, 1H), 5.68 (dd, J=2.4, 10.4 Hz, 1H), 4.17 - 4.02 (m, 2H), 3.72 - 3.60 (m, 2H), 3.43 - 3.39 (m, 2H), 3.16 (t, J=5.6 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H), LCMS: 733.2 (M+H)+ .

[0328] Biological Example 1 Biochemical assay of compounds

[0329] RON kinase ADP Glo assay material: Assay buffer: 40 mM Tris-HCl, pH 7.5, 20 mM MgCl2, 0.1 mg / mL BSA RON Kinase + ADp-Glo™ Assay (Promega #: V8071) Substrate: 1μg / μL Axltide Enzyme: 100ng / μL RON kinase ATP: 10 mM ADP-Glo™ Reagent Kinase detection reagents 384-well white assay plate

[0330] method: Kinase assays were performed according to the kit instructions. Briefly, 10-point serial dilutions of compounds were prepared in 5x assay buffer, starting with final assay concentrations of 300 nM, 100 nM, 30 nM, 10 nM, and 0 nM. Enzyme, substrate, and ATP were used at 25 ng, 2000 ng, and 25 μM, respectively. Assay plates were assembled by mixing components in a total reaction volume of 10 μL per well. Plates were gently centrifuged for 10 seconds and incubated in the dark at room temperature (RT) for 60 minutes. ADP-Glo ​​reagent and kinase detection reagent were added and incubated as recommended. Reactions were quantified by measuring luminescence on a Perkin Elmer Envision plate reader.

[0331] MET kinase ADP Glo assay material: Assay buffer: 40 mM Tris-HCl, pH 7.5, 20 mM MgCl2, 0.1 mg / mL BSA MET Kinase Assay (Promega #: V3361) Substrate: 1μg / μL polyE4Y1 substrate Enzyme: 100ng / μL MET kinase ATP: 10 mM ADP-Glo™ Reagent Kinase detection reagents 384-well white assay plate

[0332] method: Kinase assays were performed according to the kit instructions. Briefly, 10-point serial dilutions of compounds were prepared 5x in assay buffer, starting with final assay concentrations of 3000 nM, 1000 nM, 300 nM, and 100 nM·0 nM. Enzyme, substrate, and ATP were used at 25 ng, 2000 ng, and 25 μM, respectively. Assay plates were assembled by mixing components in a total reaction volume of 10 μL per well. Plates were gently centrifuged for 10 seconds and incubated in the dark at room temperature (RT) for 60 minutes. ADP-Glo ​​reagent and kinase detection reagent were added and incubated as recommended. Reactions were quantified by measuring luminescence on a Perkin Elmer Envision plate reader. [Table 2-1] [Table 2-2]

[0333] RON IC in Table 2 50 Regarding activity: * denotes values ​​greater than 5 μM and up to 60 μM ** indicates values ​​greater than 1 μM and up to 5 μM *** indicates values ​​less than 1 μM - indicates that the value has not been determined

[0334] Table 2 cMET IC 50 Regarding activity: * denotes values ​​greater than 5 μM and up to 65 μM ** indicates values ​​greater than 1 μM and up to 5 μM *** indicates values ​​less than 1 μM - indicates that the value has not been determined

[0335] Regarding the fold selectivity (cMET / RON) activity in Table 2: +++ represents a value greater than 3 and up to 50 ++ represents a value greater than 0.5 and up to 3 + indicates a value less than 0.5 - indicates that the value has not been determined

[0336] 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 non-patent publications mentioned herein and / or listed in Application Data Sheets, including U.S. Provisional Patent Application No. 63 / 413,543, filed October 5, 2022, 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 further embodiments.

[0337] 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 be construed not to limit the claims to the specific embodiments disclosed in the specification and claims, but to include all possible embodiments, along with the full range of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the present disclosure.

Claims

1. A compound having the following structure (I): 【Chemical 1】 [In the formula, R １ has the following structure: 【Chemistry 2】 and During the ceremony, R １ａ is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted 5-membered heteroaryl, or —P(═O)R ａ R ｂ where R ａ and R ｂ are each independently alkyl, or R ａ and R ｂ together with the P atom to which they are attached form an optionally substituted heterocyclyl; R １ｂ is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, unsubstituted arylalkyl, or optionally substituted heterocyclylalkyl; R １ｃ is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, or —P(═O)R ｃ R ｄ where R ｃ and R ｄ are each independently alkyl; R １ｄ is halo, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or —P(═O)R ｅ R ｆ where R ｅ and R ｆ are each independently alkyl; R １ｅ each occurrence is independently alkyl, halo, haloalkyl, cycloalkyl, hydroxyl, amino, cyano, or optionally substituted —NH-aryl-alkyl-heterocyclyl-alkenyl; R １ｆ is -P(=O)R ｅ R ｆ where R ｅ and R ｆ are each independently alkyl; R １ｇ is hydrogen or amino; R ３ each occurrence is independently alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, hydroxyl, amino, or cyano; 【Chemistry 3】 has the following structure: 【Chemistry 4】 having one of: n is 0, 1, 2, or 3; and m is 0, 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

2. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ has the following structure: 【Chemistry 5】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having the formula:

3. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ａ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: is an optionally substituted 5-membered heteroaryl.

4. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ａ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: is an optionally substituted 5-membered N-heteroaryl.

5. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ａ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein is optionally substituted imidazolyl or optionally substituted pyrazolyl.

6. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ａ has the following structure: 【Chemistry 6】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having one of:

7. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ａ has the following structure: 【Chemistry 7】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having the formula:

8. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ａ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

9. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ａ is optionally substituted with alkyl, halo, haloalkyl, cycloalkyl, hydroxyl, amino, or cyano, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

10. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ has the following structure: 【Chemistry 8】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having the formula:

11. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｂ is an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an unsubstituted arylalkyl, or an optionally substituted heterocyclylalkyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

12. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｂ is optionally substituted cyclohexyl, optionally substituted piperidinyl, optionally substituted phenyl, unsubstituted benzyl, or optionally substituted —(CH ２ ) ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which is -morpholino.

13. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｂ is alkyl, alkoxy, haloalkoxy, halo, -P(=O)-(CH ３ ) ２ , —NH—C(═O)-alkenyl, —NH—C(═O)-alkenyl-N(CH ３ ) ２ , —NH—C(═O)-alkyl-N(CH ３ )—C(═O)alkenyl-N(CH ３ ) ２ 2. The compound of claim 1, wherein the compound is cyclohexyl, piperidinyl, or phenyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl, heterocyclyl, substituted with one or more substituents selected from the group consisting of:

14. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｂ has the following structure: 【Chemistry 9-1】 【Chemistry 9-2】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having one of:

15. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｂ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

16. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｂ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: is optionally substituted with alkyl, halo, haloalkyl, cycloalkyl, hydroxyl, amino, or cyano.

17. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ has the following structure: 【Chemistry 10】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having the formula:

18. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｃ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: is an optionally substituted 5-membered heteroaryl.

19. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｃ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: is an optionally substituted 5-membered N-heteroaryl.

20. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｃ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein is optionally substituted imidazolyl or optionally substituted pyrazolyl.

21. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｃ has the following structure: 【Chemistry 11】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having one of:

22. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｃ has the following structure: 【Chemistry 12】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having the formula:

23. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ has the following structure: 【Chemistry 13】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having the formula:

24. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｄ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: is an optionally substituted 5-membered heteroaryl.

25. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｄ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: is an optionally substituted 5-membered N-heteroaryl.

26. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｄ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein is optionally substituted imidazolyl or optionally substituted pyrazolyl.

27. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｄ has the following structure: 【Chemistry 14】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having the formula:

28. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｄ has the following structure: 【Chemistry 15】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having the formula:

29. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｄ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein is bromo.

30. n is 1, 2, 3, and R １ｅ or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

31. n is 1 and R １ｅ is amino or has the following structure: 【Chemistry 16】 30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having the formula:

32. 30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein n is 0, as its stereoisomer, enantiomer, or tautomer, or a mixture thereof.

33. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ has the following structure: 【Chemistry 17】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having the formula:

34. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｆ has the following structure: 【Chemistry 18】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having the formula:

35. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ｇ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein is amino.

36. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ has the following structure: 【Chemistry 19-1】 【Chemistry 19-2】 【Chemistry 19-3】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having one of:

37. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ but has the following structure: 【Chemistry 20】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having one of:

38. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ has the following structure: 【Chemical 21】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having one of:

39. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ has the following structure: 【Chemical 22】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having one of:

40. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof １ has the following structure: 【Chemical 23】 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having one of:

41. 41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein m is 1, 2, 3, 4, or 5, as its stereoisomer, enantiomer, or tautomer, or a mixture thereof.

42. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof ３ 42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each occurrence of is independently halo or haloalkyl.

43. R as its stereoisomers, enantiomers, or tautomers, or mixtures thereof ３ 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each occurrence of is independently halo.

44. m is 1 and R ３ 44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein is fluoro.

45. as its stereoisomers, enantiomers, or tautomers, or mixtures thereof, 【Chemistry 24】 has the following structure: 【Chemistry 25】 45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having the formula:

46. 41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein m is 0, as its stereoisomer, enantiomer, or tautomer, or a mixture thereof.

47. A compound having the structure in Table 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as its stereoisomer, enantiomer, or tautomer, or mixture thereof.

48. 48. A pharmaceutical composition comprising a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as its stereoisomer, enantiomer, or tautomer, or a mixture thereof, and a pharmaceutically acceptable excipient, diluent, or carrier.

49. 49. A method of treating a disease or disorder comprising administering to a subject in need thereof a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition according to claim 48, as its stereoisomer, enantiomer, or tautomer, or a mixture thereof.

50. 50. The method of claim 49, wherein the disease is cancer.

51. 51. The method of claim 50, wherein the cancer is skin cancer, breast cancer, prostate cancer, lung cancer, pancreatic cancer, colon cancer, bone cancer, bladder cancer, rectal cancer, stomach cancer, esophageal cancer, tracheal cancer, pharyngeal cancer, cervical cancer, liver cancer, kidney cancer, brain cancer, thyroid cancer, testicular cancer, ovarian cancer, and cervical cancer.

52. 51. The method of claim 50, wherein the cancer is a carcinoma, sarcoma, lymphoma, leukemia, blastoma, or germ cell tumor.

53. 51. The method of claim 50, wherein the cancer is bone cancer.

54. 51. The method of claim 50, wherein the cancer comprises a bone tumor.

55. 50. The method of claim 49, wherein the disease is osteolysis or osteoporosis.

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