Phenyloxyamide 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 R1, R3 and m are as defined herein. Also provided are methods related to making and using such compounds, compositions comprising such compounds, and methods of using the compounds in the treatment of diseases and disorders. # imgabs0 #

Description

[0001] Government Rights Statement

[0002] This invention was made with government support under grant number W81XWH-18-1-0617 awarded by the Breast Cancer Research Program of the Congressional Directed Medical Research Programs of the United States Department of Defense. The government has certain rights in the invention. Technical Field

[0003] Embodiments of the present disclosure generally relate to compounds, methods for their preparation, and uses as therapeutic or prophylactic agents, such as for treating cancer or osteoporosis. Background Art

[0004] The Recepteur d'origine nantais (RON) receptor tyrosine kinase (RTK) and its ligand (serum macrophage-stimulating protein (MSP)) are recognized oncogenic drivers of tumorigenesis and metastasis. RON is frequently found to be alternatively spliced, resulting in various constitutively active subtypes. Thus, RON is an attractive target for cancer therapy, including small molecule inhibitors and monoclonal antibodies. Although anti-RON monoclonal antibody therapies have been developed and tested in clinical trials, their success has been limited.

[0005] Accordingly, 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 meet this need and provide further related advantages. Summary of the Invention

[0006] Briefly, embodiments of the present disclosure provide compounds, their stereoisomers, enantiomers or tautomers or mixtures thereof; or their pharmaceutically acceptable salts, solvates or prodrugs, which can modulate the RON pathway.

[0007] One embodiment provides a compound of structure (I):

[0008]

[0009] or its stereoisomers, tautomers or salts, wherein R 1 、R 3 and m are as defined herein. In another embodiment, there is also provided a pharmaceutical composition comprising the disclosed compound, and methods of using it to treat diseases and disorders. Detailed Description

[0010] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the present invention. However, those skilled in the art will understand that the present disclosure may be practiced without these details.

[0011] Unless the context requires otherwise, throughout the specification and claims, the word “comprise” and its variations, such as “comprises” and “comprising,” shall be interpreted in an open, inclusive sense, i.e., “including, but not limited to.”

[0012] In this description, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the stated range and, when appropriate, fractional values thereof (e.g., one-tenth and one-hundredth of an integer), unless otherwise indicated. Unless otherwise indicated, as used herein, the terms “about” and “approximately” mean ±20%, ±10%, ±5%, or ±1% of the stated range, value, or structure. As used herein, the terms “a” and “an” refer to “one or more” of the recited components. The use of alternatives (e.g., “or”) should be understood to mean one, both, or any combination of the alternatives.

[0013] References throughout this specification to “one embodiment” or “an embodiment” mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” throughout the specification are not necessarily all referring to the same embodiment. Moreover, in one or more embodiments, the particular features, structures, or characteristics may be combined in any suitable manner.

[0014] 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 pertains. As used in the specification and claims, unless the context clearly dictates otherwise, the singular forms “a,” “an,” and “the” include plural references.

[0015] “Amino” refers to the -NH2 group.

[0016] “Carboxy” or “carboxyl” refers to the -CO2H group.

[0017] “Cyano” refers to the -CN group.

[0018] “Hydroxy” or “hydroxyl” refers to the -OH group.

[0019] "Nitro" refers to the -NO2 group.

[0020] "Oxo" refers to the =O substituent.

[0021] "Mercapto" refers to the -SH substituent.

[0022] "Thioxo" refers to the =S substituent.

[0023] "Alkyl" refers to a saturated straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, said hydrocarbon chain group having, for example, from one to twelve carbon atoms (C1-C 12 alkyl), from one to eight carbon atoms (C1-C8 alkyl) or from one to six carbon atoms (C1-C6 alkyl), or any value within these ranges, such as C4-C6 alkyl, etc., and which is attached to the remainder of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, etc. The number of carbon atoms mentioned relates to the carbon backbone and carbon branching, but does not include the carbon atoms belonging to any substituents. Unless specifically stated otherwise in the specification, the alkyl group is optionally substituted.

[0024] "Alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, said hydrocarbon chain group containing one or more carbon-carbon double bonds, having from two to twelve carbon atoms (C2-C 12 alkenyl), from two to eight carbon atoms (C2-C8 alkenyl) or from two to six carbon atoms (C2-C6 alkenyl) or any value within these ranges, and which is attached to the remainder of the molecule by a single bond, such as vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, etc. The number of carbon atoms mentioned relates to the carbon backbone and carbon branching, but does not include the carbon atoms belonging to any substituents. Unless specifically stated otherwise in the specification, the alkenyl group is optionally substituted.

[0025] The term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon group having from 2 to 12 carbon atoms (C2-C 12 alkynyl), from 2 to 9 carbon atoms (C2-C9 alkynyl) or from 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 ethynyl, propargyl, but-1-ynyl, but-2-ynyl, etc. The number of carbon atoms mentioned relates to the carbon backbone and carbon branching, but does not include the carbon atoms belonging to any substituents. Unless specifically stated otherwise in the specification, the alkynyl group is optionally substituted.

[0026] "Alkylene" or "alkylene chain" refers to a straight-chain or branched-chain divalent hydrocarbon chain that connects the remainder of the molecule to a group, the divalent hydrocarbon chain consisting only of carbon and hydrogen, containing no unsaturation, and having from 1 to 12 carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the remainder of the molecule by a single bond and to the group by a single bond. The point of attachment of the alkylene chain to the remainder of the molecule and the point of attachment of the alkylene chain to the group can be through one carbon or any two carbons within the chain. Unless specifically stated otherwise in the specification, the alkylene chain can be optionally substituted by one of the following groups: alkyl, alkenyl, halogen, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclic, heteroaryl, oxo, trimethylsilyl, -OR 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 from 1 to 2), -S(O) t OR 22 (where t is from 1 to 2), -S(O) p R 22 (where p is from 0 to 2) and -S(O) t N(R 20 )2(where t is from 1 to 2), where each R 20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic, heterocyclicalkyl, heteroaryl or heteroarylalkyl; and each R 22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic, heterocyclicalkyl, heteroaryl or heteroarylalkyl.

[0027] "Alkoxy" refers to a group of the formula -OR a , where R a is an alkyl group as defined above and contains from 1 to 12 carbon atoms (C1-C 12 alkoxy), from 1 to 8 carbon atoms (C1-C8 alkoxy) or from 1 to 6 carbon atoms (C1-C6 alkoxy) or any value within these ranges. Unless specifically stated otherwise in the specification, the alkoxy is optionally substituted.

[0028] "Halogenated alkoxy" refers to a group of the formula -OR a wherein R a is a halogenated alkyl group as defined herein, said halogenated alkyl group containing from 1 to 12 carbon atoms (C1-C 12 halogenated alkoxy), from 1 to 8 carbon atoms (C1-C8 halogenated alkoxy) or from 1 to 6 carbon atoms (C1-C6 halogenated alkoxy) or any value within these ranges. Unless specifically stated otherwise in the specification, the halogenated alkoxy group is optionally substituted.

[0029] "Aminyl" refers to a group of the formula -NR a R b wherein R a and R b are each independently H or a C1-C6 alkyl as defined above. When both R a and R b are H, the "aminyl" group is the same as the "amino" group as defined above. Unless otherwise specified, the C1-C6 alkyl moiety of the amino group is optionally substituted.

[0030] "Aromatic ring" refers to a cyclic planar molecule or part of a molecule (i.e., a group) having resonance bonds, which exhibits increased stability relative to other connecting arrangements of the same set of atoms. Generally, an aromatic ring contains a set of covalently bonded coplanar atoms and contains a number of π electrons (e.g., alternating double and single bonds), the number of which is an even number but not a multiple of 4 (i.e., 4n + 2 π electrons, where n = 0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthyl, imidazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridyl, pyridazinyl or pyrimidinyl. Unless specifically stated otherwise in the specification, "aromatic ring" includes all groups that are optionally substituted.

[0031] "Aryl" refers to a carbocyclic system group containing from 6 to 18 carbon atoms, such as from 6 to 10 carbon atoms (C6-C10 aryl) and at least one carbocyclic aromatic ring. For the purposes of the embodiments of the present disclosure, an aryl group is a monocyclic, bicyclic, tricyclic or tetracyclic system, which may include fused ring or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, heptalene, pyrene and benzophenanthrene. Unless specifically stated otherwise in the specification, the aryl group is optionally substituted.

[0032] "Arylalkyl" refers to a group of the formula -Rb R c group, where R b is an alkylene chain as defined above, and R c is one or more aryl groups as defined above, such as benzyl, diphenylmethyl, etc. The alkylene chain portion of the aralkyl group may optionally be substituted as described above for the alkylene chain. The aryl portion of the aralkyl group may optionally be substituted as described above for the aryl group.

[0033] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic carbocyclic group consisting only of carbon and hydrogen atoms, which may include fused or bridged ring systems, having 3 to 15 ring carbon atoms (C3-C 15 cycloalkyl), 3 to 10 ring carbon atoms (C3-C 10 cycloalkyl) or 3 to 8 ring carbon atoms (C3-C8 cycloalkyl), or any value within these ranges, such as 3 to 4 carbon atoms (C3-C4 cycloalkyl), and which is saturated or partially unsaturated and is attached to the rest of the molecule by a single bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, and cyclooctyl. Polycyclic groups include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specifically stated in the specification, the cycloalkyl group is optionally substituted.

[0034] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0035] "Haloalkyl" refers to an alkyl group as defined above substituted by one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specifically stated in the specification, the haloalkyl group is optionally substituted.

[0036] "Hydroxylalkyl" or "hydroxyalkyl" refers to an alkyl group as defined above substituted by one or more hydroxyl groups. The hydroxylalkyl group is attached at the main chain through an alkyl carbon atom. Unless otherwise specifically stated in the specification, the hydroxylalkyl group is optionally substituted.

[0037] "Heterocyclic group" refers to a non-aromatic ring group having 3 to 18 members, such as 3 to 10 members or 3 to 8 members, having 1 to 10 ring carbon atoms (e.g., 2 to 10) and from 1 to 6 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. Unless otherwise specifically stated in the specification, the heterocyclic group is partially or fully saturated and is a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may include fused rings, spiro rings, and / or bridged ring systems. The nitrogen, carbon, phosphorus, and sulfur atoms in the heterocyclic group are optionally oxidized, and the nitrogen atoms may be optionally quaternized. Examples of such heterocyclic groups include, but are not limited to, phosphinane-1-oxide, 1,4-oxaphosphinane-4-oxide, 1,4-azaphosphinane-4-oxide, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro-1H-pyrrolizine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidinonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thioxomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the heterocyclic group is optionally substituted.

[0038] "Heterocyclic alkyl" refers to a group of the formula -R b R h wherein R b is an alkylene chain as defined above, R h is a heterocyclic group as defined above, and if the heterocyclic group is a nitrogen-containing heterocyclic group, the heterocyclic group may be attached to the alkyl group at the nitrogen atom. The alkylene chain of the heterocyclic alkyl group may be optionally substituted as defined above for the alkylene chain. The heterocyclic moiety of the heterocyclic alkyl group may be optionally substituted as defined above for the heterocyclic group.

[0039] "Heteroaryl" means a 5- to 18-membered, such as a 5- to 6-membered, ring system group containing 1 to 13 ring carbon atoms, one to six ring heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. The heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic system, which can include a fused ring or a bridged ring system; and the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; 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, benzopyrone, benzofuranyl, benzofuranone, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, 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, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thienyl (i.e., thiophenyl). Unless specifically stated otherwise in the specification, the heteroaryl group is optionally substituted.

[0040] "N-Heteroaryl" means a heteroaryl group as defined above containing at least one nitrogen. The N-heteroaryl group can be optionally substituted as described above for the heteroaryl group.

[0041] The term "pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl and / or pyridone group" means a ring having the following corresponding structures:

[0042]

[0043] Each ring can be connected to the remainder of the molecule or a part of the molecule by a single bond, where the connection is achieved by replacing a hydrogen with a single bond. For example, in some embodiments of structure (I), when is pyrazolyl and R 2 is methyl, then the pyrazolyl has one of the following structures:

[0044]

[0045] In some embodiments, the pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, and / or pyridone group is optionally substituted with one or more (e.g., 1, 2, or 3) additional substituents. In certain embodiments, the pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, and / or pyridone group does not include any additional substituents.

[0046] The term “-NH-aryl-alkyl-heterocyclyl-alkenyl” refers to a group of the formula -NH-R a -R b -R c -R d wherein R a is an aryl group as defined above, R b is an alkylene chain as defined above, R c is a heterocyclyl group as defined above, and R d is an alkenyl group as defined above. Each portion of the group (i.e., aryl, alkyl or alkylene, heterocyclyl, and alkenyl) may optionally be substituted as defined above for each respective group. Examples of -NH-aryl-alkyl-heterocyclyl-alkenyl are groups having one of the following structures:

[0047]

[0048] wherein each of the above structures may optionally be substituted with one or more additional substituents (e.g., substituted with an oxo group on the alkyl or heterocyclyl portion of the group).

[0049] As used herein, the term “substituted” means any of the above groups (e.g., alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclene, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and / or hydroxyalkyl) in which at least one hydrogen atom (e.g., 1, 2, 3, or all hydrogen atoms) is replaced with a bond to a non-hydrogen substituent. Examples of non-hydrogen substituents include, but are not limited to, amino, carboxyl, cyano, hydroxy, halogen, nitro, oxo, mercapto, thio, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and / or hydroxyalkyl substituents, each of which may also optionally be substituted with one or more of the above substituents.

[0050] In some specific embodiments, the optional substituents are independently selected from halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C 10 aryl, 5- or 6-membered heteroaryl, C1-C6 alkoxy, and 3-8-membered heterocyclic group. In some embodiments, the optional substituents are independently selected from halogen, 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 halogen, 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 5-10-membered heterocyclic alkyl, optionally substituted 5-10-membered heterocyclic oxy, and optionally substituted C6-C 10 aryl.

[0051] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to affect the intended application for the treatment of a disease as defined, including but not limited to, the following. The therapeutically effective amount may vary depending on the intended therapeutic application (in vivo), or the individual being treated and the disease condition (e.g., the weight and age of the individual, the severity of the disease condition, the mode of administration, etc.), which can be readily determined by one of ordinary skill in the art. The term also applies to the dose that induces a specific response (e.g., a reduction in platelet adhesion and / or cell migration) in target cells. The specific dose will vary depending on the compound selected, the dosing regimen followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which the compound is administered, and the physical delivery system carried by the compound.

[0052] As used herein, "treatment" or "treating" refers to a method for obtaining a beneficial or desired result with respect to a disease, disorder or medical condition, said result including but not limited to a therapeutic effect and / or a prophylactic effect. A therapeutic benefit means eradicating or ameliorating the underlying disorder being treated. Additionally, a therapeutic benefit is achieved by eradicating or ameliorating one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual, even though the individual may still be afflicted with the underlying disorder. Prophylactic effects include delaying or eliminating the onset of a disease or disorder, delaying or eliminating the onset of symptoms of a disease or disorder, slowing, halting or reversing the progression of a disease or disorder, or any combination thereof. In certain embodiments, for prophylactic benefit, the compositions are administered to an individual at risk of developing a particular disease or to an individual reporting one or more physiological symptoms of a disease, even though a diagnosis of the disease may not have been made.

[0053] As used herein, the terms "co-administer", "administered in combination with" and their grammatical equivalents encompass the administration of two or more agents to an animal (including a human) such that the two agents and / or their metabolites are present in the individual at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times with a therapeutic benefit, or administration in a composition in which both agents are present.

[0054] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts.

[0055] "Pharmaceutically acceptable acid addition salts" refers to those salts that retain the biological effectiveness of the free base and are biologically tolerable or otherwise biologically suitable for administration to an individual. See generally S.M. 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. Preferred pharmaceutically acceptable acid addition salts are those that are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable acid addition salts are formed with inorganic acids and organic acids, such as but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. for inorganic acids, and 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, cyclohexanesulfamic 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, glutaric acid, 2-oxo-glutaric 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, undecylenic acid, etc. for organic acids.

[0056] "Pharmaceutically acceptable base addition salts" refers to those salts that retain the biological effectiveness of the free acid and are biologically tolerable or otherwise biologically suitable for administration to an individual. See generally S.M. 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. Preferred pharmaceutically acceptable base addition salts are those that are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation, or allergic response. 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 salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, 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, such as 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, methylglucosamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0057] In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts, such as quaternary ammonium alkyl halide salts (e.g., methyl bromide).

[0058] "Individual" refers to an animal, such as a mammal, such as a human. The methods described herein can be used for human therapy and veterinary applications. In some embodiments, the individual is a mammal, and in some embodiments, the individual is a human.

[0059] "Mammal" includes both humans and domestic animals (e.g., laboratory animals and domestic pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits)) and non-domestic animals (e.g., wild animals, etc.).

[0060] "Prodrug" means a compound that can be converted into a biologically active compound (e.g., a compound of structure (I)) described herein under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active compound. In some embodiments, the prodrug is inactive when administered to an individual but is converted into an active compound in vivo (e.g., by hydrolysis). Prodrug compounds generally offer the advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions of prodrugs are provided in Higuchi, T. et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety. The term "prodrug" also means to include any covalently bonded carrier that releases an active compound in vivo when such prodrug is administered to a mammalian individual. Prodrugs of the active compounds described herein are generally prepared by modifying the functional groups present in the active compound in such a way that the modification cleaves in a conventional operation or in vivo to form the parent active compound. Prodrugs include compounds in which a hydroxyl, amino, or mercapto group is bonded to any group that cleaves, respectively, to form a free hydroxyl, free amino, or free mercapto group when the prodrug of the active compound is administered to a mammalian individual. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of a hydroxyl functional group, or acetamide, formamide, and benzamide derivatives of an amine functional group in the active compound, etc.

[0061] The term "in vivo" refers to events that occur within an individual.

[0062] The embodiments disclosed herein also mean to cover all pharmaceutically acceptable compounds of structure (I), including their stereoisomers, enantiomers, or tautomers or mixtures thereof; or their pharmaceutically acceptable salts, solvates, or prodrugs.

[0063] Certain embodiments also are meant to encompass in vivo metabolites of the disclosed compounds. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, mainly due to enzymatic reactions. Accordingly, embodiments include compounds produced by a method comprising administering a compound of the present disclosure to a mammal for a period of time sufficient to produce its metabolites. Such products are typically identified by administering a detectable dose of a radiolabeled compound of the present disclosure to an animal (e.g., rat, mouse, guinea pig, monkey, or human), allowing sufficient time for metabolism to occur, and isolating the conversion products from urine, blood, or other biological samples.

[0064] "Stable compound" and "stable structure" mean a compound that is sufficiently robust to be isolated from a reaction mixture in useful purity and formulated as an effective therapeutic agent.

[0065] Crystallization typically produces solvates of the compounds disclosed herein. As used herein, the term "solvate" refers to an aggregate that contains one or more compounds of the present disclosure and one or more solvent molecules. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Accordingly, the compounds of the present disclosure can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as the corresponding solvated forms. In some embodiments, the compounds of the present disclosure are true solvates, while in other cases, the compounds of the present disclosure merely retain adventitious water or are a mixture of water plus some adventitious solvent.

[0066] "Optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes the case where the event or circumstance occurs and the case where it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and the description includes both substituted aryl groups and unsubstituted aryl groups ("unsubstituted"). When a functional group is described as "optionally substituted" and, in turn, the substituents on the functional group are also "optionally substituted", etc., for the purposes of the present disclosure, such iteration is limited to five, four, or three times. In some embodiments, such iteration is limited to two times. In some embodiments, such iteration is limited to one time. In some embodiments, when a functional group is described as "optionally substituted", the substituents on the functional group are unsubstituted.

[0067] "Pharmaceutical composition" means a formulation of a compound of the present disclosure and a medium commonly accepted in the art for delivering the compound of the present disclosure to a mammal (e.g., a human). Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients.

[0068] "Pharmaceutically acceptable carriers, diluents or excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.

[0069] "Stereoisomers" refer to compounds that are composed of the same atoms bonded by the same bonds but have different non-interchangeable three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers", which refer to two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0070] The compounds of the present disclosure (i.e., the compounds of structure (I)) or pharmaceutically acceptable salts thereof may contain one or more geometrically asymmetric centers and may thus give rise to stereoisomers (e.g., enantiomers, diastereomers and other stereoisomeric forms), which are defined as (R)- or (S)- in terms of absolute stereochemistry, or (D)- or (L)- for amino acids. Accordingly, the embodiments include all such possible isomers, as well as their racemic and optically pure forms. The 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 / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center, and unless otherwise specified, it is intended that the compounds include both the E geometric isomer and the Z geometric isomer. Similarly, all tautomeric forms are also intended to be included.

[0071] The embodiments of the present disclosure include all forms of rotamers and conformationally restricted states of the compounds of the present disclosure. Atropisomers are also included, which are generated due to hindered rotation around a single bond, where the rotational energy barrier caused by steric hindrance or other factors is high enough to allow the separation of individual conformational isomers. As an example, certain compounds of the present disclosure may exist as a mixture of atropisomers, or the presence of one atropisomer is purified or enriched.

[0072] In some embodiments, the compounds of structure (I) are a mixture of enantiomers or diastereomers. In other embodiments, the compounds of structure (I) are substantially one enantiomer or diastereomer.

[0073] "Tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. Accordingly, embodiments include tautomers of the disclosed compounds.

[0074] The chemical nomenclature and structural diagrams used herein are a modified form of the I.U.P.A.C. nomenclature 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 the complex chemical names employed herein, substituent groups are generally named before the group to which they are attached. For example, cyclopropyl ethyl contains an ethyl backbone with a cyclopropyl substituent; cyanoalkyl contains an alkyl backbone with a cyano substituent. Except as otherwise noted below, all bonds are depicted in the chemical structural diagrams herein, except for all bonds on some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to satisfy the valency.

[0075] Compound

[0076] The present disclosure provides compounds having the following structure (I), their stereoisomers, enantiomers or tautomers or mixtures thereof; or their pharmaceutically acceptable salts, solvates or prodrugs:

[0077]

[0078] Wherein:

[0079] R 1 Has one of the following structures:

[0080]

[0081] Wherein:

[0082] R 1a Is an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, 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 an alkyl;

[0083] R 1b Is an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl;

[0084] R 1c Is an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or -P(=O)R c R d Where R cand R d each independently is an alkyl group;

[0085] R 1d is halogen, optionally substituted cycloalkyl, optionally substituted heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, or -P(=O)R e R f wherein R e and R f each independently is an alkyl group;

[0086] Each occurrence of R 1e is independently an alkyl group, halogen, haloalkyl, cycloalkyl, hydroxy, amino, or cyano;

[0087] R 2 is an alkyl group, haloalkyl, or -P(=O)R g R h wherein R g and R h each independently is an alkyl group;

[0088] Each occurrence of R 3 is independently an alkyl group, halogen, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, hydroxy, amino, or cyano;

[0089] is pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridone group;

[0090] n is 0, 1, 2 or 3; and

[0091] m is 0, 1, 2, 3, 4 or 5.

[0092] One embodiment provides a compound having the following structure (I), its stereoisomers, enantiomers or tautomers or a mixture thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0093]

[0094] Wherein:

[0095] R 1 has one of the following structures:

[0096]

[0097] Wherein:

[0098] R 1a is optionally substituted cycloalkyl, optionally substituted heterocyclic group, optionally substituted aryl, optionally substituted 5-membered heteroaryl, or -P(=O)R a Rb , wherein R a and R b are each independently an alkyl group or R a and R b together with the P atom to which they are attached join to form an optionally substituted heterocyclic group;

[0099] R 1b is an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an unsubstituted arylalkyl group, or an optionally substituted heterocyclic alkyl group;

[0100] R 1c is an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or -P(=O)R c R d , wherein R c and R d are each independently an alkyl group;

[0101] R 1d is a halogen, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or -P(=O)R e R f , wherein R e and R f are each independently an alkyl group;

[0102] Each occurrence of R 1e is independently an alkyl group, a halogen, a haloalkyl group, a cycloalkyl group, a hydroxyl group, an amino group, or a cyano group;

[0103] R 1f is -P(=O)R e R f , wherein R e and R f are each independently an alkyl group;

[0104] R 1g is hydrogen or an amino group;

[0105] Each occurrence of R 3 is independently an alkyl group, a halogen, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a hydroxyl group, an amino group, or a cyano group;

[0106] has one of the following structures:

[0107]

[0108] n is 0, 1, 2, or 3; and

[0109] m is 0, 1, 2, 3, 4, or 5.

[0110] In some embodiments, R 1 has the following structure:

[0111]

[0112] 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 an optionally substituted imidazolyl or an optionally substituted pyrazolyl. In some embodiments, R 1a has one of the following structures:

[0113]

[0114] 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:

[0115]

[0116] In some embodiments, R 1a has one of the following structures:

[0117]

[0118] Wherein:

[0119] X is -CH2-, -N(R a' )- or -O-; and

[0120] R a' is hydrogen or a C1-C6 alkyl.

[0121] In certain embodiments, R 1a is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, or an optionally substituted aryl. In some embodiments, R 1a is optionally substituted with an alkyl, a halogen, a haloalkyl, a cycloalkyl, a hydroxyl, an amino, or a cyano. In some embodiments, R 1a is unsubstituted.

[0122] In some embodiments, R 1 has the following structure:

[0123]

[0124] In certain embodiments, R 1b is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, an optionally substituted aryl, an unsubstituted arylalkyl, or an optionally substituted heterocyclic alkyl. In some embodiments, R 1b is an optionally substituted cyclohexyl, an optionally substituted piperidinyl, an optionally substituted phenyl, an unsubstituted benzyl or an optionally substituted -(CH2)2-morpholino. In certain embodiments, R 1b is a cyclohexyl, piperidinyl or phenyl substituted with one or more substituents selected from alkyl, alkoxy, haloalkoxy, halogen, -P(=O)-(CH3)2, -NH-C(=O)-alkenyl, -NH-C(=O)-alkenyl-N(CH3)2, -NH-C(=O)-alkyl-N(CH3)-C(=O) alkenyl-N(CH3)2, an optionally substituted heterocyclic group and an optionally substituted heterocyclic alkyl.

[0125] In some embodiments, R 1b is an optionally substituted aryl. In certain embodiments, R 1b is an optionally substituted phenyl. In some embodiments, R 1b is a substituted phenyl. In some embodiments, R 1b is a phenyl substituted with a heterocyclic group.

[0126] In certain embodiments, R 1b has one of the following structures:

[0127]

[0128] In some embodiments, R 1b has one of the following structures:

[0129]

[0130] In certain embodiments, R 1b is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl. In some embodiments, R 1b is optionally substituted with alkyl, halogen, haloalkyl, cycloalkyl, hydroxy, amino, or cyano.

[0131] In some embodiments, R 1 has the following structure:

[0132]

[0133] In certain embodiments, R1c 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 an optionally substituted imidazolyl or an optionally substituted pyrazolyl. In some embodiments, R 1c has one of the following structures:

[0134]

[0135] 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:

[0136]

[0137] In some embodiments, R 1c has one of the following structures:

[0138]

[0139] Wherein:

[0140] X is -CH2-, -N(R c' )- or -O-; and

[0141] R c' is hydrogen or a C1-C6 alkyl.

[0142] In some embodiments, R 1 has the following structure:

[0143]

[0144] 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 an optionally substituted imidazolyl or an optionally substituted pyrazolyl. In some embodiments, R 1d has the following structure:

[0145]

[0146] In some embodiments, R 1cis - 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:

[0147]

[0148] In some embodiments, R 1d has one of the following structures:

[0149]

[0150] wherein:

[0151] X is - CH2 -, - N(R d' ) - or - O -; and

[0152] R d' is hydrogen or a C1 - C6 alkyl group.

[0153] In certain embodiments, R 1d is fluorine, chlorine, bromine or iodine. In some embodiments, R 1d is chlorine or fluorine. In some embodiments, R 1d is bromine.

[0154] In some embodiments, n is 0. In certain embodiments, n is 1, 2, 3 and each occurrence of R 1e is independently a halogen, a hydroxyl group, or an amino group. In some embodiments, n is 1 and R 1e is an amino group. In some embodiments, n is 0. In certain embodiments, n is 1, 2, 3, and each occurrence of R 1e is independently a halogen, a hydroxyl group, an amino group or - NH - aryl - alkyl - heterocyclic - alkenyl. In some embodiments, n is 1 and R 1e is an amino group or has the following structure.

[0155]

[0156] In certain embodiments, R 1 has the following structure:

[0157]

[0158] In some embodiments, R 1f has the following structure:

[0159]

[0160] In some embodiments, R 1f has one of the following structures:

[0161]

[0162] wherein:

[0163] X is -CH2-, -N(R f' )-, or -O-; and

[0164] R f’ is hydrogen or a C1-C6 alkyl group.

[0165] In some embodiments, R 1g is an amino group. In some embodiments, R 1g is hydrogen.

[0166] In certain embodiments, R 1 has one of the following structures:

[0167]

[0168]

[0169]

[0170] In some embodiments, R 1 has one of the following structures:

[0171]

[0172] In some embodiments, R 1 has one of the following structures:

[0173]

[0174]

[0175]

[0176] In some embodiments, R 1 has one of the following structures:

[0177]

[0178] In certain embodiments, R 1 has one of the following structures:

[0179]

[0180] In certain embodiments, R1 has one of the following structures:

[0181]

[0182] In some embodiments, R 1 has one of the following structures:

[0183]

[0184] In certain embodiments, R 1 has one of the following structures:

[0185]

[0186] In some embodiments, R 1 has one of the following structures:

[0187]

[0188] In some embodiments, R 2 is a haloalkyl. In certain embodiments, R 2 is trifluoromethyl. In some embodiments, R 2 is an alkyl. In certain embodiments, R 2 is methyl. In some embodiments, R 2 has the following structure:

[0189]

[0190] In some embodiments, R 2 has one of the following structures:

[0191]

[0192] Wherein:

[0193] X is -CH2-, -N(R 2' )-, or -O-; and

[0194] R 2a' is hydrogen or a C1-C6 alkyl.

[0195] In certain embodiments, has one of the following structures:

[0196]

[0197] In some embodiments, has one of the following structures:

[0198]

[0199] In certain embodiments, has one of the following structures:

[0200]

[0201] In some embodiments, m is 0. In certain embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, each occurrence of R 3 is independently halogen or haloalkyl. In some embodiments, each occurrence of R 3 is halogen. In certain embodiments, m is 1 and R 3 is fluorine.

[0202] In some embodiments, the portion of structure (I) has the following structure:

[0203]

[0204] One embodiment provides a compound having one of the structures listed in Table 1, its stereoisomers, enantiomers, or tautomers, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The compounds in Table 1 are prepared as described in the Examples or by methods known in the art and are analyzed by mass spectrometry (MS) and / or nuclear magnetic resonance spectroscopy (NMR).

[0205] Table 1: Representative Compounds of Structure (I)

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216] 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.

[0217] In additional embodiments, various compounds of the present disclosure that exist in free base or free acid form can be converted into their pharmaceutically acceptable salts by methods known to those skilled in the art with appropriate inorganic or organic bases or acids. Salts of compounds of the present disclosure can be converted into their free base or free acid forms by standard techniques.

[0218] Pharmaceutical composition

[0219] Other embodiments relate to pharmaceutical compositions. 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 more embodiments, the pharmaceutical composition comprises a compound as disclosed herein and an additional therapeutic agent (e.g., an anticancer agent). Non-limiting examples of such therapeutic agents are described below.

[0220] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ear, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0221] In certain embodiments, the compound as described herein is usually applied locally rather than systemically in a depot preparation or a sustained release preparation, for example, the compound is injected directly into an organ. In a specific embodiment, the long-acting preparation is applied by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. In addition, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such an embodiment, the liposome is targeted to an organ and selectively absorbed by the organ. In other embodiments, the compound as described herein is provided in the form of a rapid release preparation, a prolonged release preparation, or an intermediate release preparation. In other embodiments, the compound as described herein is applied topically.

[0222] In a method of treatment according to an embodiment of the present disclosure, an effective amount of at least one compound of structure (I) is administered to an individual suffering from or diagnosed with such a disease, disorder or medical condition. The effective amount or effective dose can be determined by methods such as modeling, dose escalation studies or clinical trials, for example, the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder or condition, the individual's prior or ongoing therapy, the individual's health status and response to the drug, and the judgment of the treating physician.

[0223] The compounds according to the present disclosure are effective over a wide range of doses. For example, in the treatment of adults, doses of 10 mg / day to 5000 mg / day, 100 mg / day to 5000 mg / day, 1000 mg / day to 4000 mg / day and 1000 mg / day to 3000 mg / day are examples of doses used in some embodiments. The exact dose will depend on the route of administration, the form of the compound administered, the individual to be treated, the weight of the individual to be treated, and the preference and experience of the attending physician.

[0224] In some embodiments, the compounds of the present disclosure are administered in a single dose. Generally, such administration will be by injection, for example intravenous injection, to rapidly introduce the agent. However, other routes may be used as appropriate. A single dose of the compounds of the present disclosure can also be used to treat acute conditions.

[0225] In some embodiments, the compounds of the present disclosure are administered in multiple doses. In some embodiments, the administration is about once, twice, three times, four times, five times, six times or more than six times per day. In other embodiments, the administration is about once per month, once every two weeks, once per week or once every other day. In another embodiment, the compounds of the present disclosure and another agent (e.g., an anti-cancer agent) are administered together about once to about 6 times per day. In another embodiment, the compounds of the present disclosure and the agent are administered for less than about 7 days. In another embodiment, the administration continues for more than about 6 days, 10 days, 14 days, 28 days, 2 months, 6 months or 1 year. In some cases, continuous administration is achieved and maintained for the necessary time.

[0226] The administration of the compounds of the present disclosure can continue for the necessary time. In some embodiments, the compounds of the present disclosure are administered for more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days or 28 days. In some embodiments, the compounds of the present disclosure are administered for less than 28 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day. In some embodiments, the compounds of the present disclosure are administered long-term on an ongoing basis, for example for treating chronic effects.

[0227] In some embodiments, the compounds of the present disclosure are administered in separate dosage forms. It is known in the art that due to the differences in compound pharmacokinetics among individuals, the individualization of the dosing regimen is necessary for optimal treatment.

[0228] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, the pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, which carriers include excipients and adjuvants that facilitate processing the disclosed compounds into pharmaceutically acceptable formulations. Suitable formulations depend on the chosen route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients are used to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999).

[0229] The present disclosure provides pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

[0230] The present disclosure provides pharmaceutical compositions comprising one or more compounds selected from the compounds of formula (I) and pharmaceutically acceptable diluents, excipients, and carriers. In certain embodiments, the described compounds are administered as pharmaceutical compositions, wherein one or more compounds selected from the compounds of formula (I) are mixed with other active ingredients, such as in combination therapies. All combinations of the active substances set forth in the following combination therapy section and throughout the present disclosure are encompassed herein. In specific embodiments, the pharmaceutical composition comprises one or more compounds of formula (I).

[0231] 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 such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates the 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 to a mammal suffering from a disease, disorder, or medical condition to be treated in a pharmaceutical composition. In a specific embodiment, the mammal is a human. In certain embodiments, the therapeutically effective amount varies depending on the severity of the disease, the age and relative health of the individual, 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.

[0232] In one embodiment, one or more compounds selected from the compounds of structure (I) are formulated in an aqueous solution. In a specific embodiment, by way of example only, the aqueous solution is selected from physiologically compatible buffers such as Hank's solution, Ringer's solution, or saline buffer. In other embodiments, 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 suitable for the barrier to be penetrated. In other embodiments, 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.

[0233] In another embodiment, the compounds described herein are formulated for oral administration. The compounds described herein are formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compounds described herein are formulated into oral dosage forms including, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, pastes, suspensions, etc.

[0234] In certain embodiments, pharmaceutical formulations for oral use are obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after addition of suitable auxiliaries if required, 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, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or other substances such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, a disintegrant is optionally added. Disintegrants include (by way of example only) croscarmellose sodium, polyvinylpyrrolidone, agar or alginic acid or its salts (such as sodium alginate).

[0235] In one embodiment, the dosage forms, such as dragee cores and tablets, are provided with one or more suitable coatings. In specific embodiments, concentrated sugar solutions are used to coat the dosage forms. The sugar solutions optionally contain additional components such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbomer gels, 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. In addition, dyes and / or pigments are optionally used to characterize different combinations of the active compound dosage.

[0236] In certain embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated 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 (such as glycerol or sorbitol). In specific embodiments, the push-fit capsules contain the active ingredient admixed with one or more fillers. Fillers include (by way of example only) lactose, binders (such as starch) and / or lubricants (such as talc or magnesium stearate) and optionally stabilizers. In other embodiments, 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, stabilizers are optionally added.

[0237] In other embodiments, the compounds described herein are formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, the formulations for injection are provided in unit dosage forms (e.g., in ampoules) or in multi-dose containers. A preservative is optionally added to the injection formulation. In other embodiments, the pharmaceutical composition is formulated in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in an oily or aqueous vehicle. The parenteral injection formulation optionally contains formulating agents such as suspending agents, stabilizers and / or dispersing agents. In specific embodiments, the pharmaceutical formulation for parenteral administration comprises an aqueous solution of the active compound in water-soluble form. In additional embodiments, a suspension of one or more compounds selected from the compounds of structure (I) is prepared as a suitable oily injection suspension. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include (by way of example only) fatty oils (e.g., sesame oil) or synthetic fatty acid esters (e.g., ethyl oleate or triglycerides) or liposomes. In certain specific embodiments, the aqueous injection suspension contains a substance that increases the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension contains a suitable stabilizer or a reagent that increases the solubility of the compound to permit the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for combination with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

[0238] The pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, diluent or excipient, and one or more compounds selected from the compounds of structure (I) described herein as the active ingredient. The active ingredient is in the free acid or free base form or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as 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 provided herein. In addition, the compounds described herein encompass non-solvated as well as solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). The solvated forms of the compounds provided herein are also considered to be disclosed herein. In addition, the pharmaceutical composition optionally includes other drugs or agents, carriers, adjuvants (e.g., preservatives, stabilizers, wetting or emulsifying agents, solubilizing agents), salts for adjusting osmotic pressure, buffers and / or other therapeutically valuable substances.

[0239] Methods for preparing a composition comprising a compound described herein include formulating the compound with one or more inert pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles or nanoparticles comprising the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. Forms of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms adapted to be dissolved or suspended in a liquid prior to use, or as emulsions. These compositions also optionally contain small amounts of non-toxic auxiliary substances such as wetting agents or emulsifying agents, pH buffering agents, and the like.

[0240] In some embodiments, a pharmaceutical composition comprising one or more compounds selected from the compounds of structure (I) exemplary takes the form of a liquid, where the agent is present in a solution, a suspension, or both. Generally, when the composition is administered as a suspension, a first portion of the reagent is present in solution and a second portion of the reagent is present in suspension in particulate form in a liquid matrix. In some embodiments, the liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

[0241] In certain embodiments, the aqueous suspension contains one or more polymers as suspending agents. Polymers include water-soluble polymers such as cellulose polymers (e.g., hydroxypropyl methylcellulose) and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein contain 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.

[0242] The pharmaceutical composition also optionally contains solubilizing agents to aid in the solubility of one or more compounds selected from the compounds of structure (I). The term "solubilizing agent" generally encompasses agents that result in the formation of a micellar solution or a true solution of the reagent. Certain acceptable nonionic surfactants (e.g., polysorbate 80) can be used as solubilizing agents, and ophthalmically acceptable diols, polyglycols (e.g., polyethylene glycol 400), and diol ethers can also be used as solubilizing agents.

[0243] In addition, the pharmaceutical composition optionally includes one or more pH regulators or buffers, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in the amounts required to maintain the pH of the composition within an acceptable range.

[0244] Optionally, the composition further comprises an amount of one or more salts necessary to bring the osmolality of the composition to an acceptable range. Such salts include salts having a sodium cation, potassium cation or ammonium cation and a chloride anion, citrate anion, ascorbate anion, borate anion, phosphate anion, bicarbonate anion, sulfate anion, thiosulfate anion or bisulfite anion; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0245] Other pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thimerosal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[0246] 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 alkyl phenyl ethers such as octoxynol 10, octoxynol 40.

[0247] The composition may contain one or more antioxidants to enhance chemical stability when needed. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0248] In certain embodiments, the aqueous suspension composition is packaged in a single-dose non-reclosable container. Alternatively, a multi-dose reclosable container is used, in which case a preservative is typically included in the composition.

[0249] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers that can be used herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained-release system, such as a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent. A variety of sustained-release materials are available herein. In some embodiments, the sustained-release capsule releases the compound for several weeks up to over 100 days. Additional protein stabilization strategies are employed depending on the chemical nature and biostability of the therapeutic agent.

[0250] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other common 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 and zinc; or (n) combinations thereof.

[0251] 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 greater than 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%, 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 0.0001% w / w, w / v or v / v.

[0252] 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%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v or v / v.

[0253] In some embodiments, the amount of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical compositions of the present disclosure is equal to or less than 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, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g or 0.0001 g.

[0254] In some embodiments, the amount of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical compositions of the present disclosure is 0.0001 - 10 g, 0.0005 - 9 g, 0.001 - 8 g, 0.005 - 7 g, 0.01 - 6 g, 0.05 - 5 g, 0.1 - 4 g, 0.5 - 4 g or 1 - 3 g.

[0255] The packaging materials for the pharmaceutical compositions described herein include those recited in U.S. Pat. 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, flasks, and any packaging material suitable for the selected formulation and the intended mode of administration and treatment. For example, a container contains one or more of the compounds described herein, optionally in a composition or in combination with another agent as 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 that can be pierced by a hypodermic needle). Such a kit optionally contains a compound with an identifying description or label or instructions related to its use in the methods described herein.

[0256] For example, a kit generally includes one or more additional containers, each containing one or more of the various materials (e.g., reagents, optionally in concentrated form, and / or devices) desired for using the compounds described herein from a commercial and user perspective. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; labels for carriers, packages, containers, vials, and / or tubes listing the contents and / or instructions for use, and package inserts with instructions for use. A set of instructions is generally also included. The label is optionally located on or associated with the container. For example, the label is located on the container when the letters, numbers, or other characters forming the label are attached, molded, or etched into the container itself, and the label is associated with the container when the label is present in a container or carrier that also houses the container, such as a package insert. In addition, the label is used to indicate that the contents are for a specific therapeutic application. In addition, the label indicates the instructions for use of the contents, e.g., in the methods described herein. In certain embodiments, the pharmaceutical composition is present in a packaging or dispensing device containing one or more unit dosage forms containing the compounds provided herein. The packaging contains, for example, a metal or plastic foil, such as a blister pack. Alternatively, the packaging or dispensing device is accompanied by instructions for administration. Alternatively, the packaging or dispenser is accompanied by a notice prescribed by a government agency that regulates the manufacture, use, or sale of the drug, the notice reflecting the form of the drug approved by the agency for human or veterinary administration. Such a notice is, for example, the approved prescription drug label of the U.S. Food and Drug Administration, or an approved product insert. In some embodiments, a composition containing a compound provided herein formulated in a compatible pharmaceutical carrier is prepared, placed in a suitable container, and labeled for the treatment of a designated condition.

[0257] Method

[0258] RON belongs to a subfamily of receptor tyrosine kinases. 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 in regulating certain physiological processes. Activation of RON leads to the activation of downstream signaling pathways of co-receptor tyrosine kinases, such as the activation of MAPK, PI3K, RAS-ERK, and β-catenin. In addition, RON is involved in crosstalk with other signaling pathways, such as the insulin-like growth factor 1 (IGF1R) and the EGF receptor (EGFR), which are common oncogenic mechanisms. Certain embodiments provide methods or compositions for modulating these signaling pathways.

[0259] Embodiments of the present disclosure can be used as modulators of the RON pathway in host species. RON inhibitors can also inhibit the activity of the RON pathway (including MSP, MBD4, SR C and PI3K). Thus, the compounds of structure (I) can also be used to treat conditions mediated by these kinases.

[0260] The host or patient can belong to any mammalian species, such as primate species, particularly humans; rodents, including mice, rats, and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental studies, providing models for treating human diseases.

[0261] A method of treating a disease or condition, the method comprising administering to an individual in need thereof a compound of the present disclosure as its stereoisomers, enantiomers, or tautomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, or a pharmaceutical composition of the present disclosure.

[0262] 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, gastric cancer, esophageal cancer, tracheal cancer, laryngeal 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.

[0263] In certain embodiments, the disease is osteolysis or osteoporosis. Inhibiting or treating osteolysis can include reducing bone turnover, reducing the process of bone loss, inhibiting osteoclasts, or a combination thereof. In some embodiments, the individual has been diagnosed with a condition selected from inflammation, cysts, cancer, cancer with bone metastasis, and cancer-mediated bone destruction. Methods for treating osteoporosis in an individual in need thereof are provided herein. Treating osteoporosis can include preventing osteoporosis, reducing the process of osteoporosis, or a combination thereof.

[0264] In some embodiments, the inhibitor can act independently of the RANKL and / or TGFβ pathways. In certain embodiments, the compound can not affect the functions of RANKL and / or TGFβ. In some embodiments, the compound can be selective or specific for RON. As used herein, a RON-selective inhibitor inhibits the activity of RON greater than it inhibits the activity of another protein (e.g., taking another receptor tyrosine kinase as an example) under physiological conditions. Receptor tyrosine kinases other than RON include, for example, Met and Axl. For example, under physiological conditions, a RON-selective inhibitor can inhibit RON more than it inhibits Met. For example, under physiological conditions, a RON-selective inhibitor can inhibit RON more than it inhibits Axl.

[0265] In some embodiments, the activity of the compound of the present disclosure in inhibiting RON can 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 the activity of inhibiting another receptor tyrosine kinase (e.g., Met or Axl).

[0266] In some embodiments, the IC 50 of the compound of the present disclosure for another receptor tyrosine kinase 50 can 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 the IC

[0267] Embodiments of the present disclosure also relate to the use of a compound according to structure (I) and / or its physiologically acceptable salt for prophylactic or therapeutic treatment and / or monitoring of a disease caused, mediated, and / or regulated by RON pathway activity. In addition, embodiments of the present disclosure relate to the use of a compound according to structure (I) and / or its physiologically acceptable salt for the manufacture of a medicament for prophylactic or therapeutic treatment and / or monitoring of a disease caused, mediated, and / or regulated by RON pathway activity. In certain embodiments, the present disclosure provides the use of a compound according to structure (I) or its physiologically acceptable salt for the manufacture of a medicament for prophylactic or therapeutic treatment of a RON-mediated disorder.

[0268] The therapeutic agent may also include agents for pain and inflammation, such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, serotonin (serotonin), lipid substances generated by the biotransformation of selective hydrolysis products of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, non-steroidal anti-inflammatory drugs, antipyretics, drugs 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 in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, β-adrenergic agonists, ipratropium bromide, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers, and leukotriene inhibitors.

[0269] Other embodiments of the present disclosure relate to combinations in which at least one anti-inflammatory compound is a monoclonal antibody (such as eculizumab or pecilizumab), a TNF antagonist (such as etanercept), or infliximab (an anti-TNF-α monoclonal antibody).

[0270] The compounds of the disclosed 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 patient suffering from cancer for the purpose of treating cancer.

[0271] In some embodiments, the anti-tumor drugs belong to the following categories:

[0272] Alkylating agents: such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan tosylate, lomustine, melphalan, dibromomannitol, dibromodulcitol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechlorethamine, carboquone; apaqinone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH-3024, VAL-0834;

[0273] Platinum compounds: such as carboplatin, cisplatin, iproplatin, miloplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;

[0274] DNA modifying agents: such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; aclarubicin, brostallicin, pixantrone, laromustine;

[0275] Topoisomerase inhibitors: for example, etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptinium acetate, voreloxin;

[0276] Microtubule regulators: for example, cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin, tesetaxel;

[0277] Antimetabolites: for example, asparaginase 3, azacitidine, calcium folinate, capecitabine, cladribine, cytarabine, entecavir, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elsamitrucin, raltitrexed, sapacitabine, tegafur, trimetrexate;

[0278] Anticancer antibiotics: for example, bleomycin, actinomycin D, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, lomofungin, streptozocin, valrubicin, nesiritide, zorubicin, daunorubicin, plicamycin; aclacinomycin, peplomycin, peplomycin;

[0279] Hormones / antagonists: for example, abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, flocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol acetate, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alpha, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, cyproterone acetate, TAK-700 (or teronel), enzalutamide;

[0280] Aromatase inhibitors: for example, aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane;

[0281] Small molecule kinase inhibitors: crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib.

[0282] In some embodiments, the drugs co-administered with the compounds described herein include any suitable drug deliverable by inhalation, such as analgesics, such as codeine, dihydromorphine, ergotamine, fentanyl or morphine; antianginal agents, such as diltiazem; antiallergic agents, such as cromoglycate, ketotifen or nedocromil; anti-infective agents, such as cephalosporins, penicillins, streptomycins, sulfonamides, tetracyclines or pentamidine; antihistamines, such as methapyrilene; anti-inflammatory agents, such as beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone; antitussives, such as noscapine; bronchodilators, such as ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutaline, isoetharine, tulobuterol, orciprenaline or (-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridyl)ethoxy]hexyl]-amino]methyl]benzyl alcohol; diuretics, such as amiloride; anticholinergics, such as ipratropium bromide, atropine or oxitropium bromide; 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. Those skilled in the art will appreciate that, where appropriate, the drugs are used in the form of salts (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimize the activity and / or stability of the drug.

[0283] The medicaments disclosed herein or other suitable medicaments are administered according to the condition being treated. Thus, in some embodiments, one or more compounds of the present disclosure will be co-administered with other medicaments as described above. When used in combination therapy, the compounds described herein are administered simultaneously or separately from the second medicament. Such co-administration can include administering the two medicaments simultaneously in the same dosage form, administering them simultaneously in separate dosage forms, and administering them separately. That is, the compounds described herein and any of the above-mentioned medicaments can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present disclosure and any of the above-mentioned medicaments can be administered simultaneously, where both medicaments are present in separate formulations. In another alternative, the compounds of the present disclosure can be administered only after any of the above-mentioned medicaments, or vice versa. In some embodiments of the separate administration scenario, the compounds of the present disclosure and any of the above-mentioned medicaments are administered at intervals of a few minutes, a few hours, or a few days apart.

[0284] In some embodiments, the compounds of structure (I) are administered as monotherapy.

[0285] To identify signal transduction or mechanism pathways and to detect the interactions between various signal transduction pathways, numerous scientists have developed suitable models or model systems, such as cell culture models and models of transgenic animals. To determine certain stages in the signal transduction cascade, interacting compounds can be utilized to modulate the signal. The compounds of the embodiments of the present disclosure can also be used as reagents for testing kinase-dependent signal transduction pathways in animal and / or cell culture models or in the clinical diseases mentioned in this application.

[0286] The methods of the embodiments of the present disclosure can be carried out in vitro or in vivo. The sensitivity of a particular cell to treatment with the compounds of structure (I) can be determined particularly by in vitro assays, whether during research applications or clinical applications. Generally, a cell culture is combined with various concentrations of the compound for a period of time (usually about 1 hour to 1 week), which is sufficient to allow the active agent to inhibit kinase activity. Cultured cells from biopsy samples or cell lines can be used for in vitro treatment.

[0287] In some embodiments, the IC of the compounds of structure (I) for inhibiting kinase activity 50 is determined by the concentration of the compound required to inhibit 50% of the kinase activity. The compounds of structure (I) exhibit an IC 50 potency value of less than about 5 mM, preferably less than about 1 mM, and even more preferably less than about 0.100 mM, as described in further detail in the examples.

[0288] The following Examples and Preparation Examples further illustrate and exemplify the compounds of the present disclosure and methods for preparing and testing such compounds. It is understood that the scope of the present disclosure is not limited in any way to the scope of the following Examples and Preparations. In the following Examples, and throughout the specification and claims, unless otherwise stated, molecules having a single stereocenter are present as a racemic mixture. Those molecules having two or more stereocenters are present as a racemic mixture of diastereomers, unless otherwise stated. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0289] Methods for producing the compounds described herein are provided below. Generally, starting components can be obtained from sources such as SigmaAldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and FluorochemUSA, or 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.

[0290] Examples

[0291] The following Examples are provided for illustrative purposes.

[0292] Abbreviations

[0293] °C (degrees Celsius); 1 1H NMR (proton nuclear magnetic resonance); ACN (acetonitrile); Boc (tert-butoxycarbonyl); (Boc)2O (di-tert-butyl dicarbonate); DCM (dichloromethane); DIPEA (N,N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); DMF (N,N-dimethylformamide); DMSO-d6 (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 (millimole); Pd(PPh3)4 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).

[0294] Intermediate Example 1

[0295] Synthesis of N-(4-((2-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0296]

[0297] Step 1: Synthesis of ethyl 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate:

[0298]

[0299] To a stirred solution of ethyl (2E)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (7.39 g, 30.8 mmol, 1.0 eq.) and 4-fluorophenylhydrazine hydrochloride (5 g, 30.8 mmol, 1.0 eq.) in toluene (25 mL) at 0 °C was added dropwise 10% aqueous sodium hydroxide solution (25 mL). Subsequently, the mixture was stirred at the same temperature for 10 minutes. The progress of the reaction was monitored by TLC. After the SM was consumed on TLC, concentrated hydrochloric acid was added to the reaction solution to make it acidic, and then it was diluted with water (100 mL). Then the mixture was extracted with ethyl acetate (300 mL × 3) and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the title compound ethyl 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (9.2 g, 98.99% yield) as a brown oil.

[0300] 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).

[0301] Step 2: Synthesis of 2-methyl-5-[(3-phenyloxetan-3-yl)amino]pyridine-4-carboxylic acid

[0302]

[0303] To a stirred solution of ethyl 2-methyl-5-[(3-phenyloxetan-3-yl)amino]pyridine-4-carboxylate (9 g, 29.8 mmol, 1.0 eq) in THF:MeOH (1:1) (90 mL) was added sodium hydroxide (5.96 g, 149 mmol, 5.0 eq) dissolved in water (50 mL). 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, 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 (3 × 300 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound 2-methyl-5-[(3-phenyloxetan-3-yl)amino]pyridine-4-carboxylic acid as an off-white solid (6 g, 73.49% yield).

[0304] LCMS: 273.1 (M-H) + . 1 1H 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).

[0305] Step 3: Synthesis of N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide:

[0306]

[0307] To a stirred solution of 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (5.5 g, 20.1 mmol, 1.0 eq), 4-amino-2-fluorophenol (3.83 g, 30.1 mmol, 1.5 eq) and DIPEA (7.16 mL, 40.1 mmol, 2 eq) in DCM (100 mL) was added T3P (50% in EtOAc) (7.72 mL, 30.1 mmol, 3 eq) 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 and extracted with ethyl acetate (350 mL × 3). The combined organic layers were 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 using (100 - 200 mesh silica) with 30% EtOAc in hexane as the eluent to afford the title compound N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide as an off-white solid (4 g, 52% yield).

[0308] 1 1H 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) + 。

[0309] Step 4: Synthesis of N-{4-[(2-chloropyrimidin-4-yl)oxy]-3-fluorophenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide:

[0310]

[0311] To a solution of N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (2 g, 5.22 mmol, 1 eq) and 2,4-dichloropyrimidine (777 mg, 5.22 mmol, 1 eq) in DMF (20 mL) was added K2CO3 (517 mg, 5.22 mmol, 1 eq). 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 and the mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product as a brown gummy liquid. The crude compound was purified by flash column chromatography using 50% EtOAc in hexane (100 - 200 mesh silica) as the eluent to give the title compound N-{4-[(2-chloropyrimidin-4-yl)oxy]-3-fluorophenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide as a light brown solid (1.5 g, 57.98% yield).

[0312] 1 1H 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) + 。

[0313] Intermediate Example 2

[0314] Synthesis of N-(4-((2-((3-aminocyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0315]

[0316] 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 eq) in DMF (10 mL) was added (1S)-(+)-10-camphorsulfonic acid (1.41 g, 6.05 mmol, 3 eq), followed by the addition of 1,3-cyclohexanediamine (461 mg, 4.03 mmol, 2 eq). The reaction mixture was stirred at 90 °C for 3 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was cooled to room temperature and ice-cold water (50 mL) was added and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine solution (30 mL), then dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude compound was purified by prep-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.

[0317] 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) + 。

[0318] Intermediate Example 3

[0319] Synthesis of N-(4-((2-((3-aminophenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0320]

[0321] 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:

[0322]

[0323] To a stirred solution of m-nitroaniline (418 mg, 3.03 mmol, 1.5 eq) 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 eq) at room temperature was added 4-methylbenzene-1-sulfonic acid hydrate (1.53 g, 8.07 μmol, 4 eq). The reaction mixture was then stirred at 90 °C for 10 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the RM was cooled to room temperature and ice-cold water (50 mL) was added, and then it was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine solution and dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The obtained crude residue was purified by column chromatography to give the title compound N-{3-fluoro-4-[2-(m-nitrophenylamino)-4-pyrimidyloxy]phenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (630 mg, 52.28% yield).

[0324] 1 H 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) + 。

[0325] 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:

[0326]

[0327] At 0 °C, iron (243 mg, 4.35 mmol, 10 eq) and ammonium chloride (466 mg, 8.7 mmol, 20 eq) were added 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 eq) in ethanol (4 mL), water (2 mL), and DMF (1 mL). The reaction mixture was then stirred at 80 °C for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOH and then filtered through a pad of celite (i.e., ) and washed with water:DMF (2:1). Water (10 mL) and sodium bicarbonate solution (3 mL) were added and the filtrate was extracted with 10% MeOH in DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude residue obtained 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.

[0328] 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 -

[0329] 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) + 。

[0330] Synthesis Example 1

[0331] Synthesis of N-(3-fluoro-4-((2-((3-morpholinophenyl)amino)pyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0332]

[0333] Step 1: Synthesis of Ethyl 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate

[0334]

[0335] Cool a stirred solution of ethyl (2E)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (7.39 g, 30.8 mmol, 1 eq) and 4-fluorophenylhydrazine hydrochloride (5 g, 30.8 mmol, 1 eq) in toluene (25 mL) in ice and add dropwise thereto an aqueous 10% sodium hydroxide solution (2.5 g sodium hydroxide in 25 mL water). Subsequently, stir the mixture at the same temperature for 10 minutes. Add concentrated hydrochloric acid to the reaction solution to make it acidic, then add water (100 mL) and extract the mixture with ethyl acetate (30 mL×3), and then combine the organic layers. After drying over Na2SO4, remove the solvent under reduced pressure to obtain ethyl 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (10 g, crude) as a brown oil. LCMS: 303.1 (M+H) + 。 1 1H 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).

[0336] Step 2: Synthesis of 2-Methyl-5-[(3-phenyloxetan-3-yl)amino]pyridine-4-carboxylic Acid

[0337]

[0338] To a stirred solution of ethyl 2-methyl-5-[(3-phenyloxetan-3-yl)amino]pyridine-4-carboxylate (10 g, 33.1 mmol, 1.0 eq.) in THF:MeOH (50 mL:50 mL), add sodium hydroxide (6.62 g, 165 mmol, 5.0 eq) and dissolve sodium hydroxide (6.62 g, 165 mmol, 5.0 eq) in water (50 mL) added to the reaction mixture at room temperature and stir for 2 h. After complete conversion by TLC, concentrate the reaction mixture under reduced pressure and dilute with water. Acidify the reaction mixture with concentrated HCl while cooling and extract with ethyl acetate. Dry the organic layer and concentrate under reduced pressure to obtain the title compound 2-methyl-5-[(3-phenyloxetan-3-yl)amino]pyridine-4-carboxylic acid (6 g, 66.14%) as an off-white solid. 1HNMR (400MHz, DMSO-d6): δ = 13.39 (br.s, 1H), 8.24 (s, 1H), 7.65-7.62 (m, 2H), 7.45-7.41 (m, 2H).

[0339] Step 3: N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0340]

[0341] To a mixture of 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (260 mg, 948 μmol, 1 eq), 4-amino-2-fluorophenol (181 mg, 1.42 mmol, 1.5 eq) and diisopropylethylamine (339 μL, 1.9 mmol, 2 eq) in DCM (2.6 mL) was added tripropyl-1,3,5,2λ 5 ,4λ 5 ,6λ 5 -trioxatriphosphine-2,4,6-trione (tripropyl-1,3,5,2λ 5 ,4λ 5 ,6λ 5 -trioxatriphosphinane-2,4,6-trione)(365 μL, 1.42 mmol, 1.5 eq). The reaction mixture was then stirred at room temperature for 16 h. 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), then dried over anhydrous Na2SO4, filtered and concentrated to give the crude product as a brown gummy liquid. The crude product was purified by flash column using 100-200 mesh silica with 30% EtOAc mobile phase in n-hexane to obtain 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 (400MHz, 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 = 10Hz, 1H), 6.93 (t, J = 9.6Hz, 1H).

[0342] Step 4: Synthesis of N-{4-[(2-chloropyrimidin-4-yl)oxy]-3-fluorophenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0343]

[0344] At room temperature, K2CO3 (85.3 mg, 861 μmol, 1.1 eq) was added to a solution of N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (300 mg, 783 μmol, 1 eq) and 2,4-dichloropyrimidine (233 mg, 1.57 mmol, 2 eq) in acetonitrile (20 mL), and then the reaction mixture was 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, and then it was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a crude compound as a brown gummy liquid. The crude product was purified by flash column using silica gel of 100 - 200 mesh with a mobile phase of 30% EtOAc in n-hexane to obtain 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).

[0345] 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

[0346]

[0347] At room temperature, 4-methylbenzenesulfonic acid hydrate (230 mg, 1.21 mmol, 4 eq) was added 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 eq) and 3-(morpholin-4-yl)aniline (53.9 mg, 303 μmol, 1 eq) in DMF (5 mL). Then the reaction mixture was stirred at 90 °C for 16 h. The reaction was cooled to room temperature, quenched with water (25 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a light brown gummy crude compound. The crude product was purified by flash column using silica gel 100 - 200 mesh with a mobile phase of 50% EtOAc in n-hexane to obtain 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%.

[0348] Synthesis Example 2

[0349] 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

[0350]

[0351] 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

[0352]

[0353] To a stirred solution of N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (307 mg, 802 μmol, 1 eq) in DMF (5 mL) was added potassium carbonate (522 mg, 1.6 mmol, 2 eq), and the mixture was stirred at room temperature for 0.5 h. Then 6-bromo-4-chlorothieno[3,2-d]pyrimidine (0.2 g, 802 μmol, 1 eq) was added. The reaction mixture was stirred at room temperature for 2 h. After 2 h, the reaction mixture was quenched with ice water (30 mL), a solid precipitate formed and was filtered, and the solid was 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 (400 mg, 83.68%) as an off-white solid. 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).

[0354] Step 2: Synthesis protocol of 1-methyl-4-(tributylstannyl)-1H-imidazole.

[0355]

[0356] To a stirred solution of 4-iodo-1-methylimidazole (2 g, 9.62 mmol, 1 eq) in DCM (5 mL) under nitrogen protection at room temperature was added dropwise 3M ethylmagnesium bromide (2.66 mL, 7.69 mmol, 0.8 eq) continuously. After 30 minutes, tributyl(chloro)stannane (3.29 mL, 11.5 mmol, 1.2 eq) was added and the mixture was stirred at room temperature for 16 h. Then the reaction mixture was 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 which was used directly in the next step without further purification (3.3 g, 92.47%). LCMS: 373.2 (M+H) + .

[0357] 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

[0358]

[0359] 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 eq) and 1-methyl-4-(tributylstannyl)-1H-imidazole (187 mg, 503 μmol, 1.5 eq) in DMF (3 mL) was degassed with nitrogen for 10 minutes. Then tetrakis(triphenylphosphine)palladium (38 mg, 33.5 μmol, 0.1 eq) was added and the mixture was degassed with nitrogen for an additional 3 minutes. The reaction was then stirred at 130 °C for 16 h. 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 product was purified by flash column using silica gel of 100 - 200 mesh with a mobile phase of 10% MeOH in DCM to afford 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 (79 mg, 39.42%) as an off-white solid. 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%.

[0360] Synthesis Example 3

[0361] 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

[0362]

[0363] Step 1: Synthesis of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine

[0364]

[0365] A mixture of 4-chloro-3-iodopyridin-2-amine (1.5 g, 5.89 mmol, 1 eq), 2-fluoro-4-nitrophenol (1.85 g, 11.8 mmol, 2 eq) and DIPEA (1.54 mL, 8.84 mmol, 1.5 eq) in NMP (5 mL) was placed in a glass pressure vessel and quickly heated to 170 °C. The heating was continued for 18 h. The volatile components were distilled off 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, then extracted with ethyl acetate (3 × 100 mL). The combined ethyl acetate layers were washed with brine, then dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by combi-flash using a gradient elution of 10 - 15% EtOAc in n-hexane (40 g) 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).

[0366] Step 2: 4-(2-fluoro-4-nitrophenoxy)-3-(1-methyl-1H-imidazol-4-yl)pyridin-2-amine

[0367]

[0368] A stirred solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (600 mg, 1.6 mmol, 1 eq) and 1-methyl-4-(tributylstannyl)-1H-imidazole (891 mg, 2.4 mmol, 1.5 eq) in DMF (5 mL) was degassed with nitrogen for 15 minutes. After 15 minutes, tetrakis(triphenylphosphine)palladium(0) (185 mg, 160 μmol, 0.1 eq) was added to the reaction mixture and heated to 130 °C for 16 h. 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 was purified by flash column using silica gel 100 - 200 mesh with a mobile phase of 50% EtOAc in hexane to afford 4-(2-fluoro-4-nitrophenoxy)-3-(1-methyl-1H-imidazol-4-yl)pyridin-2-amine (160 mg, 30.38%) as a light brown solid. LCMS: 330.1 (M+H) + 。 1 1H 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).

[0369] Step 3: Synthesis of 4-(4-amino-2-fluorophenoxy)-3-(1-methyl-1H-imidazol-4-yl)pyridin-2-amine

[0370]

[0371] 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 eq) in a mixture of ethanol (1 mL) and DMF (1 mL) at 0 °C was added iron powder (170 mg, 3.04 mmol, 10 eq) and NH4Cl (325 mg, 6.07 mmol, 20 eq). 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., ) Filtration. The filtrate was concentrated, diluted 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 product was purified by flash column using silica gel 100 - 200 mesh with 50% EtOAc in hexane as the mobile phase to obtain 4-(4-amino-2-fluorophenoxy)-3-(1-methyl-1H-imidazol-4-yl)pyridin-2-amine (30 mg, 22%) as a light brown solid. LCMS: 300.39 (M+H) + .

[0372] 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

[0373]

[0374] To a mixture of 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (27.5 mg, 0.1 mmol, 1 eq), 4-(4-amino-2-fluorophenoxy)-3-(1-methyl-1H-imidazol-4-yl)pyridin-2-amine (30 mg, 0.1 mmol, 1 eq) in DMF (3 mL) at room temperature was added DIPEA (0.035 mL, 0.2 mmol, 2 eq) and HATU (47.2 mg, 0.2 mmol, 2 eq.). 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 product was purified by flash column using silica gel 100 - 200 mesh with 10% MeOH in DCM as the mobile phase to obtain 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) + . 11H 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%.

[0375] Synthesis Example 4

[0376] Synthesis of N-(4-((2-bromopyrazolo[1,5-a]pyrimidin-7-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0377]

[0378] 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

[0379]

[0380] To a stirred solution of N-(3-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (330 mg, 860 μmol, 1 eq) in DMF (5 mL) at RT was added cesium carbonate (561 mg, 1.72 mmol, 2 eq). The reaction mixture was stirred at room temperature for 0.5 h. Then 2-bromo-7-chloropyrazolo[1,5-a]pyrimidine (200 mg, 860 μmol, 1 eq) 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), extracted with ethyl acetate (3 × 5 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude compound. The crude product was purified by flash column using silica gel of 100 - 200 mesh with a mobile phase of 50% EtOAc in hexane to afford N-(4-((2-bromopyrazolo[1,5-a]pyrimidin-7-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (200 mg, 40.13%) as an off-white solid. LCMS: 579.62 (M)+ 。 1 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%.

[0381] Synthesis Example 5

[0382] 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

[0383]

[0384] Step 1: Synthesis of 4-(4-Amino-2-fluorophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine

[0385]

[0386] To a stirred solution of 4-(4-Amino-2-fluorophenoxy)-3-iodopyridin-2-amine (170 mg, 493 μmol, 1 eq) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (154 mg, 739 μmol, 1.5 eq) in 1,4-dioxane (5 mL) and water (2 mL) was added potassium carbonate (204 mg, 1.48 mmol, 3 eq) and the mixture was degassed with nitrogen for 5 minutes. Then tetrakis(triphenylphosphine)palladium (57 mg, 49.3 μmol, 0.1 eq) was added at room temperature and the mixture was degassed again with nitrogen. Then the reaction mixture was stirred at 90 °C for 16 h. The progress of the reaction 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 product was purified by flash column using silica gel 100 - 200 mesh with a mobile phase of 5% MeOH in DCM to obtain 4-(4-Amino-2-fluorophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (65 mg, 44.09%). LCMS: 300.28 (M + H) + 。 11H 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).

[0387] 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

[0388]

[0389] At room temperature, DIPEA (77.5 μL, 434 μmol, 2 eq) and HATU (102 mg, 434 μmol, 2 eq) were added to a stirred solution of 4-(4-amino-2-fluorophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (65 mg, 217 μmol, 1 eq) and 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (59.5 mg, 217 μmol, 1 eq) in DMF (2 mL). The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was 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 product was purified by flash column chromatography using silica gel 100 - 200 mesh with a mobile phase of 10% MeOH in DCM to afford 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) + . 11H 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%.

[0390] Synthesis Example 6

[0391] 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

[0392]

[0393] Step 1: Synthesis of 1-azido-4-fluorobenzene

[0394]

[0395] To a stirred solution of 4-fluoroaniline (1 g, 9 mmol, 1 eq) in 10 mL of 15% HCl (5 mL water: 5 mL concentrated HCl) at 0 °C was added dropwise a solution of NaNO2 (745 mg, 10.8 mmol, 1.2 eq) in water (30 mL). After the addition was complete, the reaction mixture was stirred at this temperature for 30 min. Then, a solution of sodium azide (1.17 g, 18 mmol, 2 eq) 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 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the product was extracted with ethyl acetate (50 mL) and then washed with water to neutral pH. Then the organic layer was dried over anhydrous sodium sulfate and then concentrated by distillation at room temperature to obtain 1-azido-4-fluorobenzene as a crude product (1 g, crude) and used in the next step without further purification. 1 1H NMR (400 MHz, CDCl3): δ = 7.10 - 7.04 (m, 2H), 7.03 - 6.99 (m, 2H).

[0396] Step 2: Synthesis of ethyl 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylate

[0397]

[0398] A stirred solution of an appropriate amount of 1-azido-4-fluorobenzene (1 g, 7.29 mmol, 1 eq), ethyl 4,4,4-trifluoro-3-oxobutanoate (1.09 mL, 7.29 mmol, 1 eq) and diethylamine (377 μL, 3.65 mmol, 0.5 eq) in DMSO (10 mL) was heated at 80 °C for 4 h. After 4 h, the reaction mixture was poured into ice water, and the organic phase was extracted and separated with dichloromethane (50 mL), washed with brine, dried over Na2SO4, filtered and concentrated to obtain the crude product. The crude product was purified by flash column using silica gel of 100 - 200 mesh with a mobile phase of 20% EtOAc in hexane to obtain ethyl 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylate (1.4 g, 63.31%) as a red oil. LCMS: 304.36 (M+H) + . 1 1H 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).

[0399] Step 3: Synthesis of 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylic acid

[0400]

[0401] Sodium hydroxide (369 mg, 9.23 mmol, 2.0 eq) was added 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 eq) in EtOH:H2O (10 mL:10 mL) at room temperature and stirred at 50 °C for 4 h. After complete conversion by TLC, the reaction mixture was concentrated under reduced pressure to obtain a crude residue. The crude residue was diluted with water and washed with DCM. The aqueous layer was acidified with 10% HCl solution under cooling to obtain a precipitate. The precipitate was collected by filtration and dried under reduced pressure to obtain 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylic acid (1.15 g, 90.52%) as an off-white solid. LCMS: 274.0 (M-H) + 。 1 1H NMR (400 MHz, DMSO-d6): δ = 14.14 (br, 1H), 7.82 - 7.79 (m, 2H), 7.54 - 7.49 (m, 2H).

[0402] 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

[0403]

[0404] At room temperature, DIPEA (119 μL, 668 μmol, 2 eq) and HATU (157 mg, 668 μmol, 2 eq) were added to a mixture of 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylic acid (91.9 mg, 334 μmol, 1 eq) and 4-(4-amino-2-fluorophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (100 mg, 334 μmol, 1.2 eq) in DMF (5 mL). The reaction mixture was then stirred at room temperature for 16 h. Then the reaction mixture was 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 product was purified by flash column using silica gel 100 - 200 mesh with a mobile phase of 10% MeOH in DCM to obtain 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 (85 mg, 45%) as an off-white solid. LCMS: 557.46 (M+H) + 。 1 HNMR (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%.

[0405] Synthesis Example 7

[0406] 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

[0407]

[0408] Step 1: Synthesis of 3-(1-methyl-1H-imidazol-4-yl)-1H-pyrazol-5-amine

[0409]

[0410] To a stirred solution of 3-bromo-1H-pyrazol-5-amine (1 g, 6.17 mmol, 1 eq) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.28 g, 6.17 mmol, 1 eq) in 1,4-dioxane (20 mL) and water (5 mL) was added potassium carbonate (1.71 g, 12.3 mmol, 2 eq). The reaction mixture was then degassed with nitrogen for 5 min, tetrakis(triphenylphosphine)palladium (357 mg, 309 μmol, 0.05 eq) was added and degassed for a further 3 min. After degassing, the reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of celite (i.e., ) and the filtrate was concentrated under reduced pressure to afford the crude product. The crude was purified by flash column using silica gel 100 - 200 mesh with a mobile phase of 10% to 20% MeOH in DCM to afford 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, 1H), 7.87 (s, 1H), 7.63 (s, 1H), 5.49 (s, 1H), 4.59 (br.s, 2H), 3.83 (s, 3H).

[0411] Step 2: Synthesis of ethyl 2-(1-methyl-1H-imidazol-4-yl)-7-oxo-4H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylate

[0412]

[0413] At room temperature, 1-ethyl 3-propyl (2Z)-2-(ethoxymethylene) malonate (269 μL, 1.29 mmol, 1.5 eq) was added to a suspension of 3-(1-methyl-1H-imidazol-4-yl)-1H-pyrazol-5-amine (140 mg, 858 μmol, 1 eq) in acetic acid (3 mL). The resulting suspension was heated at 120 °C for 4 h. The suspension was cooled to room temperature and concentrated in vacuo to obtain the crude product. The crude product was triturated with cooled ethanol, the solid precipitate was filtered and washed with cooled ethanol, and dried in vacuo to obtain ethyl 2-(1-methyl-1H-imidazol-4-yl)-7-oxo-4H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylate (100 mg, 40.57%) as an off-white solid. 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).

[0414] Step 3: Synthesis of 2-(1-methyl-1H-imidazol-4-yl)-7-oxo-4H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid

[0415]

[0416] At room temperature, 2 mL of NaOH (73.1 mg, 1.83 mmol, 2.5 eq) dissolved in 2 mL of water was added 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 eq) in EtOH (3 mL). The resulting suspension was heated to 100 °C for 3.5 h. The suspension was cooled to room temperature and the EtOH was concentrated in vacuo, diluted with water (10 mL), acidified by using 5% citric acid solution (5 mL) to form a white suspension. The suspension was stirred for another 30 min, 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).

[0417] Step 4: Synthesis of 2-(1-methyl-1H-imidazol-4-yl)-4H,7H-pyrazolo[1,5-a]pyrimidin-7-one

[0418]

[0419] 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 to 240 °C for 2.5 h. At this time, the mixture was cooled to room temperature and diluted with hexane (100 mL). The tan precipitate was filtered, resuspended and stirred in hexane (100 mL), filtered, and washed with hexane (100 mL) to obtain 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) + 。 1 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).

[0420] Step 5: Synthesis of 2-bromo-7-chloropyrazolo[1,5-a]pyrimidine

[0421]

[0422] POCl3 (5 mL) and N,N-diisopropylethylamine (196 μL, 1.12 mmol, 2.2 eq) were slowly added to 2-(1-methyl-1H-imidazol-4-yl)-4H,7H-pyrazolo[1,5-a]pyrimidin-7-one (110 mg, 511 μmol, 1 eq) 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) and slowly poured 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 obtain the crude compound. The crude product was purified by flash column using silica gel 100 - 200 mesh with a mobile phase of 5% MeOH in DCM to give 2-bromo-7-chloropyrazolo[1,5-a]pyrimidine as an off-white solid (50 mg, 41.87%). LCMS: 234.1 (M+H) + 。 11H 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).

[0423] 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

[0424]

[0425] 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 eq) in DMF (5 mL) at room temperature was added cesium carbonate (112 mg, 342 μmol, 2 eq), and then the mixture was stirred for 0.5 h. Then 4-{7-chloropyrazolo[1,5-a]pyrimidin-2-yl}-1-methyl-1H-pyrazole (40 mg, 171 μmol, 1 eq) was added to the reaction mixture at room temperature. The reaction mixture was stirred again at room temperature for 2 h. Then ice water (10 mL) was added to the reaction mixture and it was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude compound. The crude product was purified by combi-flash using a gradient elution of 60% ethyl acetate in hexane (12 g) 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 (30 mg, 30.19%) as a white solid. LCMS: 581.53 (M+H) + . 1 1H 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%.

[0426] Synthesis Examples 8 - 10

[0427] The following compounds were prepared in a similar manner as described herein using appropriately substituted starting materials and intermediates.

[0428]

[0429]

[0430] Synthesis Example 11

[0431] 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)

[0432]

[0433] 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 eq) and 2-(morpholin-4-yl)ethan-1-amine (52.5 mg, 403 μmol, 1 eq) in DMF (5 mL) was added ethyldiisopropylamine (215 μL, 1.21 mmol, 3 eq) at room temperature. 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, ice water (20 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude residue was purified by Prep-HPLC to give 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.

[0434] 1 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) + .

[0435] Synthesis Example 12

[0436] 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)

[0437]

[0438] 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 eq) and 1-methylpiperidin-4-amine (46.1 mg, 403 μmol, 1 eq) in DMF (5 mL) at room temperature was added ethyldi(propan-2-yl)amine (215 μL, 1.21 mmol, 3 eq). The reaction mixture was stirred at room temperature for 16 h. 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 and the mixture was extracted with ethyl acetate (3 × 25 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 Prep-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.

[0439] 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) + 。

[0440] Synthesis Example 13

[0441] In a similar manner as described above, using appropriately substituted starting materials and intermediates, the synthesis of the following compounds was prepared:

[0442]

[0443] Synthesis Example 14

[0444] 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)

[0445]

[0446] 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:

[0447]

[0448] 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 eq) and 3-Iodoaniline (88.4 mg, 403 μmol, 1 eq) in DMF (20 mL) at room temperature was added 4-Methylbenzenesulfonic acid hydrate (307 mg, 1.61 mmol, 4 eq). The reaction mixture was stirred at 90 °C for 10 h. 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 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 solution and dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude compound was purified by combiflash using 20 - 25% EtOAc 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.

[0449] 11H 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 (s, 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).

[0450] 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:

[0451]

[0452] 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 eq) in 1,4-dioxane (3 mL) was added tripotassium phosphate (34.4 mg, 162 μmol, 1.1 eq) and the mixture was purged with N2 gas for 10 min. Subsequently, [5-(Diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (8.53 mg, 14.7 μmol, 0.1 eq) and dimethyl(oxo)-λ 5 -phosphanylium (28.4 mg, 369 μmol, 2.5 eq) were added. The reaction mixture was purged with N2 gas for 3 min and then Pd2(dba)3 (6.75 mg, 7.37 μmol, 0.05 eq) was added. The reaction mixture was irradiated in a microwave oven at 110 °C for 2 h. 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., ) and concentrated under reduced pressure to give the crude product. The crude compound was purified by prep-HPLC to give 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.

[0453] 11H 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 =

[0454] 13.20 Hz, 6H), LCMS: 629.3 (M + H) + 。

[0455] Synthesis Example 15

[0456] 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)

[0457]

[0458] 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 eq) and 4-fluoroaniline (44.8 mg, 403 μmol, 1 eq) in DMF (8 mL) at room temperature was added 4-methylbenzene-1-sulfonic acid hydrate (307 mg, 1.61 mmol, 4 eq). The reaction mixture was stirred at 90 °C for 10 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 × 75 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 prep-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.

[0459] 1 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 -

[0460] 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) + 。

[0461] Synthesis Example 16 - 26

[0462] The following compounds were prepared in a similar manner as described herein using appropriately substituted starting materials and intermediates.

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469] Synthesis Example 27

[0470] 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)

[0471]

[0472] Step 1: Synthesis of 4-(2-Fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine:

[0473]

[0474] To a mixture of 4-chloro-3-iodopyridin-2-amine (80 g, 314 mmol) and 2-fluoro-4-nitrophenol (98.8 g, 2 eq., 629 mmol) in N-methyl-2-pyrrolidone (240 mL) was added ethyldi(propan-2-yl)amine (82.1 mL, 1.5 eq., 472 mmol). The mixture was placed in a glass pressure vessel (sealed tube) and rapidly 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 distilled off under reduced pressure and the viscous residue was poured into ice water (500 mL). Then the pH of the mixture was adjusted to 7.5 with saturated aqueous NaHCO3. The aqueous layer was extracted with ethyl acetate (3 × 600 mL). The EtOAc phases were separated, washed with brine solution (100 mL), and then dried over Na2SO4. The organic layer was concentrated in vacuo to give a crude residue. The crude compound was purified by column chromatography using silica 60-120 (eluted with 10%-15% EtOAc 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.

[0475] LCMS: 376.00 (M+H) + . 1 1H 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).

[0476] Step 2: Synthesis of 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine:

[0477]

[0478] To a stirred solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (40 g, 10.7 mmol, 1 eq) in ethanol (400 mL), water (40 mL), and DMF (40 mL) at 0 °C was added iron powder (59.6 g, 107 mmol, 10 eq) and ammonium chloride (2.28 g, 214 mmol, 20 eq). Then the reaction mixture was stirred at 80 °C for 1 h. The hot reaction mixture was passed through a Celite pad (i.e., ) Filtration, 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 Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column using silica gel 100 - 200 mesh with 30% EtOAc in hexane as the eluent to obtain 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine (22 g, 59.76% yield).

[0479] LCMS: 346.00 (M + H) + . 1 1H 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).

[0480] Step 3: Synthesis of (2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)dimethylphosphine oxide:

[0481]

[0482] 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) was added tripotassium phosphate (21.6 g, 1.6 eq., 102 mmol). Subsequently, [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (5.53 mg, 0.15 eq., 9.56 mmol) was added to the above reaction mixture and purged with N2 gas for 30 min. After 30 min, dimethyl(oxo)-λ 5-Phosphanylium (14.7 g, 3 eq., 191 mmol) and palladium(II) diacetate (2.15 g, 0.15 eq., 9.56 mmol) were added to the reaction mixture and purged with N2 gas again for 30 min. The reaction mixture was stirred at 130 °C for 3 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated to give a crude residue. The crude compound was purified by combi flash 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.

[0483] LCMS: 296.23 (M+H) + 。 1 1H 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).

[0484] 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:

[0485]

[0486] At 0 °C, 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 eq., 36.6 mmol) in tetrahydrofuran (100 mL, 10 vol.) was added chloro(dimethylamino)methylene bis(methyl)ammonium hexafluorophosphate(1-) (25.7 g, 3 eq., 91.4 mmol) and N-ethylbis(isopropyl)amine (27.2 mL, 5 eq., 152 mmol). 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 (100 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 150 mL). The EtOAc layer was separated, washed with brine (100 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to give a crude residue. The crude compound was purified by column chromatography using silica 60-120 (eluting with 2-3% MeOH in DCM) to give the desired compound (60% purity by LCMS). The compound was again purified by reverse phase chromatography (using 0.1% TFA in water and acetonitrile as the 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.

[0487] LCMS: 552.58 (M+H) + . 1 1H 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).

[0488] Synthesis Example 28

[0489] 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)

[0490]

[0491] Step 1: Synthesis of tert-Butyl 5-(m-Nitrophenyl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate:

[0492]

[0493] To a stirred solution of m-Bromonitrobenzene (1 g, 4.95 mmol, 1 eq), 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 eq., 5.94 mmol) and Potassium carbonate (205 mg, 3 eq., 1.49 mmol) in 1,4-Dioxane (6 mL, 70.3 mmol) and water (4 mL, 222 mmol), the reaction mixture was purged with argon for 5 min. Subsequently, [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (362 mg, 0.1 eq., 495 μmol) was added. The reaction mixture was degassed with argon again for 3 min and stirred at 80 °C for 4 h. The progress of the reaction 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 Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude compound was purified by combi-flash on a silica column using 0 - 50% EtOAc 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%).

[0494] 1 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).

[0495] Step 2: Synthesis of tert-Butyl 3-(m-Aminophenyl)-1-piperidinecarboxylate:

[0496]

[0497] Under inert conditions at 0 °C, platinum dioxide (0.4 g, 1.76 mmol) was added 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). The reaction temperature was raised to room temperature and stirred overnight under H2 gas. The progress of the reaction was monitored by TLC and crude LCMS. The reaction mass was concentrated in vacuo. Then, it was dissolved in ethyl acetate (100 mL) and washed with brine solution (100 mL). The collected organic layer was dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The 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%).

[0498] 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).

[0499] Step 3: Synthesis of N-(4-{2-[m-(1-acryloyl-3-piperidyl)phenylamino]-4-pyrimidyloxy}-3-fluorophenyl)-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide:

[0500]

[0501] To a stirred solution of N-[4-(2-chloro-4-pyrimidyloxy)-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 eq, 1.31 mmol) in dimethylformamide (10 mL, 129 mmol) was added 4-methylbenzenesulfonic acid hydrate (767 mg, 4 eq, 4.03 mmol). Then, the reaction mixture was stirred at 90 °C for 10 h. The reaction was then monitored by TLC and LCMS. Then ice water (40 mL) was added to the reaction mixture and it was extracted with ethyl acetate (3 × 75 mL). The combined organic layers were dried over anhydrous Na2SO4 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-piperidinyl)phenylamino]-4-pyrimidyloxy}phenyl)-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (180 mg, 28.08% yield).

[0502] 1 H 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 + )。

[0503] Step 4: Synthesis of N-(4-{2-[m-(1-acryloyl-3-piperidinyl)phenylamino]-4-pyrimidyloxy}-3-fluorophenyl)-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide:

[0504]

[0505] At 0 °C, triethylamine (98.7 μL, 3 eq, 708 μmol) was added dropwise to a stirred solution of N-(3-fluoro-4-{2-[m-(3-piperidinyl)phenylamino]-4-pyrimidyloxy}phenyl)-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (150 mg, 236 μmol) in dichloromethane (15 mL, 234 mmol). After 5 min, acryloyl chloride (17.2 μL, 0.9 eq., 212 μmol) was added dropwise under inert conditions. The reaction mixture was stirred at the reaction temperature for 6 h. The progress of the reaction was monitored 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 Prep-HPLC to give the title compound N-(4-{2-[m-(1-acryloyl-3-piperidinyl)phenylamino]-4-pyrimidyloxy}-3-fluorophenyl)-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (12 mg, 7.37% yield).

[0506] 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 + )。

[0507] Synthesis Example 29

[0508] (E)-N-(4-((2-((3-(4-(dimethylamino)but-2-enoylamino)phenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 40) Synthesis

[0509]

[0510] N-{4-[2-(m-Aminophenylamino)-4-pyrimidyloxy]-3-fluorophenyl}-2-(p-fluorophenyl)-3-(trifluoromethyl)-1,2λ 5 To a stirred solution of N-{4-[2-(m-aminophenylamino)-4-pyrimidyloxy]-3-fluorophenyl}-2-(p-fluorophenyl)-3-(trifluoromethyl)-1,2λ 5 -diazole-4-carboxamide (100 mg, 176 μmol, 1 eq) and (E)-4-(dimethylamino)-2-butenoic acid (27.3 mg, 211 μmol, 1.2 eq) in DMF (5 mL) was added 2-methyl-2,6,8-triaza-6,7-decadiene—hydrochloride (1 / 1) (50.7 mg, 264 μmol, 1.5 eq) and 1H-1,2,3-benzotriazol-1-ol with water (1:1) (40.5 mg, 264 μmol, 1.5 eq) and then N-ethylbis(isopropyl)amine (92.1 μL, 529 μmol, 3 eq) at room temperature. The reaction mixture 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 and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude product was purified by prep-HPLC to give the title compound N-[4-(2-{m-[(E)-3-(dimethylamino)-1-propenylcarbonylamino]phenylamino}-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (20 mg, 16.72% yield) as a white solid.

[0511] 1 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) + 。

[0512] Synthesis Example 30

[0513] Synthesis of N-(4-((2-((3-acrylaminophenyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 42)

[0514]

[0515] To a stirred solution of N-{4-[2-(m-aminophenylamino)-4-pyrimidyloxy]-3-fluorophenyl}-2-(p-fluorophenyl)-3-(trifluoromethyl)-1,2λ 5 -diazole-4-carboxamide (150 mg, 264 μmol, 1 eq) in DCM (7.5 mL) was added trimethylamine (110 μL, 792 μmol, 3 eq). After stirring for 5 min, acryloyl chloride (1.71 μL, 21.1 μmol, 1.2 eq) was added at room temperature. The reaction mixture was stirred at RT for 10 min. The progress of the reaction 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 was purified by prep-HPLC to give the title compound N-(3-fluoro-4-{2-[m-(vinylcarbonylamino)phenylamino]-4-pyrimidyloxy}phenyl)-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (40 mg, 24.35% yield) as a white solid.

[0516] 1 1H 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) + 。

[0517] Synthesis Example 31

[0518] Synthesis of N-(4-((2-((3-((S)-2-((E)-4-(dimethylamino)-N-methylbut-2-enoylamino)propionylamino)cyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 41)

[0519]

[0520] Step 1: Synthesis of (E)-N-(4-(dimethylamino)but-2-enoyl)-N-methyl-L-alanine tert-butyl ester:

[0521]

[0522] To a stirred solution of (E)-4-(dimethylamino)but-2-enoic acid (100 mg, 0.774 mmol, 1 eq) in DCM (5 mL) at 0 °C was added oxalyl chloride (0.1 mL, 1.16 mmol, 1.5 eq), followed by DMF (cat.). The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After consumption of the starting material on TLC, to this solution was added at 0 °C a stirred solution of N-methyl-L-alanine tert-butyl ester (123 mg, 0.774 mmol, 1 eq) and trimethylamine (0.32 mL, 2.32 mmol, 3 eq) in DCM (5 mL). The reaction mixture was stirred for 2 h until complete consumption of the starting material. 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 Na2SO4 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-alanine tert-butyl ester (70 mg, 33% yield) as a pale yellow syrup.

[0523] 1 1H 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) + 。

[0524] Step 2: Synthesis of (E)-N-(4-(dimethylamino)but-2-enoyl)-N-methyl-L-alanine:

[0525]

[0526] At 0 °C, 4 M HCl in dioxane (0.5 mL) was added to a stirred solution of (E)-N-(4-(dimethylamino)but-2-enoyl)-N-methyl-L-alanine tert-butyl ester (50 mg, 0.185 mmol, 1 eq) in 1,4-dioxane (2 mL). 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-alanine-HCl salt (50 mg).

[0527] 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) + 。

[0528] Step 3: Synthesis of N-(4-((2-((3-((S)-2-((E)-4-(dimethylamino)-N-methylbut-2-enoylamino)propionamido)cyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide:

[0529]

[0530] 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 eq) in DCM (3 mL) was added triethylamine (47.6 mg, 0.471 mmol, 3 eq) and HATU (119 mg, 0.314 mmol, 2 eq) and the reaction mixture was stirred for 5 min, then (E)-N-(4-(dimethylamino)but-2-enoyl)-N-methyl-L-alanine (33.6 mg, 0.157 mmol, 1 eq) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored 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 solution (20 mL), then dried over Na2SO4 and concentrated under reduced pressure to give a crude residue. The crude compound was purified by prep-HPLC using 0.1% FA in acetonitrile ACN to give N-(4-((2-((3-((S)-2-((E)-4-(dimethylamino)-N-methylbut-2-enoylamino)propionylamino)cyclohexyl)amino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (35 mg, 28.97% yield) as a white solid.

[0531] 1 H 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 (M - H) + 。

[0532] Synthesis Example 32

[0533] 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)

[0534]

[0535] 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 eq) in DCM (3 mL) was added triethylamine (47.6 mg, 0.471 mmol, 3 eq), followed by the addition of HATU (119 mg, 0.314 mmol, 2 eq) and the reaction mixture was stirred for 5 min, then (E)-4-(dimethylamino)but-2-enoic acid (31.1 mg, 0.188 mmol, 1.2 eq) was added. 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 solution (20 mL), then dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by prep-HPLC using 0.1% FA in acetonitrile to afford (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.

[0536] 11H 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) + 。

[0537] Synthesis Example 33

[0538] 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)

[0539]

[0540] 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 eq) in DMF (5 mL) was added DIPEA (135 mg, 1.05 mmol, 3 eq), EDCI (100 mg, 0.523 mmol, 1.5 eq), HOBt (70.7 mg, 0.523 mmol, 1.5 eq) and acrylic acid (27.6 mg, 0.384 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 16 h. 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 Na2SO4 and concentrated under reduced pressure. The crude compound obtained was purified by prep-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.

[0541] Conclusion: In prep-HPLC, two peaks were separated, Peak 1 (10 mg) and Peak 2 (15 mg).

[0542] 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) + 。

[0543] Analysis of Peak 2: 11H 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) + 。

[0544] Synthesis Example 34

[0545] 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)

[0546]

[0547] Step 1: Synthesis of 4-(2-Fluoro-4-nitrophenoxy)-3-iodopyridine:

[0548]

[0549] In a glass pressure vessel (sealed tube), N,N-diisopropylethylamine (2.18 mL, 3 eq, 12.5 mmol) was added to a mixture of 4-chloro-3-iodopyridine (1 g, 4.18 mmol) and 2-fluoro-4-nitrophenol (984 mg, 1.5 eq., 6.26 mmol) in N-methyl-2-pyrrolidone (15 mL). 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 distilled off under reduced pressure and the viscous residue was poured into ice water (500 mL). The pH of the mixture was adjusted to ~7.5 with saturated aqueous NaHCO3 and then extracted with ethyl acetate (100 mL). The EtOAc layer was separated, washed with brine (30 mL) and then dried over Na2SO4. The organic layer was concentrated under reduced pressure to give a crude residue. The crude compound was purified by column chromatography using silica gel 60-120 (10-15% EtOAc 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.

[0550] 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) + 。

[0551] Step 2: Synthesis of 3-fluoro-4-((3-iodopyridin-4-yl)oxy)aniline:

[0552]

[0553] 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 eq., 11.1 mmol) and ammonium chloride (1.19 g, 20 eq., 22.2 mmol) were added. The reaction mixture was then stirred at 80 °C for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOH (10 mL) and filtered through a pad of diatomaceous earth (i.e., )Filter and wash with water: DMF (2:1). Concentrate the filtrate, then quench the aqueous layer with aqueous sodium bicarbonate solution (50 mL) and extract with 10% MeOH in DCM (3 × 200 mL). Dry the combined organic layers over Na2SO4 and concentrate under reduced pressure to obtain the crude compound. Purify the crude compound by column chromatography on silica gel (100 - 200 mesh) using 10% MeOH in DCM as the eluent to obtain the title compound 3-fluoro-4-(3-iodo-4-pyridyloxy)aniline (250 mg, 757 μmol) as a colorless semi-solid.

[0554] 1 1H 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) + 。

[0555] Step 3: Synthesis of (4-(4-amino-2-fluorophenoxy)pyridin-3-yl)dimethylphosphine oxide:

[0556]

[0557] 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 tripotassium phosphate (772 mg, 3 eq., 3.64 mmol). The reaction mixture was purged with N2 gas for 20 min. Subsequently, dimethyl(oxo)-λ 5 -phosphanylium (280 mg, 3 eq., 3.64 mmol) and palladium(II) diacetate (136 mg, 0.5 eq., 606 μmol) were added. The reaction mixture was again purged with N2 gas for 10 min. Then the reaction mixture was stirred at 120 °C for 6 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the excess dioxane was evaporated under reduced pressure to obtain a crude residue. Purify the crude compound by column chromatography on silica gel (100 - 200 mesh) using 10% MeOH in DCM as the eluent to obtain the title compound [4-(4-amino-2-fluorophenoxy)-3-pyridyl]dimethylphosphine oxide (250 mg, 892 μmol) as a semi-solid.

[0558] 11H 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, J = 13.2 Hz, 1H), 6.45 - 6.39 (m, 1H), 5.54 (s, 2H), 1.77 (d, J = 13.6 Hz, 6H), LCMS: 281.1 (M+H) + .

[0559] 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:

[0560]

[0561] At 0 °C, 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 eq., 1.28 mmol) in tetrahydrofuran (135 mL, 1.66 mol) was added chloro(dimethylamino)methylene bis(methyl)ammonium hexafluorophosphate(1-) (601 mg, 2 eq., 2.14 mmol) and N-ethylbis(isopropyl)amine (956 μL, 5 eq., 5.35 mmol). 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 in EtOAc (3 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a 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, purity 62% by LCMS) and fraction 2 (170 mg, purity 42% by LCMS). Fraction 1 was again purified by prep-HPLC using 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 again purified by prep-HPLC using 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.

[0562] Analysis of compound 52: 1 H 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) + 。

[0563] Analysis of compound 53: 11H 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) + 。

[0564] Synthesis Example 35

[0565] Synthesis of N-{4-[5-(Dimethylphosphoryl)-4-pyrimidyloxy]-3-fluorophenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 54)

[0566]

[0567] Step 1: Synthesis of 3-Fluoro-4-(5-iodo-4-pyrimidyloxy)aniline:

[0568]

[0569] To a mixture of 4-Chloro-5-iodopyrimidine (1 g, 4.16 mmol, 1 eq) and 4-Amino-2-fluorophenol (793 mg, 1.5 eq, 6.24 mmol) in dimethylformamide (20 mL) was added cesium carbonate (2.03 g, 1.5 eq., 6.24 mmol), and the mixture was placed in a glass pressure vessel (sealed tube) and rapidly heated to 150 °C. The heating was continued for 3 hours. The progress of the reaction was monitored 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 solution (30 mL), dried over Na2SO4 and concentrated under reduced pressure to give a crude residue. The crude compound was purified by flash column using silica gel of 100 - 200 mesh with 2 - 3% MeOH in DCM as the eluent to give the title compound 3-Fluoro-4-(5-iodo-4-pyrimidyloxy)aniline (0.4 g, 29.05% yield) as an off-white solid.

[0570] 11H 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) + 。

[0571] Step 2: Synthesis of [4-(4-amino-2-fluorophenoxy)-5-pyrimidinyl]dimethylphosphine oxide:

[0572]

[0573] To a stirred solution of 3-fluoro-4-(5-iodo-4-pyrimidyloxy)aniline (0.4 g, 1.21 mmol, 1 eq) in 1,4-dioxane (7.69 mL) was added tripotassium phosphate (410 mg, 1.6 eq., 1.93 mmol). The reaction mixture was degassed with argon for 20 min. Then [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (105 mg, 0.15 eq., 0.181 mmol) and dimethyl(oxo)-λ 5 -phosphanylium (0.244 mL, 3 eq., 3.62 mmol) were added. Then the reaction mixture was degassed again with argon for 10 min. Subsequently, palladium(II) diacetate (13.6 mg, 0.05 eq., 0.060 mmol) was added at room temperature. The reaction mixture was stirred at 130 °C for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a crude compound. The crude compound was purified by combi-flash using 3% MeOH in DCM as the eluent to give the title compound [4-(4-amino-2-fluorophenoxy)-5-pyrimidinyl]dimethylphosphine oxide (150 mg, 44.15% yield) as a pale green solid.

[0574] 1 1H 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) + 。

[0575] Step 3: Synthesis of N-{4-[5-(dimethylphosphoryl)-4-pyrimidyloxy]-3-fluorophenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide:

[0576]

[0577] To a stirred solution of 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (97.5 mg, 0.356 mmol, 1 eq) in dimethylformamide (5 mL) was added N,N-diisopropylethylamine (0.191 mL, 3 eq., 1.07 mmol) and [bis(dimethylamino)methylene]({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl})oxidanium (167 mg, 2 eq., 0.711 mmol). The reaction mixture was stirred for 5 min and then [4-(4-amino-2-fluorophenoxy)-5-pyrimidinyl]dimethylphosphine oxide (0.1 g, 0.356 mmol, 1 eq) was added. The reaction mixture was stirred at room temperature for 16 h. 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 EtOAc (3 × 15 mL). The combined organic layers were washed with brine solution (10 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude compound was purified by prep-HPLC using 0.1% TFA in acetonitrile and water to give the title compound N-{4-[5-(dimethylphosphoryl)-4-pyrimidyloxy]-3-fluorophenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (8 mg, 4.19% yield) as a white solid.

[0578] 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) + 。

[0579] Synthesis Example 36

[0580] Synthesis of N-{4-[6-amino-5-(dimethylphosphoryl)-4-pyrimidyloxy]-3-fluorophenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 55)

[0581]

[0582] Step 1: Synthesis of 6-(4-amino-2-fluorophenoxy)-5-iodo-4-pyrimidinamine:

[0583]

[0584] To a stirred mixture of 6-chloro-5-iodo-4-pyrimidinylamine (1 g, 3.91 mmol, 1 eq) and 4-amino-2-fluorophenol (746 mg, 1.5 eq, 5.87 mmol) in dimethylformamide (40 mL) was added cesium carbonate (1.91 g, 1.5 eq, 5.87 mmol). The mixture was placed in a glass pressure vessel (sealed tube) and quickly heated to 150 °C. The heating was continued for 3 hours. The progress of the reaction was monitored 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 solution (30 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column using silica gel 100 - 200 mesh with 2 - 3% MeOH in DCM as the eluent to give the title compound 6-(4-amino-2-fluorophenoxy)-5-iodo-4-pyrimidinamine as an off-white solid (0.7 g, 51.66% yield).

[0585] 1 1H 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) + 。

[0586] Step 2: Synthesis of [6-amino-4-(4-amino-2-fluorophenoxy)-5-pyrimidinyl]dimethylphosphine oxide:

[0587]

[0588] To a stirred solution of 6-(4-amino-2-fluorophenoxy)-5-iodo-4-pyrimidinamine (0.7 g, 2.02 mmol, 1 eq) in 1,4-dioxane (6.98 mL) was added tripotassium phosphate (687 mg, 1.6 eq, 3.24 mmol) and the mixture was degassed with argon for 20 min. Then [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (176 mg, 0.15 eq, 0.303 mmol) and dimethyl(oxo)-λ 5 -phosphanylium (0.408 mL, 3 eq., 6.07 mmol) were added and the reaction mixture was degassed again with argon for 10 min. Subsequently, palladium(II) diacetate (22.7 mg, 0.05 eq, 0.101 mmol) was added to the reaction mixture under an argon atmosphere at room temperature. The reaction mixture was stirred at 130 °C for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a 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.

[0589] 1 1H 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) + 。

[0590] Step 3: Synthesis of N-{4-[6-amino-5-(dimethylphosphoryl)-4-pyrimidinyl]oxy}-3-fluorophenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide:

[0591]

[0592] 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-diisopropylethylamine (0.362 mL, 3 eq., 2.03 mmol) and [bis(dimethylamino)methylene]({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl})oxonium hexafluorophosphate (318 mg, 2 eq., 1.35 mmol). The reaction mixture was stirred for 5 min at RT and then [6-amino-4-(4-amino-2-fluorophenoxy)-5-pyrimidinyl]dimethylphosphine oxide (0.2 g, 0.675 mmol, 1 eq) was added. The reaction mixture was stirred at room temperature for 16 h. 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 EtOAc (3 × 15 mL). The combined organic layers were washed with brine solution (15 mL) and dried over Na2SO4 and then concentrated under reduced pressure to give a crude residue. The crude compound was purified by prep-HPLC using 0.1% TFA in acetonitrile and water to give the title compound N-{4-[6-amino-5-(dimethylphosphoryl)-4-pyrimidinyl]oxy}-3-fluorophenyl}-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (40 mg, 10.73% yield) as a white solid.

[0593] 1 H 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) + 。

[0594] Synthesis Example 37

[0595] Synthesis of N-{4-[6-amino-5-(dimethylphosphoryl)-4-pyrimidinyl]oxy}-3-fluorophenyl}-4-ethoxy-1-(p-fluorophenyl)-2-oxo-1,2-dihydronicotinamide (Compound 56)

[0596]

[0597] Step 1: Synthesis of ethyl (E)-2-cyano-3-ethoxybut-2-enoate:

[0598]

[0599] A stirred solution of 1,1,1-triethoxyethane (14.7 mL, 80.1 mmol, 1 eq) and acetic acid (1.11 mL, 18.4 mmol, 0.23 eq) was added successively to ethyl cyanoacetate (4.53 mL, 40.1 mmol, 0.5 eq) 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 RT and concentrated under vacuum to afford crude ethyl (E)-2-cyano-3-ethoxybut-2-enoate (14 g, crude). The crude residue was carried on to the next reaction without further purification (as reported in US2022 / 0288043A1).

[0600] Step 2: Synthesis of ethyl (2E,4E)-2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate:

[0601]

[0602] A mixture of ethyl (E)-2-cyano-3-ethoxybut-2-enoate (14 g, 76.4 mmol, 1 eq, theoretical 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 afford crude ethyl (2E,4E)-2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate (16 g, crude). The residue was carried on to the next step without further purification (as reported in US Publication No. 2022 / 0288043).

[0603] Step 3: Synthesis of ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate:

[0604]

[0605] A mixture of ethyl (2E,4E)-2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate (16 g, 67.1 mmol, 0.89 eq) and acetic acid (35 mL) was refluxed for 16 h. The progress of the reaction 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 EtOAc (30 mL) to remove impurities. The pH of the aqueous layer was adjusted to pH 9 - 10 with aqueous NaHCO3 solution. 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 a 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.

[0606] 1 1H 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) + 。

[0607] Step 4: Synthesis of ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate:

[0608]

[0609] Pyridine (3.06 mL, 37.9 mmol, 4 eq) was added to a stirred solution of ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (2 g, 9.47 mmol, 1 eq), (4-fluorophenyl)boronic acid pinacol ester (3.97 g, 28.4 mmol, 3 eq) and copper(II) acetate (3.44 g, 18.9 mmol, 2 eq) in DCM (20 mL). The reaction mixture was stirred for 16 h at room temperature in the presence of air. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with DCM (100 mL) and passed through a pad of diatomaceous earth (i.e., )Filter and wash 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% EtOAc in hexanes to afford the title compound ethyl 4 - ethoxy - 1-(4 - fluorophenyl)-2 - oxo - 1,2 - dihydropyridine - 3 - carboxylate as a yellow solid (1.5 g, 51.89% yield).

[0610] 1 1H 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) + 。

[0611] Step 5: Synthesis of 4 - ethoxy - 1-(4 - fluorophenyl)-2 - oxo - 1,2 - dihydropyridine - 3 - carboxylic acid:

[0612]

[0613] To a stirred suspension of ethyl 4 - ethoxy - 1-(4 - fluorophenyl)-2 - oxo - 1,2 - dihydropyridine - 3 - carboxylate (1 g, 3.28 mmol, 1 eq) in ethanol (15 mL) and water (7.5 mL) was added lithium hydroxide monohydrate (550 mg, 13.1 mmol, 4 eq). The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the total solvent was evaporated under reduced pressure and the residue was diluted with water (20 mL), cooled to 0 °C and acidified with 1 N HCl and stirred for 10 min. The solid obtained was filtered, washed with water (20 mL), diethyl ether (30 mL). Then dried in vacuo to afford the title compound 4 - ethoxy - 1-(4 - fluorophenyl)-2 - oxo - 1,2 - dihydropyridine - 3 - carboxylic acid as a white solid (650 mg, 71.58% yield).

[0614] 11H 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) + 。

[0615] Step 6: Synthesis of N-{4-[6-amino-5-(dimethylphosphoryl)-4-pyrimidyloxy]-3-fluorophenyl}-4-ethoxy-1-(p-fluorophenyl)-2-oxo-1,2-dihydronicotinamide:

[0616]

[0617] 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-diisopropylethylamine (0.362 mL, 3 eq., 2.03 mmol) and [bis(dimethylamino)methylene]({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl})oxonium (318 mg, 2 eq., 1.35 mmol). The reaction mixture was stirred for 5 min and then [6-amino-4-(4-amino-2-fluorophenoxy)-5-pyrimidinyl]dimethylphosphine oxide (0.2 g, 0.675 mmol, 1 eq) was added. The reaction mixture was stirred at room temperature for 16 h. 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 EtOAc (3 × 15 mL). The combined organic layers were washed with brine solution (15 mL) and dried over Na2SO4 and concentrated under reduced pressure to give a crude residue. The crude compound was purified by prep-HPLC using 0.1% TFA in water and acetonitrile to give the title compound N-{4-[6-amino-5-(dimethylphosphoryl)-4-pyrimidyloxy]-3-fluorophenyl}-4-ethoxy-1-(p-fluorophenyl)-2-oxo-1,2-dihydronicotinamide (80 mg, 21.33% yield) as a white solid.

[0618] 11H 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) + 。

[0619] Synthesis Example 38

[0620] 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)

[0621]

[0622] Step 1: Synthesis of tert-butyl 4-(2-(3-bromophenyl)acetyl)piperazine-1-carboxylate:

[0623]

[0624] To a stirred solution of (3-bromophenyl)acetic acid (1 g, 4.65 mmol) and tert-butyl 1-piperazinecarboxylate (1.04 g, 1.2 eq., 5.58 mmol) in DMF (5 mL) was added 1H-1,2,3-benzotriazol-1-ol—water (1 / 1) (855 mg, 1.2 eq., 5.58 mmol) and N-ethylbis(isopropyl)amine (1.62 mL, 2 eq., 9.3 mmol). After stirring for 5 min, 2-methyl-2,6,8-triaza-6,7-decadiene:hydrochloride (1:1) (1.07 g, 1.2 eq., 5.58 mmol) was added at room temperature. The reaction mixture 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 (30 mL) was added to the reaction mixture and the mixture was 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 tert-butyl 4-[2-(3-bromophenyl)acetyl]-1-piperazinecarboxylate (1.4 g, 3.65 mmol) as a colorless gummy solid. The crude compound was carried on to the next step.

[0625] 1 H 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).

[0626] Step 2: Synthesis of 2-(3-bromophenyl)-1-(piperazin-1-yl)ethan-1-one (4):

[0627]

[0628] To a stirred solution of tert-butyl 4-[2-(3-bromophenyl)acetyl]-1-piperazinecarboxylate (1.4 g, 3.65 mmol) in dichloromethane (15.7 mL, 245 mmol) at 0 °C was added trifluoroacetic acid (5 mL, 10 eq., 36.5 mmol), and the temperature was raised to RT. Then, the reaction mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a crude compound, which was washed with diethyl ether (2 × 20 mL) to give the title compound 2-(3-bromophenyl)-1-(piperazin-1-yl)ethan-1-one (1 g, 3.53 mmol, 96.68% yield) as a colorless gum. The crude compound was carried on to the next step.

[0629] 11H 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).

[0630] Step 3: Synthesis of 1-(4-(2-(3-bromophenyl)acetyl)piperazin-1-yl)prop-2-en-1-one:

[0631]

[0632] At 10 °C, triethylamine (1.07 g, 3 eq., 10.6 mmol) was added dropwise to a stirred solution of 2-(m-bromophenyl)-1-(1-piperazinyl)-1-ethanone (1 g, 3.53 mmol) in dichloromethane (10 mL, 156 mmol). 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 monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold NaHCO3 solution (3 × 20 mL), and then extracted with DCM (3 × 30 mL). The combined organic layers were collected, dried over Na2SO4 and concentrated in vacuo to give a crude residue. The crude compound was purified by combi-flash 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.

[0633] 1 1H 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).

[0634] 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:

[0635]

[0636] A stirred solution of N-{4-[2-amino-3-(dimethylphosphoryl)-4-pyridyloxy]-3-fluorophenyl}-1-(4-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (0.1 g, 181 μmol), 1-(1-acryloyl-4-piperidinyl)-2-(m-bromophenyl)-1-ethanone (85.4 mg, 1.4 eq., 254 μmol), and cesium carbonate (118 mg, 2 eq., 363 μmol) in isopropanol (10 mL, 131 mmol) was purged with argon for 20 min. Then bis(tert-butyl)[2',4',6'-tris(isopropyl)-2-biphenyl]phosphine (7.7 mg, 0.1 eq., 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 eq., 9.07 μmol) were added to the reaction mixture at RT and the reaction mixture was purged with argon again for 15 min. The reaction mixture was stirred at 80 °C for 12 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to RT, then diluted with acetone (15 mL) and the reaction mixture was stirred for 10 min, then filtered through a Celite pad (i.e., ) The filtrate was concentrated in vacuo to afford the crude compound. The crude compound was purified by prep-HPLC to give 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.

[0637] 1 H 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) +。

[0638] Synthesis Example 40

[0639] 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)

[0640]

[0641] To a stirred solution of [2-amino-4-(4-amino-2-fluorophenoxy)-3-pyridyl]dimethylphosphine oxide (0.2 g, 677 μmol, 1 eq) and 2-ethoxy-5-(4-fluorophenyl)-6-oxo-1,3-cyclohexadiene-1-carboxylic acid (187 mg, 677 μmol, 1 eq) in tetrahydrofuran (85.5 mL, 1.05 mol) at 0 °C was added chloro(dimethylamino)methylene bis(methyl)ammonium hexafluorophosphate(1-) (570 mg, 3 eq, 2.03 mmol) and N-ethylbis(isopropyl)amine (605 μL, 5 eq, 3.39 mmol). 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 (50 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 60 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 combi flash using 3% MeOH in DCM as the eluent to give the title compound (with 59% purity by LCMS). The compound was then purified again by prep-HPLC to give 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.

[0642] 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) + 。

[0643] Synthesis Example 39 Synthesis of N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 43)

[0644]

[0645] Step 1: Synthesis of 1-(methanesulfonyloxy)-2-(m-nitrophenyl)ethane:

[0646]

[0647] To a stirred solution of 2-(m-nitrophenyl)ethanol (1 g, 5.98 mmol) in DCM (15 mL) at 0 °C under a nitrogen atmosphere was added triethylamine (1.08 mL, 1.3 eq, 7.78 mmol). Then methanesulfonyl chloride (926 μL, 2 eq, 12 mmol) was added dropwise, and the reaction temperature was raised to room temperature and stirred for another 16 h. The progress of the reaction was monitored by TLC. After the reaction solvent was completely removed, the residue was dissolved in DCM (100 mL), then washed with water (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound 1-(methanesulfonyloxy)-2-(m-nitrophenyl)ethane as a colorless liquid (1.2 g, 81.79% yield).

[0648] 1 1H 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).

[0649] Step 2: Synthesis of tert-butyl 4-[2-(m-nitrophenyl)ethyl]-1-piperazinecarboxylate:

[0650]

[0651] At room temperature, cesium carbonate (4.98 g, 2.5 eq, 15.3 mmol) was added to a stirred solution of 1-(methylsulfonyloxy)-2-(m-nitrophenyl)ethane (1.5 g, 6.12 mmol) in dimethylformamide (15 mL, 194 mmol). After some time, tert-butyl 1-piperazinecarboxylate (1.37 g, 1.2 eq., 7.34 mmol) was added and the reaction mixture was heated to 100 °C for an additional 4 h. The progress of the reaction was monitored 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 Na2SO4 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).

[0652] 1 1H 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) + 。

[0653] Step 3: Synthesis of tert-butyl 4-[2-(m-aminophenyl)ethyl]-1-piperazinecarboxylate:

[0654]

[0655] 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) at 0 °C was added iron (599 mg, 10 eq., 10.7 mmol) and ammonium chloride (1.15 g, 20 eq., 21.5 mmol). Subsequently, the temperature was raised to RT, 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 in vacuo. Subsequently, the reaction mass was dissolved in ethyl acetate (30 mL) and washed with water (40 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo 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).

[0656] 1 1H 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) + 。

[0657] Step 4: Synthesis of N-[3-fluoro-4-(2-{m-[2-(1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide:

[0658]

[0659] To a stirred solution of N-[4-(2-chloro-4-pyrimidyloxy)-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 eq., 242 μmol) in dimethylformamide (4 mL, 51.7 mmol) was added 4-methylbenzenesulfonic acid hydrate (153 mg, 4 eq., 807 μmol). The reaction mixture was stirred at 90 °C for 10 h. The progress of the reaction 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 was purified by flash chromatography using 5% MeOH in DCM as the eluent to afford the title compound N-[3-fluoro-4-(2-{m-[2-(1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (80 mg, 59% yield) as a brown solid.

[0660] 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).

[0661] Step 5: Synthesis of N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide:

[0662]

[0663] At 0 °C, triethylamine (25.2 μL, 181 μmol, 3 eq.) was added to a stirred solution of N-[3-fluoro-4-(2-{m-[2-(1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (40 mg, 60.2 μmol, 1 eq.), and the mixture was stirred for 2 min. Then, acryloyl chloride (4.38 μL, 54.2 μmol, 0.9 eq.) was added to the reaction mixture at 0 °C, and the reaction mixture was stirred for 5 min. The progress of the reaction was monitored 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 NaHCO3, dried over Na2SO4 and concentrated under reduced pressure to give a crude residue. The crude compound was purified by prep-HPLC to give the desired product N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (12 mg, 27.9% yield) as an off-white solid.

[0664] 1 H 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) + 。

[0665] Alternative synthetic route for the synthesis of Example 39B N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 43)

[0666]

[0667] Step 1: Synthesis of tert-butyl 4-[2-(m-nitrophenyl)acetyl]-1-piperazinecarboxylate:

[0668]

[0669] To a stirred solution of (m-nitrophenyl)acetic acid (10.0 g, 55.2 mmol, 1.0 eq) and tert-butyl 1-piperazinecarboxylate (11.3 g, 60.7 mmol, 1.1 eq) in DMF (100 mL) was added 1H-1,2,3-benzotriazol-1-ol:water (1:1) (10.1 g, 66.2 mmol, 1.2 eq), followed by N-ethylbis(isopropyl)amine (19.2 mL, 110 mmol, 2 eq). Subsequently, EDC—HCl (12.7 g, 66.2 mmol, 1.2 eq) was added to the above reaction mixture at 0 °C. Then the reaction mass was 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 formed was filtered. The solid compound was dissolved in DCM (150 mL) and washed with NaHCO3 solution (60 mL) and brine solution (40 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give pure tert-butyl 4-[2-(m-nitrophenyl)acetyl]-1-piperazinecarboxylate (10.0 g, 51.85% yield) as an off-white solid.

[0670] 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).

[0671] Step 2: Synthesis of tert-butyl 4-[2-(m-nitrophenyl)ethyl]-1-piperazinecarboxylate:

[0672]

[0673] To a stirred solution of tert-butyl 4-[2-(m-nitrophenyl)acetyl]-1-piperazinecarboxylate (10.0 g, 28.6 mmol, 1 eq) in THF (100 mL) at 0 °C was added dropwise 1 M borane-tetrahydrofuran (60 mL, 57.2 mmol, 2 eq), and then the reaction mixture was refluxed for 2 h. 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. Subsequently, the reaction mixture was concentrated under reduced pressure to give the crude compound. The obtained crude product was purified by combi-flash using 50% EtOAc in hexane as the eluent to give the title compound tert-butyl 4-[2-(m-nitrophenyl)ethyl]-1-piperazinecarboxylate (6.3 g, 65.63% yield) as an off-white solid.

[0674] 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) + 。

[0675] Step 3: Synthesis of 1-[2-(m-nitrophenyl)ethyl]piperazine TFA salt:

[0676]

[0677] At room temperature, a stirred solution of tert-butyl 4-[2-(m-nitrophenyl)ethyl]-1-piperazinecarboxylate (6.3 g, 18.8 mmol, 1 eq) in trichloroacetic acid / dichloromethane (1:1) (20 mL) was stirred for 8 h. After completion of the reaction on TLC, the reaction mixture was concentrated in vacuo, and the obtained residue was triturated with diethyl ether and pentane to give the title compound 1-[2-(m-nitrophenyl)ethyl]piperazine-TFA salt (6 g crude) as an off-white solid.

[0678] 1 H 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)+ 。

[0679] Step 4: Synthesis of 1-{4-[2-(m-nitrophenyl)ethyl]-1-piperazinyl}-2-propen-1-one:

[0680]

[0681] To a stirred solution of 1-[2-(m-nitrophenyl)ethyl]piperazine (1 g, 4.25 mmol, 1 eq) in DCM (10 mL) at 0 °C was added triethylamine (2.96 mL, 5 eq., 21.3 mmol) and the mixture was stirred for 20 min. Then acryloyl chloride (343 μL, 4.25 mmol, 1 eq) was added at 0 °C. The reaction mixture was stirred at RT 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) and extracted with EtOAc (3 × 50 mL), and washed with saturated NaHCO3 solution (50 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 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).

[0682] 1 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).

[0683] Step 5: Synthesis of 1-{4-[2-(m-aminophenyl)ethyl]-1-piperazinyl}-2-propen-1-one:

[0684]

[0685] At 0 °C, 4,4'-bipyridine (32.4 mg, 0.15 eq., 207 μmol) was added to a stirred solution of 1-{4-[2-(m-nitrophenyl)ethyl]-1-piperazinyl}-2-propen-1-one (0.4 g, 1.38 mmol, 1 eq) in dimethyl sulfoxide (4 mL). After stirring for 5 min, 1,1,2,2-ethanetetrol (4) (496 mg, 4 eq., 5.53 mmol) was added in portions and the reaction was carried out at room temperature. The reaction was completed within 10 min on 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 obtained crude product was purified by column chromatography (gradient elution with 0 - 6% MeOH in DCM) to give the title compound 1-{4-[2-(m-aminophenyl)ethyl]-1-piperazinyl}-2-propen-1-one as a gummy liquid (350 mg, 97.62% yield).

[0686] 1 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) + 。

[0687] Step 6: N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide;

[0688]

[0689] At room temperature, 4-methylbenzenesulfonic acid hydrate (767 mg, 4 eq., 4.03 mmol) was added to a stirred solution of N-[4-(2-chloro-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (0.5 g, 1.01 mmol, 1 eq) in DMF (10 mL) and 1-{4-[2-(m-aminophenyl)ethyl]-1-piperazinyl}-2-propen-1-one (314 mg, 1.2 eq., 1.21 mmol). 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 and the mixture was 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 product was purified by prep-HPLC to give the title compound N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (52 mg, 72.4 μmol) (52 mg, 7.17% yield) as a white solid.

[0690] 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) + 。

[0691] Synthesis Example 40

[0692] Synthesis of N-[3-fluoro-4-(2-{m-[2-(4-propionyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 59)

[0693]

[0694] Step 1: Synthesis of 1-{4-[2-(m-nitrophenyl)ethyl]-1-piperazinyl}-1-propanone:

[0695]

[0696] At 0 °C, triethylamine (2.96 mL, 5 eq., 21.3 mmol) was added to a stirred solution of 1-[2-(m-nitrophenyl)ethyl]piperazine (1 g, 4.25 mmol, 1 eq) in DCM (10 mL) and stirred for 20 min, then propionyl chloride (443 μL, 1.2 eq., 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) and extracted with EtOAc (3 × 50 mL). The organic layer was washed with saturated NaHCO3. The combined organic layers were dried over Na2SO4 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.

[0697] 1 H 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) + 。

[0698] Step 2: Synthesis of 1-{4-[2-(m-aminophenyl)ethyl]-1-piperazinyl}-1-propanone:

[0699]

[0700] At 0 °C, to a stirred solution of 1-{4-[2-(m-nitrophenyl)ethyl]-1-piperazinyl}-1-propanone (530 mg, 1.82 mmol, 1 eq) in dimethyl sulfoxide (5 mL). Then 4,4'-bipyridine (42.6 mg, 0.15 eq., 273 μmol) was added to the reaction mixture. After stirring for 5 min, 1,1,2,2-ethanetetrol (4) (652 mg, 4 eq., 7.28 mmol) was added portionwise at room temperature and the reaction was stirred. The reaction was completed within 10 min on 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 crude product obtained was purified by column chromatography (gradient elution with 0 - 6% MeOH in DCM) to give the title compound 1-{4-[2-(m-aminophenyl)ethyl]-1-piperazinyl}-1-propanone as a gummy liquid (250 mg, 52.58% yield).

[0701] 1 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) + 。

[0702] Step 3: Synthesis of N-[3-fluoro-4-(2-{m-[2-(4-propionyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide:

[0703]

[0704] At room temperature, 4-methylbenzenesulfonic acid hydrate (384 mg, 4 eq., 2.02 mmol) was added to a stirred solution of N-[4-(2-chloro-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (250 mg, 504 μmol, 1 eq) and 1-{4-[2-(m-aminophenyl)ethyl]-1-piperazinyl}-1-propanone (198 mg, 1.5 eq., 756 μmol) in DMF (4 mL), and the reaction mixture was stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, water (20 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude product was purified by prep-HPLC to give the title compound N-[3-fluoro-4-(2-{m-[2-(4-propionyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)phenyl

[0705] -1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (60 mg, 16.51% yield).

[0706] 1 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) + .

[0707] Synthesis Example 41

[0708] Synthesis of N-[3-Fluoro-4-(2-{m-[2-(1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)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-pyrimidyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 45)

[0709]

[0710] Step 1: Synthesis of tert-Butyl 4-[2-(m-aminophenyl)ethyl]-1-piperazinecarboxylate:

[0711]

[0712] To a stirred solution of tert-butyl 4-[2-(m-nitrophenyl)ethyl]-1-piperazinecarboxylate (0.8 g, 2.39 mmol, 1 eq) in dimethyl sulfoxide (8 mL, 112 mmol) at 0 °C, 4,4'-bipyridine (55.9 mg, 0.15 eq., 358 μmol) was added to the reaction mixture. After stirring for 5 min, 1,1,2,2-tetraboron tetrol (4) (855 mg, 4 eq., 9.54 mmol) was added portionwise at room temperature and the reaction was stirred. The reaction was completed within 10 min by TLC. Then the reaction mixture was 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 crude compound obtained was purified by column chromatography (gradient elution with 0 - 6% MeOH in DCM) to give the title compound tert-butyl 4-[2-(m-aminophenyl)ethyl]-1-piperazinecarboxylate as a gummy solid (0.6 g, 82.36% yield).

[0713] 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).

[0714] Step 2: Synthesis of N-[3-Fluoro-4-(2-{m-[2-(1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide:

[0715]

[0716] At room temperature, 4-methylbenzenesulfonic acid hydrate (537 mg, 4 eq, 2.82 mmol) was added to a stirred solution of N-[4-(2-chloro-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (350 mg, 706 μmol, 1 eq) and 4-fluoroaniline (44.8 mg, 403 μmol, 1 eq) in DMF (5 mL), and then the reaction mixture was stirred at 90 °C for 16 h. 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 and the mixture was 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 product was purified by prep-HPLC to give the title compound N-[3-fluoro-4-(2-{m-[2-(1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (70 mg, 14.92% yield) as an off-white solid.

[0717] 1 1H 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) + 。

[0718] Step 3: Synthesis of N-[3-fluoro-4-(2-{m-[2-(4-methyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide:

[0719]

[0720] At 0 °C, formaldehyde (44.9 μL, 5 eq., 451 μmol) and acetic acid (2.01 mL, 35.1 mmol) were added to a stirred solution of N-[3-fluoro-4-(2-{m-[2-(1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (60 mg, 90.3 μmol, 1 eq) in methanol (2 mL), and then the reaction mixture was stirred at 0 °C for 30 min. After stirring for 30 min, sodium bis(acetyloxy)boranuidyl acetate (57.4 mg, 3 eq., 271 μmol) was added to the reaction mixture at room temperature. Then the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated directly under reduced pressure, and the obtained crude product was diluted with ethyl acetate (10 mL) and washed with saturated NaHCO3 solution (10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a crude product. The crude product was purified by prep-HPLC to give the title compound N-[3-fluoro-4-(2-{m-[2-(4-methyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (12 mg, 19.59% yield) as an off-white solid.

[0721] 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) + 。

[0722] Synthesis Example 42

[0723] 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)

[0724]

[0725] Step 1: Synthesis of 1-Ethyl-4-(3-nitrophenethyl)piperazine:

[0726]

[0727] At 10 °C, K2CO3 (1.76 g, 4.25 mmol) was added to a stirred solution of 1-[2-(m-nitrophenyl)ethyl]piperazine (1 g, 4.25 mmol) in acetonitrile and stirred for 15 min. Then, iodoethane (683 μL, 4.25 mmol) was added dropwise to the solution and stirred at RT for 3 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (3 × 10 mL). The combined organic layers were collected, dried over Na2SO4 and concentrated under vacuum to give the crude compound. The residue obtained was purified by flash chromatography (3% MeOH in DCM) to give 1-ethyl-4-(3-nitrophenethyl)piperazine (2) as a liquid (0.56 g, 50% yield).

[0728] 1 1H 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).

[0729] Step 2: Synthesis of 3-(2-(4-Ethylpiperazin-1-yl)ethyl)aniline:

[0730]

[0731] 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 added slowly and stirred for 5 - 10 min until the reaction was complete (the progress of the reaction was monitored by TLC). Then, after the reaction was complete, ice water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 20 mL). The organic layers were collected, dried over Na2SO4 and concentrated under reduced pressure to give a crude residue. The crude product was washed with pentane to give 3-(2-(4-ethylpiperazin-1-yl)ethyl)aniline as a viscous solid (120 mg, 24.1% yield).

[0732] 1 1H 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).

[0733] 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:

[0734]

[0735] (N-[4-(2-chloro-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide) (0.2 g, 403 μmol) was dissolved in DMF (5 mL) in a sealed tube. pTSA (278 mg, 1.61 mmol) and 3-(2-(4-ethylpiperazin-1-yl)ethyl)aniline (3) (120 mg, 444 μmol) were added to the above solution in sequence. After the addition of the reagents was completed, the reaction was heated to 90 °C and stirred overnight until the starting materials were completely consumed (the progress of the reaction was monitored by TLC). Then, after the reaction was completed, ice water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to obtain the crude compound. The crude product was purified by prep HPLC to obtain the desired product (14 mg, yield 14.11%) as a white fluffy solid.

[0736] 1 1H 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] + 。

[0737] Synthesis Example 43

[0738] 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)

[0739]

[0740] Step 1: Synthesis of 1-(3-nitrophenethyl)-4-propylpiperazine:

[0741]

[0742] To a stirred solution of 1-[2-(m-nitrophenyl)ethyl]piperazine TFA salt (0.5 g, 2.13 mmol) in acetonitrile at 10 °C was added K2CO3 (0.88 g, 2.13 mmol) and the mixture was stirred for 10 min. Then, 1-iodopropane (206 μL, 2.13 mmol) was added dropwise to the solution and the mixture was stirred at RT for 5 h. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (3 × 15 mL). The organic layer was collected, dried over Na2SO4 and concentrated under vacuum to give the crude compound. The obtained residue was purified by flash chromatography (5% MeOH in DCM) to give the title compound 1-(3-nitrophenethyl)-4-propylpiperazine (3) as a viscous substance (0.53 g, yield 44.96%).

[0743] 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.

[0744] Step 2: Synthesis of 3-(2-(4-propylpiperazin-1-yl)ethyl)aniline:

[0745]

[0746] 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 was added 4,4'-bipyridine (59.1 mg, 379 μmol). After 5 min, B2(OH)4 (905 mg, 10.1 mmol) was added slowly and stirred for 5 - 10 min until the reaction was complete (the progress of the reaction was monitored by TLC). Then, ice water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 20 mL). The organic layer 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 as a viscous solid (340 mg, yield 54.46%).

[0747] 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] + 。

[0748] 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:

[0749]

[0750] In a sealed tube, N-[4-(2-chloro-4-pyrimidyloxy)-3-fluorophenyl]-1-(4-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (0.5 g, 1.01 mmol) was dissolved in DMF (5 mL). pTSA (695 mg, 4.03 mmol) and 3-(2-(4-propylpiperazin-1-yl)ethyl)aniline (299 mg, 1.21 mmol) were added to the solution in sequence. After the addition of the reagents was completed, the reaction was heated to 90 °C and stirred overnight until the starting materials were completely consumed (the progress of the reaction was monitored by TLC). Then, ice water (10 mL) was added to the reaction mixture and it was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum to give a crude residue. The crude compound was purified by prep 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, yield 11.22%) as a white solid.

[0751] 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] + 。

[0752] Synthesis Example 44

[0753] N-[3-Fluoro-4-(2-{m-[2-(4-isopropyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)benz

[0754] yl]-1-(4-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 48) Synthesis

[0755]

[0756] Step 1: Synthesis of 1-isopropyl-4-(3-nitrophenethyl)piperazine:

[0757]

[0758] At room temperature, cesium carbonate (4.15 g, 3 eq., 12.8 mmol) and 2-iodopropane (509 μL, 5.1 mmol) were added to a stirred solution of 1-[2-(m-nitrophenyl)ethyl]piperazine-TFA salt (0.5 g, 2.13 mmol) in acetonitrile. Then, the reaction mixture was refluxed for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction on TLC, the reaction mixture was cooled to room temperature and filtered through a pad of celite (i.e., ) and washed with EtOAc (20 mL). The collected filtrate was evaporated under reduced pressure to give a crude residue. The crude compound was purified by flash chromatography using 0-50% EtOAc in hexane as the eluent to give 1-isopropyl-4-(3-nitrophenethyl)piperazine (2) as a gummy solid (520 mg, yield 44.11%).

[0759] 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] + 。

[0760] Step 2: Synthesis of 3-(2-(4-isopropylpiperazin-1-yl)ethyl)aniline:

[0761]

[0762] 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 added slowly and stirred for 5 - 10 min until the reaction was complete (the progress of the reaction was monitored by TLC). After completion of the reaction, ice water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were collected, dried over Na2SO4 and concentrated under reduced pressure to give a 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, yield 77.62%) as a yellow solid.

[0763] 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] + 。

[0764] Step 3: Synthesis of N-[3-fluoro-4-(2-{m-[2-(4-isopropyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide:

[0765]

[0766] Dissolve RT-001 (N-[4-(2-chloro-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide) (460 mg, 928 μmol) in DMF (5 mL) in a sealed tube. To the above stirred solution, add camphorsulfonic acid (862 mg, 3.71 mmol) and 3-(2-(4-isopropylpiperazin-1-yl)ethyl)aniline (298 mg, 1.21 mmol) successively. After the addition of the reagents is completed, heat the reaction mixture to 100 °C and stir overnight. The progress of the reaction is monitored by TLC. After the reaction is completed, add ice water (10 mL) and extract with ethyl acetate (3 × 30 mL). The combined organic layers are dried over anhydrous Na2SO4 and concentrated under vacuum to give a crude residue. The crude product is purified by prep HPLC to give the title compound N-[3-fluoro-4-(2-{m-[2-(4-isopropyl-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)phenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (50 mg, yield 7.63%) as a white solid.

[0767] 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] + 。

[0768] Synthesis Example 45

[0769] 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)

[0770]

[0771] Step 1: Synthesis of 1-cyclopropyl-4-(3-nitrophenethyl)piperazine:

[0772]

[0773] To a stirred solution of 1-[2-(m-nitrophenyl)ethyl]piperazine-trifluoroacetic acid (1 / 1) (1.0 g, 2.86 mmol) in a mixture of the solvents tetrahydrofuran (15 mL) and MeOH (15 mL) was added (1-ethoxycyclopropoxy)tris(methyl)silane (1.16 mL, 2 eq., 5.73 mmol) and sodium cyanoborohydride (270 mg, 1.5 eq., 4.29 mmol), followed by acetic acid (258 μL, 1.5 eq., 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 Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash silica column chromatography using 3-5% MeOH in DCM to afford 4-cyclopropyl-1-[2-(m-nitrophenyl)ethyl]piperazine as a colorless oil (450 mg, 57.09% yield).

[0774] 1 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] + 。

[0775] Step 2: Synthesis of 3-(2-(4-cyclopropylpiperazin-1-yl)ethyl)aniline:

[0776]

[0777] To a stirred solution of 1-cyclopropyl-4-(3-nitrophenethyl)piperazine (0.45 g, 1.66 mmol, 1 eq) in dimethyl sulfoxide (10 mL) was added 4,4'-bipyridine (38.6 mg, 0.15 eq., 0.245 mmol) and the mixture was stirred for 5 min. Then 1,1,2,2-tetraboron tetrol (591 mg, 4 eq., 6.54 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 10 min. 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 Na2SO4 and concentrated under reduced pressure to give a crude residue. The crude residue was purified by flash column chromatography (gradient elution with 5-10% MeOH in DCM) to afford the title compound 3-(2-(4-cyclopropylpiperazin-1-yl)ethyl)aniline as a pale yellow solid (180 mg, 45.0% yield).

[0778] 1 1H 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).

[0779] 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:

[0780]

[0781] At room temperature, 4-methylbenzenesulfonic acid hydrate (334 mg, 4 eq., 1.96 mmol) was added to a stirred solution of N-[4-(2-chloro-4-pyrimidyloxy)-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 eq., 0.734 mmol) in dimethylformamide (6 mL). 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 and the mixture was extracted with ethyl acetate (3 × 15 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 prep 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-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (100 mg, 19.34% yield) as a white solid.

[0782] 1 H 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] + 。

[0783] Synthesis Example 46

[0784] Synthesis of N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)-2-oxoethyl]phenylamino}-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 50)

[0785]

[0786] Step 1: 1-(4-Acryloyl-1-piperazinyl)-2-(m-nitrophenyl)-1-ethanone

[0787]

[0788] At 10 °C, triethylamine (0.959 mL, 5 eq., 6.88 mmol) was added dropwise to a stirred solution of 2-(m-nitrophenyl)-1-(1-piperazinyl)-1-ethanone:trifluoroacetic acid (1:1) (0.5 g, 1.38 mmol, 1 eq) in dichloromethane (25 mL), and the reaction mixture was maintained at the reaction temperature. After 10 min, acryloyl chloride (0.133 mL, 1.2 eq., 1.65 mmol) was added dropwise and the reaction was carried out at room temperature. The reaction was stirred for 1 h and the progress of the reaction was monitored 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 Na2SO4 and concentrated in vacuo to give the crude compound 1-(4-acryloyl-1-piperazinyl)-2-(m-nitrophenyl)-1-ethanone (500 mg). The crude compound was used for the next step.

[0789] 1 1H 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).

[0790] Step 2: 1-(4-Acryloyl-1-piperazinyl)-2-(m-aminophenyl)-1-ethanone

[0791]

[0792] At 0 °C, 4,4'-bipyridine (38.6 mg, 0.15 eq., 0.247 mmol) was added to a stirred solution of 1-(4-acryloyl-1-piperazinyl)-2-(m-nitrophenyl)-1-ethanone (0.5 g, 1.65 mmol, 1 eq) in dimethyl sulfoxide (10 mL) and stirred for 5 min, then 1,1,2,2-tetraboranoltetrol (591 mg, 4 eq., 6.59 mmol) was added. The reaction mixture was stirred at room temperature for 10 min. 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 Na2SO4 and concentrated under reduced pressure to give a crude residue. The crude residue was purified by flash column chromatography (gradient elution with 5-10% MeOH in DCM) to give the title compound 1-(4-acryloyl-1-piperazinyl)-2-(m-aminophenyl)-1-ethanone as a pale yellow solid (160 mg, 35.51% yield).

[0793] 1 1H 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

[0794] [M+H] + 。

[0795] Step 3: N-[4-(2-{m-[2-(4-acryloyl-1-piperazinyl)-2-oxoethyl]phenylamino}-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide

[0796]

[0797] At room temperature, 4-methylbenzenesulfonic acid hydrate (230 mg, 4 eq., 1.21 mmol) was added to a stirred solution of N-[4-(2-chloro-4-pyrimidyloxy)-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 eq., 0.454 mmol) in dimethylformamide (6 mL). 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 and the mixture was extracted with ethyl acetate (3 × 15 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 prep 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-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (45 mg, 20.3% yield) as a white solid.

[0798] 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] + 。

[0799] Synthesis Example 47

[0800] Synthesis of N-[4-(2-{m-[2-(4-acryloyl-2-oxo-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (Compound 51)

[0801]

[0802] Step 1: Synthesis of 2-(m-nitrophenyl)ethanol:

[0803]

[0804] To a stirred solution of (m-nitrophenyl)acetic acid (5 g, 27.6 mmol) in THF (50 mL) at 0 °C was added tetrahydrofuran-borane (1 / 1) in THF (55 mL, 2 eq., 55.2 mmol) 1 M, and the reaction mixture was refluxed for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with methanol at 0 °C. Then it was concentrated under reduced pressure to give the crude product. The crude compound was purified by combi-flash using 50% EtOAc 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.

[0805] 1 1H 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).

[0806] Step 2: Synthesis of 1-(methanesulfonyloxy)-2-(m-nitrophenyl)ethane:

[0807]

[0808] To a solution of 2-(m-nitrophenyl)ethanol (3.8 g, 22.7 mmol, 1 eq) in dichloromethane (38 mL) at 0 °C under a nitrogen atmosphere was added triethylamine (4.12 mL, 1.3 eq., 29.6 mmol). After stirring for 30 min at 0 °C, (chlorosulfonyl)methane (3.52 mL, 2 eq., 45.5 mmol) was added dropwise to the above reaction mixture. After the addition was complete, the reaction was heated to room temperature and stirred for another 2 h. After completion of the reaction on TLC, the solvent was removed and the residue was dissolved in DCM (100 mL). The organic layer was washed with water (40 mL), then dried over Na2SO4 and concentrated to give 1-(methanesulfonyloxy)-2-(m-nitrophenyl)ethane (6 g crude, 24.5 mmol) without further purification.

[0809] 11H 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).

[0810] Step 3: Synthesis of 2-(m-nitrophenyl)ethylamine:

[0811]

[0812] To 1-(methanesulfonyloxy)-2-(m-nitrophenyl)ethane (5 g, 20.4 mmol) was added 25% ammonium hydroxide (50 mL), and the mixture was stirred at 80 °C for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction on TLC, 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 Na2SO4 and concentrated to give crude 2-(m-nitrophenyl)ethylamine as a gummy solid (2.6 g crude, 76.74% yield). This crude product was used for the next step without further purification.

[0813] 1 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) + 。

[0814] Step 4: Synthesis of tert-butyl 2-[2-(m-nitrophenyl)ethylamino]ethylcarbamate:

[0815]

[0816] To a stirred solution of 2-(m-nitrophenyl)ethylamine (2 g, 12 mmol, 1 eq) in DMF (10 mL) at room temperature was added potassium carbonate (4.99 g, 3 eq., 36.1 mmol). Then 2-bromoethyl N-Boc carbamate (3.24 g, 1.2 eq., 14.4 mmol) was added to the reaction mixture and stirred at 60 °C for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction on TLC, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (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 give the title compound tert-butyl 2-[2-(m-nitrophenyl)ethylamino]ethylcarbamate as a brown solid (900 mg, 24.17% yield).

[0817] 1 1H 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) + 。

[0818] Step 5: Synthesis of 2-{[2-(m-nitrophenyl)ethyl](bromomethyl)carbonylamino}ethyl 2-methyl-2-propanylcarbamate:

[0819]

[0820] At 0 °C, triethylamine (1.22 mL, 3 eq., 8.73 mmol) was added to a stirred solution of 2-[2-(m-nitrophenyl)ethylamino]ethyl 2-methyl-2-propanylcarbamate (0.9 g, 2.91 mmol, 1 eq) in DCM (10 mL), and the mixture was then stirred for 20 min and bromoacetyl bromide (304 μL, 1.2 eq., 3.49 mmol) was added at 0 °C. The reaction mixture was stirred at RT for 30 min. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction on TLC, the reaction mixture was diluted with water (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude compound obtained was purified by column chromatography using a gradient elution of 25-75% EtOAc in hexane to give the title compound, 2-{[2-(m-nitrophenyl)ethyl](bromomethyl)carbonylamino}ethyl 2-methyl-2-propanylcarbamate (600 mg, 47.93% yield) as a yellow solid.

[0821] 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) + 。

[0822] Step 6: Synthesis of N-2-aminoethyl-N-[2-(m-nitrophenyl)ethyl]bromoacetamide:

[0823]

[0824] Compound 2-{[2-(m-nitrophenyl)ethyl](bromomethyl)carbonylamino}ethyl-2-methyl-2-propanylcarbamate (0.6 g, 1.39 mmol, 1 eq) was added to trifluoroacetic acid:dichloromethane (1:1) (12 mL) and stirred at room temperature for 2 h. After completion of the reaction on TLC, the reaction was concentrated in vacuo and the residue obtained 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.

[0825] 11H 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) + 。

[0826] Step 7: Synthesis of 1-[2-(m-nitrophenyl)ethyl]-2-piperazinone:

[0827]

[0828] To a stirred solution of N-2-aminoethyl-N-[2-(m-nitrophenyl)ethyl]bromoacetamide (0.5 g, 1.51 mmol) in ethanol (5 mL) at room temperature was added potassium carbonate (1.05 g, 5 eq., 7.57 mmol). The reaction mixture was stirred at 80 °C for 20 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 25 mL) and dried over Na2SO4, then concentrated under reduced pressure. The crude compound obtained was purified by column chromatography using a gradient elution of 0 - 5% MeOH in DCM to give the title compound 1-[2-(m-nitrophenyl)ethyl]-2-piperazinone as a yellow solid (350 mg, 92.72% yield).

[0829] 1 1H 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) + 。

[0830] Step 8: Synthesis of 4-acryloyl-1-[2-(m-nitrophenyl)ethyl]-2-piperazinone:

[0831]

[0832] At 0 °C, triethylamine (587 μL, 3 eq., 4.21 mmol) was added to a stirred solution of 1-[2-(m-nitrophenyl)ethyl]-2-piperazinone (350 mg, 1.4 mmol) in dichloromethane (4 mL). The reaction mixture was stirred for 20 min, then acryloyl chloride (136 μL, 1.2 eq., 1.68 mmol) was added at 0 °C and the reaction mixture was stirred at RT 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 NaHCO3 solution, the total organic layer was dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude compound was purified by combi-flash using 1-6% MeOH in DCM as 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.

[0833] 1 H 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).

[0834] Step 9: Synthesis of 4-acryloyl-1-[2-(m-aminophenyl)ethyl]-2-piperazinone:

[0835]

[0836] 4,4'-Bipyridine (15.4 mg, 0.15 eq., 98.9 μmol) was added to a stirred solution of 4-acryloyl-1-[2-(m-nitrophenyl)ethyl]-2-piperazinone (0.2 g, 659 μmol, 1 eq.) in dimethyl sulfoxide (2 mL) at 0 °C. After stirring for 5 min, 1,1,2,2-ethanetetrol (4) (236 mg, 4 eq., 2.64 mmol) was added portionwise at room temperature and the reaction was stirred. The reaction was completed by TLC in 10 min. Subsequently, the reaction mixture was poured into ice-cold water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude compound obtained was purified by gradient elution using 0 - 6% MeOH in DCM to give the title compound 4-acryloyl-1-[2-(m-aminophenyl)ethyl]-2-piperazinone as a gummy solid (90 mg, 49.94% yield).

[0837] 1 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) + 。

[0838] Step 10: Synthesis of N-[4-(2-{m-[2-(4-acryloyl-2-oxo-1-piperazinyl)ethyl]phenylamino}-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide:

[0839]

[0840] At room temperature, 4-acryloyl-1-[2-(m-aminophenyl)ethyl]-2-piperazinone (74.4 mg, 1.5 eq., 272 μmol) was added to a stirred solution of N-[4-(2-chloro-4-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (90 mg, 182 μmol) in dimethylformamide (2 mL). The reaction mixture was stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, water (20 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude product was purified by prep-HPLC using a 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-pyrimidyloxy)-3-fluorophenyl]-1-(p-fluorophenyl)-5-(trifluoromethyl)-4-pyrazolecarboxamide (5 mg, 3.76% yield) as a white solid.

[0841] 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 =

[0842] 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) + 。

[0843] Biological Example 1

[0844] Biochemical Assay of the Compound

[0845] RON Kinase ADP Glo Assay

[0846] Materials:

[0847] Assay buffer: 40 mM Tris-HCl, pH 7.5, 20 mM MgCl2, 0.1 mg / mL BSARON kinase + ADP-Glo TM Assay (Promega#: V8071)

[0848] Substrate: 1 μg / μL Axltide

[0849] Enzyme: 100 ng / μL RON kinase

[0850] ATP: 10 mM

[0851] ADP-Glo TM Reagents

[0852] Kinase detection reagent

[0853] 384-well white assay plate

[0854] Method:

[0855] Perform the kinase assay according to the following instructions of the kit. Briefly, prepare ten-point serial dilutions of the compound in 5× assay buffer, with final assay concentrations starting from 300 nM, 100 nM, 30 nM, 10 nM…0 nM. The enzyme, substrate, and ATP are used at 25 ng, 2000 ng, and 25 μM respectively. The assay plate is prepared by mixing the components with a total reaction volume of 10 μL per well. The plate is gently centrifuged for 10 seconds and incubated at room temperature (RT) in the dark for 60 minutes. Add and incubate the ADP-Glo reagent and kinase detection reagent as recommended. The reaction is quantified by measuring luminescence on a Perkin Elmer Envision microplate reader.

[0856] MET kinase ADP Glo assay

[0857] Materials:

[0858] Assay buffer: 40 mM Tris-HCl, pH 7.5, 20 mM MgCl2, 0.1 mg / mL BSA

[0859] MET kinase assay (Promega#: V3361)

[0860] Substrate: 1 μg / μL Poly E4Y1 substrate

[0861] Enzyme: 100 ng / μL MET kinase

[0862] ATP: 10 mM

[0863] ADP-Glo TM Reagents

[0864] Kinase Detection Reagent

[0865] 384-Well White Assay Plate

[0866] Method:

[0867] Perform the kinase assay according to the following instructions of the kit. Briefly, prepare ten-point serial dilutions of the compound in 5× assay buffer, with final assay concentrations starting from 3000 nM, 1000 nM, 300 nM, 100 nM…0 nM. The enzyme, substrate, and ATP are used at 25 ng, 2000 ng, and 25 μM, respectively. The assay plate is prepared by mixing the components of a total reaction volume of 10 μL per well. The plate is gently centrifuged for 10 seconds and incubated at room temperature in the dark for 60 minutes. Add and incubate the ADP-Glo reagent and the kinase detection reagent as recommended. The reaction is quantified by measuring luminescence on a Perkin Elmer Envision microplate reader.

[0868] Table 2: Activities of Representative Compounds

[0869]

[0870]

[0871] For RON IC in Table 2 50 Activity:

[0872] * indicates values greater than 5 μM up to 60 μM

[0873] ** indicates values greater than 1 μM up to 5 μM

[0874] *** indicates values below 1 μM

[0875] - indicates values not determined

[0876] For cMET IC in Table 2 50 Activity:

[0877] * indicates values greater than 5 μM up to 65 μM

[0878] ** indicates values greater than 1 μM up to 5 μM

[0879] *** indicates values below 1 μM

[0880] - indicates values not determined

[0881] For the activity of the fold selectivity (cMET / RON) in Table 2:

[0882] +++ indicates values greater than 3 up to 50

[0883] ++ represents values greater than 0.5 up to 3

[0884] + represents values below 0.5

[0885] - represents values not measured

[0886] ******

[0887] The various embodiments described above can be combined to provide other embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications (including U.S. Provisional Patent Application No. 63 / 413,543, filed October 5, 2022) mentioned in this specification and / or listed in the Application Data Sheet are hereby incorporated by reference in their entirety. Aspects of the embodiments may be modified, if necessary, to employ concepts of the various patents, applications, and publications to provide other embodiments.

[0888] Based on the above detailed description, these and other changes may be made to the embodiments. In general, in the following claims, the terms used should not be construed as limiting the claims to the specific embodiments disclosed in the specification and claims, but should be construed to include all possible embodiments and the full scope of equivalents to which these claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

1. A compound having the following structure (I), its stereoisomers, enantiomers or tautomers, or a mixture thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof: Wherein: R 1 has one of the following structures: Wherein: R 1a is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, 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 an alkyl or R a and R b together with the P atom to which they are attached join to form an optionally substituted heterocyclic group; R 1b is an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an unsubstituted arylalkyl group, or an optionally substituted heterocyclic alkyl group; R 1c is an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or -P(=O)R c R d , where R c and R d are each independently an alkyl group; R 1d is halogen, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or -P(=O)R e R f , where R e and R f are each independently alkyl; Each occurrence of R 1e independently is alkyl, halogen, haloalkyl, cycloalkyl, hydroxy, amino, cyano, or optionally substituted -NH-aryl-alkyl-heterocyclic-alkenyl; R 1f is - P(=O)R e R f wherein R e and R f are each independently alkyl; R 1g is hydrogen or an amino group; Each occurrence of R 3 independently is alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, hydroxy, amino, or cyano; Has one of the following structures: n is 0, 1, 2 or 3; and m is 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1 has the following structure:

3. The compound according to claim 1, its stereoisomers, enantiomers or tautomers, or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1a is an optionally substituted 5-membered heteroaryl.

4. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1a is an optionally substituted 5-membered N-heteroaryl.

5. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1a is an optionally substituted imidazolyl or an optionally substituted pyrazolyl.

6. The compound according to claim 1, its stereoisomers, enantiomers or tautomers, or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1a has one of the following structures:

7. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1a has the following structure:

8. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1a is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, or an optionally substituted aryl.

9. The compound according to claim 8, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1a is optionally substituted by alkyl, halogen, haloalkyl, cycloalkyl, hydroxy, amino, or cyano.

10. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1 has the following structure:

11. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1b is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, an optionally substituted aryl, an unsubstituted arylalkyl, or an optionally substituted heterocyclic alkyl.

12. The compound according to claim 1, its stereoisomers, enantiomers or tautomers, or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1b is an optionally substituted cyclohexyl, an optionally substituted piperidinyl, an optionally substituted phenyl, an unsubstituted benzyl, or an optionally substituted -(CH2)2-morpholino.

13. The compound according to claim 1, its stereoisomers, enantiomers or tautomers, or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1b is cyclohexyl, piperidinyl or phenyl substituted with one or more substituents selected from alkyl, alkoxy, haloalkoxy, halogen, -P(=O)-(CH3)2, -NH-C(=O)-alkenyl, -NH-C(=O)-alkenyl-N(CH3)2, -NH-C(=O)-alkyl-N(CH3)-C(=O)alkenyl-N(CH3)2, optionally substituted heterocyclic group, and optionally substituted heterocyclic alkyl, heterocyclic group.

14. A compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1b has one of the following structures:

15. The compound according to claim 1, its stereoisomers, enantiomers or tautomers, or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1b is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl.

16. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1b is optionally substituted by alkyl, halogen, haloalkyl, cycloalkyl, hydroxy, amino, or cyano.

17. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1 has the following structure:

18. The compound according to claim 1, its stereoisomers, enantiomers or tautomers, or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1c is an optionally substituted 5-membered heteroaryl.

19. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1c is an optionally substituted 5-membered N-heteroaryl.

20. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1c is an optionally substituted imidazolyl or an optionally substituted pyrazolyl.

21. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1c has one of the following structures:

22. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1c has the following structure:

23. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1 has the following structure:

24. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1d is an optionally substituted 5-membered heteroaryl.

25. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1d is an optionally substituted 5-membered N-heteroaryl.

26. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1d is an optionally substituted imidazolyl or an optionally substituted pyrazolyl.

27. The compound according to claim 1, its stereoisomers, enantiomers or tautomers, or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1d has the following structure:

28. The compound according to claim 1, its stereoisomers, enantiomers or tautomers, or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1d has the following structure:

29. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1d is bromine.

30. A compound, a stereoisomer, an enantiomer or a tautomer or a mixture thereof according to any one of claims 1 to 29; or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein n is 1, 2, 3, and each occurrence of R 1e is independently halogen, hydroxy, amino or -NH-aryl-alkyl-heterocyclyl-alkenyl.

31. A compound according to any one of claims 1 to 29, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein n is 1 and R 1e is amino, or has the following structure:

32. The compound according to any one of claims 1 to 29, its stereoisomers, enantiomers or tautomers, or a mixture thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein n is 0.

33. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1 has the following structure:

34. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1f has the following structure:

35. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1g is amino.

36. The compound according to claim 1, its stereoisomers, enantiomers or tautomers, or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1 has one of the following structures:

37. The compound according to claim 1, its stereoisomers, enantiomers or tautomers, or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1 has one of the following structures:

38. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1 has one of the following structures:

39. The compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1 has one of the following structures:

40. A compound according to claim 1, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R 1 has one of the following structures:

41. The compound according to any one of claims 1 to 40, its stereoisomers, enantiomers or tautomers, or a mixture thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein m is 1, 2, 3, 4 or 5.

42. A compound, a stereoisomer, an enantiomer or a tautomer or a mixture thereof according to any one of claims 1 to 41; or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein each occurrence of R 3 is independently halogen or haloalkyl.

43. A compound, a stereoisomer, an enantiomer or a tautomer or a mixture thereof according to any one of claims 1 to 42; or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R as it occurs each time 3 is halogen.

44. A compound according to any one of claims 1 to 43, its stereoisomers, enantiomers or tautomers or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein m is 1 and R 3 is fluorine.

45. A compound, a stereoisomer, an enantiomer or a tautomer or a mixture thereof according to any one of claims 1 to 44; or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein has the following structure:

46. The compound according to any one of claims 1 to 40, its stereoisomers, enantiomers or tautomers, or a mixture thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein m is 0.

47. A compound having the structure in Table 1, its stereoisomers, enantiomers or tautomers, or a mixture thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

48. A pharmaceutical composition comprising the compound according to any one of claims 1 to 47, its stereoisomers, enantiomers or tautomers, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and a pharmaceutically acceptable excipient, diluent or carrier.

49. A method for treating a disease or disorder, the method comprising administering to an individual in need the compound according to any one of claims 1 to 47, its stereoisomers, enantiomers or tautomers, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; or the pharmaceutical composition according to claim 48.

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

51. The method according to claim 50, wherein the cancer is skin cancer, breast cancer, prostate cancer, lung cancer, pancreatic cancer, colon cancer, bone cancer, bladder cancer, rectal cancer, gastric cancer, esophageal cancer, tracheal cancer, laryngeal cancer, neck cancer, liver cancer, kidney cancer, brain cancer, thyroid cancer, testicular cancer, ovarian cancer and cervical cancer.

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

53. The method according to claim 50, wherein the cancer is bone cancer.

54. The method according to claim 50, wherein the cancer includes bone tumors.

55. The method according to claim 49, wherein the disease is osteolysis or osteoporosis.

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