MET kinase inhibitors

Abstract

Provided herein are inhibitors of MET receptor tyrosine kinase, pharmaceutical compositions comprising such inhibitory compounds, and methods of using such MET kinase inhibitory compounds for the treatment of disease. [Formula 1] TIFF2025500917000193.tif3953

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Patent Application No. 63 / 290,291, filed December 16, 2021, U.S. Patent Application No. 63 / 301,267, filed January 20, 2022, U.S. Patent Application No. 63 / 380,049, filed October 18, 2022, and U.S. Patent Application No. 63 / 386,647, filed December 8, 2022, each of which is incorporated by reference herein in its entirety. [Background technology]

[0002] MET is a member of the class IV receptor tyrosine kinase family and is expressed on the surface of many different cell types, including epithelial cells in many organs, including the liver, pancreas, prostate, kidney, muscle, and bone marrow, during both embryonic development and adulthood. Hepatocyte growth factor binding induces receptor dimerization and activation. MET regulates many essential cellular processes during development and wound healing, including cell proliferation, survival, motility, and morphogenesis. Aberrant MET activity is observed in many different human cancers. Therefore, therapeutics targeting MET kinase activity are desirable for the treatment of cancer and other diseases characterized by aberrant MET pathway signaling. Summary of the Invention

[0003] Provided herein are inhibitors of MET kinase, pharmaceutical compositions containing the inhibitory compounds, and methods of using the inhibitory compounds for the treatment of disease.

[0004] One embodiment is a compound of formula (I)

[0005] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein V is independently N or CLR; X is independently N or CL 1 -R 1 and Z is N or CR 2 where V, X, and Z are not all N, W is CH or N; Y 1 are independently N or CR 3 and Y 2 are independently N or CR 4 and Y 3 are independently N or CR 3 and Y 4 are independently N or CR 3 and L is a bond, —O—, —NH—, —NHCO—, or —CONH—; L 1 is a bond, -O-, -NH-, -NHCO-, or -CONH-, R is selected from the group consisting of H, halogen, —CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; R 1 is selected from the group consisting of H, halogen, —CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; R 2is H, halogen, —CN, optionally substituted C1-C6 alkyl, —NH(optionally substituted C1-C6 alkyl), or optionally substituted C1-C4 alkoxy; R 3 are each selected from H, halogen, —CN, —NH, —NH(optionally substituted C-C alkyl), —N(optionally substituted C-C alkyl), optionally substituted C-C alkoxy, or optionally substituted C-C alkyl; R 4 are independently selected from H, halogen, —CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C6 cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —NH2, —NH(optionally substituted C1-C6 alkyl), or —N(optionally substituted C1-C6 alkyl)2; R 5 is fluoro, R 6 , R 7 , and R 8 are each independently selected from H, halogen, optionally substituted C-C alkyl, optionally substituted C-C alkoxy, or -CN, with the proviso that R 6 , R 7 , or R 8 At least one of is not H, Q is F or -L 2 -R 9 and L 2 is -O- or an optionally substituted C1-C5 alkylene, and R 9is selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 alkenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl.

[0006] One embodiment provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0007] One embodiment provides a method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the above method, wherein the disease or disorder is cancer.

[0008] Incorporation by Reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the particular purposes identified herein. DETAILED DESCRIPTION OF THE INVENTION

[0009] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents, a reference to "a cell" includes a reference to one or more cells (or cells), and equivalents known to those of skill in the art, and so forth. When ranges relating to physical properties, such as molecular weight, or chemical properties, such as formula, are used herein, all combinations and subcombinations of ranges, and specific embodiments within the ranges, are intended to be encompassed. The term "about," when referring to a number or range of numbers, means that the referenced number or range of numbers is approximate within experimental variation (or within statistical experimental error), and thus the number or range of numbers may, in some cases, vary by 1% to 15% of the stated number or range of numbers. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other specific embodiments, such as, for example, any composition of matter, composition of matter, method, or process described herein, "consist of" or "consist essentially of" the described feature.

[0010] definition As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings specified below.

[0011] "Amino" refers to the -NH2 radical.

[0012] "Cyano" refers to the -CN radical.

[0013] "Nitro" refers to the -NO2 radical.

[0014] "Oxa" refers to the -O- radical.

[0015] "Oxo" refers to the =O radical.

[0016] "Thioxo" refers to the =S radical.

[0017] "Imino" refers to the =NH radical.

[0018] "Oximo" refers to the =N-OH radical.

[0019] "Hydrazino" refers to the =N-NH2 radical.

[0020] "Alkyl" refers to a group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having 1 to 15 carbon atoms (e.g., C1-C 15 Alkyl) refers to a straight or branched hydrocarbon chain radical. In certain embodiments, alkyl contains 1 to 13 carbon atoms (e.g., C1-C 13 In certain embodiments, alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (e.g., C5-C 15In other embodiments, an alkyl group contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl group contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl group contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, an alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). An alkyl is attached to the remainder of the molecule by a single bond. Unless otherwise specified in the specification, an alkyl group may include the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0021] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0022] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. In certain embodiments, alkenyl contains from 2 to 8 carbon atoms. In other embodiments, alkenyl contains from 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond and is, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like. Unless otherwise specified in the specification, an alkenyl group may be selected from the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O- ... a , -SR a, -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0023] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having from 2 to 12 carbon atoms. In certain embodiments, alkynyl contains from 2 to 8 carbon atoms. In other embodiments, alkynyl contains from 2 to 6 carbon atoms. In other embodiments, alkynyl contains from 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless otherwise specified in the specification, an alkynyl group may include the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O- ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0024] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting of carbon and hydrogen, containing no unsaturation, and having 1 to 12 carbon atoms (e.g., methylene, ethylene, propylene, n-butylene, etc.), that connects the rest of the molecule to the radical group. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon atom in the alkylene chain or any two carbon atoms within the chain. In certain embodiments, alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (e.g., C1 alkylene). In other embodiments, alkylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, alkylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, alkylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specified in the specification, an alkylene chain may include any of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O, -O- ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a(t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0025] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms, linking the radical group to the rest of the molecule. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, the alkenylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, the alkenylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, the alkenylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, the alkenylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, the alkenylene contains 2 carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, an alkenylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise in the specification, an alkenylene chain may include any of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a)2 (t is 1 or 2), where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0026] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having 2 to 12 carbon atoms, linking the radical group to the rest of the molecule. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, the alkynylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, the alkynylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, the alkynylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, the alkynylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, the alkynylene contains 2 carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise in the specification, an alkynylene chain may include any of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a)2 (t is 1 or 2), where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0027] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains hydrogen and carbon atoms from 5 to 18 carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise specified in the specification, the term "aryl" or the prefix "ar" (as in "aralkyl") refers to an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b-OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2, where t is 1 or 2, where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted).

[0028] "Aralkyl" is a group of the formula -R c -refers to the aryl radical, R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0029] "Aralkenyl" refers to a group of the formula -R d -refers to the aryl radical, R dis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as defined above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0030] "Aralkynyl" has the formula -R e -refers to the aryl radical, R e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as defined above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0031] "Aralkoxy" has the formula -OR c -refers to an aryl radical attached by an oxygen atom, R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0032] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, having 3 to 15 carbon atoms. In certain embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains 5 to 7 carbon atoms. A carbocyclyl is attached to the rest of the molecule by a single bond. A carbocyclyl is saturated (i.e., contains only a single C-C bond) or unsaturated (i.e., contains one or more double or triple bonds). A fully saturated carbocyclyl radical is also referred to as a "cycloalkyl." Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also referred to as "cycloalkenyls." Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise specified in this specification, the term "carbocyclyl" includes optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c-C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2, where t is 1 or 2, where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R bare each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted).

[0033] A "carbocyclylalkyl" is a group of the formula -R c - refers to the carbocyclyl radical, R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0034] "Carbocyclylalkynyl" refers to a group of the formula -R c - refers to the carbocyclyl radical, R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0035] "Carbocyclylalkoxy" refers to a group of the formula -OR c - refers to a radical attached by an oxygen atom of a carbocyclyl, R c is an alkylene chain as defined below: The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0036] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0037] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0038] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified herein, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule by any atom of the ring. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise stated in this specification, the term "heterocyclyl" includes any of the following: optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a)2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), wherein R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R bare each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted).

[0039] "N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. The N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0040] "C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one heteroatom, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. The C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2-piperidinyl or 3-piperidinyl or 4-piperidinyl, 2-piperazinyl, 2-pyrrolidinyl or 3-pyrrolidinyl, and the like.

[0041] "Heterocyclylalkyl" refers to a group of the formula -R c - refers to the heterocyclyl radical, R cis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0042] "Heterocyclylalkoxy" refers to a group of the formula -OR c - refers to a radical attached by an oxygen atom of a heterocyclyl, R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0043] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, where at least one ring in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Heteroaryl includes fused or bridged ring systems. Heteroatoms in a heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imino dazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridaz ...10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxo Azepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyridinyl Lido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5 ] thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-d]pridinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, the term "heteroaryl" includes optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -R, b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b-N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), wherein R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted).

[0044] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen, and the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0045] "C-heteroaryl" refers to a heteroaryl radical as defined above, where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0046] "Heteroarylalkyl" has the formula -R c - refers to the heteroaryl radical, R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0047] "Heteroarylalkoxy" has the formula -OR c - refers to a heteroaryl radical attached by an oxygen atom, R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0048] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R) or (S). Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are contemplated by the present disclosure. When a compound described herein contains an alkene double bond, and unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, their racemic and optically pure forms, and all tautomers are intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0049] As used herein, a "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits similar physical, biological, and / or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to:

[0050] [ka] Examples include:

[0051] "Tautomer" refers to a molecule in which a proton transfer from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein exist as tautomers in certain embodiments. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on various factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium are:

[0052] [ka] Includes.

[0053] In some embodiments, the compounds disclosed herein are available in various isotopically enriched forms, e.g., 2 H, 3 H, 11 C. 13 C, and / or 14 The compound is enriched to a C content and used. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be made by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability or efficacy, thereby increasing the duration of action of pharmaceuticals.

[0054] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0055] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 It can be labeled with an isotope such as C. 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F,17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 All isotopic substitutions with I are contemplated. In some embodiments, 18 Isotopic substitution with F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0056] In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 The compound is substituted with an atom of H. Methods for the synthesis of deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0057] Deuterium-substituted compounds are synthesized using a variety of methods, such as those described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000;6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989,45(21),6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981,64(1-2),9-32.

[0058] Deuterated starting materials are readily available and amenable to the synthetic methods described herein for the synthesis of deuterated compounds. Many deuterated reagents and building blocks are commercially available from chemical companies such as Aldrich Chemical Co.

[0059] Deuterium transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and may be used to transfer a deuterated carbon atom to a reaction substrate under nucleophilic substitution reaction conditions. The use of CD3I is illustrated, by way of example only, in the following reaction scheme:

[0060] [ka]

[0061] A deuterium transfer reagent, such as lithium aluminum deuteride (LiAlD4), is used to transfer deuterium to the reaction substrate under the above reducing conditions. The use of LiAlD4 is illustrated, by way of example only, in the following reaction scheme:

[0062] [ka]

[0063] Deuterium gas and a palladium catalyst are used to reduce unsaturated carbon-carbon bonds and, by way of example only, to effect reductive displacement of aryl carbon-halogen bonds as illustrated in the following reaction scheme:

[0064] [ka]

[0065] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compounds disclosed herein are fully substituted with deuterium atoms and are non-exchangeable. 1 In one embodiment, the level of deuterium incorporation is determined by the synthetic method in which deuterated synthetic building blocks are used as starting materials.

[0066] "Pharmaceutically acceptable salts" include both acid and base addition salts. A pharmaceutically acceptable salt of any one of the MET kinase inhibitor compounds described herein is intended to encompass any pharmaceutically suitable salt form. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0067] "Pharmaceutically acceptable acid addition salts" refer to those salts which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and are formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, hydroiodic, hydrofluoric, phosphorous, etc. Also included are salts formed with organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids, including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Similarly, salts of amino acids such as arginate, gluconate, and galacturonate are contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared, in some embodiments, by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to those skilled in the art.

[0068] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, made with metals or amines, such as alkali and alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. 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 isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0069] A "pharmaceutically acceptable solvate" refers to a composition of a substance in a solvent addition form. In some embodiments, solvates contain either stoichiometric or non-stoichiometric solvents and are formed during manufacturing processes using pharmaceutically acceptable solvents such as water or ethanol. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in solvated or unsolvated forms. The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the following mammalian classes: humans, non-human primates such as chimpanzees, and other ape and monkey species; livestock such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. In one aspect, the mammal is a human.

[0070] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" are used interchangeably. These terms refer to an approach for obtaining a beneficial or desired result, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. A "therapeutic benefit" refers to the eradication or amelioration of the underlying disease being treated. Similarly, a therapeutic benefit is achieved by the eradication or amelioration of one or more physiological symptoms associated with an underlying disease, such that an improvement is observed in a patient despite the patient still suffering from the underlying disease. For a prophylactic effect, the composition, in some embodiments, is administered to a patient at risk of contracting a particular disease or to a patient reporting one or more physiological symptoms of the disease, even if the disease has not been diagnosed.

[0071] MET tyrosine kinase The MET protein is a member of the class IV receptor tyrosine kinase family and is expressed on the surface of many different cell types, including epithelial cells of many organs, such as the liver, pancreas, prostate, kidney, muscle, and bone marrow, during both embryonic development and adulthood. MET regulates many essential cellular processes during development and wound healing, including cell proliferation, survival, motility, and morphogenesis. Abnormal MET activity is observed in many different human cancers, including non-small cell lung cancer, medulloblastoma, lymphoma, melanoma, glioma, breast cancer, pancreatic cancer, colorectal cancer, ovarian cancer, and prostate cancer, as well as osteosarcoma and some soft tissue sarcomas.

[0072] The c-MET proto-oncogene is located on chromosome 7q21-31, and its transcription is regulated by Ets (E-twenty six), Pax3 (paired box 3), AP2 (activator protein-2), and Tcf-4 (transcription factor 4). It is expressed as multiple mRNA transcripts of 8, 7, 4.5, 3, and 1.5 kilobases. The protein product of this gene is the MET receptor tyrosine kinase.

[0073] Structurally, MET is a single-pass transmembrane protein with an extracellular domain, a transmembrane hydrophobic sequence, and an intracellular portion containing a tyrosine kinase domain. The extracellular domain of MET is composed of three domain types: a semaphorin (Sema) domain, a PSI domain, and four immunoglobulin-plexin-transcription (IPT) domains. The N-terminal 500 residues fold to form a large Sema domain, which shares sequence homology with domains found in the semaphorin and plexin families. The PSI domain (found in plexins, semaphorins, and integrins) follows the Sema domain and spans approximately 50 residues, connecting it to the IPT domain. The four IPT domains are related to immunoglobulin-like domains and are found in integrins, plexins, and transcription factors. The C-terminal IPT domain is then connected to a single transmembrane helix that connects the extracellular domain to the intracellular domain. The intracellular domain of the MET receptor contains a juxtamembrane domain containing residue Y1003, which is involved in receptor downregulation, a tyrosine kinase catalytic domain containing residues Y1234 and Y1235, which is involved in signal transduction, and a docking site for adaptor proteins containing residues Y1349 and Y1356.

[0074] The extracellular portion of MET binds to its cognate ligand, hepatocyte growth factor (HGF), and its native isoform, NK1, resulting in the dimerization of the two MET proteins. Dimerization leads to trans-autophosphorylation of two tyrosine residues (Y1234 and Y1235) located within the catalytic loop of the tyrosine kinase domain of the intracellular portion. Subsequently, tyrosine residues 1349 and 1356 in the carboxy-terminal tail are phosphorylated, thereby forming a unique tandem SH2 recognition motif, leading to the recruitment of signal effector proteins (e.g., GAB1, GRB2, SHC, CRK, PI3K, PLCγ1, SHP2, and STAT3) involved in downstream signal transduction.

[0075] HGF, the primary ligand for MET, is a secreted, single-chain 83 kDa precursor protein. Full-length HGF contains an N-terminal (N) domain, four consecutive kringle (K1-K4) domains, and a serine protease homology (SPH) domain. Proteolytic cleavage between Arg494 and Val495 of HGF generates a 57 kDa α subunit and a 26 kDa β subunit, which are covalently linked by a disulfide bond between Cys487 of the α subunit and Cys604 of the β subunit. Although both pro-HGF and cleaved HGF can bind to MET with high affinity, only cleaved mature HGF can activate MET signaling. NK1, a natural isoform of HGF, can also bind to and activate MET.

[0076] In malignant solid tumors, HGF is primarily expressed and released by surrounding stromal cells, allowing tumor and stromal cells to communicate with each other through HGF, creating a microenvironment that contributes to cancer progression. For example, HGF derived from the tumor stroma acts on tumor cells, stimulating not only proliferation and metastasis but also the production of HGF inducers. These HGF inducers, including bFGF, IL-1β, TGF-α, PDGF, and prostaglandin E2 (PGE2), act on stromal fibroblasts, inducing further HGF expression. This creates a feedback loop that promotes increased MET activation in tumors. Thus, interactions between tumor and stromal cells continuously promote tumor growth, invasion, and metastasis. Furthermore, HGF can also be produced by the tumor itself; this phenomenon has been detected in renal cell carcinoma, colorectal cancer, breast cancer, glioma, multiple myeloma, as well as synovial sarcoma, osteosarcoma, and fibrosarcoma.

[0077] Dysregulation of the MET pathway in cancer occurs through various mechanisms, including gene mutation, amplification, rearrangement, and protein overexpression. Several MET fusions have been identified, including the fusion between c-MET and TPR (translocated promoter region nuclear basket protein gene) found in mutagenized osteosarcoma cell lines and the fusion between c-MET and KIF5B (kinesin family member 5B gene) detected in patients with lung adenocarcinoma. Furthermore, mutations at the MET splice site leading to exon 14 skipping are important molecular drivers in non-small cell lung cancer (NSCLC). Such exon skipping mutations have recently been shown to occur in 3%–4% of NSCLC adenocarcinomas, 2% of squamous cell carcinomas, and 1%–8% of other lung cancer subtypes. These exon skipping mutations often result in persistent MET activation, driving tumorigenesis through downstream signaling pathways.

[0078] MET activation and intracellular signaling pathways MET activation initiates a series of intracellular signaling pathways, including PI3K / AKT, Ras / MAPK, JAK / STAT, SRC, Wnt / β-catenin, and other signaling pathways, thereby regulating proliferation, motility, migration, and invasion. Under normal physiological conditions, MET is important in controlling tissue homeostasis and wound healing, but in cancer, aberrant MET activation promotes tumor growth, enhanced metastasis, and drug resistance through these pathways.

[0079] The Ras / MAPK / ERK signaling pathway transmits signals from cell surface receptors, including MET, to DNA in the cell's nucleus, where regulation of gene expression occurs. Although the signaling cascade involves many different proteins that propagate signals through protein phosphorylation, the pathway can generally be divided into three steps: (i) Ras activation, (ii) the kinase signaling cascade, and (iii) regulation of translation and transcription. Briefly, MET activation leads to Ras activation, which phosphorylates and activates the protein kinase activity of RAF kinase. RAF kinase then phosphorylates and activates MEK (MEK1 and MEK2), which phosphorylates and activates MAPK (also known as ERK) proteins. MAPK activation regulates the activity of several transcription factors, regulating protein expression. MAPK alters the levels and activity of transcription factors, thereby altering the transcription of genes important for the cell cycle. Depending on the stimulus and cell type, this pathway can transmit signals that result in the prevention or induction of apoptosis or cell cycle progression. In cancer, aberrant Ras activation can lead to tumor growth, evasion of apoptosis, local tissue invasion, and metastasis.

[0080] The phosphatidylinositol 3-kinase (PI3K) / protein kinase B (PKB / AKT) signaling pathway is involved in regulating multiple cellular physiological processes, including metabolism, proliferation, cell survival, growth, and angiogenesis. PI3K is a member of the lipid kinase family and is activated by phosphorylation of the 3-hydroxyl group of phosphatidylinositol lipids in the plasma membrane, forming phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 binds to PKB / Akt at the plasma membrane, allowing pyruvate dehydrogenase kinase 1 (PDK1) to access and phosphorylate T308 in the "activation loop" of Akt, resulting in partial PKB / Akt activation. Subsequent phosphorylation of Akt at S473 in the carboxy-terminal hydrophobic motif by either mTOR or DNA-PK stimulates full Akt activity. Activation of Akt leads to additional substrate-specific phosphorylation events in both the cytoplasm and nucleus, including activation of CREB, inhibition of p27, cytoplasmic localization of FOXO, activation of PtdIns-3ps, and activation of mTOR. Through these downstream effectors, the PI3K / Akt pathway mediates many cellular functions that promote cancer progression, including angiogenesis, metabolism, growth, proliferation, survival, protein synthesis, transcription, and apoptosis.

[0081] The JAK-STAT pathway is essential for a wide range of cytokines and growth factors, resulting in crucial cellular events such as cell differentiation, hematopoiesis, and immune system development. The JAK / STAT signaling pathway also plays a key role in the proliferation and survival of various cancer types. Activation of Janus kinase (JAK) by MET leads to the phosphorylation of signal transducer and activator of transcription (STAT) proteins, which then dimerize and translocate to the nucleus, where they regulate gene expression and promote tumor growth. For example, STAT3 is a key driver of tumorigenesis, regulating the expression of many oncogenes, including BCL-XL, c-MYC, Mcl1, survivin, BEGF, HIF-1α, HGF, IL-12, and MMPs. In this way, the JAK / STAT pathway promotes tumor progression by enhancing cell proliferation, angiogenesis, metastasis, and immune evasion.

[0082] The Wnt / β-catenin signaling pathway is a conserved signaling axis involved in diverse physiological processes such as proliferation, differentiation, apoptosis, migration, invasion, and tissue homeostasis. Activation of the Wnt / β-catenin signaling pathway leads to increased cytosolic concentrations of β-catenin, which translocates to the nucleus and interacts with T cell-specific factors (TCFs) / lymphoid enhancer-binding factors (LEFs) and their coactivators, such as Pygopus and Bcl-9. This then enhances the expression of target genes, including c-Myc, cyclin D1, and CDKN1A, which promote cancer stem cell renewal, cell proliferation, and differentiation, thus playing an important role in tumorigenesis and therapeutic response. Therefore, by regulating various tumorigenic signaling pathways, MET is a major driver of tumor growth, survival, invasion, and metastasis.

[0083] MET kinase inhibitors Several drugs targeting MET or HGF, including small molecule inhibitors and monoclonal antibodies, have been developed. Monoclonal antibodies currently approved by the FDA or undergoing clinical evaluation include anti-MET antibodies (e.g., onartuzumab and emibetuzumab), anti-HGF antibodies (e.g., ficlatuzumab and rilotumumab), and anti-MET / EGFR bispecific antibodies (e.g., amivantamab). These therapies prevent HGF from binding to MET, thereby terminating MET activation. In addition, many small molecule MET inhibitors, including capmatinib, tepotinib, crizotinib, cabozantinib, MGCD265, AMG208, altiratinib, and golvatinib, have been approved by the FDA for the treatment of cancer. Of these, two selective MET inhibitors, capmatinib (Tabrecta®) and tepotinib (Tepmetko®), are FDA-approved for the treatment of patients with advanced NSCLC harboring MET exon 14 skipping mutations. Cabozantinib (Cabometyx®) is FDA-approved for the treatment of locally advanced or metastatic differentiated thyroid cancer.

[0084] Small molecule MET-specific inhibitors are divided into two functionally distinct classes: type I inhibitors (e.g., crizotinib, capmatinib, tepotinib, and savolitinib), which preferentially bind to the active conformation of MET, and type II inhibitors (e.g., cabozantinib and glesatinib), which preferentially bind to the inactive conformation of MET. Furthermore, selective MET inhibitors include adenosine triphosphate-competitive inhibitors and adenosine triphosphate-noncompetitive inhibitors (e.g., tivantinib). Type I MET inhibitors are further subdivided into type Ia inhibitors (e.g., crizotinib), which interact with the solvent-leading G1163 residue, and type Ib inhibitors (e.g., capmatinib, tepotinib, and savolitinib), which bind to the kinase domain.

[0085] Type I and type II MET inhibitors each have unique efficacy profiles with respect to secondary MET mutations that confer resistance to MET inhibitors. For example, mutations at residues D1228 and Y1230 in the kinase domain confer resistance to type I MET inhibitors in vitro by weakening the interaction between the drug and the MET kinase domain. Resistance to all type I MET inhibitors has been identified in clinical trials in patients with secondary mutations at these positions. In addition, a mutation at the solvent-edge G1163R confers resistance to the type Ia MET inhibitor crizotinib but not to type Ib MET inhibitors such as tepotinib, savolitinib, or capatinib in vitro. However, type II MET inhibitors retain varying degrees of efficacy against many cancers harboring these mutations that render type I inhibitors ineffective. Given the significant resistance these mutations confer to MET inhibitors, there is a significant unmet clinical need for MET inhibitors that maintain efficacy against tumors harboring these and other mutations.

[0086] MET kinase inhibitor compounds In one aspect, provided herein are MET kinase inhibitor compounds.

[0087] One embodiment is a compound of formula (I)

[0088] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein V is independently N or CLR; X is independently N or CL 1 -R 1 and Z is N or CR 2 where V, X, and Z are not all N, W is CH or N; Y 1 are independently N or CR 3 and Y 2 are independently N or CR 4 and Y 3 are independently N or CR 3 and Y 4 are independently N or CR 3 and L is a bond, —O—, —NH—, —NHCO—, or —CONH—; L 1 is a bond, -O-, -NH-, -NHCO-, or -CONH-, R is selected from the group consisting of H, halogen, —CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; R 1 is selected from the group consisting of H, halogen, —CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; R 2 is H, halogen, —CN, optionally substituted C1-C6 alkyl, —NH(optionally substituted C1-C6 alkyl), or optionally substituted C1-C4 alkoxy; R 3are each selected from H, halogen, —CN, —NH, —NH(optionally substituted C-C alkyl), —N(optionally substituted C-C alkyl), optionally substituted C-C alkoxy, or optionally substituted C-C alkyl; R 4 are independently selected from H, halogen, —CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C6 cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —NH2, —NH(optionally substituted C1-C6 alkyl), or —N(optionally substituted C1-C6 alkyl)2; R 5 is fluoro, R 6 , R 7 , and R 8 are each independently selected from H, halogen, optionally substituted C-C alkyl, optionally substituted C-C alkoxy, or -CN, with the proviso that R 6 , R 7 , or R 8 At least one of is not H, Q is F or -L 2 -R 9 and L 2 is -O- or an optionally substituted C1-C5 alkylene, and R 9 is selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 alkenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl.

[0089] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein V is N.

[0090] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein V is CLR.

[0091] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

[0092] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CL 1 -R 1 is.

[0093] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is N.

[0094] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is CR 2 is.

[0095] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH.

[0096] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein W is N.

[0097] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1 is N.

[0098] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1 is CR 3 is.

[0099] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y 2 is N.

[0100] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y 2 is CR 3 is.

[0101] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y 3 is N.

[0102] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y 3 is CR 4 is.

[0103] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y 4 is N.

[0104] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y 4 is CR 3 is.

[0105] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L 2 Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl.

[0106] Another embodiment is a compound of formula (II)

[0107] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 , R 7 , and R 8 are each independently selected from H or halogen, with the proviso that R 6 , R 7 , or R 8 At least one of is not H, R 9 is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted cycloalkylalkyl; R 10 is H, R 11 is H, halogen, —NH, —CN, optionally substituted C-C alkyl, optionally substituted C-C alkoxy, —NH(optionally substituted C-C alkyl), or —N(optionally substituted C-C alkyl), R 12 is H, halogen, —NH 2 , —CN, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 alkoxy.

[0108] Another embodiment provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CL 1 -R 1 is.

[0109] Another embodiment provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is -O-.

[0110] Another embodiment provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is a single bond.

[0111] Another embodiment provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H.

[0112] Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is optionally substituted C1-C6 alkyl. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is optionally substituted C1-C2 alkyl. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted C1 alkyl.

[0113] Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is a single bond, and R 1 is hydrogen.

[0114] Another embodiment provides a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -O-.

[0115] Another embodiment provides a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C-C alkyl. Another embodiment provides a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C-C alkyl. Another embodiment provides a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C-C alkyl.

[0116] Another embodiment is a compound of formula (III)

[0117] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 , R 7 , and R 8 are each independently selected from H or halogen, with the proviso that R 6 , R 7 , or R 8 At least one of is not H, R 9 is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted cycloalkylalkyl; R 10 is H, R 11 is H, halogen, —NH, —CN, optionally substituted C-C alkyl, optionally substituted C-C alkoxy, —NH(optionally substituted C-C alkyl), or —N(optionally substituted C-C alkyl), R 12 is H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkoxy.

[0118] Another embodiment provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein V is CLR. Another embodiment provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -O-. Another embodiment provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L is a single bond. Another embodiment provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is H.

[0119] Another embodiment provides a compound of Formula (I) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C6 alkyl. Another embodiment provides a compound of Formula (I) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C2 alkyl. Another embodiment provides a compound of Formula (I) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1 alkyl.

[0120] Another embodiment provides a compound of formula (I) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L is a single bond and R is hydrogen. Another embodiment provides a compound of formula (I) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is -O-.

[0121] Another embodiment provides a compound of formula (I) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is optionally substituted C1-C6 alkyl. Another embodiment provides a compound of formula (I) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is optionally substituted C1-C4 alkyl. Another embodiment provides a compound of formula (I) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted C1-C2 alkyl.

[0122] Another embodiment is a compound of formula (IV)

[0123] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 , R 7 , and R8 are each independently selected from H or halogen, with the proviso that R 6 , R 7 , or R 8 At least one of is not H, R 9 is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted cycloalkylalkyl; R 10 is H, R 11 is H, halogen, —NH, —CN, optionally substituted C-C alkyl, optionally substituted C-C alkoxy, —NH(optionally substituted C-C alkyl), or —N(optionally substituted C-C alkyl), R 12 is H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkoxy.

[0124] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein V is CLR. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -O-. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L is a single bond. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is H.

[0125] Another embodiment provides a compound of formula (I) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C6 alkyl. Another embodiment provides a compound of formula (I) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C2 alkyl. Another embodiment provides a compound of formula (I) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1 alkyl.

[0126] Another embodiment provides a compound of formula (I) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L is a single bond and R is hydrogen. Another embodiment provides a compound of formula (I) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is -O-.

[0127] Another embodiment provides a compound of formula (I) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is optionally substituted C1-C6 alkyl. Another embodiment provides a compound of formula (I) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is optionally substituted C1-C4 alkyl. Another embodiment provides a compound of formula (I) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted C1-C2 alkyl.

[0128] Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is optionally substituted C1-C6 alkyl. Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9is optionally substituted C1-C4 alkyl. Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is optionally substituted C1-C2 alkyl. Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is an optionally substituted C alkyl. Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is CH3.

[0129] Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is an optionally substituted C-C cycloalkyl. Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is an optionally substituted C-C cycloalkyl. Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is an optionally substituted C5-C6 cycloalkyl. Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is optionally substituted cyclopropyl. Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is cyclopropyl.

[0130] Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R11 is hydrogen.

[0131] Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 is hydrogen.

[0132] Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is hydrogen.

[0133] Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 Another embodiment provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is fluoro.

[0134] Another embodiment provides a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Q is -L 2 -R 9 is.

[0135] In some embodiments, a MET kinase inhibitor compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, has the structure provided in Table 1.

[0136] [Table 1-1]

[0137]

Table 1-2

[0138]

Table 1-3

[0139]

Table 1-4

[0140]

Table 1-5

[0141]

Table 1-6

[0142]

Table 1-7

[0143]

Table 1-8

[0144]

Table 1-9

[0145]

Table 1-10

[0146]

Table 1-11

[0147] [Table 1-12]

[0148] [Table 1-13]

[0149] [Table 1-14]

[0150] [Table 1-15]

[0151] [Table 1-16]

[0152] [Table 1-17]

[0153] [Table 1-18]

[0154] [Table 1-19]

[0155] Preparation of compounds The compounds used in the synthetic chemical reactions described herein are made according to organic synthesis techniques known to those skilled in the art, beginning with commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" refers to Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI; includes Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CT), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Products, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0156] Suitable books and articles that detail the synthesis of reactants useful in preparing the compounds described herein or that provide references to literature describing the preparation include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions," 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L.G. Gilchrist, "Heterocyclic Chemistry," 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley Interscience, New York, 1992. Additional suitable references and papers detailing the synthesis of or referencing articles describing the preparation of reactants useful in the preparation of the compounds described herein include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons, ISBN: 3 527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J.“Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups”(1992)Interscience ISBN:0-471-93022-9;Solomons,TWG“Organic Chemistry”7th Edition(2000)John Wiley & Sons,ISBN:0-471-19095-0;Stowell,JC,“Intermediate Organic Chemistry”2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; the 8-volume "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X; the 55-volume "Organic Reactions" (1942-2000) John Wiley & Sons; and the 73-volume "Chemistry of Functional Groups" John Wiley & Sons.

[0157] Certain similar reactants are optionally identified by indexes of known chemical products prepared by the American Chemical Society's Chemical Abstract Service, available at most public and university libraries and via online data services (for more information, contact the American Chemical Society in Washington, D.C.). Known chemicals not sold in catalogs are optionally prepared by custom chemical synthesis houses, and many of the standard drug supply companies (e.g., those listed above) offer custom synthesis services. For information on the preparation and selection of pharmaceutical salts of the compounds described herein, see P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0158] General synthetic method 1 (below) was used to prepare Examples 1-51, 121-134, 137-140, and 145-147. Haloheterocycle (a) was reacted with nitrophenol (b) in the presence of a base such as DIEA (N,N-diisopropylethylamine) to give nitro compound (c). Compound (c) was reduced with a reducing agent such as hydrogen gas in the presence of Pd / C to give amine compound (d). Amine (d) was then coupled with acid (e) using a coupling agent such as HATU to give compound of formula (A). Alternatively, amine (d) was reacted with acid chloride (f) in the presence of a base such as DIEA to give compound of formula (A).

[0159] [ka] Reaction of halo-heterocycle (g) with 2-fluoro-4-nitrophenol (h) gave ether (i), which was reduced to amine (j) using the same method as described in General Synthetic Method 1.

[0160] [ka]

[0161] General synthetic method 2 (below) was used to prepare Examples 52-108, 135-136, and 143. Amine (j) was coupled with acid (k) using a coupling agent such as HATU to give (l). Compound (l) was then reacted with alcohol (m) using a base such as DBU to give compounds having formula (B).

[0162] [ka]

[0163] General synthetic method 3 (below) was used to prepare Examples 109-120, 141-142, 144, 148-149. Ester (n) was reacted with alcohol (m) using a base such as DBU to give intermediate (o), which was then saponified to acid (p) using a base such as lithium hydroxide in water. Acid (p) was then coupled with amine (j) using a coupling agent such as HATU to give compounds having formula (C).

[0164] [ka]

[0165] Using the appropriate starting materials, the MET kinase inhibitor compounds described herein by Table 1 or Formula (I), (II), (III), or (IV) were synthesized using general synthetic method 1, 2, or 3 described above for the synthesis of compounds having Formula (A), (B), or (C).

[0166] Pharmaceutical Composition In certain embodiments, the MET kinase inhibitor compounds described herein are administered as pure chemicals. In other embodiments, the MET kinase inhibitor compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the chosen route of administration and standard pharmaceutical practice, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0167] Provided herein are pharmaceutical compositions comprising at least one MET kinase inhibitor compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient of the composition (i.e., the subject or patient).

[0168] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0169] One embodiment provides a method of preparing a pharmaceutical composition, comprising the step of mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0170] In certain embodiments, the MET kinase inhibitor compounds as described by Formula (I) are substantially pure in that they contain less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic process.

[0171] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof.

[0172] One embodiment provides a method of preparing a pharmaceutical composition, comprising the step of mixing a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0173] In certain embodiments, the MET kinase inhibitor compound as described by Formula (II) is substantially pure in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic process.

[0174] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof.

[0175] One embodiment provides a method of preparing a pharmaceutical composition, comprising the step of mixing a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0176] In certain embodiments, the MET kinase inhibitor compound as described by Formula (III) is substantially pure in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic process.

[0177] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof.

[0178] One embodiment provides a method of preparing a pharmaceutical composition, comprising the step of mixing a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0179] In certain embodiments, a MET kinase inhibitor compound as described by Formula (IV) is substantially pure in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic process.

[0180] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0181] One embodiment provides a method of preparing a pharmaceutical composition, comprising mixing a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0182] In certain embodiments, the MET kinase inhibitor compounds described by Table 1 are substantially pure in that they contain less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic process.

[0183] Suitable oral dosage forms include tablets, pills, sachets, or capsules made of, for example, hard or soft gelatin, methylcellulose, or another suitable material that dissolves readily in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like (see, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005))).

[0184] In some embodiments, a MET kinase inhibitor compound as described by Formula (I), (II), (III), or (IV), or Table 1, or a pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some examples, the injection formulation is an aqueous formulation. In some examples, the injection formulation is a non-aqueous formulation. In some examples, the injection formulation is an oil-based formulation, such as sesame oil.

[0185] The dosage of the compositions comprising at least one MET kinase inhibitor compound as described herein varies depending on the condition of the subject or patient (e.g., human). In some embodiments, such factors include health status, age, and other factors.

[0186] The pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration are determined by factors such as the patient's disease, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition in an amount sufficient to bring about a therapeutic and / or preventive benefit (e.g., improved clinical outcome), such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduced severity of symptoms. The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose varies depending on the patient's body type, weight, or blood volume.

[0187] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four or more times per day.

[0188] Treatment method One embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0189] One embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or a neoplastic disease.

[0190] One embodiment provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or a neoplastic disease.

[0191] One embodiment provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

[0192] In some embodiments, methods are provided for treating cancer in a patient, comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods are provided for treating cancer in a patient, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0193] One embodiment provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0194] One embodiment provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or a neoplastic disease.

[0195] One embodiment provides a pharmaceutical composition comprising a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or a neoplastic disease.

[0196] One embodiment provides the use of a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

[0197] In some embodiments, methods are provided for treating cancer in a patient, comprising administering to the patient a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods are provided for treating cancer in a patient, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0198] One embodiment provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0199] One embodiment provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or a neoplastic disease.

[0200] One embodiment provides a pharmaceutical composition comprising a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or a neoplastic disease.

[0201] One embodiment provides the use of a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

[0202] In some embodiments, methods are provided for treating cancer in a patient, comprising administering to the patient a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods are provided for treating cancer in a patient, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0203] One embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0204] One embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or a neoplastic disease.

[0205] One embodiment provides a pharmaceutical composition comprising a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or a neoplastic disease.

[0206] One embodiment provides the use of a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

[0207] In some embodiments, methods are provided for treating cancer in a patient, comprising administering to the patient a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods are provided for treating cancer in a patient, comprising administering to the patient a pharmaceutical composition comprising a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0208] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0209] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or a neoplastic disease.

[0210] One embodiment provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or a neoplastic disease.

[0211] One embodiment provides the use of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

[0212] In some embodiments, methods are provided for treating cancer in a patient, comprising administering to the patient a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods are provided for treating cancer in a patient, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0213] Provided herein are methods wherein the pharmaceutical composition is administered orally.Provided herein are methods wherein the pharmaceutical composition is administered by injection.

[0214] One embodiment provides a method of inhibiting MET kinase, comprising contacting MET kinase with a compound of formula (I), (II), (III), or (IV), or Table 1. Another embodiment provides a method of inhibiting MET kinase, wherein the MET kinase is contacted in an in vivo setting. Another embodiment provides a method of inhibiting MET kinase, wherein the MET kinase is contacted in an in vitro setting.

[0215] Other embodiments and uses will be apparent to those skilled in the art in light of the present disclosure. The following examples are provided only as illustrative of various embodiments and are not to be construed as limiting the invention in any way. [Example]

[0216] I. Chemical synthesis In some embodiments, MET kinase inhibitor compounds disclosed herein are synthesized according to the following example: As used below, and throughout the description of the invention, the following abbreviations shall be understood to have the following meanings, unless otherwise specified: ℃ Celsius δ H Chemical shifts in parts per million (ppm) downfield from tetramethylsilane DCM dichloromethane (CH2Cl2) DMF Dimethylformamide DMSO dimethyl sulfoxide EA Ethyl acetate ESI electrospray ionization Et Ethyl g grams h time(s) HPLC High Performance Liquid Chromatography Hz Hertz J coupling constant (NMR spectroscopy) LCMS Liquid Chromatography Mass Spectrometry μ Micro m multiplet (spectrum), meter, millimeter M mole M + Parent molecular ion Me methyl MHz Megahertz min minutes(s) mol mole, molecule (mol weight) mL milliliter MS mass spectrometry nm nanometer NMR nuclear magnetic resonance pH Hydrogen ion potential, a measure of the acidity or basicity of an aqueous solution PE Petroleum Ether RT room temperature s Singlet (spectrum) t doublet (spectrum) T temperature TFA trifluoroacetic acid THF tetrahydrofuran

[0217] Example 1: N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-methoxypyridine-3-carboxamide

[0218] [ka]

[0219] Step 1: tert-butyl N-{2-[(4-chloro-6-methoxyquinolin-7-yl)oxy]ethyl}-N-methylcarbamate

[0220] To a stirred solution of tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (627 mg, 3.578 mmol) and 4-chloro-6-methoxyquinolin-7-ol (500 mg, 2.385 mmol) in tetrahydrofuran (10 mL) was added triphenylphosphine (1.25 g, 4.770 mmol) and diisopropyl azodicarboxylate (965 mg, 4.772 mmol) at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1 / 1). Fractions containing the desired product were collected and concentrated under reduced pressure to give tert-butyl N-{2-[(4-chloro-6-methoxyquinolin-7-yl)oxy]ethyl}-N-methylcarbamate (850 mg, 97%) as a tan oil. MS ESI calculated for C 18 H 23 ClN2O4[M+H] + ,367.13,369.13 found 367.10,369.10. 1 H NMR(400MHz,CDCl3)δ8.59(d,J=4.8Hz,1H),7.43(d,J=3.6Hz,2H),7.38(d,J=4.8Hz,1H ),4.31(s,2H),4.05(s,3H),3.75(q,J=5.2Hz,2H),3.07(s,3H),1.48(d,J=3.2Hz,9H).

[0221] Step 2: tert-butyl N-(2-{[4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methylcarbamate

[0222] To a stirred mixture of tert-butyl N-{2-[(4-chloro-6-methoxyquinolin-7-yl)oxy]ethyl}-N-methylcarbamate (500 mg, 1.363 mmol) and 2,6-difluoro-4-nitrophenol (286 mg, 1.636 mmol) in 1-methyl-2-pyrrolidinone (5 mL), N,N-diisopropylethylamine (528 mg, 4.089 mmol) was added at room temperature. The resulting mixture was stirred at 140° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature. The reaction was quenched by the addition of room temperature water (100 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×60 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (3 / 7). Fractions containing the desired product were collected and concentrated under reduced pressure to give tert-butyl N-(2-{[4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methylcarbamate (370 mg, 54%) as a pale yellow solid. MS ESI calculated for C 24 H 25 F2N3O7[M+H] + ,506.17 found 506.20, 1 H NMR(400MHz,CDCl3)δ8.55(d,J=5.2Hz,1H),8.11-8.04(m,2H),7.56(s,1H),7.48(s,1H),6.42 (d,J=5.2Hz,1H),4.42-4.29(m,2H),4.06(s,3H),3.82-3.71(m,2H),3.08(s,3H),1.48(s,9H). 19 F NMR(376MHz,CDCl3)δ-119.85(2F).

[0223] Step 3: tert-butyl N-(2-{[4-(4-amino-2,6-difluorophenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methylcarbamate

[0224] To a stirred mixture of tert-butyl N-(2-{[4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methylcarbamate (380 mg, 0.752 mmol) in tetrahydrofuran (5 mL) and water (2.5 mL), iron powder (210 mg, 3.760 mmol) and ammonium chloride (80 mg, 1.504 mmol) were added at room temperature. The resulting mixture was stirred at 70° C. for 3 hours. The mixture was cooled to room temperature. The reaction was quenched by the addition of room temperature water (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate / ethyl alcohol (2 / 3 / 1). Fractions containing the desired product were collected and concentrated under reduced pressure to give tert-butyl N-(2-{[4-(4-amino-2,6-difluorophenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methyl-carbamate (280 mg, 73%) as a pale yellow solid. MS ESI calculated for C 24 H 27 F2N3O5[M+H] + ,476.19 found 476.15, 1 H NMR(400MHz,CDCl3)δ8.51(d,J=5.2Hz,1H),7.62(s,1H),7.45(s,1H),6.48(d,J=5.2Hz,1H),6 .41-6.32(m,2H),4.39-4.27(m,2H),4.05(s,3H),3.81-3.71(m,2H),3.07(s,3H),1.48(s,9H). 19 F NMR(377MHz,CDCl3)δ-126.68(2F).

[0225] Step 4: tert-butyl N-[2-({4-[2,6-difluoro-4-(4-methoxypyridin-3-amido)phenoxy]-6-methoxyquinolin-7-yl}oxy)ethyl]-N-methylcarbamate

[0226] To a stirred mixture of 4-methoxypyridine-3-carboxylic acid (39 mg, 0.252 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.315 mmol) in N,N-dimethylformamide (1 mL) was added tert-butyl N-(2-{[4-(4-amino-2,6-difluorophenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methylcarbamate (100 mg, 0.210 mmol) and N,N-diisopropylethylamine (81 mg, 0.630 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 24 hours. The mixture was cooled to room temperature. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate / ethyl alcohol (1 / 6 / 2). Fractions containing the desired product were collected and concentrated under reduced pressure to give tert-butyl N-[2-({4-[2,6-difluoro-4-(4-methoxypyridin-3-amido)phenoxy]-6-methoxyquinolin-7-yl}oxy)ethyl]-N-methylcarbamate (100 mg, 78%) as a white solid. MS ESI calculated for C 31 H 32 F2N4O7[M+H] + ,611.22 found 611.20, 1 H NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.64(s,1H),8.62(d,J=5.6Hz,1H),8.51(d,J=5.2Hz,1H),7.80-7.71(m,2H),7.57(s,1H),7.48(s,1 H),7.28(d,J=5.6Hz,1H),6.62(d,J=5.2Hz,1H),4.35-4.24(m,2H),4.01-3.92(m,6H),3.68-3.60(m,2H),2.92(s,3H),1.44-1.30(m,9H). 19F NMR(377MHz,DMSO-d6)δ-126.60(2F).

[0227] Step 5: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-methoxypyridine-3-carboxamide

[0228] To a stirred mixture of tert-butyl N-[2-({4-[2,6-difluoro-4-(4-methoxypyridin-3-amido)phenoxy]-6-methoxyquinolin-7-yl]oxy)ethyl]-N-methylcarbamate (100 mg, 0.164 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (plus 10 mmol / L ammonium bicarbonate); Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 22% to 32% B in 8 min; Detector: UV 254 / 220 nm). Fractions containing the desired product were collected, concentrated, and lyophilized to give N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-methoxypyridine-3-carboxamide (32.6 mg, 39%) as a white solid. MS ESI calculated for C 26 H 24 F2N4O5[M+H] + ,511.17 found 511.20, 1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.67-8.57(m,2H),8.50(d,J=5.2Hz,1H),7.80-7.70(m,2H),7.56(s,1H),7.45(s,1H) ,7.28(d,J=5.6Hz,1H),6.61(d,J=5.2Hz,1H),4.22(t,J=5.6Hz,2H),4.02-3.94(m,6H),2.94(t,J=5.6Hz,2H),2.39(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-126.58(2F).

[0229] Example 2: N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4,5-difluoro-2-methoxybenzamide

[0230] [ka]

[0231] Synthesized using a method similar to that of Example 1. Followed the same procedure as previously described. Off-white solid. MS ESI calculated for C 27 H 23 F4N3O5[M+H] + , 1 H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.50(d,J=5.2Hz,1H),7.80-7.70(m,3H),7.56(s,1H),7.50-7.38(m,2H) ),6.60(d,J=5.2Hz,1H),4.22(t,J=5.6Hz,2H),3.98(s,3H),3.93(s,3H),2.95(d,J=5.6Hz,2H),2.39(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-126.63(2F),-131.31(1F),-148.45(1F).

[0232] Example 3: 6-chloro-N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-methoxypyridine-3-carboxamide

[0233] [ka]

[0234] The synthesis was carried out using the same method as in Example 1. A white solid was obtained. MS ESI calculated for C 26 H 23 ClF2N4O5[M+H] + ,545.13,547.13 found 545.20,547.20. 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.3-8.65(m,2H),7.7-7.76(m,2H),7.55(s,1H),7.46-7.42(m,2H),6 .61(d,J=5.2Hz,1H),4.22(t,J=5.6Hz,2H),4.01(s,3H),3.98(s,3H),2.94(m,t,J=5.6Hz,2H),2.38(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-126.44(2F).

[0235] Example 4: N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-2-fluoro-4-methoxypyridine-3-carboxamide

[0236] [ka]

[0237] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C 26 H 23 F3N4O5[M+H] + ,529.16 found 529.15,1 H NMR(400MHz,DMSO-d6)δ11.20-11.12(m,1H),8.55-8.45(m,1H),8.33-8.21(m,2H),7.71-7.63(m,2H),7.57(s,1H),7.46(s,1) H),7.28(d,J=6.0Hz,1H),6.66(d,J=5.2Hz,1H),4.33-4.23(m,2H),4.00-3.94(m,6H),3.11-3.00(m,2H),2.47-2.41(m,2H). 19 F NMR(377MHz,DMSO-d6)δ-72.53(1F),-126.11(2F).

[0238] Example 5: N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-methoxypyridine-3-carboxamide

[0239] [ka]

[0240] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C 27 H 26 F2N4O5[M+H] + ,525.19 found 525.20. 1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.64(s,1H),8.59(d,J=5.6Hz,1H),8.51(d,J=5.2Hz,1H),7.69-7.79(m,2H),7.45(s,1H),7.56(s,1 H),7.25(d,J=5.6Hz,1H),6.62(d,J=5.2Hz,1H),4.18-4.32(m,4H),3.98(s,3H),2.94(t,J=5.6Hz,2H),2.39(s,3H),1.41(t,J=6.8Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-126.51(2F).

[0241] Example 6: N-(3-chloro-5-fluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-methoxypyridine-3-carboxamide

[0242] [ka]

[0243] Synthesized using the same method as in Example 1. Off-white solid. MS ESI calculated for C 26 H 24 ClFN4O5[M+H] + ,527.00,529.00 found 527.20,529.20. 1 H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.65(s,1H),8.62(d,J=6.0Hz,1H),8.49(d,J=5.2Hz,1H),7.99-7.92(m,2H),7.57(s,1H), 7.45(s,1H),7.28(d,J=6.0Hz,1H),6.50(d,J=5.2Hz,1H),4.22(t,J=5.6Hz,2H),3.98(s,6H),2.94(t,J=5.6Hz,2H),2.39(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-125.17(1F).

[0244] Example 7: N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinazolin-4-yl)oxy)phenyl)-2-fluoro-4-methoxypyridine-3-carboxamide

[0245] [ka]

[0246] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C 25 H 22 F3N5O5[M+H]+ ,530.16,found 530.30, 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H),8.59(s,1H),8.29(d,J=6.0Hz,1H),7.64(s,1H),7.62-7.59(m,2H),7.47(s ,1H),7.28(d,J=6.0Hz,1H),4.28(t,J=5.2Hz,2H),4.01(s,3H),3.99(s,3H),2.96(t,J=5.2Hz,2H),2.39(s,3H), 19 F NMR(376MHz,DMSO-d6)δ-72.56(1F),-125.40(1F),-125.83(1F).

[0247] Example 8: N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinazolin-4-yl)oxy)phenyl)-4-methoxypyridine-3-carboxamide

[0248] [ka]

[0249] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C 25 H 23 F2N5O5[M+H] + ,512.17,found 512.30, 1 H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.64-8.59(m,3H),7.71-7.69(m,2H),7.60-7.46(m,2H),7.60(s,1H),7.4 7(s,1H),7.30-7.26(m,1H),4.27(t,J=5.6Hz,2H),4.01(s,3H),3.97(s,3H),2.94(t,J=5.6Hz,2H),2.37(s,3H), 19 F NMR(376MHz,DMSO-d6)δ-125.90(2F).

[0250] Example 9: N-(3,5-difluoro-4-((7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-2-fluoro-4-methoxypyridine-3-carboxamide

[0251] [ka]

[0252] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C 25 H 21 F3N4O4[M+H] + ,499.15 found 499.10. 1 H NMR(400MHz,DMSO-d6)δ11.16(s,1H),8.63(d,J=5.2Hz,1H),8.30(d,J=6.0Hz,1H),8.26(d,J=9.2Hz,1H),7.71-7.64(m,2H),7.45(d,J=2.4Hz,1H) ,7.35(dd,J=9.2,2.4Hz,1H),7.28(d,J=6.0Hz,1H),6.67(d,J=5.2Hz,1H ),4.22(t,J=5.6Hz,2H),3.98(s,3H),2.93(d,J=5.6Hz,2H),2.38(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-72.56(1F),-126.28(2F).

[0253] Example 10: N-(3,5-difluoro-4-((7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-methoxypyridine-3-carboxamide

[0254] [ka]

[0255] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C 25 H 22F2N4O4[M+H] + ,481.16,found 481.15. 1 H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.67-8.59(m,3H),8.27(d,J=9.2Hz,1H),7.79-7.71(m,2H),7.45(s,1H),7.35 (d,J=9.2Hz,1H),7.28(d,J=6.0Hz,1H),6.64(d,J=5.2Hz,1H),4.22(t,J=5.6Hz,2H),3.97(s,3H),3.27-3.21(m,1H) 2.94(t,J=5.6Hz,2H),2.38(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-126.76(2F).

[0256] Example 11: N-(3,5-difluoro-4-((7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-ethoxypyridine-3-carboxamide

[0257] [ka]

[0258] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C 26 H 24 F2N4O4[M+H] + ,495.18,found 495.30. 1 H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.66-8.62(m,2H),8.59(d,J=6.0Hz,1H), 8.26(d,J=9.2Hz,1H),7.80-7.70(m,2H),7.45(d,J=2.4Hz,1H),7.35(dd,J=9.2, 2.4Hz,1H),7.26(d,J=6.0Hz,1H),6.64(d,J=5.2Hz,1H),4.27(q,J=6.8Hz,2H), 4.22(t,J=5.6Hz,2H),2.92(t,J=5.6Hz,2H),2.38(s,3H),1.40(t,J=6.8Hz,3H).19 F NMR(376MHz,DMSO)δ-126.68(2F).

[0259] Example 12: (S)—N-(4-((7-(2-aminopropoxy)quinolin-4-yl)oxy)-3,5-difluorophenyl)-4-cyclopropoxypyridine-3-carboxamide

[0260] [ka]

[0261] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C 27 H 24 F2N4O4[M+H] + ,507.18 found 507.15. 1 H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.66-8.60(m,3H),8.27(d,J=9.2Hz,1H),7.74-7.68(m,2H),7.51(d,J=6.0Hz,1H),7.44(d,J=2.4Hz,1 H),7.37(dd,J=9.2,2.4Hz,1H),6.64(d,J=5.2Hz,1H),4.13-3.90(m,3H),3.30-3.22(m,1H),1.14(dd,J=6.4,1.6Hz,3H),0.92-0.78(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-126.67(2F).

[0262] Example 13: (R)—N-(4-((7-(2-aminopropoxy)quinolin-4-yl)oxy)-3,5-difluorophenyl)-4-cyclopropoxypyridine-3-carboxamide

[0263] [ka]

[0264] Synthesized using the same method as in Example 1. Off-white solid. MS ESI calculated for C 27 H 24 F2N4O4[M+H] + ,507.18,found 507.10. 1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.67-8.59(m,3H),8.27(d,J=9.2Hz,1H ),7.76-7.67(m,2H),7.51(d,J=6.0Hz,1H),7.43(d,J=2.4Hz,1H),7.36(dd,J= 9.2,2.4Hz,1H),6.64(d,J=5.2Hz,1H),4.12-4.09(m,1H),4.00-3.88(m,2H),3 .29-3.19(m,1H),1.26-1.22(m,2H),1.12(d,J=6.8Hz,3H),0.98-0.76(m,4H).

[0265] Example 14: N-(2,3-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-methoxypyridine-3-carboxamide

[0266] [ka]

[0267] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C 26 H 24 F2N4O5[M+H] + ,511.17 found 511.20. 1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.79(s,1H),8.63(d,J=5.6Hz,1H),8.52(d,J=5.2Hz,1H),7.99-7.92(m,1H),7.55(s,1H),7.45 (s,1H),7.40-7.27(m,2H),6.62(d,J=5.2Hz,1H),4.22(t,J=5.6Hz,2H),4.03(s,3H),3.97(s,3H),2.94(t,J=5.6Hz,2H),2.39(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-144.18(1F),-152.75(1F).

[0268] Example 15: N-(2,3-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-2-fluoro-4-methoxypyridine-3-carboxamide

[0269] [ka]

[0270] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C 26 H 23 F3N4O5[M+H] + ,529.16 found 529.20. 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.51(d,J=5.2Hz,1H),8.26(d,J=6.0Hz,1H),7.90-7.88(m,1H),7.54(s,1H),7.44(s,1H),7.37- 7.35(m,1H),7.24(d,J=6.0Hz,1H),6.66(d,J=5.2Hz,1H),4.22(t,J=5.6Hz,2H),4.01-3.92(m,6H),2.94(t,J=5.6Hz,2H),2.39(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-72.71(1F),-143.54(1F),-152.46(1F).

[0271] Example 16: N-(2,3-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-ethoxypyridine-3-carboxamide

[0272] [ka]

[0273] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C 27 H 26 F2N4O5[MH] - ,523.19 found 523.20. 1 H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.87(s,1H),8.61(d,J=5.6Hz,1H), 8.51(d,J=5.2Hz,1H),8.20-8.07(m,1H),7.54(s,1H),7.44(s,1H),7.39- 7.37(m,1H),7.29(d,J=5.6Hz,1H),6.62(d,J=5.2Hz,1H),4.42-4.16(m,4 H),3.96(s,3H),2.93(t,J=5.6Hz,2H),2.38(s,3H),1.48(t,J=7.2Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-146.26(1F),-152.68(1F).

[0274] Example 17: N-[2,3-difluoro-4-({6-methoxy-7-[3-(methylamino)propoxy]quinolin-4-yl}oxy)phenyl]-4-ethoxypyridine-3-carboxamide

[0275] [ka]

[0276] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C28 H 28 F2N4O5.[M+H] + ,539.20 found 539.35. 1 H NMR(400MHz,CD3OD)δ9.07(s,1H),8.60(d,J=6.0Hz,1H),8.48(d,J=5.4Hz,1H) ,8.38-8.33(m,1H),7.67(s,1H),7.40(s,1H),7.32(d,J=6.0Hz,1H),7.31-7.28 (m,1H),6.67-6.61(m,1H),4.47-4.43(m,2H),4.31(t,J=6.0Hz,2H),4.05(s,3H) ),2.91(t,J=6.8Hz,2H),2.50(s,3H),2.17-2.13(m,2H),1.65(t,J=7.0Hz,3H). 19 F NMR(376MHz,CD3OD)δ-150.01(1F),-154.42(1F).

[0277] Example 18: N-[2,3-difluoro-4-({6-methoxy-7-[3-(methylamino)propoxy]quinolin-4-yl}oxy)phenyl]-4-methoxypyridine-3-carboxamide

[0278] [ka]

[0279] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C 27 H 26 F2N4O5[M+H] + ,525.20 found 525.15. 1H NMR(400MHz,CD3OD)δ9.01(s,1H),8.66-8.60(m,1H),8.51-8.49(m,1H),8.17-8.1 5(m,1H),7.67(dd,J=4.4,2.0Hz,1H),7.43-7.38(m,1H),7.38-7.33(m,1H),7.28( t,J=8.8Hz,1H),6.64(s,1H),4.31(s,2H),4.19(d,J=1.2Hz,3H),4.05(dd,J=3.4, 1.6Hz,3H),2.93(d,J=7.6Hz,2H),2.52(dd,J=8.4,3.4Hz,3H),2.21-2.14(m,2H). 19 F NMR(376MHz,CD3OD)δ-148.81(1F),-154.31(1F).

[0280] Example 19: N-(3,5-difluoro-4-((6-methoxy-7-(3-(methylamino)propoxy)quinolin-4-yl)amino)phenyl)-4-methoxypyridine-3-carboxamide

[0281] [ka]

[0282] Synthesized using a similar method to Example 1. Light brown solid as the TFA salt. 1 H NMR(400MHz,DMSO-d6):δ14.27(brs,1H),10.85(s,1H),10.26(s,1H),8.68( d,J=8.8Hz,2H),8.46(brs,3H),8.04(s,1H),7.78(d,J=10Hz,2H),7.41(s,1H) ),7.36(d,J=6.0Hz,1H),6.57(d,J=7.2Hz,1H),4.29(t,J=5.6Hz,2H),4.01( s,3H),3.99(s,3H),3.12(brs,2H),2.65(t,J=5.6Hz,3H),2.18(brs,2H)ppm, 19 F NMR(400MHz,DMSO-d6):δ-117.104.LCMS m / z:524.59[M+H] +

[0283] Example 20: N-(3,5-difluoro-4-((6-methoxy-7-(3-(methylamino)propoxy)quinolin-4-yl)oxy)phenyl)-2-fluoro-4-methoxypyridine-3-carboxamide

[0284] [ka]

[0285] Synthesized using the same method as in Example 1. Light brown solid. 1 H NMR(400MHz,DMSO-d6)δ11.21(s,1H),8.69(brs,1H),8.59(brs,2H),8.29( d,J=6.0Hz,1H),7.72(s,1H),7.69(S,1H),7.56(s,1H),7.28(d,J=6.0Hz,1H ),6.99(brs,1H),4.32(t,J=6.0Hz,2H),4.03(s,3H),3.98(s,3H),3.15-3. 08(m,2H),2.63(t,J=5.2Hz,3H),2.21-2.16(m,2H),1.24(brs,1H)ppm, LCMS m / z:543[M+H] + .

[0286] Example 21: N-(3,5-difluoro-4-((6-methoxy-7-(3-(methylamino)propoxy)quinolin-4-yl)oxy)phenyl)-4-methoxypyridine-3-carboxamide

[0287] [ka]

[0288] Synthesized using a similar method to Example 1. Off-white solid. 1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.82(s,1H),8.79-8.70(m,4H),7.79(d,J=10.0Hz,1H),7.52( d,J=5.6Hz,1H),7.07(brs,1H),4.40-4.31(m,4H),4.04(s,3H),3.55-3.38(m,2H),3.11(t,J=6.8Hz 2H),2.61(t,J=5.2Hz,3H),2.22(t,J=6.0Hz,2H),1.41(t,J=5.6Hz,3H),1.23(brs,1H)ppm, LCMS m / z:539[M+H] + .

[0289] Example 22: N-[2,5-difluoro-4-({6-methoxy-7-[3-(methylamino)propoxy]quinolin-4-yl}oxy)phenyl]-4-methoxypyridine-3-carboxamide

[0290] [ka]

[0291] Synthesized using the same method as in Example 1. Off-white solid. MS ESI calculated for C 27 H 26 F2N4O5[M+H] + ,525.19 found 525.35. 1 H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.82(s,1H),8.65(d,J=5.8Hz,1H),8.52(d,J=5 .2Hz,1H),8.30(dd,J=12.4,6.8Hz,1H),7.73(dd,J=10.8,7.4Hz,1H),7.53(s,1H),7. 43(s,1H),7.32(d,J=5.8Hz,1H),6.59(d,J=5.2Hz,1H),4.23(t,J=6.4Hz,2H),4.05(s ,3H),3.97(s,3H),2.67(t,J=6.6Hz,2H),2.32(s,3H),2.00-1.96(m,2H),1.24(s,1H). 19F NMR(376MHz,DMSO-d6)δ-126.89(1F),-132.81(1F).

[0292] Example 23: N-(4-((7-(3-(dimethylamino)propoxy)-6-methoxyquinolin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxypyridine-3-carboxamide

[0293] [ka]

[0294] Synthesized using the same method as in Example 1. Light brown solid. 1 H NMR(400MHz,DMSO-d6)δ10.26(brs,1H),8.86(s,1H),8.59(d,J=6.0Hz,1H),8.50 -8.43(m,2H),7.67(brs,1H),7.52(s,1H),7.40(s,1H),7.26(d,J=5.2Hz,1H),6.5 7(d,J=4.8Hz,1H),4.33(q,J=7.2Hz,2H),4.19(t,J=6.4Hz,2H),3.96(s,3H),2.4 0(t,J=7.2Hz,2H),2.17(s,6H),1.99-1.91(m,2H),1.47(t,J=7.2Hz,3H)ppm, LCMS m / z:[M+H] + 553.

[0295] Example 24: N-[2,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-methoxypyridine-3-carboxamide

[0296] [ka]

[0297] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C 28 H 24 F2N4O5[M+H]+ ,511.17 found 511.15. 1 H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.82(s,1H),8.64(d,J=5.6Hz,1H),8.5 1(d,J=5.2Hz,1H),8.29(dd,J=12.0,7.2Hz,1H),7.71(dd,J=10.8,7.2Hz,1H), 7.53(s,1H),7.44(s,1H),7.31(d,J=5.6Hz,1H),6.59(d,J=5.2Hz,1H),4.21( t,J=5.6Hz,2H),4.04(s,3H),3.97(s,3H),2.94(t,J=5.6Hz,2H),2.38(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-127.00(1F),-132.86(1F).

[0298] Example 25: N-[2,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-2-fluoro-4-methoxypyridine-3-carboxamide

[0299] [ka]

[0300] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C 26 H 23 F3N4O5[M+H] + ,529.16 found 529.20. 1 H NMR(400MHz,DMSO-d6)δ10.84-10.79(m,1H),8.50(d,J=5.2Hz,1H),8.25(dd,J=10.2,6.4Hz,2H),7.68(dd,J=10.6,7.4Hz,1H),7.53(s, 1H),7.44(s,1H),7.24(d,J=6.0Hz,1H),6.62(dd,J=5.2,1.2Hz,1H),4.21(t,J=5.6Hz,2H),3.97(s,6H),2.99-2.90(m,2H),2.38(s,3H).19 F NMR(376MHz,DMSO-d6)δ-72.69(1F),-125.42(1F),-132.70(1F).

[0301] Example 26: 6-chloro-N-[2,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-methoxypyridine-3-carboxamide

[0302] [ka]

[0303] Synthesized using the same method as in Example 1. White solid. MS ESI calculated for C 26 H 23 ClF2N4O5[M+H] + ,545.13,547.13 found 545.15,547.15. 1 H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.60(s,1H),8.51(d,J=5.2Hz,1H),8.24(dd,J=12.0,6.8Hz,1H),7.70(dd,J=10.8,7.2Hz,1H),7. 53(s,1H),7.47-7.41(m,2H),6.59(d,J=5.2Hz,1H),4.22(t,J=5.6Hz,2H),4.06(s,3H),3.97(s,3H),2.97(t,J=5.6Hz,2H),2.40(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-126.40(1F),-132.83(1F).

[0304] Example 27: N-[2,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)phenyl]-4-methoxypyridine-3-carboxamide

[0305] [ka]

[0306] A solution of 4-methoxypyridine-3-carboxylic acid (68 mg, 0.448 mmol) in ethyl acetate was treated with propanephosphonic acid cyclic anhydride (2 mL) and N,N-diisopropylethylamine (0.2 mL). The resulting mixture was stirred at room temperature for 10 minutes, and then 2,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)aniline (100 mg, 0.224 mmol) in ethyl acetate (2 mL) was added dropwise. The resulting mixture was stirred at 70° C. for 12 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane / methyl alcohol (10 / 1). Fractions containing the desired product were collected and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 19 x 250 mm, 10 μm; Mobile phase A: water (plus 10 mmol / L ammonium bicarbonate); Mobile phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 44% to 49% B in 8 min; Detector: UV 254 / 220 nm. Fractions containing the desired product were pooled, concentrated, and lyophilized to give N-[2,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)phenyl]-4-methoxypyridine-3-carboxamide (34.4 mg, 26%) as a pale yellow solid. MS ESI calculated for C 30 H 30 F2N4O6[M+H] + ,581.21 found 581.25. 1H NMR(400MHz,DMSO-d6)δ10.30-10.25(m,1H),8.82(s,1H),8.64(d,J=6.0Hz,1H),8.51(d, J=5.2Hz,1H),8.29(dd,J=12.0,7.2Hz,1H),7.71(dd,J=10.8,7.2Hz,1H),7.53(s,1H),7. 43(s,1H),7.31(d,J=6.0Hz,1H),6.59(d,J=5.2Hz,1H),4.21(t,J=6.4Hz,2H),4.04(s,3H) ),3.96(s,3H),3.60(t,J=6.4Hz,4H),2.49-2.45(m,2H),2.40(s,4H),2.03-1.95(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-129.93(1F),132.86(1F).

[0307] Example 28: N-[3,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)phenyl]-4-ethoxypyridine-3-carboxamide

[0308] [ka]

[0309] Synthesized using the same method as in Example 27. White solid. MS ESI calculated for C 31 H 32 F2N4O6[M+H] + ,595.23 found 595.25, 1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.64(s,1H),8.59(d,J=5.6Hz,1H),8. 50(d,J=5.2Hz,1H),7.74(d,J=10.2Hz,2H),7.55(s,1H),7.43(s,1H),7.26(d ,J=5.6Hz,1H),6.62(d,J=5.2Hz,1H),4.37-4.15(m,4H),3.97(s,3H),3.68- 3.60(m,4H),2.51-2.46(m,6H),1.99(t,J=6.8Hz,2H),1.40(d,J=6.8Hz,3H). 19 F NMR(376MHz,DMSO)δ-126.49(2F).

[0310] Example 29: N-[3,5-difluoro-4-({6-methoxy-7-[2-(morpholin-4-yl)ethoxy]quinolin-4-yl}oxy)phenyl]-4-methoxypyridine-3-carboxamide

[0311] [ka]

[0312] Synthesized using the same method as in Example 27. White solid. MS ESI calculated for C 29 H 28 F2N4O6[M+H] + ,567.20 found 567.25, 1 H NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.67-8.58(m,2H),8.51(d,J=5.2Hz,1H),7.80-7.71(m,2H),7.56(s,1H),7.47(s,1H),7.28(d, J=6.0Hz,1H),6.61(d,J=5.2Hz,1H),4.30(t,J=6.0Hz,2H),3.97(s,6H),3.63-3.56(m,4H),2.81(t,J=5.6Hz,2H),2.57-2.52(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-126.58(2F).

[0313] Example 30: N-(3,5-difluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-4-methoxypyridine-3-carboxamide

[0314] [ka]

[0315] Synthesized using a similar method to Example 27. Off-white solid. 1 H NMR(400MHz,CDCl3)δ8.62(t,J=10.0,2H),8.51(t,J=11.6,1H),7.76(d,J=10.0Hz,2H),7.54(s,1H),7.42(s,1H),7.28(d,J=6.0,1H) ),6.61(d,J=5.2,1H),4.23(t,J=12.8Hz,2H),3.96(s,6H),3.60(t,J=9.2Hz,4H),2.47(d,J=7.2Hz,2H),2.39(s,4H),2.0(t,J=13.6 2H)ppm, LCMS m / z:581.48[M+H] + .

[0316] Example 31: 6-amino-N-(2,5-difluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-4-methoxypyridine-3-carboxamide

[0317] [ka]

[0318] Step 1: 4-chloro-6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinoline

[0319] A solution of 3-(morpholin-4-yl)propan-1-ol (1.52 g, 10.49 mmol) and 4-chloro-6-methoxyquinolin-7-ol (2.00 g, 9.541 mmol) in tetrahydrofuran (10 mL) was stirred at 0° C. under a nitrogen atmosphere for 20 minutes. Diisopropyl azodicarboxylate (3.86 g, 19.08 mmol) was added dropwise to the above mixture at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methyl alcohol (10 / 1), and concentrated under reduced pressure to give 4-chloro-6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinoline (2.66 g, 82%) as a pale yellow solid. MS ESI calculated for C 17 H 21 ClN2O3[M+H] + ,337.12,339.12 found 337.10,339.10. 1 H NMR(400MHz,CDCl3)δ8.59(d,J=4.8Hz,1H),7.46(s,1H),7.42(s,1H),7.36(d,J=4.8Hz,1H),4.28(t,J=6.8 Hz,2H),4.06(s,3H),3.78-3.75(m,4H),2.60(t,J=7.2Hz,2H),2.51(t,J=4.8Hz,4H),2.15(d,J=6.8Hz,2H).

[0320] Step 2: 4-(2,5-difluoro-4-nitrophenoxy)-6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinoline

[0321] To a stirred solution of 4-chloro-6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinoline (1.8 g, 5.34 mmol) and 2,5-difluoro-4-nitrophenol (1.87 g, 10.21 mmol) in 1-methyl-2-pyrrolidinone (20 mL) was added dropwise N,N-diisopropylethylamine (1.38 g, 10.68 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 140° C. for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (1×150 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / methanol (10 / 1), and concentrated under reduced pressure to give 4-(2,5-difluoro-4-nitrophenoxy)-6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinoline (1.28 g, 50%) as a crude brown oil. MS ESI calculated for C 23 H 23 F2N3O6[M+H] + ,476.16 found 476.15. 1 H NMR(400MHz,CD3OD)δ8.54(d,J=3.2Hz,1H),8.28(d,J=6.8Hz,1H),7.56-7.48(m,2H),7.42(d,J=6.8Hz,1H),6.84(d,J=5 .2Hz,1H),4.28(d,J=6.4Hz,2H),4.02(d,J=11.6Hz,3H),3.74(d,J=6.4Hz,5H),3.32(d,J=1.6Hz,5H),2.67-2.65(m,2H).

[0322] Step 3: 2,5-Difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)aniline

[0323] To a stirred solution of 4-(2,5-difluoro-4-nitrophenoxy)-6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinoline (1.28 g, 2.69 mmol), iron powder (375 mg, 6.730 mmol), and ammonium chloride (288 mg, 5.384 mmol) in tetrahydrofuran (8 mL) was added water (4 mL) at room temperature. The resulting mixture was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methyl alcohol (10 / 1), and concentrated under reduced pressure to give 2,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)aniline (820 mg, 68%) as a brown solid. MS ESI calculated for C 23 H 25 F2N3O4[M+H] + ,446.18 found 446.20. 1 H NMR(400MHz,CDCl3)δ8.51(d,J=5.2Hz,1H),7.57(s,1H),7.47(s,1H),7.02-6.98(m,1H),6.70(d,J=8.4Hz,1H),6.45(d,J=1.2Hz,1H ),4.30(d,J=6.8Hz,2H),4.06(s,3H),3.89(s,2H),3.77(d,J=4.8Hz,4H),2.65(d,J=7.2Hz,2H),2.56(s,4H),2.18(d,J=6.8Hz,2H).

[0324] Step 4: 6-chloro-N-[2,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)phenyl]-4-methoxypyridine-3-carboxamide

[0325] A solution of 6-chloro-4-methoxypyridine-3-carboxylic acid (101 mg, 0.539 mmol) in sulfinyl chloride (260 mg, 0.673 mmol) was stirred at 75° C. for 3 hours, and to the above mixture, N,N-diisopropylethylamine (0.3 mL) and 2,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)aniline (200 mg, 0.449 mmol) in dichloromethane (3 mL) were added dropwise at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane / methyl alcohol = 10 / 1) and concentrated under reduced pressure to give 6-chloro-N-[2,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]-quinolin-4-yl}oxy)phenyl]-4-methoxypyridine-3-carboxamide (200 mg, 72%) as a brown solid. MS ESI calculated for C 30 H 29 ClF2N4O6[M+H] + ,615.17,617.17 found 615.20,617.20. 1 H NMR(400MHz,CDCl3)δ9.84(d,J=3.6Hz,1H),9.18(s,1H),8.64(d,J=7.2Hz,1H),8.5 2(d,J=5.2Hz,1H),7.56(d,J=6.4Hz,1H),7.48(s,1H),7.14(d,J=6.8Hz,1H),7.08- 6.92(m,1H),6.48(d,J=5.2Hz,1H),4.30(d,J=2.8Hz,2H),4.20(s,2H),4.06(d,J=1 .6Hz,3H),3.92-3.74(m,5H),2.66(d,J=7.2Hz,2H),2.58(s,4H),2.28-2.14(m,2H).

[0326] Step 5: N-[2,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)phenyl]-4-methoxy-6-{[(4-methoxyphenyl)methyl]amino}pyridine-3-carboxamide

[0327] A solution of 6-chloro-N-[2,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)-phenyl]-4-methoxypyridine-3-carboxamide (100 mg, 0.163 mmol), (4-methoxyphenyl)methanamine (110 mg, 0.815 mmol), BrettPhos (CAS: 1070663-78-3) (17 mg, 0.033 mmol), BrettPhos Pd G3 (CAS: 1470372-59-8) (15 mg, 0.016 mmol), and sodium tert-butoxide (32 mg, 0.326 mmol) in 1,4-dioxane (5 mL) was stirred at 90° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane / methyl alcohol = 10 / 1) and concentrated under reduced pressure to give compound N-[2,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]-quinolin-4-yl}oxy)-phenyl]-4-methoxy-6-{[(4-methoxyphenyl)methyl]amino}-pyridine-3-carboxamide (60 mg, 51%) as a brown solid. MS ESI calculated for C 38 H 39 F2N5O7[M+H] + ,716.28 found 716.25.

[0328] Step 6: 6-amino-N-[2,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)phenyl]-4-methoxypyridine-3-carboxamide

[0329] A solution of N-[2,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)phenyl]-4-methoxy-6-{[(4-methoxyphenyl)methyl]amino}pyridine-3-carboxamide (60 mg, 0.084 mmol) and trifluoromethanesulfonic acid (0.5 mL) in dichloromethane (6 mL) was stirred at room temperature under a nitrogen atmosphere for 12 hours. The reaction was quenched with room temperature water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane / methyl alcohol = 10 / 1) to give the crude product. The crude product was purified by preparative HPLC using the following conditions: (Column: XBridge Prep OBD C18 column, 30 × 15 mm, 5 μm; Mobile phase A: water (plus 10 mmol / L ammonium bicarbonate); Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 28% to 38% B in 8 min, 38%; Wavelength: 254 / 220 nm). Fractions containing the desired product were collected, concentrated, and lyophilized to give the compound 6-amino-N-[2,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]-quinolin-4-yl}oxy)phenyl]-4-methoxypyridine-3-carboxamide (4.2 mg, 8%) as a white solid. MS ESI calculated for C 30 H 31 F2N5O6[M+H] + ,596.22 found 596.25. 1H NMR(400MHz,DMSO-d6)δ9.86(d,J=2.8Hz,1H),8.52-8.40(m,3H),7.74-7.6 8(m,1H),7.52(s,1H),7.42(s,1H),6.76(s,2H),6.57(dd,J=5.2,1.2Hz,1H) ,6.13(s,1H),4.22(d,J=6.4Hz,2H),3.98(d,J=13.2Hz,6H),3.60(d,J=4.8 Hz,4H),2.47(d,J=7.2Hz,2H),2.40(d,J=4.8Hz,4H),1.99(d,J=6.8Hz,2H). 19 F NMR(377MHz,DMSO-d6)δ-130.61(1F),-132.70(1F).

[0330] Example 32: 6-amino-N-[2,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)phenyl]-4-ethoxypyridine-3-carboxamide

[0331] [ka]

[0332] Synthesized using the same method as in Example 31. White solid. MS ESI calculated for C 31 H 33 F2N5O6[M+H] + ,610.24 found 610.25. 1 H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.62-8.53(m,1H),8.57(s,1H),8.50(d,J=5 .2Hz,1H),7.71(dd,J=11.2,7.2Hz,1H),7.52(s,1H),7.42(s,1H),6.77(s,2H),6 .57(d,J=5.2Hz,1H),6.11(s,1H),4.26-4.22(m,4H),3.96(s,3H),3.63-3.57(m, 4H),2.50-2.45(m,2H),2.43-2.37(m,4H),2.02-1.95(m,2H),1.55-1.47(m,3H).19 F NMR(376MHz,DMSO)δ-131.21(1F),-132.43(1F).

[0333] Example 33: 6-amino-N-[2,3-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-methoxypyridine-3-carboxamide

[0334] [ka]

[0335] Synthesized using the same method as in Example 31. White solid. MS ESI calculated for C 26 H 25 F2N5O5[M+H] + ,526.18 found 526.20. 1 H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.54-8.48(m,2H),8.19-8.04(m,1H),7.54(s,1H),7.44(s,1H),7.38-7.29(m,1H),6 .75(s,2H),6.61-6.57(m,1H),6.13(s,1H),4.21(t,J=5.6Hz,2H),4.01-3.94(m,6H),2.93(t,J=5.6Hz,2H),2.38(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-147.81(1F),-153.14(1F).

[0336] Example 34: N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)-4-methoxypyridine-3-carboxamide

[0337] [ka]

[0338] Step 1: 4-(2,6-difluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline

[0339] To a stirred mixture of 4-chloro-6,7-dimethoxyquinoline (200 mg, 0.894 mmol) and 2,6-difluoro-4-nitrophenol (187 mg, 1.073 mmol) in 1-methyl-2-pyrrolidinone (5 mL) was added N,N-diisopropylethylamine (346 mg, 2.682 mmol) at room temperature. The resulting mixture was stirred at 140° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product 4-(2,6-difluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (330 mg, 90%) was obtained as a brown solid and used in the next step without further purification. MS ESI calculated for C 17 H 12 BrF2N2O5[M+H] + ,363.07 found 363.05.

[0340] Step 2: 4-[(6,7-dimethoxyquinolin-4-yl)oxy]-3,5-difluoroaniline

[0341] To a stirred solution of 4-(2,6-difluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (330 mg, 0.806 mmol) in tetrahydrofuran (7 mL) and water (7 mL) was added iron powder (225 mg, 4.030 mmol) and ammonium chloride (86 mg, 1.612 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 16 hours. The mixture was cooled to room temperature. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (1 × 150 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1 / 10). Fractions containing the desired product were collected and dried under reduced pressure to give 4-[(6,7-dimethoxyquinolin-4-yl)oxy]-3,5-difluoroaniline (180 mg, 67%) as a yellow solid. MS ESI calculated for C 17 H 14 F2N2O3[M+H] + ,333.10 found 333.10, 1 H NMR(400MHz,DMSO-d6)δ8.49(d,J=5.2Hz,1H),7.51(s,1H),7.41(s,1H),6.51(d,J=5.2Hz,1H),6.43(s,1H),6.39(s,1H),5.82(s,2H),3.95(s,6H). 19 F NMR(37MHz,DMSO-d6)δ-129.14(2F).

[0342] Step 3: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]-3,5-difluorophenyl}-4-methoxypyridine-3-carboxamide

[0343] To a stirred mixture of 4-methoxypyridine-3-carboxylic acid (92 mg, 0.600 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (171 mg, 0.450 mmol) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (78 mg, 0.600 mmol) and 4-[(6,7-dimethoxyquinolin-4-yl)oxy]-3,5-difluoroaniline (50 mg, 0.150 mmol) at room temperature. The mixture was stirred for 16 hours at room temperature. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (1 x 80 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: Column: C18 column 120 g, Mobile phase A: water (plus 10 mmol / L ammonium bicarbonate), Mobile phase B: acetonitrile, Flow rate: 80 mL / min, Gradient: 40% to 80% B in 30 min, Detector: UV 220 / 254 nm). Fractions containing the desired product were pooled, concentrated, and lyophilized to give N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]-3,5-difluorophenyl}-4-methoxypyridine-3-carboxamide (22 mg, 31%) as a white solid. MS ESI calculated for C 24 H 19 F2N3O5[M+H] + 468.13 found 468.15. 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.68-8.55(m,2H),8.51(d,J=5.2Hz,1H),7.81-7.71(m, 2H),7.56(s,1H),7.44(s,1H),7.28(d,J=6.0Hz,1H),6.62(d,J=5.2Hz,1H),3.99-3.96(m,9H). 19 F NMR(376MHz,DMSO-d6)δ-126.56(2F).

[0344] Example 35: N-{3,5-difluoro-4-[(7-methoxyquinolin-4-yl)oxy]phenyl}-4-methoxypyridine-3-carboxamide

[0345] [ka]

[0346] Synthesized using the same method as in Example 34. White solid. MS ESI calculated for C 23 H 17 F2N3O4[M+H] + ,437.12 found 438.20. 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.68-8.59(m,3H),8.27(d,J=9.2Hz,1H),7.81-7.71 (m,2H),7.46(d,J=2.4Hz,1H),7.35-7.18(m,2H),6.67-6.61(m,1H),3.97(d,J=5.2Hz,6H). 19 F NMR(376MHz,DMSO-d6)δ-127.17(2F).

[0347] Example 36: N-{3,5-difluoro-4-[(7-methoxy-1,6-naphthyridin-4-yl)oxy]phenyl}-4-methoxypyridine-3-carboxamide

[0348] [ka]

[0349] Synthesized using a method similar to that of Example 34. Off-white solid. MS ESI calculated for C 22 H 16 F2N4O4[M+H] + ,439.11 found 439.10. 1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),9.51(s,1H),8.82(d,J=5.2Hz,1H),8.64(s,1H),8.62(d,J=6.0 Hz),7.83-7.73(m,2H),7.32-7.28(m,2H),6.73(d,J=5.2Hz,1H),4.04(s,3H),3.98(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-126.63(2F).

[0350] Example 37: N-(3,5-difluoro-4-((6-methoxy-7-(trifluoromethoxy)quinolin-4-yl)oxy)phenyl)-4-methoxypyridine-3-carboxamide

[0351] [ka]

[0352] Step 1: 7-(bromodifluoromethoxy)-4-chloro-6-methoxyquinoline

[0353] To a stirred mixture of 4-chloro-6-methoxyquinolin-7-ol (1.20 g, 5.72 mmol) and potassium carbonate (2.37 g, 17.17 mmol) in N,N-dimethylformamide (120 mL) was added dibromodifluoromethane (2.40 g, 11.44 mmol) at -60 °C. The resulting mixture was stirred at 100 °C for 2 hours. The mixture was cooled to room temperature. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with ethyl acetate (3 × 300 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1 / 1) and concentrated under reduced pressure to give 7-(bromodifluoromethoxy)-4-chloro-6-methoxyquinoline (238.2 mg, 12%) as a white solid. MS ESI calculated for C 11 H7BrClF2NO2[M+H] +,337.90,339.90 found 338.10,340.10. 1 H NMR (400MHz, CDCl3) δ8.72(d,J=4.8Hz,1H),8.11(d,J=1.8Hz,1H),7.59(s,1H),7.55(s,1H),4.09(s,3H).

[0354] Step 2: 4-chloro-6-methoxy-7-(trifluoromethoxy)quinoline

[0355] A mixture of 7-(bromodifluoromethoxy)-4-chloro-6-methoxyquinoline (238 mg, 0.704 mmol) and silver tetrafluoroborate (274 mg, 1.408 mmol) in dichloromethane (1 mL) was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (Column: WelFlash™ C18-I, 20-40 μm, 120 g, Eluent A: water (plus 10 mmol / L ammonium bicarbonate), Eluent B: acetonitrile, Gradient: 65% to 85% B in 25 min, Flow Rate: 60 mL / min, Detector: 220 / 254 nm). The desired fractions were collected and concentrated under reduced pressure to give 4-chloro-6-methoxy-7-(trifluoromethoxy)quinoline (130 mg, 66%) as a white solid. MS ESI calculated for C 11 H7ClF3NO2[M+H] + ,278.01,280.01 found 278.20,280.20. 1 H NMR (400MHz, CDCl3) δ8.71(d,J=4.8Hz,1H),8.04(d,J=1.6Hz,1H),7.56(s,1H),7.54(s,1H),4.09(s,3H).

[0356] Step 3: 4-(2,6-difluoro-4-nitrophenoxy)-6-methoxy-7-(trifluoromethoxy)quinoline

[0357] To a stirred mixture of 4-chloro-6-methoxy-7-(trifluoromethoxy)quinoline (100 mg, 0.360 mmol) and 2,6-difluoro-4-nitrophenol (75 mg, 0.432 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was added N,N-diisopropylethylamine (93 mg, 0.720 mmol) at room temperature. The resulting mixture was stirred at 140° C. for 16 hours. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 25% to 45% B in 25 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm). The desired fractions were collected and concentrated under reduced pressure to give 4-(2,6-difluoro-4-nitrophenoxy)-6-methoxy-7-(trifluoromethoxy)quinoline (111 mg, 74%) as a yellow solid. MS ESI calculated for C 17 H9F5N2O5[M+H] + ,417.04 found 417.25. 1 H NMR(400MHz, CDCl3) δ8.68(d,J=5.2Hz,1H),8.14-8.10(m,3H),7.72(s,1H),7.28(s,1H),4.11(s,3H).

[0358] Step 4: 3,5-Difluoro-4-{[6-methoxy-7-(trifluoromethoxy)quinolin-4-yl]oxy}aniline

[0359] To a stirred mixture of 4-(2,6-difluoro-4-nitrophenoxy)-6-methoxy-7-(trifluoromethoxy)quinoline (111 mg, 0.267 mmol) and Fe (74 mg, 1.335 mmol) in tetrahydrofuran (2 mL) and water (1 mL) was added ammonium chloride (28 mg, 0.534 mmol) at room temperature. The resulting mixture was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 65% to 85% B in 25 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm). The desired fractions were collected and concentrated under reduced pressure to give 3,5-difluoro-4-{[6-methoxy-7-(trifluoromethoxy)quinolin-4-yl]oxy}aniline (93 mg, 90%) as a yellow solid. MS ESI calculated for C 17 H 11 F5N2O3[M+H] + ,387.27 found 387.30.

[0360] Step 5: N-(3,5-difluoro-4-{[6-methoxy-7-(trifluoromethoxy)quinolin-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide

[0361] To a stirred mixture of 3,5-difluoro-4-{[6-methoxy-7-(trifluoromethoxy)quinolin-4-yl]oxy}aniline (90 mg, 0.233 mmol) and 4-methoxypyridine-3-carboxylic acid (71 mg, 0.466 mmol) in N,N-dimethylformamide (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (132 mg, 0.350 mmol) and N,N-diisopropylethylamine (90 mg, 0.699 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30–150 mm, 5 μm; Mobile phase A: water (plus 10 mmol / L ammonium bicarbonate); Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 45%–55% B in 8 min, 55% B; Wavelength: 254 / 220 nm; RT1 (min): 7; Run number: 0). Fractions containing the desired product were pooled, concentrated, and lyophilized to give N-(3,5-difluoro-4-{[6-methoxy-7-(trifluoromethoxy)quinolin-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide (13.5 mg, 11%) as a white solid. MS ESI calculated for C 24 H 16 F5N3O5[M+H] + ,522.10 found 522.25. 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.73-8.53(m,3H),8.08-8.03(m,1H),7.85(s,1H),7. 78(d,J=10.4Hz,2H),7.28(d,J=5.8Hz,1H),6.87(d,J=5.2Hz,1H),4.08(s,3H),3.98(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-57.01(2F),-128.45(3F).

[0362] Example 38: N-(4-((7-(difluoromethoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)-4-ethoxypyridine-3-carboxamide

[0363] [ka]

[0364] Step 1: 4-chloro-7-(difluoromethoxy)-6-methoxyquinoline

[0365] To a stirred solution of 4-chloro-6-methoxyquinolin-7-ol (500 mg, 2.385 mmol) and sodium 2-chloro-2,2-difluoroacetate (727 mg, 4.770 mmol) in N,N-dimethylformamide (5 mL) and water (0.5 mL) was added potassium carbonate (495 mg, 3.577 mmol) in portions at room temperature. The resulting mixture was stirred at 120° C. for 45 minutes. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 80 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 25% to 45% B in 25 min; Flow rate: 60 mL / min; Detector: UV 220 / 254 nm). The desired fraction was collected at 42% B and concentrated under reduced pressure to give 4-chloro-7-(difluoromethoxy)-6-methoxyquinoline (69 mg, 11%) as a brown solid. MS ESI calculated for C 11 H8ClF2NO2[M+H] + ,260.60 found 260.20.

[0366] Step 2: 4-(2,6-difluoro-4-nitrophenoxy)-7-(difluoromethoxy)-6-methoxyquinoline

[0367] To a stirred solution of 4-chloro-7-(difluoromethoxy)-6-methoxyquinoline (90 mg, 0.347 mmol) and 2,6-difluoro-4-nitrophenol (61 mg, 0.347 mmol) in 1-methyl-2-pyrrolidinone (0.5 mL), N,N-diisopropylethylamine (134 mg, 1.041 mmol) was added dropwise at room temperature. The resulting mixture was stirred at 140° C. for 16 hours. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 40 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 30% to 60% B in 25 min; Flow rate: 60 mL / min; Detector: UV 220 / 254 nm). The desired fractions were collected and concentrated under reduced pressure to give 4-(2,6-difluoro-4-nitrophenoxy)-7-(difluoromethoxy)-6-methoxyquinoline (47 mg, 34%) as a brown solid. MS ESI calculated for C 17 H 10 F4N2O5[M+H] + ,399.30 found 399.25. 1 H NMR(400MHz,CDCl3)δ8.64(d,J=5.2Hz,1H),8.14-8.04(m,2H),7.88(s,1H),7.69(s,1H),6.97-6.57(m,1H),6.51(d,J=5.2Hz,1H),4.10(s,3H).

[0368] Step 3: 4-{[7-(difluoromethoxy)-6-methoxyquinolin-4-yl]oxy}-3,5-difluoroaniline

[0369] To a stirred solution of 4-(2,6-difluoro-4-nitrophenoxy)-7-(difluoromethoxy)-6-methoxyquinoline (47 mg, 0.118 mmol) and iron powder (27 mg, 0.472 mmol) in tetrahydrofuran (0.5 mL) and water (0.1 mL) was added ammonium chloride (32 mg, 0.590 mmol) portionwise at room temperature. The resulting mixture was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature. The resulting mixture was filtered. The resulting mixture was filtered, and the filter cake was washed with dichloromethane (3×100 mL). The filtrate was concentrated under reduced pressure to give 4-{[7-(difluoromethoxy)-6-methoxyquinolin-4-yl]oxy}-3,5-difluoroaniline (15 mg, 35%) as a pale yellow solid. MS ESI calculated for C 17 H 12 F4N2O3[M+H] + ,369.30 found 369.25. 1 H NMR(400MHz,CDCl3)δ8.62(d,J=5.2Hz,1H),7.99(s,1H),7.76(s,1H),6.98-6.42(m,2H),6.42-6.37(m,2H),4.10(s,3H).

[0370] Step 4: N-(4-{[7-(difluoromethoxy)-6-methoxyquinolin-4-yl]oxy}-3,5-difluorophenyl)-4-methoxypyridine-3-carboxamide

[0371] To a stirred solution of 4-{[7-(difluoromethoxy)-6-methoxyquinolin-4-yl]oxy}-3,5-difluoroaniline (15 mg, 0.041 mmol), 4-methoxypyridine-3-carboxylic acid (8 mg, 0.049 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (24 mg, 0.061 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (16 mg, 0.123 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The crude product was purified by preparative HPLC using the following conditions: Column: Xselect CSH C18 OBD column, 30x150mm 5µm, Mobile phase A: water (plus 10mmol / L ammonium bicarbonate), Mobile phase B: acetonitrile, Flow rate: plus 60mL / min, Gradient: 25% to 30% B in 12min, Detector: UV 220 / 254nm). Fractions containing the desired product were pooled, concentrated, and lyophilized to give N-(4-{[7-(difluoromethoxy)-6-methoxyquinolin-4-yl]oxy}-3,5-difluorophenyl)-4-methoxypyridine-3-carboxamide (2mg, 8%) as an off-white solid. MS ESI calculated for C 24 H 17 F4N3O5[M+H] + ,504.40 found 504.10. 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.66-8.59(m,3H),7.83-7.73(m,4H),7.66-7.26(m,2H),6.79(d,J=5.2Hz,1H),4.04(s,3H),3.97(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-82.82(2F),-126.56(2F).

[0372] Example 39: N-(3,5-difluoro-4-((7-(2-hydroxy-2-methylpropoxy)-6-methoxyquinolin-4-yl)oxy)phenyl)-4-methoxypyridine-3-carboxamide

[0373] [ka]

[0374] Step 1: 1-[(4-chloro-6-methoxyquinolin-7-yl)oxy]-2-methylpropan-2-ol

[0375] To a stirred mixture of 4-chloro-6-methoxyquinolin-7-ol (500 mg, 2.385 mmol) and potassium carbonate (659 mg, 4.770 mmol) in N,N-dimethylformamide was added 2,2-dimethyloxirane (206 mg, 2.862 mmol) in portions at room temperature. The resulting mixture was stirred at 120° C. for 2 hours. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 80 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 25% to 45% B in 25 min; Flow rate: 50 mL / min; Detector: UV 220 / 254 nm). The desired fractions were collected and concentrated under reduced pressure to give 1-[(4-chloro-6-methoxyquinolin-7-yl)oxy]-2-methylpropan-2-ol (354 mg, 52%) as a yellow oil. MS ESI calculated for C 14 H 16 ClNO3[M+H] + ,282.08,284.08 found 282.05,284.05. 1 H NMR (400MHz, CDCl3) δ8.59(d,J=4.8Hz,1H),7.42(s,1H),7.41(s,1H),7.37(d,J=4.8Hz,1H),4.04(s,3H),4.00(s,2H),1.43(s,6H).

[0376] Step 2: 1-{[4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl]oxy}-2-methylpropan-2-ol

[0377] To a stirred mixture of 1-[(4-chloro-6-methoxyquinolin-7-yl)oxy]-2-methylpropan-2-ol (350 mg, 1.242 mmol) and 2,6-difluoro-4-nitrophenol (217 mg, 1.242 mmol) in 1-methyl-2-pyrrolidinone, N,N-diisopropylethylamine (321 mg, 2.484 mmol) was added at room temperature. The resulting mixture was stirred at 140° C. for 16 hours. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 35% to 75% B in 25 min; Flow rate: 60 mL / min; Detector: UV 220 / 254 nm). The desired fractions were collected and concentrated under reduced pressure to give 1-{[4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl]oxy}-2-methylpropan-2-ol (250 mg, 47%) as a brown oil. MS ESI calculated for C 20 H 18 F2N2O6[M+H] + ,421.37 found 421.30. 1 H NMR(400MHz,CDCl3)δ8.55(d,J=5.2Hz,1H),8.02-8.12(m,2H),7.56(s,1H) ,7.47(s,1H),6.42(d,J=5.2Hz,1H),4.06(s,3H),4.02(s,2H),1.44(s,6H).

[0378] Step 3: 1-{[4-(4-amino-2,6-difluorophenoxy)-6-methoxyquinolin-7-yl]oxy}-2-methylpropan-2-ol

[0379] To a stirred mixture of 1-{[4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl]oxy}-2-methylpropan-2-ol (250 mg, 0.595 mmol) and iron powder (166 mg, 2.975 mmol), ammonium bicarbonate (63 mg, 1.190 mmol) and water (2 mL) were added at room temperature. The resulting mixture was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered, and the filter cake was washed with methanol (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 80 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 45% to 65% B in 25 min; Flow rate: 50 mL / min; Detector: UV 220 / 254 nm). The desired fractions were collected and concentrated under reduced pressure to give 1-{[4-(4-amino-2,6-difluorophenoxy)-6-methoxyquinolin-7-yl]oxy}-2-methylpropan-2-ol (136 mg, 58%) as a brown solid. MS ESI calculated for C 20 H 20 F2N2O4[M+H] + ,391.14 found 391.35. 1 H NMR(400MHz,CDCl3)δ8.52(d,J=5.2Hz,1H),7.62(s,1H),7.46(s,1H),6.49 (d,J=5.2Hz,1H),6.33-6.43(m,2H),4.05(s,3H),4.02(s,2H),1.43(s,6H).

[0380] Step 4: N-(3,5-difluoro-4-{[7-(2-hydroxy-2-methylpropoxy)-6-methoxyquinolin-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide

[0381] To a stirred mixture of 1-{[4-(4-amino-2,6-difluorophenoxy)-6-methoxyquinolin-7-yl]oxy}-2-methylpropan-2-ol (136 mg, 0.348 mmol) and 4-methoxypyridine-3-carboxylic acid (64 mg, 0.418 mmol) in N,N-dimethylformamide was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (198 mg, 0.522 mmol) and N,N-diisopropylethylamine (180 mg, 1.392 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The mixture was purified by preparative HPLC (Column: XBridge Shield RP18 OBD column, 19 × 250 mm, 10 μm, Mobile Phase A: water (plus 10 mmol / L ammonium bicarbonate), Mobile Phase B: methanol, Flow Rate: 25 mL / min, Gradient: 44% to 64% B in 8 min, Detector: UV 220 / 254 nm) and concentrated under reduced pressure to give the compound N-(3,5-difluoro-4-{[7-(2-hydroxy-2-methylpropoxy)-6-methoxy-quinolin-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide (23 mg, 12%) as a white solid. MS ESI calculated for C 27 H 25 F2N3O6[M+H] + ,526.51 found 526.25. 1 H NMR(400MHz,DMSO-d6)δ10.69(s,1H) 8.64(s,1H),8.62(d,J=6.0 Hz),8.50(d,J=5.2Hz,1H),7.80-7.72(m,2H),7.57(s,1H),7.42(s,1H),7.28(d,J=6.0Hz,1 H),6.61(d,J=5.2Hz,1H),4.68(s,1H),3.99(s,3H),3.98(s,3H),3.92(s,2H),1.28(s,6H). 19 F NMR(377MHz,DMSO-d6)δ-126.58(2F).

[0382] Example 40: N-(3,5-difluoro-4-{[7-(2-hydroxy-2-methylpropoxy)quinolin-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide

[0383] [ka]

[0384] Synthesized using the same method as in Example 39. White solid. MS ESI calculated for C 26 H 23 F2N3O5[M+H] + ,496.16 found 496.20. 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.64(d,J=5.2Hz,1H),8.64(s,1H),8.62(d,J=6.0Hz,1H),8.27(d,J=9.2Hz,1H),7.81-7.71(m,2H),7.42 (d,J=2.4Hz,1H),7.37(dd,J=9.2,2.4Hz,1H),7.28(d,J=6.0Hz,1H),6.63(d,J=5.2Hz,1H),4.74(s,1H),3.97(s,3H),3.93(s,2H),1.27(s,6H). 19 F NMR(376MHz,DMSO-d6)δ-126.51(2F).

[0385] Example 41: N-(3,5-difluoro-4-((7-(2-hydroxyethoxy)quinolin-4-yl)oxy)phenyl)-4-methoxypyridine-3-carboxamide

[0386] [ka]

[0387] Step 1: 2-[(4-chloroquinolin-7-yl)oxy]ethanol

[0388] To a stirred mixture of 4-chloroquinolin-7-ol (300 mg, 1.670 mmol) and triphenylphosphine (657 mg, 2.505 mmol) in tetrahydrofuran (5 mL) was added diisopropyl azodicarboxylate (675 mg, 3.340 mmol) and ethylene glycol (124 mg, 2.004 mmol) at 0° C. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1 / 2), and concentrated under reduced pressure to give 2-[(4-chloroquinolin-7-yl)oxy]ethanol (200 mg, 53%) as a pale yellow oil. MS ESI calculated for C 11 H 10 ClNO2[M+H] + .224.04,226.04 found 224.10,226.10. 1 H NMR(400MHz,CDCl3)δ8.68(d,J=4.8Hz,1H),8.14(d,J=9.2Hz,1H),7.67(d,J=1.4Hz,1H), 7.52-7.51(m,1H),7.38(d,J=4.8Hz,1H),4.27(dd,J=5.2,4.2Hz,2H),4.10-4.06(m,2H).

[0389] Step 2: 2-{[4-(2,6-difluoro-4-nitrophenoxy)quinolin-7-yl]oxy}ethanol

[0390] To a stirred mixture of 2-[(4-chloroquinolin-7-yl)oxy]ethanol (200 mg, 0.894 mmol) and 2,6-difluoro-4-nitrophenol (188 mg, 1.073 mmol) in 1-methyl-2-pyrrolidinone (4 mL), N,N-diisopropylethylamine (173 mg, 1.341 mmol) was added at room temperature. The resulting mixture was stirred at 100 °C for 16 hours. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; eluent A: water (plus 10 mmol / L ammonium bicarbonate); eluent B: acetonitrile; gradient: 30% to 45% B in 15 min; detector: UV 254 / 220 nm). Fractions containing the desired product were collected, concentrated, and lyophilized to give 2-{[4-(2,6-difluoro-4-nitrophenoxy)quinolin-7-yl]oxy}ethanol (200 mg, 62%) as a yellow solid. MS ESI calculated for C 17 H 12 F2N2O5[M+H] + ,363.07 found 363.05. 1 H NMR(400MHz,CDCl3)δ8.70(d,J=5.4Hz,1H),8.30(s,1H),8.10(d,J=3.4Hz,1H),7.72(d,J=1.8Hz,1H),7.55 (d,J=1.6Hz,1H),7.51(d,J=2.8Hz,1H),7.38(dd,J=9.2,2.4Hz,1H),4.34-4.30(m,2H),4.13-4.08(m,2H). 19 F NMR(377MHz,CDCl3)δ-119.75(2F).

[0391] Step 3: 2-{[4-(4-amino-2,6-difluorophenoxy)quinolin-7-yl]oxy}ethanol

[0392] To a stirred mixture of 2-{[4-(2,6-difluoro-4-nitrophenoxy)quinolin-7-yl]oxy}ethanol (200 mg, 0.552 mmol) in water (1 mL) and tetrahydrofuran (2 mL), Fe (154 mg, 2.760 mmol) and ammonium chloride (59 mg, 1.104 mmol) were added at room temperature. The resulting mixture was stirred at 70 °C for 16 h. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; eluent A: water (plus 10 mmol / L ammonium bicarbonate); eluent B: acetonitrile; gradient: 30% to 50% B in 25 min; detector: UV 254 / 220 nm). Fractions containing the desired product were collected and concentrated under reduced pressure to give 2-{[4-(4-amino-2,6-difluorophenoxy)quinolin-7-yl]oxy}ethanol (50 mg, 27%) as a white solid. MS ESI calculated for C 17 H 14 F2N2O3[M+H] + ,332.10 found 333.05. 1 H NMR(400MHz,DMSO-d6)δ8.62(d,J=5.2Hz,1H),8.22(d,J=9.2Hz,1H),7.45-7.41(m,1H),7.31(dd,J=9.2,2.4Hz,1H ),6.52(dd,J=5.2,1.2Hz,1H),6.45-6.39(m,1H),5.83(s,1H),4.32-4.27(m,2H),3.78-3.73(m,2H),3.35(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-129.34(2F).

[0393] Step 4: N-(3,5-difluoro-4-{[7-(2-hydroxyethoxy)quinolin-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide

[0394] To a stirred mixture of 4-methoxypyridine-3-carboxylic acid (27 mg, 0.180 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (86 mg, 0.225 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (49 mg, 0.375 mmol) and 2-{[4-(4-amino-2,6-difluorophenoxy)quinolin-7-yl]oxy}ethanol (50 mg, 0.150 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 16 h. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 19 x 250 mm, 10 μm; Mobile phase A: water (10 mmol / L ammonium bicarbonate); Mobile phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 42% to 45% B in 4.5 min; Detector: UV 254 / 220 nm. Fractions containing the desired product were pooled, concentrated, and lyophilized to give N-(3,5-difluoro-4-{[7-(2-hydroxyethoxy)quinolin-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide (1.3 mg, 2%) as a white solid. MS ESI calculated for C 24 H 19 F2N3O5[M+H] + ,468.13 found 468.15. 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.69-8.59(m,3H),8.27(d,J=9.1Hz,1H),7.80-7.71(m,2H),7.45(d,J=2.4Hz,1H),7.35(dd,J=9. 2,2.4Hz,1H),7.28(d,J=5.8Hz,1H),6.63(d,J=5.2Hz,1H),4.98(t,J=5.4Hz,1H),4.20(t,J=4.8Hz,2H),3.97(s,3H),3.88-3.82(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-126.76(2F).

[0395] Example 42: N-(3,5-difluoro-4-{[7-(2-methoxyethoxy)quinolin-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide

[0396] [ka]

[0397] Synthesized using the same method as in Example 41. White solid. MS ESI calculated for C 25 H 21 F2N3O5[M+H] + ,482.14 found 482.15. 1 H NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.67-8.63(m,2H),8.62(d,J=6.0Hz,1H),8.27(d,J=9.2Hz,1H),7.80-7.72(m,2H),7.47(d,J=2.4Hz, 1H),7.36(dd,J=9.2,2.4Hz,1H),7.28(d,J=6.0Hz,1H),6.66-6.60(m,1H),4.36-4.26(m,2H),3.98(s,3H),3.79-3.72(m,2H),3.36(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-126.77(2F).

[0398] Example 43: N-(4-((6,7-bis(2-methoxyethoxy)quinolin-4-yl)oxy)-3,5-difluorophenyl)-4-methoxypyridine-3-carboxamide

[0399] [ka]

[0400] Step 1: 4-chloroquinoline-6,7-diol

[0401] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (5.00 g, 22.35 mmol) in dichloromethane (50 mL) was added boron tribromide (21 mL, 223.55 mmol) dropwise at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The reaction was quenched by the addition of methanol (100 mL) at 0 °C. The mixture was concentrated under reduced pressure. The residual product was purified by reverse-phase chromatography, eluting with 30% acetonitrile in water (plus 10 mmol / L ammonium bicarbonate). Fractions containing the desired product were collected and concentrated under reduced pressure to give 4-chloroquinoline-6,7-diol (4 g, 91%) as a brown solid. MS ESI calculated for C9H6ClNO2 [M+H] + ,196.01,198.01 found 195.90,197.90.

[0402] Step 2: 4-chloro-6,7-bis(2-methoxyethoxy)quinoline

[0403] To a stirred solution of 4-chloroquinoline-6,7-diol (2.00 g, 10.22 mmol) and 2-bromoethyl methyl ether (3.55 g, 25.56 mmol) in 1-methyl-2-pyrrolidinone (20 mL) was added potassium carbonate (4.24 g, 30.67 mmol) at room temperature. The resulting mixture was stirred at 80° C. for 16 hours. The mixture was cooled to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residual product was purified by reverse-phase chromatography, eluting with 50% acetonitrile in water (plus 10 mmol / L ammonium bicarbonate). Fractions containing the desired product were collected and concentrated under reduced pressure to give 4-chloro-6,7-bis(2-methoxyethoxy)quinoline (800 mg, 25%) as a yellow solid. MS ESI calculated for C 15 H 18 ClNO4[M+H] + ,312.09,314.09 found 312.30,314.30.1 H NMR(400MHz,CDCl3)δ8.58(d,J=4.8Hz,1H),7.46(s,1H),7.44(s,1H),7.36(d, J=4.8Hz,1H),4.36-4.34(m,4H),3.94-3.86(m,4H),3.52(s,3H),3.51(s,3H).

[0404] Step 3: 4-(2,6-difluoro-4-nitrophenoxy)-6,7-bis(2-methoxyethoxy)quinoline

[0405] To a stirred solution of 4-chloro-6,7-bis(2-methoxyethoxy)quinoline (0.50 g, 1.60 mmol) and 2,6-difluoro-4-nitrophenol (0.34 g, 1.925 mmol) in 1-methyl-2-pyrrolidinone (0.5 mL) was added N,N-diisopropylethylamine (0.62 g, 4.81 mmol) at room temperature. The resulting mixture was stirred at 140 °C for 16 hours. The mixture was cooled to room temperature. The residual product was purified by reverse-phase chromatography, eluting with 45% acetonitrile in water (plus 10 mmol / L ammonium bicarbonate). Fractions containing the desired product were collected and concentrated under reduced pressure to give 4-(2,6-difluoro-4-nitrophenoxy)-6,7-bis(2-methoxyethoxy)quinoline (490 mg, 68%) as a yellow solid. MS ESI calculated for C 21 H 20 F2N2O7[M+H] + ,451.12,found 451.35. 1 H NMR(400MHz,CDCl3)δ8.55(d,J=5.2Hz,1H),8.12-8.02(m,2H),7.60(s,1H),7.48 (s,1H),6.41(d,J=5.2Hz,1H),4.40-4.32(m,4H),3.95-3.87(m,4H),3.52(s,6H).

[0406] Step 4: 4-{[6,7-bis(2-methoxyethoxy)quinolin-4-yl]oxy}-3,5-difluoroaniline

[0407] To a stirred solution of 4-(2,6-difluoro-4-nitrophenoxy)-6,7-bis(2-methoxyethoxy)quinoline (0.20 g, 0.44 mmol) and iron (0.12 g, 2.22 mmol) in tetrahydrofuran (2 mL) and water (1 mL) was added ammonium chloride (0.11 g, 2.220 mmol) at room temperature. The resulting mixture was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with methanol (3×100 mL). The filtrate was concentrated under reduced pressure. The residual product was purified by reverse-phase chromatography, eluting with 45% acetonitrile in water (plus 0.05% ammonium bicarbonate); fractions containing the desired product were pooled and concentrated under reduced pressure to give 4-{[6,7-bis(2-methoxyethoxy)quinolin-4-yl]oxy}-3,5-difluoroaniline (180 mg, 96%) as a white solid. MS ESI calculated for C 21 H 22 F2N2O5[M+H] + ,421.15 found 421.35. 1 H NMR(400MHz,CDCl3)δ8.51(d,J=5.2Hz,1H),7.65(s,1H),7.45(s,1H),6.46(d,J=5.2Hz, 1H),6.42-6.31(m,2H),4.39-4.31(m,4H),3.91-3.90(m,4H),3.52(s,3H),3.51(s,3H).

[0408] Step 5: N-(4-{[6,7-bis(2-methoxyethoxy)quinolin-4-yl]oxy}-3,5-difluorophenyl)-4-methoxypyridine-3-carboxamide

[0409] To a stirred solution of 4-methoxypyridine-3-carboxylic acid (27 mg, 0.170 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (90 mg, 0.231 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (46 mg, 0.35 mmol) at room temperature. The resulting mixture was stirred for 30 minutes at room temperature. To the above mixture was added 4-{[6,7-bis(2-methoxyethoxy)quinolin-4-yl]oxy}-3,5-difluoroaniline (50 mg, 0.112 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 16 hours. The mixture was cooled to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product (40 mg) was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile Phase A: water (plus 10 mmol / L ammonium bicarbonate); Mobile Phase B: acetonitrile; Flow Rate: 60 mL / min; Gradient: 31% to 41% B in 8 min; Detector: UV 254 / 220 nm. Fractions containing the desired product were collected, concentrated, and lyophilized to give N-(4-{[6,7-bis(2-methoxyethoxy)quinolin-4-yl]oxy}-3,5-difluorophenyl)-4-methoxypyridine-3-carboxamide (14.2 mg, 21%) as a white solid. MS ESI calculated for C 28 H 27 F2N3O7[M+H] + ,556.18,found 556.20. 1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.63(s,1H),8.62(d,J=6.0Hz,1H),8.51(d,J=5.2Hz,1H),7.81-7.71(m,2H),7.60(s,1H),7.4 7(s,1H),7.28(d,J=6.0Hz,1H),6.62(d,J=5.2Hz,1H),4.35-4.28(m,4H),3.97(s,3H),3.83-3.74(m,4H),3.38(s,3H),3.37(s,3H). 19 F-NMR(376MHz,DMSO-d6)-126.57(2F).

[0410] Example 44: N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-6-fluoro-4-methoxypyridine-3-carboxamide

[0411] [ka]

[0412] Step 1: Methyl 6-fluoro-4-methoxypyridine-3-carboxylate

[0413] To a stirred mixture of methyl 6-chloro-4-methoxypyridine-3-carboxylate (1 g, 4.96 mmol) in dimethyl sulfoxide (20 mL) was added colony-stimulating factor (3.77 g, 24.80 mmol) in portions at room temperature. The resulting mixture was stirred at 90° C. for 16 hours. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with dimethyl sulfoxide (10 mL). The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 30% to 50% B in 25 min; Flow rate: 70 mL / min; Detector: UV 220 / 254 nm). The desired fractions were collected and concentrated under reduced pressure to give methyl 6-fluoro-4-methoxypyridine-3-carboxylate (380 mg, 41%) as a white solid. MS ESI calculated for C8H8FNO3 [M+H]. + ,186.05,found 186.20. 1 H NMR (400MHz, CDCl3) δ8.65(s,1H),6.49(s,1H),4.00(s,3H),3.93(s,3H).

[0414] Step 2: 6-Fluoro-4-methoxypyridine-3-carboxylic acid

[0415] To a stirred mixture of methyl 6-fluoro-4-methoxypyridine-3-carboxylate (380 mg, 2.052 mmol) in water (2 mL) and tetrahydrofuran (4 mL), lithium hydroxide (245 mg, 10.230 mmol) was added portionwise at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The residue was acidified to pH 5 with hydrochloric acid. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (Column: WelFlash™ C18-I, 20-40 μm, 120 g, Eluent A: water (plus 10 mmol / L formic acid), Eluent B: acetonitrile, Gradient: 15% to 35% B in 25 min, Flow rate: 60 mL / min, Detector: UV 220 / 254 nm). The desired fractions were collected and concentrated under reduced pressure to give 6-fluoro-4-methoxypyridine-3-carboxylic acid (120 mg, 34%) as a white solid. MS ESI calculated for C7H6FNO3[M+H] + ,172.03 found 172.00. 1 H NMR (400MHz, CDCl3) δ8.89(s,1H),6.57(s,1H),4.12(s,3H).

[0416] Step 3: tert-butyl N-[2-({4-[2,6-difluoro-4-(6-fluoro-4-methoxypyridin-3-amido)phenoxy]-6-methoxyquinolin-7-yl}oxy)ethyl]-N-methylcarbamate

[0417] To a stirred mixture of 6-fluoro-4-methoxypyridine-3-carboxylic acid (120 mg, 0.701 mmol) and propylphosphonic anhydride (1N in ethyl acetate, 2 mL) in ethyl acetate (2 mL) was added N,N-diisopropylethylamine (181 mg, 1.400 mmol) and tert-butyl N-(2-{[4-(4-amino-2,6-difluorophenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methylcarbamate (266 mg, 0.559 mmol) at room temperature. The resulting mixture was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The mixture was basified to pH 8 with saturated sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3×100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 55% to 75% B in 25 min; Flow rate: 60 mL / min; Detector: UV 220 / 254 nm). The desired fractions were collected and concentrated under reduced pressure to give tert-butyl N-[2-({4-[2,6-difluoro-4-(6-fluoro-4-methoxypyridin-3-amido)phenoxy]-6-methoxyquinolin-7-yl}oxy)ethyl]-N-methylcarbamate (150 mg, 34%) as a yellow solid. MS ESI calculated for C 31 H 31 F3N4O7[M+H] + ,629.21,found 629.05. 1 H NMR(400MHz,CDCl3)δ9.35(s,1H),9.05(s,1H),8.54(d,J=5.2Hz,1H),7.63(s,1H),7.58-7.45(m,3H),6.61(s,1H) ,6.48(d,J=5.2Hz,1H),4.42-4.29(m,2H),4.21(s,3H),4.07(s,3H),3.84-3.71(m,2H),3.08(s,3H),1.49(s,9H).

[0418] Step 4: N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-6-fluoro-4-methoxypyridine-3-carboxamide hydrochloride

[0419] To a stirred mixture of tert-butyl N-[2-({4-[2,6-difluoro-4-(6-fluoro-4-methoxypyridin-3-amido)phenoxy]-6-methoxyquinolin-7-yl]oxy)ethyl]-N-methylcarbamate (150 mg, 0.239 mmol) in dioxane (4 mL) was added hydrochloric acid (gas, 4N in 1,4-dioxane, 1 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L hydrochloric acid); Eluent B: acetonitrile; Gradient: 25% to 45% B in 25 min; Flow rate: 60 mL / min; Detector: UV 220 / 254 nm). The desired fractions were collected and concentrated under reduced pressure to give N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-6-fluoro-4-methoxypyridine-3-carboxamide hydrochloride (33 mg, 26%) as a pale yellow solid. MS ESI calculated for C 26 H 23 F3N4O5[M+H] + ,529.16,found 529.30. 1 H NMR(400MHz,DMSO-d6)δ8.92-8.84(m,1H),8.36(s,1H),7.88-7.71(m,4H),7.26-7.16(m,1H ),7.08(s,1H),4.62-4.53(m,2H),4.07(s,3H),4.01(s,3H),3.55-3.45(m,2H),2.71(s,3H). 19 F NMR(DMSO-d6)δ-62.94(1F),-126.40(2F).

[0420] Example 45: N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-methoxy-6-methylpyridine-3-carboxamide

[0421] [ka]

[0422] Step 1: Methyl 4-methoxy-6-methylpyridine-3-carboxylate

[0423] To a stirred mixture of methyl 6-chloro-4-methoxypyridine-3-carboxylate (600 mg, 2.976 mmol) and methylboronic acid (534 mg, 8.928 mmol) in dioxane (5 mL) and water (1 mL), cesium carbonate (2909 mg, 8.928 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (218 mg, 0.298 mmol) were added at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The residue was purified by reverse-phase flash chromatography using the following conditions: column, silica gel, mobile phase, acetonitrile in water, 0% to 10% B in 20 min, detector, UV 254 / 220 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to give methyl 4-methoxy-6-methylpyridine-3-carboxylate as a pale yellow oil. MS ESI calculated for C9H 11 NO3[M+H] + ,182.07 found 182.30. 1 H NMR(400MHz,DMSO-d6)δ8.66(s,1H),7.17(d,J=1.8Hz,1H),3.92(s,3H),3.81(s,3H),3.46(s,3H).

[0424] Step 2: 4-Methoxy-6-methylpyridine-3-carboxylic acid

[0425] To a stirred mixture of methyl 4-methoxy-6-methylpyridine-3-carboxylate (130 mg, 0.717 mmol) in water (2 mL) and tetrahydrofuran (4 mL) was added lithium hydroxide (172 mg, 7 mmol) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The residue was purified by reverse-phase flash chromatography (column, silica gel, mobile phase, acetonitrile in water, 40% to 60% B in 4.5 min, detector, UV 254 / 220 nm). Fractions containing the desired product were collected and concentrated under reduced pressure to give 4-methoxy-6-methylpyridine-3-carboxylic acid (100 mg, 83%) as a white solid. MS ESI calculated for C8H9NO3 [M+H] + ,167.06 found 168.15. 1 H NMR(400MHz,DMSO-d6)δ14.00(s,1H),8.70(s,1H),7.63(d,J=4.2Hz,1H),4.07(s,3H),2.69(s,3H).

[0426] Step 3: tert-butyl N-[2-({4-[2,6-difluoro-4-(4-methoxy-6-methylpyridin-3-amido)phenoxy]-6-methoxyquinolin-7-yl}oxy)ethyl]-N-methylcarbamate

[0427] To a stirred mixture of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (299 mg, 0.789 mmol) and tert-butyl N-(2-{[4-(4-amino-2,6-difluorophenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methylcarbamate (250 mg, 0.526 mmol) in N,N-dimethylformamide (5 mL) was added 4-methoxy-6-methylpyridine-3-carboxylic acid (105 mg, 0.631 mmol) and N,N-diisopropylethylamine (170 mg, 1.315 mmol) at room temperature. The resulting mixture was stirred at 70°C for 16 hours. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography using the following conditions: column: silica gel; mobile phase: acetonitrile in water, 40% to 60% B in 4.5 min; detector: UV 254 / 220 nm). Fractions containing the desired product were pooled and concentrated under reduced pressure to give tert-butyl N-[2-({4-[2,6-difluoro-4-(4-methoxy-6-methylpyridin-3-amido)-phenoxy]-6-methoxyquinolin-7-yl}oxy)ethyl]-N-methylcarbamate (50 mg, 15%) as a white solid. MS ESI calculated for C 32 H 34 F2N4O7[M+H] + ,625.24 found 625.20. 1 H NMR(400MHz,DMSO-d6)δ10.54(s,1H),8.54(d,J=1.8Hz,1H),8.51(dd,J=5.2,2.0Hz,1H),7.77(d,J=11.2Hz,2H),7.57(d,J=1.8Hz,1H),7.48( s,1H),7.16(s,1H),6.61(d,J=5.2Hz,1H),4.31(s,2H),3.97(d,J=1.8 Hz,6H),3.65(s,2H),2.94(d,J=12.0Hz,3H),2.53(s,3H),1.39(s,9H). 19 F NMR(377MHz,DMSO-d6)δ-126.72(2F).

[0428] Step 4: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-methoxy-6-methylpyridine-3-carboxamide

[0429] To a stirred mixture of tert-butyl N-[2-({4-[2,6-difluoro-4-(4-methoxy-6-methylpyridin-3-amido)phenoxy]-6-methoxyquinolin-7-yl]oxy)ethyl]-N-methylcarbamate (50 mg, 0.080 mmol) in dichloromethane (2 mL), hydrochloric acid (gas) (0.5 mL) in 1,4-dioxane was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 19 × 250 mm, 10 μm, Mobile phase A: water (10 mmol / L ammonium bicarbonate), Mobile phase B: methyl alcohol-HPLC, Flow rate: 25 mL / min, Gradient: 53% to 63% B in 8 min, Wavelength: 254 / 220 nm). Fractions containing the desired product were collected, concentrated, and lyophilized to give N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-methoxy-6-methyl-pyridine-3-carboxamide (16.2 mg, 38%) as a white solid. MS ESI calculated for C 27 H 26 F2N4O5[M+H] + ,525.19 found 482.15. 1 H NMR(400MHz,DMSO-d6)δ10.58(d,J=3.1Hz,1H),8.54-8.50(m,2H),7.78(d,J=10.6Hz,2H),7.58(s,1H),7.48(s,1H),7.16( s,1H),6.62(d,J=5.2Hz,1H),4.31(t,J=5.4Hz,2H),3.98(d,J=8.2Hz,6H),3.12(t,J=5.4Hz,2H),2.53(s,3H),2.50(s,4H). 19 F NMR(376MHz,DMSO-d6)δ-126.72(2F).

[0430] Example 46: N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-methoxy-6-((2-methoxyethyl)amino)pyridine-3-carboxamide

[0431] [ka]

[0432] Step 1: tert-butyl N-[2-({4-[4-(6-chloro-4-methoxypyridin-3-amido)-2,6-difluorophenoxy]-6-methoxyquinolin-7-yl}oxy)ethyl]-N-methylcarbamate

[0433] To a stirred mixture of tert-butyl N-(2-{[4-(4-amino-2,6-difluorophenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methylcarbamate (300 mg, 0.631 mmol) and 6-chloro-4-methoxypyridine-3-carboxylic acid (142 mg, 0.757 mmol) in N,N-dimethylformamide (6 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (360 mg, 0.947 mmol) and N,N-diisopropylethylamine (408 mg, 3.155 mmol) at room temperature. The resulting mixture was stirred at 50°C for 16 hours. The mixture was cooled to room temperature. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methyl alcohol (10 / 1) and concentrated under reduced pressure to give tert-butyl N-[2-({4-[4-(6-chloro-4-methoxypyridin-3-amido)-2,6-difluorophenoxy]-6-methoxyquinolin-7-yl}oxy)ethyl]-N-methyl-carbamate (343 mg, 84%) as a yellow solid. MS ESI calculated for C 31 H 31 ClF2N4O7[M+H] +,645.18,647.18 found 645.55,647.55. 1 H NMR(400MHz,CDCl3)δ9.38(d,J=7.6Hz,1H),9.14(s,1H),8.56-8.53(m,1H),7.63(s,1H),7.58-7.53(m,2H),7 .06(s,1H),6.49(s,1H),4.25(d,J=34.5Hz,5H),4.07(d,J=1.8Hz,3H),3.77(s,2H),3.08(s,3H),1.49(s,9H).

[0434] Step 2: tert-butyl N-(2-{[4-(2,6-difluoro-4-{4-methoxy-6-[(2-methoxyethyl)amino]pyridin-3-amido}phenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methylcarbamate

[0435] To a stirred mixture of tert-butyl N-[2-({4-[4-(6-chloro-4-methoxypyridin-3-amido)-2,6-difluorophenoxy]-6-methoxyquinolin-7-yl}oxy)ethyl]-N-methylcarbamate (350 mg, 0.543 mmol) and 2-methoxyethan-1-amine (122 mg, 1.629 mmol) in dioxane (7 mL), BrettPhos (CAS: 1070663-78-3) (58 mg, 0.109 mmol) and BrettPhos Pd G3 (CAS: 1470372-59-8) (49 mg, 0.054 mmol) were added at room temperature. The resulting mixture was stirred at 90° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methyl alcohol (10 / 1) and concentrated under reduced pressure to give tert-butyl N-(2-{[4-(2,6-difluoro-4-{4-methoxy-6-[(2-methoxyethyl)amino]pyridin-3-amido}phenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methylcarbamate (80 mg, 21%) as a yellow solid. MS ESI calculated for C 34 H 39F2N5O8[M+H] + ,684.28 found 684.60. 1 H NMR(400MHz,CDCl3)δ9.42(s,1H),8.92(s,1H),8.53(d,J=5.4Hz,1H),7.63(s,1H),7.55-7.44(m,3H),6.48(d,J=5.4Hz,1H ),5.93(s,1H),4.34(s,2H),4.19-4.02(m,6H),3.77(s,2H),3.63(d,J=3.2Hz,4H),3.43(s,3H),3.08(s,3H),1.49(s,9H).

[0436] Step 3: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-methoxy-6-[(2-methoxyethyl)amino]pyridine-3-carboxamide

[0437] A solution of tert-butyl N-(2-{[4-(2,6-difluoro-4-{4-methoxy-6-[(2-methoxyethyl)amino]-pyridin-3-amido}-phenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methylcarbamate (80 mg, 0.117 mmol) in 1,4-dioxane (1 mL) and hydrochloric acid (gas) in dioxane (1 mL) was stirred at room temperature for 2 h. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30-150 mm, 5 µm; Mobile phase A: water (plus 10 mmol / L ammonium bicarbonate); Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 25% to 35% B in 8 min, 35% B; Wavelength: 254 / 220 nm; RT1 (min): 7; Run number: 0). Fractions containing the desired product were collected, concentrated, and lyophilized to give N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)-phenyl]-4-methoxy-6-[(2-methoxyethyl)amino]pyridine-3-carboxamide (19.7 mg, 29%) as a white solid. MS ESI calculated for C 29 H31 F2N5O6[M+H] + ,584.22 found 584.25. 1 H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.50(d,J=5.2Hz,1H),8.38(s,1H),7.82(d,J=10.6Hz,2H),7.56(s,1H),7.44(s,1H),7.19(d,J=5.8Hz,1H) ,6.59(d,J=5.2Hz,1H),6.18(s,1H),4.28-4.22(m,2H),3.98(s,3H),3.9 3(s,3H),3.52-3.49(m,4H),3.29(s,3H),2.98-2.94(m,2H),2.39(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-127.19(2F).

[0438] Example 47: N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-(difluoromethoxy)pyridine-3-carboxamide

[0439] [ka]

[0440] Step 1: tert-butyl N-{2-[(4-{4-[4-(difluoromethoxy)pyridin-3-amido]-2,6-difluorophenoxy}-6-methoxyquinolin-7-yl)oxy]ethyl}-N-methylcarbamate

[0441] To a stirred mixture of tert-butyl N-[2-({4-[2,6-difluoro-4-(4-hydroxypyridin-3-amido)phenoxy]-6-methoxyquinolin-7-yl]oxy)ethyl]-N-methylcarbamate (90 mg, 0.151 mmol) and sodium 2-chloro-2,2-difluoroacetate (46 mg, 0.302 mmol) in water (0.2 mL) and N,N-dimethylformamide (2 mL) was added potassium carbonate (31 mg, 0.226 mmol) at room temperature. The resulting mixture was stirred at 120° C. for 45 minutes. The mixture was cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane / methyl alcohol (10 / 1). Fractions containing the desired product were collected, concentrated, and lyophilized to give tert-butyl N-{2-[(4-{4-[4-(difluoromethoxy)pyridin-3-amido]-2,6-difluoro-phenoxy}-6-methoxyquinolin-7-yl)oxy]ethyl}-N-methylcarbamate (45 mg, 46%) as a yellow solid. MS ESI calculated for C 31 H 30 F4N4O7[M+H] + ,647.21 found 647.55.

[0442] Step 2: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-(difluoromethoxy)pyridine-3-carboxamide

[0443] To a solution of tert-butyl N-{2-[(4-{4-[4-(difluoromethoxy)pyridin-3-amido]-2,6-difluorophenoxy}-6-methoxyquinolin-7-yl)oxy]ethyl}-N-methylcarbamate (45 mg, 0.070 mmol) in dioxane (1 mL) was added hydrochloric acid (gas, 4N in 1,4-dioxane, 1 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Prep Phenyl OBD Column, 19 × 250 mm, 5 μm; Mobile Phase A: water (plus 10 mmol / L ammonium bicarbonate); Mobile Phase B: MeOH; Flow Rate: 25 mL / min; Gradient: 30% to 70% B in 12 min; Detector: UV 254 / 220 nm). Fractions containing the desired product were collected, concentrated, and lyophilized to give N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)-ethoxy]quinolin-4-yl}oxy)phenyl]-4-(difluoromethoxy)pyridine-3-carboxamide (11.9 mg, 31%) as a white solid. MS ESI calculated for C 26 H 22 F4N4O5[M+H] + ,547.15 found 547.20. 1 H NMR(400MHz,DMSO-d6)δ12.51(s,1H),8.99(d,J=2.4Hz,1H),8.50(d,J=5.2Hz,1H),8.33(dd,J=7.8,2.4Hz,1H),8.06-7.66(m,3H),7.56( s,1H),7.45(s,1H),6.73(d,J=7.6Hz,1H),6.62(d,J=5.2Hz,1H),4.23(t,J=5.6Hz,2H),3.97(s,3H),2.96(t,J=5.6Hz,2H),2.40(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-126.46(2F),-94.62(2F).

[0444] Example 48: N-[2,3-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-(difluoromethoxy)pyridine-3-carboxamide

[0445] [ka]

[0446] Synthesized using the same method as in Example 47. White solid. MS ESI calculated for C 26 H 22 F4N4O5[M+H] + ,547.15 found 547.15. 1 H NMR(400MHz,CD3OD)δ9.00(d,J=2.4Hz,1H),8.48(dd,J=5.4,1.2Hz,1H),8.40- 8.34(m,1H),8.21(dd,J=7.8,2.4Hz,1H),7.75-7.60(m,2H),7.58-7.54(m,1H) ,7.46-7.42(m,1H),6.78(dd,J=7.8,1.2Hz,1H),6.63(dd,J=5.4,1.2Hz,1H),4 .33(t,J=5.2Hz,2H),4.05(d,J=1.0Hz,3H),3.12(d,J=5.2Hz,2H),2.54(s,3H). 19 F NMR(377MHz,CD3OD)δ-96.55(2F),-150.61(1F),-154.53(1F).

[0447] Example 49: N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-ethylpyridine-3-carboxamide

[0448] [ka]

[0449] Step 1: Methyl 4-vinylnicotinate

[0450] To a stirred solution of methyl 4-chloropyridine-3-carboxylate (500 mg, 2.914 mmol), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (898 mg, 5.828 mmol), and potassium phosphate (1.86 g, 8.742 mmol) in dioxane (5 mL) and water (0.5 mL), Pd(dba) (CAS: 60748-47-2, 531 mg, 0.583 mmol) and XantPhos (CAS: 161265-03-8, 139 mg, 0.291 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1 / 1), and concentrated under reduced pressure to give methyl 4-vinylnicotinate (316 mg, 72%) as a pale yellow oil. MS ESI calculated for C9H9NO2 [M+H] + ,164.20 found 164.10. 1 H NMR(400MHz,CDCl3)δ9.10(s,1H),8.68(d,J=5.2Hz,1H),7.59-7.47(m,2H),5.94-5.84(m,1H),5.61-5.55(m,1H),3.96(s,3H).

[0451] Step 2: Methyl 4-ethylpyridine-3-carboxylate

[0452] To a stirred solution of methyl 4-ethenylpyridine-3-carboxylate (316 mg, 1.937 mmol) in methanol (3 mL) was added palladium on carbon (272 mg, 1.937 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered, and the filter cake was washed with methanol (3 x 50 mL). The filtrate was concentrated under reduced pressure to give methyl 4-ethylpyridine-3-carboxylate (285 mg, 89%) as a pale yellow oil. MS ESI calculated for CH 11 NO2[M+H]+ ,166.20 found 166.30. 1 H NMR(400MHz,CDCl3)δ9.05(s,1H),8.61(d,J=5.2Hz,1H),7.23(d,J=5.2Hz,1H),3.95(s,3H),3.03(q,J=7.6Hz,2H),1.27(t,J=7.6Hz,3H).

[0453] Step 3: 4-Ethylpyridine-3-carboxylic acid

[0454] To a stirred solution of methyl 4-ethylpyridine-3-carboxylate (285 mg, 1.725 mmol) in tetrahydrofuran (1.5 mL) and water (1.5 mL), lithium hydroxide (165 mg, 6.900 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 70 °C for 4 hours. The mixture was cooled to room temperature and acidified to pH 6 with concentrated hydrochloric acid. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 80 g column; eluent A: water (plus 10 mmol / L ammonium bicarbonate); eluent B: acetonitrile; gradient: 25% to 45% B in 25 min; flow rate: 60 mL / min; detector: UV 220 / 254 nm). The desired fraction was collected at 42% B and concentrated under reduced pressure to give 4-ethylpyridine-3-carboxylic acid (252 mg, 96%) as a pale yellow oil. MS ESI calculated for C8H9NO2[M+H] + ,152.20 found 152.25. 1 H NMR(400MHz,CDCl3)δ9.11(s,1H),8.56(d,J=5.2Hz,1H),7.23(d,J=5.2Hz,1H),3.06(q,J=7.6Hz,2H),1.24(t,J=7.6Hz,3H).

[0455] Step 4: tert-butyl N-[2-({4-[4-(4-ethylpyridin-3-amido)-2,6-difluorophenoxy]-6-methoxyquinolin-7-yl}oxy)ethyl]-N-methylcarbamate

[0456] To a stirred solution of 4-ethylpyridine-3-carboxylic acid (230 mg, 1.522 mmol), tert-butyl N-(2-{[4-(4-amino-2,6-difluorophenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methylcarbamate (362 mg, 0.761 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (868 mg, 2.283 mmol) in N,N-dimethylformamide (2.5 mL) was added N,N-diisopropylethylamine (590 mg, 4.566 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 25% to 45% B in 25 min; Flow rate: 60 mL / min; Detector: UV 220 / 254 nm). The desired fraction was collected at 42% B and concentrated under reduced pressure to give tert-butyl N-[2-({4-[4-(4-ethylpyridin-3-amido)-2,6-difluorophenoxy]-6-methoxyquinolin-7-yl}oxy)ethyl]-N-methylcarbamate (39.8 mg, 4%) as an off-white solid. MS ESI calculated for C 32 H 34 F2N4O6[M+H] + ,609.70 found 609.50.

[0457] Step 5: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-ethylpyridine-3-carboxamide

[0458] To a stirred solution of tert-butyl N-2-({4-[4-(4-ethylpyridin-3-amido)-2,6-difluorophenoxy]-6-methoxy-quinolin-7-yl}oxy)ethyl]-N-methylcarbamate (39 mg, 0.064 mmol) in dioxane (1 mL), hydrochloric acid (gas, 4N in 1,4-dioxane, 0.6 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (plus 10 mmol / L ammonium bicarbonate); Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 36% to 46% B in 8 min; Detector: UV 220 / 254 nm. Fractions containing the desired product were collected, concentrated, and lyophilized to give N-[3,5-difluoro-4-({6-methoxy-7-[2-(methyl-amino)-ethoxy]quinolin-4-yl}oxy)phenyl]-4-ethylpyridine-3-carboxamide (16 mg, 50%) as an off-white solid. MS ESI calculated for C 27 H 26 F2N4O4[M+H] + ,509.50 found 509.30. 1 H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.70(s,1H),8.64(d,J=5.2Hz,1H),8.51(d,J=5.6Hz,1H),7.81-7.71(m,2H),7.56(s,1H),7.48-7.46(m,2H) ,6.62(d,J=5.2Hz,1H),4.24(t,J=5.6Hz,2H),3.98(s,3H),3.03-2.99(t ,J=5.6Hz,2H),2.80(q,J=7.6Hz,2H),2.42(s,3H),1.22(t,J=7.6Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-126.40(2F).

[0459] Example 50: 4-Methoxy-N-(2,3,5-trifluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)pyridine-3-carboxamide

[0460] [ka]

[0461] Step 1: tert-butyl N-(2-{[4-(4-amino-2,3,6-trifluorophenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methylcarbamate

[0462] To a stirred solution of tert-butyl N-(2-{[4-(4-amino-2,6-difluorophenoxy)-6-methoxyquinolin-7-yl]oxy]ethyl)-N-methylcarbamate (300 mg, 0.631 mmol) (from Example 1) and Selectfluor (224 mg, 0.632 mmol) in acetonitrile (2 mL) and N,N-dimethylformamide (2 mL) at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The mixture was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1 / 1). Fractions containing the desired product were collected and concentrated under reduced pressure to give tert-butyl N-(2-{[4-(4-amino-2,3,6-trifluorophenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methylcarbamate (70 mg, 22%) as a tan solid. MS ESI calculated for C 24 H 26 F3N3O5[M+H] + ,494.18 found 494.30. 1H NMR(400MHz,DMSO-d6)δ8.50(d,J=5.2Hz,1H),7.53(s,1H),7.46(s,1H),6.70-6.64(m,1H),6.62(d,J=5.2 Hz,1H),5.93(s,2H),4.29(t,J=5.6Hz,2H),3.95(s,3H),3.64(t,J=5.6Hz,2H),2.93(3,3H),1.38(s,9H).

[0463] Step 2: tert-butyl N-[2-({6-methoxy-4-[2,3,6-trifluoro-4-(4-methoxypyridin-3-amido)phenoxy]quinolin-7-yl}oxy)ethyl]-N-methylcarbamate

[0464] A solution of 4-methoxypyridine-3-carboxylic acid (44 mg, 0.287 mmol) and N,N-diisopropylethylamine (37 mg, 0.286 mmol) in propylphosphonic anhydride (1N in ethyl acetate, 1 mL) was stirred at room temperature for 20 minutes, after which tert-butyl N-(2-{[4-(4-amino-2,3,6-trifluorophenoxy)-6-methoxyquinolin-7-yl]oxy}ethyl)-N-methylcarbamate (70 mg, 0.142 mmol) was added at room temperature. The resulting mixture was stirred for 16 hours at 70° C. The mixture was cooled to room temperature. The mixture was basified to pH 8 with saturated sodium bicarbonate (aqueous). The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×10 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1 / 1). Fractions containing the desired product were collected and concentrated under reduced pressure to give tert-butyl N-[2-({6-methoxy-4-[2,3,6-trifluoro-4-(4-methoxypyridin-3-amido)phenoxy]quinolin-7-yl}oxy)ethyl]-N-methylcarbamate (30 mg, 33%) as a white solid. MS ESI calculated for C 31 H 31 F3N4O7[M+H] +,629.21 found 629.20.

[0465] Step 3: 4-Methoxy-N-[2,3,5-trifluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-pyridine-3-carboxamide

[0466] To a stirred solution of tert-butyl N-[2-({6-methoxy-4-[2,3,6-trifluoro-4-(4-methoxypyridin-3-amido)phenoxy]quinolin-7-yl}oxy)ethyl]-N-methylcarbamate (30 mg, 0.048 mmol) in dichloromethane (4 mL), hydrochloric acid (gas, 4N in 1,4-dioxane, 0.5 mL) was added at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (plus 10 mmol / L ammonium bicarbonate); Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 24% to 34% B in 8 min, 34% B; Detector: UV 254 / 220 nm). Fractions containing the desired product were collected, concentrated, and lyophilized to give 4-methoxy-N-[2,3,5-trifluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide (8 mg, 31%) as a white solid. MS ESI calculated for C 26 H 23 F3N4O5[M+H] + ,529.16 found 529.20. 1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),8.64(d,J=5.6Hz,1H),8.53(d,J=5.2Hz,1H),8.14(dd,J=12.0,4.8Hz,1H),7.56(s,1H),7.46(s,1H),7. 31(d,J=5.6Hz,1H),6.76(d,J=5.2Hz,1H),4.22(t,J=5.6Hz,2H),4.03(s,3H),3.98(s,3H),3.64(s,1H),2.95(t,J=5.6Hz,2H),2.38(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-131.73(1H),-149.78(2H).

[0467] Example 51: 4-Ethoxy-N-[2,3,5-trifluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0468] [ka]

[0469] Synthesized using the same method described for Example 50. White solid. MS ESI calculated for C 27 H 25 F3N4O5[M+H] + ,543.18 found 543.25. 1 H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.89(s,1H),8.64(d,J=6.0Hz,1H),8 .52(d,J=5.2Hz,1H),8.34-8.25(m,1H),7.56(s,1H),7.46(s,1H),7.31(d,J =6.0Hz,1H),6.77(d,J=5.2Hz,1H),4.36(q,J=6.8Hz,2H),4.24-4.22(m,2H ),3.98(s,3H),3.00-2.90(m,2H),2.38(s,3H),1.54-1.49(t,J=6.8Hz,3H). 19F NMR(376MHz,DMSO-d6)δ-131.40(1F),-149.82(1F),-151.73(1F).

[0470] Example 52: N-(2,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-propoxypyridine-3-carboxamide

[0471] [ka]

[0472] Step 1: tert-butyl N-[2-({4-[4-(4-chloropyridin-3-amido)-2,5-difluorophenoxy]-6-methoxyquinolin-7-yl}oxy)ethyl]-N-methylcarbamate

[0473] To a stirred solution of tert-butyl N-(2-{[4-(4-amino-2,5-difluorophenoxy)-6-methoxyquinolin-7-yl]oxy}-ethyl)-N-methylcarbamate (500 mg, 1.052 mmol) and 4-chloropyridine-3-carbonyl chloride (370 mg, 2.104 mmol) in dichloromethane (10 mL) was added N,N-diisopropylethylamine (272 mg, 2.104 mmol) at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The mixture was quenched with water. The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (1×20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate / ethyl alcohol (4 / 3 / 1). Fractions containing the desired product were collected and concentrated under reduced pressure to give tert-butyl N-[2-({4-[4-(4-chloropyridin-3-amido)-2,5-difluorophenoxy]-6-methoxyquinolin-7-yl}oxy)ethyl]-N-methylcarbamate (520 mg, 80%) as an off-white solid. MS ESI calculated for C30 H 29 ClF2N4O6[M+H] + ,615.17,617.17 found 615.40,617.40. 1 H NMR(400MHz,CDCl3)δ9.08(s,1H),8.68(d,J=5.2Hz,1H),8.60(dd,J=11.6,7.2Hz,1H),8.56(d,J=5.2Hz,1H),8.43(s,1H),7.56(s,1H),7.51- 7.46(m,2H),7.16(dd,J=10.4,6.8Hz,1H),6.52(d,J=5.6Hz,1H),4.40- 4.30(m,2H),4.06(s,3H),3.81-3.74(m,2H),3.08(s,3H),1.49(s,9H).

[0474] Step 2: tert-butyl (2-((4-(2,5-difluoro-4-(4-propoxynicotinamido)phenoxy)-6-methoxyquinolin-7-yl)oxy)ethyl)(methyl)carbamate

[0475] To a stirred solution of tert-butyl N-[2-({4-[4-(4-chloropyridin-3-amido)-2,5-difluorophenoxy]-6-methoxy-quinolin-7-yl}oxy)ethyl]-N-methylcarbamate (100 mg, 0.163 mmol) and propanol (98 mg, 1.630 mmol) in dimethyl sulfoxide (2 mL), sodium hydroxide (65 mg, 1.630 mmol) was added at room temperature. The resulting mixture was stirred at 70° C. for 1 hour. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 40% to 80% B in 25 min; Flow rate: 60 mL / min; Detector: UV 220 / 254 nm). Fractions containing the desired product were pooled and concentrated under reduced pressure to give tert-butyl (2-((4-(2,5-difluoro-4-(4-propoxynicotinamido)phenoxy)-6-methoxyquinolin-7-yl)oxy)ethyl)(methyl)carbamate (24 mg, 27%) as a white solid. MS ESI calculated for C 33 H 36 F2N4O7[M+H] + ,639.20 found 639.30. 1 H NMR(400MHz,DMSO-d6)δ10.23(s,1H),8.90(s,1H),8.62(d,J=5.6Hz,1H),8.57-8.49(m,1 H),8.43(dd,J=12.4,7.2Hz,1H),7.73(dd,J=10.8,7.2Hz,1H),7.54(s,1H),7.47(s,1H), 7.31(d,J=5.6Hz,1H),6.61(d,J=5.2Hz,1H),4.35-4.23(m,4H),3.96(s,3H),3.66(t,J=5 .6Hz,2H),3.00-2.90(m,3H),1.96-1.85(m,2H),1.46-1.32(m,9H),1.03(t,J=7.4Hz,3H).

[0476] Step 3: N-[2,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-propoxypyridine-3-carboxamide

[0477] To a stirred solution of N-[2,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)-phenyl]-4-propoxypyridine-3-carboxamide (20 mg, 0.037 mmol) in dichloromethane (2 mL), hydrochloric acid (gas, 4N in 1,4-dioxane, 0.5 mL) was added at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (20 mg) was purified by preparative HPLC using an XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm column; mobile phase A: water (plus 10 mmol / L ammonium bicarbonate); mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 40% to 55% B in 8 min; detector: UV 254 / 220 nm). Fractions containing the desired product were collected, concentrated, and lyophilized to give N-[2,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-propoxypyridine-3-carboxamide (11 mg, 54%) as a white solid. MS ESI calculated for C 28 H 28 F2N4O5[M+H] + ,539.20 found 539.25. 1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.90(s,1H),8.63(d,J=6.0Hz,1H),8.51(d,J =5.2Hz,1H),8.43(dd,J=12.4,7.2Hz,1H),7.74(dd,J=10.8,7.2Hz,1H),7.53(s,1H ),7.43(s,1H),7.32(d,J=6.0Hz,1H),6.60(d,J=5.2Hz,1H),4.34-4.17(m,4H),3.9 6(s,3H),2.97-2.93(m,2H),2.38(s,3H),1.90-1.89(m,2H),1.03(t,J=7.4Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-128.60(1F),-132.50(1F).

[0478] Example 53: 4-Cyclopropoxy-N-[3,5-difluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0479] [ka]

[0480] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 32 H 32 F2N4O6[M+H] + ,607.23 found 607.20, 1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.64(d,J=6.0Hz,1H),8.62(s,1H),8.50(d,J=5. 2Hz,1H),7.76-7.66(m,2H),7.55(s,1H),7.51(d,J=6.0Hz,1H),7.43(s,1H),6.61(d,J =5.2Hz,1H),4.22(t,J=6.4Hz,2H),4.14-4.06(m,1H),3.97(s,3H),3.60(t,J=4.6Hz,4 H),2.47(t,J=6.4Hz,2H),2.40(t,J=4.6Hz,4H),2.04-1.94(m,2H),0.94-0.75(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-126.25(2F).

[0481] Example 54: 4-Cyclopropoxy-N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0482] [ka]

[0483] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 28 H 26 F2N4O5[M+H] + ,537.19 found 537.20, 1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.69-8.60(m,2H),8.50(d,J=5.2Hz,1H),7.79-7.67(m,2H),7.61-7.41(m,3H),6.62 (d,J=5.2Hz,1H),4.25-4.22(m,2H),4.11-4.07(m,1H),3.98(s,3H),2.97(t,J=5.6Hz,2H),2.38(s,3H),0.93-0.78(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-126.49(2F).

[0484] Example 55: 4-Cyclobutoxy-N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)pyridine-3-carboxamide

[0485] [ka]

[0486] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 29 H 28 F2N4O5[MH] - ,549.20,found 549.25. 1 H NMR(400MHz,DMSO-d6)δ10.68(s,1H),8.63(s,1H),8.55(d,J=6.0Hz,1H),8.51(d,J=5.2Hz,1H ),7.76-7.74(m,2H),7.56(s,1H),7.45(s,1H),7.08(d,J=6.0Hz,1H),6.63(d,J=5.2Hz,1H),4 .93(p,J=7.2Hz,1H),4.22(t,J=5.6Hz,2H),3.98(s,3H),2.94(t,J=5.6Hz,2H),2.56-2.54(m, 1H),2.50-2.46(m,1H),2.38(s,3H),2.21-2.15(m,2H),1.89-1.81(m,1H),1.79-1.71(m,1H). 19 F NMR(376MHz,DMSO-d6)δ-126.49(2F).

[0487] Example 56: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-propoxypyridine-3-carboxamide

[0488] [ka]

[0489] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 28 H 28 F2N4O5[M+H] + ,539.20 found 539.25, 1 H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.63(s,1H),8.58(d,J=5.6Hz,1H), 8.51(d,J=5.2Hz,1H),7.76-7.69(m,2H),7.56(s,1H),7.45(s,1H),7.26( d,J=5.6Hz,1H),6.62(d,J=5.2Hz,1H),4.21-4.19(m,4H),3.98(s,3H),2. 94(t,J=5.6Hz,2H),2.39(s,3H),1.85-1.76(m,2H),0.99(t,J=7.2Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ-126.48(2F).

[0490] Example 57: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-(3,3-difluorocyclobutoxy)pyridine-3-carboxamide

[0491] [ka]

[0492] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 29 H 26 F4N4O5[M+H] + 587.18 found 587.20. 1H NMR(400MHz,CD3OD)δ8.77(s,1H),8.58(d,J=6.0Hz,1H),8.49(d,J=5.2Hz,1H),7.55-7.76(m,3H),7.44(s,1H),7.15(d,J=6.0Hz,1H),6.63(d, J=5.2Hz,1H),5.12-5.04(m,1H),4.34(t,J=5.2Hz,2H),4.07(s,3H),3. 32-3.24(m,2H),3.15(t,J=5.2Hz,2H),2.93-2.91(m,2H),2.56(s,3H). 19 F NMR(400MHz,CD3OD-d4)δ-86.90(1F),-97.00(1F),127.95(2F).

[0493] Example 58: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-(3-fluoropropoxy)pyridine-3-carboxamide

[0494] [ka]

[0495] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 28 H 27 F3N4O5[M+H] + ,557.19 found 557.25. 1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.65(s,1H),8.60(d,J=6.0Hz,1H),8.51(d,J=5 .2Hz,1H),7.78-7.68(m,2H),7.56(s,1H),7.45(s,1H),7.30(d,J=6.0Hz,1H),6.62(d, J=5.2Hz,1H),4.69(t,J=6.0Hz,1H),4.57(t,J=6.0Hz,1H),4.31(t,J=6.0Hz,2H),4.2 3(t,J=5.2Hz,2H),3.98(s,3H),2.96(t,J=5.2Hz,2H),2.41(s,3H),2.25-2.12(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-126.47(2F),-126.15(1F).

[0496] Example 59: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-isopropoxypyridine-3-carboxamide

[0497] [ka]

[0498] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 28 H 28 F2N4O5[M+H] + ,539.20 found 539.25. 1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.62(s,1H),8.56(d,J=5.8Hz,1H),8. 51(d,J=5.2Hz,1H),7.73(d,J=10.2Hz,2H),7.56(s,1H),7.45(s,1H),7.28( d,J=6.0Hz,1H),6.62(d,J=5.2Hz,1H),4.95-4.84(m,1H),4.22(t,J=5.6Hz, 2H),3.98(s,3H),2.95(t,J=5.4Hz,2H),2.39(s,3H),1.37(d,J=6.0Hz,6H). 19 F NMR(376MHz,DMSO-d6)δ-126.48(2F).

[0499] Example 60: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-(2,2-difluoroethoxy)pyridine-3-carboxamide

[0500] [ka]

[0501] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 27 H 24 F4N4O5[M+H] + ,561.17 found 561.15. 1 H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.68(s,1H),8.65(d,J=6.0Hz,1H),8.51(d,J=5.2Hz,1H),7.77-7.68(m,2H),7.56(s,1H),7.45(s, 1H),7.36(d,J=6.0Hz,1H),6.63-6.32(m,2H),4.60-4.59(m,2H),4.22(t,J=5.6Hz,2H),3.98(s,3H),2.94(t,J=5.6Hz,2H),2.39(s,3H). 19F NMR(376MHz,DMSO-d6)δ-125.89(2F),-126.45(2F).

[0502] Example 61: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-(2R)-2-fluoropropoxy]pyridine-3-carboxamide

[0503] [ka]

[0504] Synthesized using a similar method to Example 52 with chiral purification. A white solid was obtained. MS ESI calculated for C 28 H 27 F3N4O5[M+H] + ,557.19 found 557.15, 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.67(s,1H),8.62(d,J=5.6Hz,1H),8.51(d ,J=5.2Hz,1H),7.78-7.67(m,2H),7.56(s,1H),7.45(s,1H),7.31(d,J=5.6Hz,1H ),6.63(d,J=5.2Hz,1H),5.25-5.00(m,1H),4.49-4.26(m,2H),4.22(t,J=5.6Hz, 2H),3.98(s,3H),2.94(t,J=5.6Hz,2H),2.39(s,3H),1.40(dd,J=6.8,6.4Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-126.48(1F),-178.30(2F).

[0505] Example 62: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-(2S)-2-fluoropropoxy]pyridine-3-carboxamide

[0506] [ka]

[0507] Synthesized using a similar method to Example 52 with chiral purification. White solid. MS ESI calculated for C 28 H 27 F3N4O5[M+H] + ,557.19 found 557.15, 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.67(s,1H),8.62(d,J=5.6Hz,1H),8.51(d ,J=5.2Hz,1H),7.78-7.67(m,2H),7.56(s,1H),7.45(s,1H),7.31(d,J=5.6Hz,1H ),6.63(d,J=5.2Hz,1H),5.25-5.00(m,2H),4.49-4.26(m,2H),4.22(t,J=5.6Hz, 2H),3.98(s,3H),2.94(t,J=5.6Hz,2H),2.39(s,3H),1.40(dd,J=6.8,6.4Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-126.48(1F),-178.30(2F).

[0508] Example 63: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-(2-hydroxyethoxy)pyridine-3-carboxamide

[0509] [ka]

[0510] Synthesized using the same method as in Example 52. Yellow solid. MS ESI calculated for C 27 H 26 F2N4O6[M+H] + 541.18 found 541.25. 1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.79(s,1H),8.62(d,J=6.0Hz,1H),8.51 (d,J=5.2Hz,1H),7.71-7.84(m,2H),7.56(s,1H),7.45(s,1H),7.32(d,J=6.0Hz ,1H),6.62(d,J=5.2Hz,1H),5.24(s,1H),4.33(t,J=4.8Hz,2H),4.22(t,J=5.6 Hz,2H),3.98(s,3H),3.85(t,J=4.8Hz,2H),2.94(t,J=5.6Hz,2H),2.38(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-126.48(2F).

[0511] Example 64: (S)—N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-(2-hydroxypropoxy)pyridine-3-carboxamide

[0512] [ka]

[0513] Synthesized using a similar method to Example 52 with chiral purification. White solid. MS ESI calculated for C 28 H 28 F2N4O6[M+H] + ,555.20 found 555.15. 1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.79(s,1H),8.61(d,J=6.0Hz,1H),8.52(d,J= 5.2Hz,1H),7.83-7.75(m,2H),7.58(s,1H),7.49(s,1H),7.31(d,J=6.0Hz,1H),6.63( d,J=5.2Hz,1H),5.27(d,J=5.6Hz,1H),4.34(t,J=5.6Hz,2H),4.25-4.16(m,1H),4.15 -4.05(m,2H),3.99(s,3H),3.17(t,J=5.6Hz,2H),2.53(s,3H),1.21(d,J=5.6Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ-126.48(2F).

[0514] Example 65: (R)—N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-(2-hydroxypropoxy)pyridine-3-carboxamide

[0515] [ka]

[0516] Synthesized using a similar method to Example 52 with chiral purification. White solid. MS ESI calculated for C 28 H 28 F2N4O6[M+H] + ,555.20 found 555.15, 1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.79(s,1H),8.62(d,J=6.0Hz,1H),8.52(d,J= 5.2Hz,1H),7.80-7.77(m,2H),7.58(s,1H),7.48(s,1H),7.32(d,J=6.0Hz,1H),6.63( d,J=5.2Hz,1H),5.25(d,J=5.6Hz,1H),4.29(t,J=5.6Hz,2H),4.25-4.18(m,1H),4.14 -4.07(m,2H),3.99(s,3H),3.10(t,J=5.6Hz,2H),2.48(s,3H),1.21(d,J=5.6Hz,3H), 19 F NMR(377MHz,DMSO-d6)δ-126.47(2F).

[0517] Example 66: N-(3,5-difluoro-4-((6-methoxy-7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-4-(2-hydroxy-2-methylpropoxy)pyridine-3-carboxamide

[0518] [ka]

[0519] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 29 H 30 F2N4O6[M+H] + ,569.21 found 569.25. 1 H NMR(400MHz,DMSO-d6)δ10.73(s,1H),8.61(d,J=5.6Hz,1H),8.51(d,J=5.2Hz,1H),8.30(s,1H),7.85-7.76(m,2H),7.57(s,1H),7.46(s,1H), 7.30(d,J=5.6Hz,1H),6.62(d,J=5.2Hz,1H),4.25(d,J=5.6Hz,2H),3.9 8(s,2H),3.94(s,3H),3.03(d,J=5.6Hz,2H),2.44(s,3H),1.21(s,6H). 19F NMR(377MHz,DMSO-d6)δ-126.46(2F).

[0520] Example 67: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-(2-methoxyethoxy)pyridine-3-carboxamide

[0521] [ka]

[0522] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 28 H 28 F2N4O6[M+H] + ,555.20 found 555.35. 1 H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.72(s,1H),8.61(d,J=6.0Hz,1H),8.5 1(d,J=5.2Hz,1H),7.68-7.75(m,2H),7.56(s,1H),7.45(s,1H),7.31(d,J=6. 0Hz,1H),6.62(d,J=5.2Hz,1H),4.25-4.53(m,2H),4.23(t,J=5.6Hz,2H),3.9 8(s,3H),3.64-3.88(m,2H),3.33(s,3H),2.96(t,J=5.6Hz,2H),2.40(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-126.48(2F).

[0523] Example 68: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-(oxetan-3-yloxy)pyridine-3-carboxamide

[0524] [ka]

[0525] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 28 H 26 F2N4O6[M+H] + 553.18 found 553.20. 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.69(s,1H),8.58(d,J=6.0Hz,1H),8.51 (d,J=5.2Hz,1H),7.81-7.71(m,2H),7.57(s,1H),7.45(s,1H),6.90(d,J=6.0H z,1H),6.63(d,J=5.2Hz,1H),5.56-5.47(m,1H),5.02-4.97(m,2H),4.65-4.62 (m,2H),4.23(t,J=5.6Hz,2H),3.98(s,3H),2.95(t,J=5.6Hz,2H),2.39(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-126.49(2F).

[0526] Example 69: 4-Butoxy-N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0527] [ka]

[0528] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 29 H 30 F2N4O5[M+H] + ,553.22 found 553.25. 1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.62(s,1H),8.59(d,J=5.8Hz,1H),8.51(d ,J=5.2Hz,1H),7.69-7.76(m,2H),7.56(s,1H),7.45(s,1H),7.27(d,J=5.8Hz,1H ),6.61(d,J=5.2Hz,1H),4.21(m,J=6.8,6.2Hz,4H),3.98(s,3H),2.94(t,J=5.6H z,2H),2.39(s,3H),1.84-1.77(m,2H),1.41-1.48(m,2H),0.92(t,J=7.4Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-126.50(2F).

[0529] Example 70: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-[(3R)-oxolan-3-yloxy]pyridine-3-carboxamide

[0530] [ka]

[0531] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 29 H 28 F2N4O6[M+H] + ,567.20 found 567.20. 1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.65(s,1H),8.60(d,J=6.0Hz,1H),8.51(d,J =5.2Hz,1H),7.77-7.67(m,2H),7.55(s,1H),7.44(s,1H),7.27(d,J=6.0Hz,1H),6. 63(d,J=5.2Hz,1H),5.32-5.26(m,1H),4.22(t,J=5.6Hz,2H),3.98(s,3H),3.96-3. 74(m,4H),2.93(t,J=5.6Hz,2H),2.38(s,3H),2.34-2.27(m,1H),2.07-2.05(m,1H). 19 F-NMR(376MHz,DMSO-d6)δ-126.41(2F).

[0532] Example 71: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-[(3S)-oxolan-3-yloxy]pyridine-3-carboxamide

[0533] [ka]

[0534] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 29 H 28 F2N4O6[M+H] + ,567.20 found 567.20. 1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.65(s,1H),8.59(d,J=6.0Hz,1H),8.51(d,J =5.2Hz,1H),7.77-7.67(m,2H),7.56(s,1H),7.44(s,1H),7.27(d,J=6.0Hz,1H),6. 63(d,J=5.2Hz,1H),5.29-5.29(m,1H),4.22(t,J=5.6Hz,2H),3.98(s,3H),3.92-3. 74(m,4H),2.94(t,J=5.6Hz,2H),2.38(s,3H),2.36-2.28(m,1H),2.06-2.02(m,1H). 19 F NMR(376MHz,DMSO-d6)δ-126.41(2F).

[0535] Example 72: 4-(cyclopropylmethoxy)-N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0536] [ka]

[0537] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 29 H 28 F2N4O5[M+H] + ,551.20 found 551.30. 1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.66(s,1H),8.58(d,J=5.6Hz,1H),8.51(d,J= 5.2Hz,1H),7.80-7.68(m,2H),7.56(s,1H),7.45(s,1H),7.24(d,J=5.6Hz,1H),6.63 (d,J=5.2Hz,1H),4.22(t,J=5.6Hz,2H),4.09(d,J=7.2Hz,2H),3.98(s,3H),2.94(t, J=5.6Hz,2H),2.39(s,3H),1.39-1.27(m,1H),0.64-0.56(m,2H),0.48-0.40(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-126.20(2F).

[0538] Example 73: N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-(prop-2-yn-1-yloxy)pyridine-3-carboxamide

[0539] [ka]

[0540] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 28 H 24 F2N4O5[M+H] + ,535.17 found 535.25. 1 H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.66-8.63(m,2H),8.50(d,J=5.2Hz,1H),7.78-7.70(m,2H),7.56(s,1H),7.45(s,1H),7.32(d,J=6.0Hz, 1H),6.62(d,J=5.2Hz,1H),5.07(d,J=2.4Hz,2H),4.22(t,J=5.6Hz,2H) ,3.98(s,3H),3.77(t,J=2.4Hz,1H),2.94(t,J=5.6Hz,2H),2.39(s,3H). 19F NMR(376MHz,DMSO-d6)δ-126.49(2F).

[0541] Example 74: N-(4-{[7-(azetidin-3-yloxy)-6-methoxyquinolin-4-yl]oxy}-3,5-difluorophenyl)-4-cyclopropoxypyridine-3-carboxamide

[0542] [ka]

[0543] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 28 H 24 F2N4O5[M+H] + ,534.17 found 534.25. 1 H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.63(d,J=6.0Hz,1H),8.61(s,1H),8.50( d,J=5.2Hz,1H),7.75-7.68(m,2H),7.58(s,1H),7.51(d,J=6.0Hz,1H),7.10(s,1 H),6.63(d,J=5.2Hz,1H),5.21-5.19(m,1H),4.12-4.09(m,1H),3.99(s,3H),3. 89(t,J=7.6Hz,2H),3.61(t,J=7.6Hz,2H),0.94-0.84(m,2H),0.82-0.81(m,2H). 19 F NMR(377MHz,DMSO-d6)δ-126.52(2F).

[0544] Example 75: 4-Cyclopropoxy-N-[4-({7-[2-(ethylamino)ethoxy]-6-methoxyquinolin-4-yl}oxy)-3,5-difluorophenyl]pyridine-3-carboxamide

[0545] [ka]

[0546] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 29 H 28 F2N4O5[M+H] + ,551.20 found 551.35, 1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.64(d,J=5.6Hz,1H),8.62(s,1H),8.50(d,J=5. 2Hz,1H),7.74-7.68(m,2H),7.56(s,1H),7.51(d,J=5.6Hz,1H),7.44(s,1H),6.62(d,J =5.2Hz,1H),4.21(t,J=5.6Hz,2H),4.11-4.07(m,1H),3.98(s,3H),2.98(t,J=5.6Hz,2 H),2.65(q,J=7.2Hz,2H),1.95-1.67(m,1H),1.05(t,J=7.2Hz,3H),0.92-0.77(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-126.49(2F).

[0547] Example 76: 4-Cyclopropoxy-N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-pyrimidine-5-carboxamide

[0548] [ka]

[0549] Synthesized using the same method as in Example 52. Colorless solid. MS ESI calculated for C 27 H 25 F2N5O5[M+H] + ,538.18 found 538.25. 1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),9.00(s,1H),8.83(s,1H),8.50(d,J=5.2Hz,1H),7.69-7.78(m,2H),7.67(s,1H),7.45(s,1H), 6.61(d,J=5.2Hz,1H),4.48-4.45(m,1H),4.21(t,J=5.6Hz,2H),3.97(s,3H),2.93(t,J=5.6Hz,2H),2.37(s,3H),0.86-0.83(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-126.30(2F).

[0550] Example 77: 3-Cyclopropoxy-N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]pyridine-2-carboxamide

[0551] [ka]

[0552] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 28 H 26 F2N4O5[M+H] + 537.19 found 537.20. 1 H NMR(400MHz,DMSO-d6)δ10.87(s,1H),8.51(d,J=5.2Hz,1H),8.30(dd,J=4.8,1.2Hz,1 H),7.96(dd,J=8.4,1.2Hz,1H),7.85-7.77(m,2H),7.64(dd,J=8.4,4.8Hz,1H),7.57( s,1H),7.45(s,1H),6.62(d,J=5.2Hz,1H),4.22(t,J=5.6Hz,2H),4.06-4.01(m,1H),3 .98(s,3H),2.94(t,J=5.6Hz,2H),2.39(s,3H),0.89-0.81(m,2H),0.76-0.68(m,2H). 19F NMR(376MHz,DMSO-d6)δ-126.68(2F).

[0553] Example 78: 2-Cyclopropoxy-N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0554] [ka]

[0555] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 28 H 26 F2N4O5[M+H] + ,537.19 found 537.10, 1 H NMR(400MHz,DMSO-d6)δ10.56(s,1H),8.51(d,J=5.2Hz,1H),8.41(dd,J=4.8,2.0 Hz,1H),8.04(dd,J=7.2,2.0Hz,1H),7.77-7.68(m,2H),7.56(s,1H),7.45(s,1H) ,7.21(dd,J=7.2,4.8Hz,1H),6.61(d,J=5.2Hz,1H),4.42-4.37(m,1H),4.22(t,J =5.6Hz,2H),3.98(s,3H),2.94(t,J=5.6Hz,2H),2.39(s,3H),0.85-0.74(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-126.52(2F).

[0556] Example 79: 2-Cyclopropoxy-N-[3,5-difluoro-4-({-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0557] [ka]

[0558] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 27 H 24 F2N4O4[M+H] + ,507.18 found 507.20, 1 H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.64(d,J=5.2Hz,1H),8.41(dd,J=4.8,2.0Hz,1H), 8.26(d,J=9.2Hz,1H),8.03(dd,J=7.2,2.0Hz,1H),7.74-7.69(m,2H),7.45(d,J=2.4Hz,1 H),7.35(dd,J=9.2,2.4Hz,1H),7.21(dd,J=7.4,4.8Hz,1H),6.63(d,J=5.2Hz,1H),4.41- 4.36(m,1H),4.22(t,J=5.6Hz,2H),2.92(t,J=5.6Hz,2H),2.38(s,3H),0.82-0.77(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-126.71(2F).

[0559] Example 80: 3-Cyclopropoxy-N-[3,5-difluoro-4-({-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]pyridine-2-carboxamide

[0560] [ka]

[0561] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 27 H 24 F2N4O4[M+H] + 507.18 found 507.30. 1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.64(d,J=5.2Hz,1H),8.30(d,J=4.4Hz,1H),8.27(d ,J=9.2Hz,1H),7.96(d,J=8.8Hz,1H),7.85-7.76(m,2H),7.64(dd,J=8.8,4.4Hz,1H),7.46( d,J=2.4Hz,1H),7.35(dd,J=9.2,2.4Hz,1H),6.64(d,J=5.2Hz,1H),4.24(t,J=5.6Hz,2H),4 .05-4.03(m,1H),2.97(t,J=5.6Hz,2H),2.41(s,3H),0.93-0.79(m,2H),0.77-0.74(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-126.88(2F).

[0562] Example 81: 3-Cyclopropoxy-N-(3,5-difluoro-4-((7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)isonicotinamide

[0563] [ka]

[0564] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 27 H 24 F2N4O4[M+H] + ,507.18,found 507.25. 1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.85(s,1H),8.65(d,J=5.2Hz,1H),8.40(d,J=4 .8Hz,1H),8.28(d,J=9.2Hz,1H),7.73-7.65(m,2H),7.53(d,J=4.8Hz,1H),7.47(d,J= 2.4Hz,1H),7.36(dd,J=9.2,2.4Hz,1H),6.65(d,J=5.2Hz,1H),4.29(t,J=5.6Hz,2H), 4.14-4.12(m,1H),3.05(t,J=5.6Hz,2H),2.48(s,1H),2.46(s,3H),0.97-0.76(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-126.55(2F)

[0565] Example 82: N-[2,3-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-4-propoxypyridine-2-carboxamide

[0566] [ka]

[0567] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 28 H 28 F2N4O5[MH] - ,537.20 found 537.20. 1 H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.84(s,1H),8.61(d,J=6.0Hz,1H),8.52(d,J=5.2Hz,1H),8.12-8.07(m,1H),7.54(s,1H),7.44(s,1H),7.40 -7.27(m,2H),6.63(d,J=5.2Hz,1H),4.23-4.19(m,4H),3.97(s,3H),2.9 3(t,J=5.6Hz,2H),2.38(s,3H),1.87-1.83(m,2H),1.03(t,J=7.2Hz,3H). 19F NMR(376MHz,DMSO)δ-146.00(1F),-152.67(1F).

[0568] Example 83: 4-Cyclopropoxy-N-[2,3-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0569] [ka]

[0570] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 28 H 26 F2N4O5[M+H] + ,537.19 found 537.25. 1 H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.82(s,1H),8.66(d,J=5.8Hz,1H),8.52(d,J=5.2Hz,1H),8.03(t,J=8.6Hz,1H),7.54(d,J=3.8Hz,2H),7 .45(s,1H),7.39-7.32(m,1H),6.62(d,J=5.2Hz,1H),4.21(q,J=5.4Hz, 3H),3.97(s,3H),2.94(t,J=5.6Hz,2H),2.39(s,3H),0.98-0.87(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-145.73(1F),-152.73(1F).

[0571] Example 84: 4-Cyclopropoxy-N-(3,5-difluoro-4-((6-methoxy-7-(3-(methylamino)propoxy)quinolin-4-yl)oxy)phenyl)pyridine-3-carboxamide

[0572] [ka]

[0573] Synthesized using a similar method to Example 52. Light brown semi-solid in the TFA salt form. 1 H NMR(400MHz,DMSO-d6):δ10.71(s,1H),8.66-8.63(m,3H),8.42(bs,2H),7.72(d,J=10.4Hz ,2H),7.64(s,1H),7.57(d,J=5.6Hz,1H),7.52(s,1H),6.83(bs,1H),4.29(t,J=5.6Hz,2H) ,4.12(bs,1H),4.01(s,3H),3.35(t,J=6.8Hz,2H),3.12-3.11(m,2H),2.64(t,J=5.6Hz,3H ),2.17(t,J=6.4Hz,2H),1.66-1.55(m,6H),1.12(s,1H),0.91(bs,2H),0.81(bs,2H),ppm, LCMS: RT 4.00, m / z: 551.43[M+H] + .

[0574] Example 85: 4-Cyclobutoxy-N-(3,5-difluoro-4-((6-methoxy-7-(3-(methylamino)propoxy)quinolin-4-yl)oxy)phenyl)pyridine-3-carboxamide

[0575] [ka]

[0576] Synthesized using a similar method to Example 52. Light brown semi-solid in the TFA salt form. 1H NMR(400MHz,DMSO-d6)δ10.78(s 1H),8.71-8.61(m,3H),8.40(brs,1H),7.77(d,J=10Hz,2H),7.66(s,1H),7.52(s,1H),7.19(d,J =5.6Hz,1H),6.88(brs,1H),5.01-4.94(m,1H),4.30(t,J=5.2.Hz,2H),3.96(s,3H),3.16-3.11(m 2H),2.65-2.63,(m,3H),2.17-2.07(m,4H),1.85-1.65(m,4H),1.67-1.65(m,2H).ppm, LCMS: RT 4.20.34, m / z: 565.59[M+H] + .

[0577] Example 86: N-(3,5-difluoro-4-((6-methoxy-7-(3-(methylamino)propoxy)quinolin-4-yl)oxy)phenyl)-4-(oxetan-3-yloxy)pyridine-3-carboxamide

[0578] [ka]

[0579] Synthesized using a similar method to Example 52. Colorless semi-solid in the TFA salt form. 1 H NMR(400 MHzDMSO-d6)δ10.77(s,1H),8.68(s,1H),8.58(t,J=5.6Hz,2H),8.38(brs,1H),7.77(d ,J=10Hz,2H),7.61(s,1H),7.48(s,1H),6.92(d,J=6.0Hz,1H),6.73-6.71(brs,1H),5.5 1(t,J=5.6Hz,1H),5.00(t,J=7.2Hz,2H),4.63(dd,J=7.2Hz,5.2Hz,2H),4.30(t,J=5.6 Hz,2H),3.99(s,3H),3.20-3.10(m,2H),2.68-2.62(m,3H),2.19-2.15(m,2H)ppm.LCMS: RT 1.34, m / z: 557[M+H] + .

[0580] Example 87: 4-Cyclopropoxy-N-[3,5-difluoro-4-({7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0581] [ka]

[0582] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 27 H 24 F2N4O4[M+H] + ,507.18 found 507.25 1 H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.67-8.59(m,3H),8.26(d,J=9.2Hz,1H ),7.75-7.65(m,2H),7.51(d,J=6.0Hz,1H),7.45(d,J=2.4Hz,1H),7.35(dd,J =9.2,2.4Hz,1H),6.64(d,J=5.2Hz,1H),4.23(t,J=5.6Hz,2H),4.12-4.09(m, 1H),2.93(t,J=5.6Hz,2H),2.38(s,3H),0.91-0.89(m,2H),0.85-0.81(m,2H). 19 F NMR(377MHz,DMSO-d6)δ-126.69(2F).

[0583] Example 88: N-[4-({7-[(2R)-2-aminopropoxy]quinolin-4-yl}oxy)-3,5-difluorophenyl]-4-cyclopropoxypyridine-3-carboxamide

[0584] [ka]

[0585] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 28 H24 F2N4O4[M+H] + ,519.18 found 519.15. 1 H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.67-8.60(m,3H),8.27(d,J=9.2Hz,1H),7.74-7.68(m,2H),7.51(d,J=5.6Hz,1H),7.44 -7.36(m,2H),6.63(d,J=5.2Hz,1H),4.12-4.08(m,1H),4.06(s,2H),0.93-0.86(m,2H),0.85-0.78(m,2H),0.69-0.56(m,4H), 19 F NMR(376MHz,DMSO-d6)δ-126.68(2F).

[0586] Example 89: N-(4-{[7-(azetidin-3-yloxy)quinolin-4-yl]oxy}-3,5-difluorophenyl)-4-cyclopropoxypyridine-3-carboxamide

[0587] [ka]

[0588] Synthesized using a method similar to that of Example 52. Off-white solid. MS ESI calculated for C 27 H 22 F2N4O4[M+H] + ,505.16 found 505.15. 1 H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.82-8.63(m,3H),8.28(d,J=9.2Hz,1H),7.75-7.66(m,2H),7.51(d,J=6.0Hz,1H),7.33(dd,J=9.2,2.4Hz, 1H),7.18(d,J=2.4Hz,1H),6.65(d,J=5.2Hz,1H),5.25-5.18(m,1H),4.3 0-4.05(m,2H),3.92-3.85(m,2H),3.64-3.57(m,2H),0.93-0.77(m,4H). 19F NMR(376MHz,DMSO-d6)δ-126.72(2F).

[0589] Example 90: 4-Cyclopropoxy-N-{3,5-difluoro-4-[(7-methoxyquinolin-4-yl)oxy]phenyl}pyridine-3-carboxamide

[0590] [ka]

[0591] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 25 H 19 F2N3O4[M+H] + ,464.13 found 464.15. 1 H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.67-8.59(m,3H),8.27(d,J=9.2Hz,1H),7.75-7.66(m,2H),7.51(d,J=6.0Hz,1H),7 .46(d,J=2.4Hz,1H),7.35(dd,J=9.2,2.4Hz,1H),6.64(d,J=5.2Hz,1H),4.12-4.06(m,1H),3.96(s,3H),0.98-0.78(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-126.70(2F).

[0592] Example 91: 4-Cyclopropoxy-N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]-3,5-difluorophenyl}pyridine-3-carboxamide

[0593] [ka]

[0594] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 26 H 21F2N3O5[M+H] + ,494.14 found 494.15. 1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.64(d,J=6.0Hz,1H),8.62(s,1H),8.51(d,J=5.2Hz,1H),7.74-7.68(m,2H),7.55( s,1H),7.51(d,J=6.0Hz,1H),7.44(s,1H),6.62(d,J=5.2Hz,1H),4.12-4.06(m,1H),4.00-3.93(m,6H),0.79-0.92(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-126.49(2F).

[0595] Example 92: 4-Cyclopropoxy-N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]-2,3,5-trifluorophenyl}pyridine-3-carboxamide

[0596] [ka]

[0597] Synthesized using a method similar to that of Examples 52 and 50. White solid. MS ESI calculated for C 26 H 20 F3N3O5[M+H] + 512.14 found 512.15. 1 H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.83(s,1H),8.68(d,J=6.0Hz,1H),8.54(d,J=5.2Hz,1H),8.22(s,1H) ),7.58-7.53(m,2H),7.46(s,1H),6.77(d,J=5.2Hz,1H),4.27-7.18(m,1H),3.98(s,6H),0.99-0.83(m,4H).

[0598] Example 93: 4-Cyclopropoxy-N-[2,3,5-trifluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0599] [ka]

[0600] Synthesized using a method similar to that of Examples 52 and 50. White solid. MS ESI calculated for C 28 H 25 F3N4O5[M+H] + ,555.18 found 555.20. 1 H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.82(s,1H),8.68(d,J=6.0Hz,1H),8.52(d,J=5.2Hz,1H),8.26-8.16(m,1H),7.57-7.53 (m,2H),7.46(s,1H),6.76(d,J=5.2Hz,1H),4.26-4.18(m,3H),3.98(s,3H),2.98-2.95(m,2H),2.39(s,3H),0.99-0.86(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-131.50(1F),-149.75(1F),-151.23(1F).

[0601] Example 94: 4-Cyclopropoxy-N-[2,3,5-trifluoro-4-({7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0602] [ka]

[0603] Synthesized using a method similar to that of Examples 52 and 50. White solid. MS ESI calculated for C 27 H 23F3N4O4[M+H] + ,525.17 found 525.10, 1 H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.82(s,1H),8.69-8.64(m,2H),8.26(d,J=9.2Hz,1H),8.24-2.17(m,1H),7.55(d,J=6.0Hz,1H),7.46( d,J=2.4Hz,1H),7.36(dd,J=9.2,2.4Hz,1H),6.77(d,J=5.2Hz,1H),4.25-4.19(m,3H),2.92(d,J=5.6Hz,2H),2.37(s,3H),0.98-0.85(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-132.26(1F),-149.91(1F),-151.11(1F).

[0604] Example 95: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]-3,5-difluorophenyl}-4-(2-hydroxyethoxy)pyridine-3-carboxamide

[0605] [ka]

[0606] Synthesized using the same method as in Example 52. White solid. MS ESI calculated for C 25 H 21 F2N3O6[M+H] + ,498.14 found 498.15. 1 H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.79(s,1H),8.62(d,J=4.8Hz,1H),8.51(d,J=5.2Hz,1H),7.86-7.71(m,2H),7.55(s,1H),7 .44(s,1H),7.31(d,J=5.2Hz,1H),6.62(d,J=4.8Hz,1H),5.21(bs,1H),4.32(t,J=4.4Hz,2H),3.96(s,6H),3.84(t,J=4.4Hz,2H), 19F NMR(376MHz,CDCl3)δ-126.50(2F).

[0607] Example 96: 4-Cyclopropoxy-N-{3,5-difluoro-4-[(7-methoxy-1,6-naphthyridin-4-yl)oxy]phenyl}pyridine-3-carboxamide

[0608] [ka]

[0609] Synthesized using a method similar to that of Example 52. Off-white solid. MS ESI calculated for C 24 H 18 F2N4O4[M+H] + ,465.40 found 465.15. 1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),9.51(s,1H),8.82(d,J=5.2Hz,1H),8.64(d,J=5.6Hz,1H),8.62(s,1H),7.78-7.6 7(m,2H),7.51(d,J=5.6Hz,1H),7.28(s,1H),6.73(d,J=5.2Hz,1H),4.12-4.09(m,1H),4.04(s,3H),0.93-0.78(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-126.55(2F).

[0610] Example 97: 4-Cyclopropoxy-N-(3,5-difluoro-4-((7-(2-hydroxyethoxy)-6-methoxyquinolin-4-yl)oxy)phenyl)pyridine-3-carboxamide

[0611] [ka]

[0612] Step 1: 7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-4-chloro-6-methoxyquinoline

[0613] To a stirred mixture of 4-chloro-6-methoxyquinolin-7-ol (1 g, 4.77 mmol) and triphenylphosphine (2 g, 7.63 mmol) in tetrahydrofuran (10 mL) under a nitrogen atmosphere, diisopropyl azodicarboxylate (2 g, 9.89 mmol) and 2-[(tert-butyldimethylsilyl)oxy]ethanol (1 g, 5.67 mmol) were added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1 / 1), and concentrated under reduced pressure to give 7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-4-chloro-6-methoxyquinoline (1.5 g, 85%) as a white solid. MS ESI calculated for C 18 H 26 ClNO3Si[M+H] + ,368.14,370.14 found 368.20,370.20. 1 H NMR(400MHz,CDCl3)δ8.58(d,J=5.6Hz,1H),7.46(s,1H),7.41(s,1H),7.36(d,J=5.6Hz, 1H),4.28(t,J=4.4Hz,2H),4.12(t,J=4.4Hz,2H),4.04(s,3H),0.92(s,9H),0.13(s,6H).

[0614] Step 2: 7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinoline

[0615] To a stirred mixture of 7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-4-chloro-6-methoxyquinoline (1.5 g, 4.08 mmol) and 2,6-difluoro-4-nitrophenol (0.86 g, 4.91 mmol) in 1-methyl-2-pyrrolidinone (15 mL) was added N,N-diisopropylethylamine (0.79 g, 6.11 mmol) at room temperature. The resulting mixture was stirred at 140° C. for 16 hours. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 35% to 55% B in 25 min; Flow rate: 60 mL / min; Detector: UV 220 / 254 nm). The desired fractions were concentrated under reduced pressure to give 7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinoline (1 g, 48%) as a white solid. MS ESI calculated for C 24 H 28 F2N2O6Si[M+H] + ,507.17 found 507.20. 1 H NMR(400MHz,DMSO-d6)δ8.53(d,J=5.2Hz,1H),8.45-8.40(m,2H),7.56(s,1H),7.47(s,1H),6.76(d ,J=5.2Hz,1H),4.24(t,J=4.4Hz,2H),4.04(t,J=4.4Hz,2H),3.97(s,3H),0.89(s,9H),0.11(s,6H). 19 F NMR(376MHz,DMSO-d6)δ-122.69(2F).

[0616] Step 3: 4-[(7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-6-methoxyquinolin-4-yl)oxy]-3,5-difluoroaniline

[0617] To a stirred mixture of 7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinoline (900 mg, 1.777 mmol) in water (4 mL) and tetrahydrofuran (8 mL) was added iron powder (496 mg, 8.881 mmol) and ammonium chloride (475 mg, 8.880 mmol) at room temperature. The resulting mixture was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 85% to 100% B in 25 min; Flow rate: 60 mL / min; Detector: UV 220 / 254 nm). The desired fractions were concentrated under reduced pressure to give 4-[(7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-6-methoxyquinolin-4-yl)oxy]-3,5-difluoroaniline (500 mg, 59%) as a white solid. MS ESI calculated for C 24 H 30 F2N2O4Si[M+H] + ,477.19 found 477.20. 1 H NMR(400MHz,DMSO-d6)δ8.48(d,J=5.2Hz,1H),7.51(s,1H),7.41(s,1H),6.50(d,J=5.2Hz,1H),6.44-6.42 (m,2H),5.82(s,2H),4.21(t,J=4.4Hz,2H),4.03(t,J=4.4Hz,2H),3.95(s,3H),0.88(s,9H),0.10(s,6H). 19 F NMR(376MHz,DMSO-d6)δ-129.15(2F).

[0618] Step 4: N-{4-[(7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-6-methoxyquinolin-4-yl)oxy]-3,5-difluorophenyl}-4-chloropyridine-3-carboxamide

[0619] To a stirred mixture of 4-chloropyridine-3-carboxylic acid (149 mg, 0.946 mmol) in thionyl chloride (2 mL) at room temperature. The resulting mixture was stirred at 80° C. for 3 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The mixture obtained above was added portionwise to 4-[(7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-6-methoxyquinolin-4-yl)oxy]-3,5-difluoroaniline (300 mg, 0.629 mmol) in tetrahydrofuran (8 mL), followed by the addition of N,N-diisopropylethylamine (163 mg, 1.261 mmol) over 5 minutes at room temperature. The resulting mixture was stirred at room temperature for an additional 12 hours. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 55% to 65% B in 20 min; Flow rate: 60 mL / min; Detector: UV 220 / 254 nm). Fractions containing the desired product were pooled and concentrated under reduced pressure to give N-{4-[(7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-6-methoxyquinolin-4-yl)oxy]-3,5-difluorophenyl}-4-chloropyridine-3-carboxamide (150 mg, 39%) as a white solid. MS ESI calculated for C 30 H 32 ClF2N3O5Si[M+H] + ,616.18,618.18 found 616.20,618.20.

[0620] Step 5: 4-Cyclopropoxy-N-(3,5-difluoro-4-{[7-(2-hydroxyethoxy)-6-methoxyquinolin-4-yl]oxy}phenyl)pyridine-3-carboxamide

[0621] To a stirred mixture of N-{4-[(7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-6-methoxyquinolin-4-yl)oxy]-3,5-difluorophenyl}-4-chloropyridine-3-carboxamide (150 mg, 0.299 mmol) and cyclopropanol (35 mg, 0.603 mmol) in dimethyl sulfoxide (3 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (91 mg, 0.598 mmol) at room temperature. The resulting mixture was stirred at 70° C. for 12 hours. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 25% to 45% B in 25 min; Flow rate: 60 mL / min; Detector: UV 220 / 254 nm). Fractions containing the desired product were pooled, concentrated, and lyophilized under reduced pressure to give 4-cyclopropoxy-N-(3,5-difluoro-4-{[7-(2-hydroxyethoxy)-6-methoxyquinolin-4-yl]oxy}-phenyl)pyridine-3-carboxamide (74 mg, 57%) as a white solid. MS ESI calculated for C 27 H 23 F2N3O6[M+H] + ,524.16 found 524.10. 1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.64(d,J=5.6Hz,1H),8.62(s,1H),8 .50(d,J=5.2Hz,1H),7.74-7.67(m,2H),7.56(s,1H),7.51(d,J=5.6Hz,1H), 7.44(s,1H),6.62(d,J=5.2Hz,1H),4.97(t,J=5.2Hz,1H),4.19(t,J=4.8Hz ,2H),4.12-4.09(m,1H),3.98(s,3H),3.88-3.81(m,2H),0.92-0.78(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-126.47(2F).

[0622] Example 98: 4-Cyclopropoxy-N-[3,5-difluoro-4-({7-[(2S)-2-hydroxypropoxy]-6-methoxyquinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0623] [ka]

[0624] Synthesized using the same method as in Example 97. White solid. MS ESI calculated for C 28 H 25 F2N3O6[M+H] + ,538.17 found 538.15. 1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.64(d,J=6.0Hz,1H),8.62(s,1H),8.50(d,J=5.2Hz,1H),7.75-7.67(m,2H),7.56(s,1H),7.51(d,J=6.0H) z,1H),7.43(s,1H),6.62(d,J=5.2Hz,1H),4.96(d,J=4.4Hz,1H),4.13-4 .02(m,3H),4.01-3.95(m,4H),1.22(d,J=6.4Hz,3H),0.93-0.66(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-126.49(2F).

[0625] Example 99: 4-Cyclopropoxy-N-[3,5-difluoro-4-({7-[(2R)-2-hydroxypropoxy]-6-methoxyquinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0626] [ka]

[0627] Synthesized using the same method as in Example 97. White solid. MS ESI calculated for C 28 H 25F2N3O6[M+H] + ,538.17 found 538.20. 1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.64(d,J=6.0Hz,1H),8.62(s,1H),8.51 (d,J=5.2Hz,1H),7.75-7.67(m,2H),7.56(s,1H),7.51(d,J=6.0Hz,1H),7.43(s ,1H),6.63(d,J=5.2Hz,1H),4.99-4.93(m,1H),4.12-4.02(m,3H),3.99-3.9(m ,1H),3.97(s,3H),1.22(d,J=6.0Hz,3H),0.91-0.88(m,2H),0.83-0.79(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-126.48(2F).

[0628] Example 100: 4-Cyclopropoxy-N-(3,5-difluoro-4-{[7-(2-hydroxyethoxy)quinolin-4-yl]oxy}phenyl)pyridine-3-carboxamide

[0629] [ka]

[0630] Synthesized using the same method as in Example 97. White solid. MS ESI calculated for C 26 H 21 F2N3O5[M+H] + ,494.14 found 494.15. 1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.67-8.60(m,3H),8.27(d,J=9.2Hz,1H),7.77-7.65(m,2H),7.51(d,J=5.6Hz,1H),7.45(d,J=2.4Hz,1H),7.3 6(d,J=9.2,2.4Hz,1H),6.64(d,J=5.2Hz,1H),4.95(t,J=5.6Hz,1H),4.20 (t,J=4.8Hz,2H),4.14-4.06(m,1H),3.87-3.78(m,2H),0.98-0.78(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-126.69(2F).

[0631] Example 101: 4-Cyclopropoxy-N-[3,5-difluoro-4-({7-[(2R)-2-hydroxypropoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0632] [ka]

[0633] Synthesized using the same method as in Example 97. White solid. MS ESI calculated for C 27 H 23 F2N3O5[M+H] + ,508.20 found 508.15. 1 H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.67-8.59(m,3H),8.27(d,J=9.2Hz,1H),7.75-7.68(m,2H),7.51(d,J=5.6Hz,1H),7.43(d,J=2.4Hz, 1H),7.36(dd,J=9.2,2.4Hz,1H),6.64(d,J=5.2Hz,1H),4.96(d,J=4.4Hz,1H),4.13-3.99(m,4H),1.22(d,J=5.6Hz,3H),0.95-0.77(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-126.69(2F).

[0634] Example 102: 4-Cyclopropoxy-N-[3,5-difluoro-4-({7-[(2S)-2-hydroxypropoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0635] [ka]

[0636] Synthesized using the same method as in Example 97. White solid. MS ESI calculated for C 27 H 23 F2N3O5[M+H] + ,508.20 found 508.15. 1 H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.67-8.60(m,3H),8.27(d,J=9.2Hz,1H),7.75-7.68(m,2H),7.51(d,J=5.6Hz,1H),7.43(d,J=2.4Hz, 1H),7.36(dd,J=9.2,2.4Hz,1H),6.64(d,J=5.2Hz,1H),4.96(d,J=4.4Hz,1H),4.15-3.93(m,4H),1.22(d,J=5.6Hz,3H),0.93-0.78(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-126.69(2F).

[0637] Example 103: (R)-4-Cyclopropoxy-N-(3,5-difluoro-4-((7-(3-hydroxybutoxy)quinolin-4-yl)oxy)phenyl)pyridine-3-carboxamide

[0638] [ka]

[0639] Synthesized using a similar method to Example 97. Light brown solid. 1H NMR(400MHz,DMSO-d6)δ10.65(brs,1H),8.63(d,J=5.2Hz,1H),8.59- 8.57(brs,2H),8.26(d,J=9.2Hz,1H),7.67(d,J=10.8Hz,2H),7.47(d,J=6.0Hz,1H),7.43(d,J=2Hz,1H),7.33- 7.30(m,1H),6.61(d,J=4.8Hz,1H),4.62(brs,1H),4.27- 4.24(m,2H),4.06(brs,1H),3.89-3.86(m,1H),1.90- 1.78(m,2H),1.16(d,J=4.8Hz,3H),0.98- 0.83(m,4H)ppm, LCMS m / z: 522.44[M+H] + .

[0640] Example 104: 4-Cyclopropoxy-N-(3,5-difluoro-4-{[7-(2-hydroxy-2-methylpropoxy)quinolin-4-yl]oxy}phenyl)pyridine-3-carboxamide

[0641] [ka]

[0642] Synthesized using a method similar to that of Examples 97 and 40. White solid. MS ESI calculated for C 28 H 25 F2N3O5[M+H] + ,522.20 found 522.20. 1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.65(d,J=5.2Hz,1H),8.63(d,J=6.0Hz ,1H),8.62(s,1H),8.27(d,J=9.2Hz,1H),7.75-7.67(m,2H),7.51(d,J=6.0Hz, 1H),7.42(d,J=2.4Hz,1H),7.37(dd,J=9.2,2.4Hz,1H),6.64(d,J=5.2Hz,1H) ,4.73(s,1H),4.09-4.04(m,1H),3.93(s,2H),1.27(s,6H),0.94-0.76(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-126.68(2F).

[0643] Example 105: 4-Cyclopropoxy-N-(3,5-difluoro-4-{[7-(2-methoxyethoxy)quinolin-4-yl]oxy}phenyl)pyridine-3-carboxamide

[0644] [ka]

[0645] Synthesized using a method similar to that of Examples 97 and 41. Pale yellow solid. MS ESI calculated for C 27 H 23 F2N3O5[M+H] + ,508.10 found 508.15. 1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.66-8.59(m,3H),8.26(d,J=9.2Hz, 1H),7.73-7.67(m,2H),7.51(d,J=6.0Hz,1H),7.47(d,J=2.4Hz,1H),7.36(d d,J=9.2,2.4Hz,1H),6.64(d,J=5.2Hz,1H),4.33-4.28(m,2H),4.12-4.09(m ,1H),3.79-3.73(m,2H),3.36(s,3H),0.92-0.86(m,2H),0.86-0.80(m,2H). 19F NMR(376MHz,DMSO-d6)δ-126.68(2F).

[0646] Example 106: 4-Cyclopropoxy-N-(3,5-difluoro-4-{[6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl]oxy}phenyl)pyridine-3-carboxamide

[0647] [ka]

[0648] Synthesized using a method similar to that of Examples 97 and 41. White solid. MS ESI calculated for C 28 H 25 F2N3O6[M+H] + ,538.17 found 538.10. 1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.64(d,J=6.0Hz,1H),8.62(s,1H),8. 50(d,J=5.2Hz,1H),7.76-7.64(m,2H),7.56(s,1H),7.51(d,J=6.0Hz,1H),7. 46(s,1H),6.62(d,J=5.2Hz,1H),4.35-4.22(m,2H),4.11-4.07(m,1H),3.98( s,3H),3.80-3.69(m,2H),3.36(s,3H),0.93-0.86(m,2H),0.84-0.80(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-126.48(2F).

[0649] Example 107: 4-Cyclopropoxy-N-(3,5-difluoro-4-((6-(2-hydroxyethoxy)-7-methoxyquinolin-4-yl)oxy)phenyl)pyridine-3-carboxamide

[0650] [ka]

[0651] Step 1: 4-chloro-7-methoxyquinolin-6-ol

[0652] A mixture of 4-chloro-6,7-dimethoxyquinoline (1.50 g, 6.71 mmol) and (2S)-2-amino-4-(methylsulfanyl)butanoic acid (2.02 g, 13.55 mmol) in methanesulfonic acid (10 mL) was stirred at 120° C. for 16 hours. The mixture was cooled to room temperature. The mixture was neutralized to pH 8 with ammonium hydroxide (aqueous). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 42% to 62% B in 25 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm). The desired fractions were concentrated under reduced pressure to give 4-chloro-7-methoxyquinolin-6-ol (800 mg, 57%) as a yellow solid. MS ESI calculated for C 10 H8ClNO2[M+H] + ,210.02,212.02 found 210.00,212.00. 1 H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.54(d,J=4.8Hz,1H),7.49(d,J=4.8Hz,1H),7.43(s,1H),7.40(s,1H),3.97(s,3H).

[0653] Step 2: 6-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-4-chloro-7-methoxyquinoline

[0654] To a stirred mixture of 4-chloro-7-methoxyquinolin-6-ol (400 mg, 1.908 mmol) and 2-[(tert-butyldimethylsilyl)oxy]ethanol (404 mg, 2.290 mmol) in tetrahydrofuran (8 mL) was added triphenylphosphine (751 mg, 2.862 mmol) and diisopropyl azodicarboxylate (771 mg, 3.816 mmol) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1 / 1). The desired fractions were concentrated under reduced pressure to give 6-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-4-chloro-7-methoxyquinoline (622 mg, 88%) as a brown solid. MS ESI calculated for C 18 H 26 ClNO3Si[M+H] + ,368.14,370.14 found 368.16,370.16. 1 H NMR(400MHz,CDCl3)δ8.59(d,J=4.8Hz,1H),7.47(d,J=6.4Hz,2H),7.37(d,J=4.8Hz,1H),4.3 0(t,J=5.2Hz,2H),4.13(t,J=5.2Hz,2H),4.04(s,3H),1.30-1.27(m,9H),0.19-0.10(m,6H).

[0655] Step 3: 6-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinoline

[0656] To a stirred mixture of 6-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-4-chloro-7-methoxyquinoline (622 mg, 1.690 mmol) and 2,6-difluoro-4-nitrophenol (355 mg, 2.028 mmol) in 1-methyl-2-pyrrolidinone (15 mL), N,N-diisopropylethylamine (437 mg, 3.380 mmol) was added at room temperature. The resulting mixture was stirred at 140° C. for 16 hours. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography (eluent A: water (plus 10 mmol / L ammonium bicarbonate), eluent B: acetonitrile, gradient: 15% to 35% B in 25 min, flow rate: 60 mL / min, detector: 220 / 254 nm). The desired fractions were concentrated under reduced pressure to give 6-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinoline (178 mg, 21%) as a brown solid. MS ESI calculated for C 24 H 28 F2N2O6Si[M+H] + ,507.17 found 507.15. 1 H NMR(400MHz,CDCl3)δ8.56(d,J=5.2Hz,1H),8.16-8.02(m,2H),7.64(s,1H),7.54(s,1H),7.2 8(s,1H),4.33(t,J=5.6Hz,2H),4.14(t,J=5.6Hz,2H),4.07(s,3H),0.92(s,9H),0.14(s,6H).

[0657] Step 4: 4-[(6-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-7-methoxyquinolin-4-yl)oxy]-3,5-difluoroaniline

[0658] To a stirred mixture of 6-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinoline (178 mg, 0.351 mmol) and iron powder (98 mg, 1.755 mmol) in tetrahydrofuran (3 mL) and water (1 mL), ammonium chloride (37 mg, 0.702 mmol) was added at room temperature. The resulting mixture was stirred at 70 °C for 6 hours. The mixture was cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with methanol (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1 / 1), and concentrated under reduced pressure to give 4-[(6-{2-[(tert-butyl-dimethylsilyl)oxy]ethoxy}-7-methoxyquinolin-4-yl)oxy]-3,5-difluoroaniline (145 mg, 86%) as a yellow solid. MS ESI calculated for C 24 H 30 F2N2O4Si[M+H] + ,477.19 found 477.20. 1 H NMR(400MHz,CDCl3)δ8.51(d,J=5.2Hz,1H),7.69(s,1H),7.61(s,1H),7.31-7.28(m,2H),6.54(d,J=5.2Hz,1H ),6.39(d,J=5.2Hz,1H),4.32(t,J=5.6Hz,2H),4.13(t,J=5.6Hz,2H),4.06(s,3H),0.93(s,9H),0.14(s,6H).

[0659] Step 5: 4-chloro-N-(3,5-difluoro-4-{[6-(2-hydroxyethoxy)-7-methoxyquinolin-4-yl]oxy}phenyl)pyridine-3-carboxamide

[0660] To a stirred mixture of 4-[(6-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-7-methoxyquinolin-4-yl)oxy]-3,5-difluoroaniline (100 mg, 0.210 mmol) and 4-chloropyridine-3-carbonyl chloride (111 mg, 0.630 mmol) in tetrahydrofuran (2 mL) was added N,N-diisopropylethylamine (81 mg, 0.630 mmol) at room temperature. The resulting mixture was stirred at room temperature for 5 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 25% to 45% B in 25 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm). The desired fractions were concentrated under reduced pressure to give 4-chloro-N-(3,5-difluoro-4-{[6-(2-hydroxyethoxy)-7-methoxyquinolin-4-yl]oxy}phenyl)pyridine-3-carboxamide (71 mg, 67%) as a yellow solid. MS ESI calculated for C 24 H 18 ClF2N3O5[M+H] + ,502.09,504.09 found 502.10,504.10.

[0661] Step 6: 4-Cyclopropoxy-N-(3,5-difluoro-4-{[6-(2-hydroxyethoxy)-7-methoxyquinolin-4-yl]oxy}phenyl)pyridine-3-carboxamide

[0662] To a stirred mixture of 4-chloro-N-(3,5-difluoro-4-{[6-(2-hydroxyethoxy)-7-methoxyquinolin-4-yl]oxy}phenyl)pyridine-3-carboxamide (61 mg, 0.122 mmol) and cyclopropanol (63 mg, 1.098 mmol) in dimethyl sulfoxide (2 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (37 mg, 0.244 mmol) at room temperature. The resulting mixture was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature. The crude product was purified by preparative HPLC using the following conditions: Column: Xselect CSH C18 OBD column, 30x150mm 5µm, Mobile phase A: water (plus 10mmol / L ammonium bicarbonate), Mobile phase B: acetonitrile, Flow rate: 60mL / min, Gradient: 32% to 37% B in 8 min, Detector: 254 / 220nm). Fractions containing the desired product were pooled, concentrated, and lyophilized to give 4-cyclopropoxy-N-(3,5-difluoro-4-{[6-(2-hydroxyethoxy)-7-methoxyquinolin-4-yl]oxy}phenyl)pyridine-3-carboxamide (11.4mg, 18%) as a brown solid. MS ESI calculated for C 27 H 23 F2N3O6[M+H] + ,524.16 found 524.15. 1 H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.63(d,J=5.6Hz,1H),8.62(s,1H),8.51( d,J=5.2Hz,1H),7.72(s,1H),7.69(s,1H),7.58(s,1H),7.51(d,J=5.6Hz,1H),7 .45(s,1H),6.62(d,J=5.2Hz,1H),4.92(t,J=5.2Hz,1H),4.20(t,J=5.2Hz,2H), 4.11-4.09(m,1H),3.82(q,J=5.2Hz,2H),0.96-0.90(m,2H),0.87-0.82(m,2H), 19 F NMR(376MHz,DMSO-d6)δ-126.53(2F).

[0663] Example 108: 4-Cyclopropoxy-N-(3,5-difluoro-4-((7-((1-hydroxy-2-methylpropan-2-yl)oxy)quinolin-4-yl)oxy)phenyl)pyridine-3-carboxamide

[0664] [ka]

[0665] Step 1: Ethyl 2-[(4-chloroquinolin-7-yl)oxy]-2-methylpropanoate

[0666] To a stirred solution of 4-chloroquinolin-7-ol (2 g, 11.13 mmol) and ethyl α-bromoisobutyrate (4.34 g, 22.25 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (3.08 g, 22.28 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 16 hours. The mixture was cooled to room temperature. The reaction was quenched by the addition of room temperature water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1 / 1) and concentrated under reduced pressure to give ethyl 2-[(4-chloroquinolin-7-yl)oxy]-2-methylpropanoate (1.9 g, 57%) as a white solid. MS ESI calculated for C 15 H 16 ClNO3[M+H] + ,294.08,296.08 found 294.00,296.00. 1 H NMR(400MHz,CDCl3)δ8.69(d,J=4.8Hz,1H),8.13(d,J=9.2Hz,1H),7.36(d,J=4.8H z,1H),7.33-7.28(m,2H),4.28(q,J=7.2Hz,2H),1.74(s,6H),1.24(t,J=7.2Hz,3H)

[0667] Step 2: 2-[(4-chloroquinolin-7-yl)oxy]-2-methylpropan-1-ol

[0668] To a stirred solution of ethyl 2-[(4-chloroquinolin-7-yl)oxy]-2-methylpropanoate (2 g, 6.80 mmol) in methanol (20 mL) was added sodium borohydride (0.52 g, 13.61 mmol) at 0° C. The resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched by adding saturated ammonium chloride (aqueous) (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5 / 1) and concentrated under reduced pressure to give 2-[(4-chloroquinolin-7-yl)oxy]-2-methylpropan-1-ol (0.9 g, 50%) as a pale yellow oil. MS ESI calculated for C 13 H 14 ClNO2[M+H] + ,252.07,254.07 found 252.20,254.20, 1 H NMR(400MHz,CDCl3)δ8.74(d,J=4.8Hz,1H),8.15(d,J=9.2Hz,1H),7.73(d,J=2.4Hz ,1H),7.42(d,J=4.8Hz,1H),7.33(dd,J=9.2,2.4Hz,1H),3.72(s,2H),1.48(s,6H).

[0669] Step 3: 2-{[4-(2,6-difluoro-4-nitrophenoxy)quinolin-7-yl]oxy}-2-methylpropan-1-ol

[0670] To a stirred solution of 2-[(4-chloroquinolin-7-yl)oxy]-2-methylpropan-1-ol (900 mg, 3.576 mmol) and 2,6-difluoro-4-nitrophenol (751 mg, 4.291 mmol) in 1-methyl-2-pyrrolidinone (10 mL), N,N-diisopropylethylamine (924 mg, 7.152 mmol) was added at room temperature. The resulting mixture was stirred at 140° C. for 16 hours. The mixture was cooled to room temperature. The reaction was quenched by the addition of room temperature water (100 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1 / 1), and concentrated under reduced pressure to give 2-{[4-(2,6-difluoro-4-nitrophenoxy)quinolin-7-yl]oxy}-2-methylpropan-1-ol (650 mg, 46%) as a pale yellow solid. MS ESI calculated for C 19 H 16 F2N2O5[M+H] + ,391.10 found 391.10, 1 H NMR(400MHz,CDCl3)δ8.64(d,J=5.2Hz,1H),8.34(d,J=9.2Hz,1H),8.14-8.00(m,2H),7.75(d ,J=2.4Hz,1H),7.291(dd,J=9.2,2.4Hz,1H),6.43(d,J=5.2Hz,1H),3.73(s,2H),1.53(s,6H).

[0671] Step 4: 2-{[4-(4-amino-2,6-difluorophenoxy)quinolin-7-yl]oxy}-2-methylpropan-1-ol

[0672] To a stirred mixture of 2-{[4-(2,6-difluoro-4-nitrophenoxy)quinolin-7-yl]oxy}-2-methylpropan-1-ol (650 mg, 1.665 mmol) and iron powder (465 mg, 8.327 mmol) in tetrahydrofuran (8 mL) and water (4 mL), ammonium chloride (356 mg, 6.655 mmol) was added at room temperature. The resulting mixture was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3×20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10 / 1), and concentrated under reduced pressure to give 2-{[4-(4-amino-2,6-difluorophenoxy)quinolin-7-yl]oxy}-2-methylpropan-1-ol (520 mg, 86%) as a pale yellow solid. MS ESI calculated for C 19 H 18 F2N2O3[M+H] + ,361.13 found 361.15. 1 H NMR(400MHz,CDCl3)δ8.66(d,J=5.2Hz,1H),8.34(d,J=9.2Hz,1H),7.72(d,J=2.4Hz,1H),7.29(dd, J=9.2,2.4Hz,1H),6.51(d,J=5.2Hz,1H),6.41-6.34(m,2H),3.96(s,2H),3.72(s,2H),1.47(s,6H).

[0673] Step 5: 4-chloro-N-[3,5-difluoro-4-({7-[(1-hydroxy-2-methylpropan-2-yl)oxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0674] To a stirred solution of 2-{[4-(4-amino-2,6-difluorophenoxy)quinolin-7-yl]oxy}-2-methylpropan-1-ol (300 mg, 0.832 mmol) and 4-chloropyridine-3-carbonyl chloride (176 mg, 1.000 mmol) in dichloromethane (5 mL) was added N,N-diisopropylethylamine (215 mg, 1.663 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate / ethanol (4 / 3 / 1) and concentrated under reduced pressure to give 4-chloro-N-[3,5-difluoro-4-({7-[(1-hydroxy-2-methylpropan-2-yl)oxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide (240 mg, 57%) as an off-white solid. MS ESI calculated for C 25 H 20 ClF2N3O4[M+H] + ,500.11,502.11 found 500.00,501.65. 1 H NMR(400MHz,CDCl3)δ8.97(s,1H),8.65(d,J=5.2Hz,1H),8.64(d,J=5.2Hz,1H),8.51(s,1H),8.34(d,J=9.2Hz,1H),7.69(d,J=2. 4Hz,1H),7.61-7.53(m,2H),7.45(d,J=5.2Hz,1H),7.32(dd,J=9.2,2.4Hz,1H),6.48(d,J=5.2Hz,1H),3.73(s,2H),1.48(s,6H).

[0675] Step 6: 4-Cyclopropoxy-N-[3,5-difluoro-4-({7-[(1-hydroxy-2-methylpropan-2-yl)oxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0676] To a stirred solution of 4-chloro-N-[3,5-difluoro-4-({7-[(1-hydroxy-2-methylpropan-2-yl)oxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide (240 mg, 0.480 mmol) and cyclopropanol (279 mg, 4.800 mmol) in dimethyl sulfoxide (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (731 mg, 4.800 mmol) at room temperature. The resulting mixture was stirred for 16 hours at 70° C. The mixture was cooled to room temperature. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate / ethanol (4 / 3 / 1) and concentrated under reduced pressure to give the crude product (150 mg). The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Prep Phenyl OBD Column, 19 x 250 mm, 5 μm; Mobile Phase A: water (plus 10 mmol / L ammonium bicarbonate); Mobile Phase B: acetonitrile; Flow Rate: 25 mL / min; Gradient: 45% to 50% B in 10 min; Detector: UV 220 / 254 nm. Fractions containing the desired product were pooled, concentrated, and lyophilized to give 4-cyclopropoxy-N-[3,5-difluoro-4-({7-[(1-hydroxy-2-methylpropan-2-yl)oxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide (81 mg, 32%) as a white solid. MS ESI calculated for C 28 H 25 F2N3O5[M+H] + ,522.18 found 522.20. 1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.66(d,J=5.2Hz,1H),8.64(dJ=6.0Hz,1H),8.62 (s,1H),8.27(d,J=9.2Hz,1H),7.77-7.66(m,2H),7.62(d,J=2.4Hz,1H),7.51(d,J=6.0 Hz,1H),7.40(dd,J=9.2,2.4Hz,1H),6.68(d,J=5.2Hz,1H),5.04(t,J=5.6Hz,1H),4.12 -4.09(m,1H),3.51(d,J=5.6Hz,2H),1.35(s,6H),0.94-0.84(m,2H),0.82-0.81(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-126.69(2F).

[0677] Example 109: 4-Cyclopropoxy-N-(3,5-difluoro-4-((7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-6-fluoropyridine-3-carboxamide

[0678] [ka]

[0679] Step 1: Ethyl 6-chloro-4-cyclopropoxypyridine-3-carboxylate

[0680] To a stirred mixture of ethyl 4,6-dichloropyridine-3-carboxylate (10 g, 45.44 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (34.6 g, 227.22 mmol) in dimethyl sulfoxide (100 mL) was added cyclopropanol (13.2 g, 227.22 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 16 hours. The mixture was cooled to room temperature. The reaction was quenched with room temperature water (500 mL). The resulting mixture was extracted with ethyl acetate (5 × 300 mL). The mixture was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5 / 1) and concentrated under reduced pressure to give ethyl 6-chloro-4-cyclopropoxypyridine-3-carboxylate (3.8 g, 33%) as a white solid. MS ESI calculated for C 11 H 12 ClNO3[M+H] + ,242.05,244.05 found 242.00,244.00. 1 H NMR(400MHz,CDCl3)δ8.70(s,1H),7.31(s,1H),4.36(q,J=7.2Hz,2H),3.93-3.84(m,1H),1.38(t,J=7.2Hz,3H),1.02-0.89(m,4H).

[0681] Step 2: Ethyl 4-cyclopropoxy-6-fluoropyridine-3-carboxylate

[0682] To a stirred mixture of ethyl 6-chloro-4-cyclopropoxypyridine-3-carboxylate (500 mg, 2.069 mmol) and cesium fluoride (3.14 g, 20.69 mmol) in dimethyl sulfoxide (10 mL) at room temperature. The resulting mixture was stirred at 90° C. for 16 hours. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1 / 1) and concentrated under reduced pressure to give ethyl 4-cyclopropoxy-6-fluoropyridine-3-carboxylate (428 mg, 80%) as a white solid. MS ESI calculated for C 11 H 12 FNO3[M+H] + ,226.08 found 226.05. 1 H NMR(400MHz,CDCl3)δ8.62(s,1H),6.86(s,1H),4.37(q,J=7.2Hz,2H),3.94-3.85(m,1H),1.39(t,J=7.2Hz,3H),0.95-0.82(m,4H).

[0683] Step 3: 4-Cyclopropoxy-6-fluoropyridine-3-carboxylic acid

[0684] To a stirred mixture of ethyl 4-cyclopropoxy-6-fluoropyridine-3-carboxylate (420 mg, 1.865 mmol) in tetrahydrofuran (4 mL) and water (4 mL) was added lithium hydroxide (223 mg, 9.325 mmol) at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 6 with hydrochloric acid (aq). The precipitated solid was collected by filtration and washed with water (3 x 5 mL) to give 4-cyclopropoxy-6-fluoropyridine-3-carboxylic acid (198 mg, 48%) as a white solid. MS ESI calculated for C9H8FNO3 [M+H] +,198.05 found 198.05. 1 H NMR(400MHz,CDCl3)δ8.85(s,1H),6.93(s,1H),4.11-4.00(m,1H),1.05-0.99(m,4H).

[0685] Step 4: tert-butyl N-[2-({4-[4-(4-cyclopropoxy-6-fluoropyridin-3-amido)-2,6-difluorophenoxy]quinolin-7-yl}oxy)ethyl]-N-methylcarbamate

[0686] To a stirred mixture of 4-cyclopropoxy-6-fluoropyridine-3-carboxylic acid (80 mg, 0.406 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (231 mg, 0.609 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (209 mg, 1.624 mmol) and tert-butyl N-(2-{[4-(4-amino-2,6-difluorophenoxy)quinolin-7-yl]oxy}ethyl)-N-methylcarbamate (180 mg, 0.406 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The mixture was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 40 g column, eluent A: water (plus 10 mmol / L ammonium bicarbonate), eluent B: acetonitrile, gradient: 25% to 65% B, flow rate: 30 mL / min, detector: UV 220 / 254 nm). The desired fractions were collected and concentrated under reduced pressure to give tert-butyl N-[2-({4-[4-(4-cyclopropoxy-6-fluoropyridin-3-amido)-2,6-difluorophenoxy]quinolin-7-yl}oxy)ethyl]-N-methylcarbamate (101 mg, 39%) as a white solid. MS ESI calculated for C 32 H 31 F3N4O6[M+H] + ,625.22 found 625.20. 1H NMR(400MHz,CDCl3)δ9.33(s,1H),9.04(s,1H),8.65(d,J=5.2Hz,1H),8.34(d,J=9.2Hz,1H),7.53-7.43(m,3H),6.98(s,1H),6.47(d,J=5. 2Hz,1H),4.30(t,J=5.2Hz,2H),4.18-4.13(m,1H),3.73(t,J=5.2Hz,2H),3.05(s,3H),1.50(s,9H),1.20-1.10(m,2H),1.13-1.02(m,2H).

[0687] Step 5: 4-Cyclopropoxy-N-[3,5-difluoro-4-({7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-6-fluoropyridine-3-carboxamide

[0688] A mixture of tert-butyl N-[2-({4-[4-(4-cyclopropoxy-6-fluoropyridin-3-amido)-2,6-difluorophenoxy]-quinolin-7-yl}oxy)ethyl]-N-methylcarbamate (101 mg, 0.162 mmol) and hydrochloric acid (gas, 4N in 1,4-dioxane, 1 mL) in 1,4-dioxane (1 mL) was stirred for 2 h at room temperature. The precipitated solid was collected by filtration and washed with diethyl ether (3 × 5 mL). The crude product (101 mg) was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (plus 10 mmol / L ammonium bicarbonate); Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 34% to 44% B; Detector: UV 220 / 254 nm. Fractions containing the desired product were collected, concentrated, and lyophilized to give 4-cyclopropoxy-N-[3,5-difluoro-4-({7-[2-(methyl-amino)ethoxy]quinolin-4-yl}oxy)phenyl]-6-fluoropyridine-3-carboxamide (35.8 mg, 42%) as a white solid. MS ESI calculated for C 27 H 23 F3N4O4[M+H] +,525.17 found 525.25. 1 H NMR(400MHz,CD3OD)δ8.61(d,J=5.2Hz,1H),8.48(s,1H),8.36(d,J=9.2Hz,1H),7.69-7.58(m,2H),7.44(d,J=2.4Hz,1H),7.41(dd,J=9.2,2. 4Hz,1H),7.20(s,1H),6.66(d,J=5.2Hz,1H),4.33(t,J=5.2Hz,2H),4.21-4.16(m,1H),3.12(t,J=5.2Hz,2H),2.55(s,3H),1.06-0.91(m,4H). 19 F NMR(377MHz,CD3OD)δ-64.57(1F),-128.09(2F).

[0689] Example 110: 4-Cyclopropoxy-N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-6-fluoropyridine-3-carboxamide

[0690] [ka]

[0691] Synthesized using the same method as in Example 109. White solid. MS ESI calculated for C 28 H 25 F3N4O5[M+H] + ,555.18 found 555.15. 1 H NMR(400MHz,CD3OD)δ8.49(d,J=5.2Hz,1H),8.48(s,1H),7.71(s,1H),7.68-7.61(m,2H),7.44(s,1H),7.20(s,1H),6.62(d, J=5.2Hz,1H),4.36(t,J=5.2Hz,2H),4.21-4.16(m,1H),4.07(s,3H),3.18(t,J=5.2Hz,2H),2.58(s,3H),1.06-0.94(m,4H). 19F NMR(377MHz,DMSO-d6)δ-63.19(1F),-126.45(2F).

[0692] Example 111: 4-Cyclopropoxy-N-(3,5-difluoro-4-((7-(2-hydroxyethoxy)-6-methoxyquinolin-4-yl)oxy)phenyl)-6-methoxypyridine-3-carboxamide

[0693] [ka]

[0694] Synthesized using the same method as in Example 109. White solid. MS ESI calculated for C 28 H 25 F2N3O7[M+H] + ,554.17,found.554.20. 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.53(d,J=5.2Hz,1H),8.35(s,1H),7.76-7.68(m,2H),7.57(s,1H),7.45(s,1H),6.81(s,1H),6.66(d,J= 5.2Hz,1H),4.96(t,J=4.8Hz,1H),4.20(t,J=4.8Hz,2H),4.11-4.04(m, 1H),3.99(s,3H),3.94(s,3H),3.84(t,J=4.8Hz,2H),0.94-0.78(m,4H). 19 F NMR(376MHz,CDCl3)δ-126.63(2F).

[0695] Example 112: 6-chloro-4-cyclopropoxy-N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0696] [ka]

[0697] Synthesized using the same method as in Example 109. White solid. MS ESI calculated for C 28 H 25 ClF2N4O5[M+H] + ,570.15,572.15 found 570.20,572.20. 1 H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.56-8.45(m,2H),7.78-7.67(m,2H),7.56(s,1H),7.45(s,1H),7.23(s,1H),6.62(d,J=5.2Hz,1H),4. 31(tt,J=6.3,3.0Hz,1H),4.22(t,J=5.6Hz,2H),3.98(s,3H),2.95(q,J=6.2,5.6Hz,2H),2.39(s,3H),0.89-0.81(m,2H),0.81-0.69(m,2H). 19 F NMR(377MHz,DMSO-d6)δ-126.28(2F).

[0698] Example 113: 6-chloro-4-cyclopropoxy-N-[3,5-difluoro-4-({7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]pyridine-3-carboxamide

[0699] [ka]

[0700] Synthesized using the same method as in Example 109. White solid. MS ESI calculated for C 27 H 23 ClF2N4O4[M+H] + ,541.14,543.14,found 541.25,543.25, 1H NMR(400MHz,DMSO-d6)δ8.64(d,J=5.2Hz,1H),8.48(s,1H),8.26(d,J=9.2Hz,1H),7.72-7.64(m,2H),7.59(s,1H),7.45(d,J=2.4Hz,1H),7.35 (dd,J=9.2,2.4Hz,1H),6.63(d,J=5.2Hz,1H),4.22(t,J=5.6Hz,2H),4.20-4.15(m,1H),2.92(t,J=5.6Hz,2H),2.38(s,3H),0.95-0.80(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-126.57(2F).

[0701] Example 114: 4-Cyclopropoxy-N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-2-methylpyrimidine-5-carboxamide

[0702] [ka]

[0703] Synthesized using a method similar to that of Example 109. Off-white solid. MS ESI calculated for C 28 H 27 F2N5O5[M+H] + ,552.60 found 552.30. 1 H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.73(s,1H),8.50(d,J=5.2Hz,1H),7.74-7.64(m,2H),7.56(s,1H),7.45(s,1H),6.61(d,J=5. 2Hz,1H),4.55-4.46(m,1H),4.22(t,J=5.6Hz,2H),3.98(s,3H),2.95(d,J=5.6Hz,2H),2.64(s,3H),2.39(s,3H),0.88-0.81(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-126.42(2F).

[0704] Example 115: 4-Cyclopropoxy-N-(3,5-difluoro-4-((7-(2-(methylamino)ethoxy)quinolin-4-yl)oxy)phenyl)-6-methylpyridine-3-carboxamide

[0705] [ka]

[0706] Step 1: Methyl 6-bromo-4-cyclopropoxypyridine-3-carboxylate

[0707] To a stirred mixture of methyl 6-bromo-4-chloropyridine-3-carboxylate (1 g, 3.99 mmol) and cyclopropanol (1.16 g, 19.96 mmol) in dimethyl sulfoxide (10.00 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.19 mL, 7.984 mmol) at room temperature. The resulting mixture was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature. The mixture was purified by reverse-phase flash chromatography (Column: WelFlash™ C18-I, 20-40 μm, 120 g, Eluent A: water (plus 10 mmol / L ammonium bicarbonate), Eluent B: acetonitrile, Gradient: 2% to 5% B, Flow Rate: 40 mL / min, Detector: UV 220 / 254 nm). The desired fractions were collected and concentrated under reduced pressure to give methyl 6-bromo-4-cyclopropoxypyridine-3-carboxylate (190 mg, 19%) as a yellow solid. MS ESI calculated for C 10 H 10 BrNO3[M+H] + ,271.98,273.98 found 272.05,274.05.

[0708] Step 2: Methyl 4-cyclopropoxy-6-methylpyridine-3-carboxylate

[0709] To a stirred mixture of methyl 6-bromo-4-cyclopropoxypyridine-3-carboxylate (190 mg, 0.698 mmol), trimethyl-1,3,5,2,4,6-trioxatriborinane (175 mg, 1.396 mmol), and potassium carbonate (337 mg, 2.443 mmol) in dioxane (2 mL), Pd(dppf)Cl2 (51 mg, 0.070 mmol, CAS: 72287-26-4) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate / ethanol (4 / 3 / 1), and concentrated under reduced pressure to give methyl 4-cyclopropoxy-6-methylpyridine-3-carboxylate (110 mg, 76%) as a white solid. MS ESI calculated for C 11 H 13 NO3[M+H] + ,208.10 found 208.10. 1 H NMR(400MHz,CDCl3)δ8.84(s,1H),7.16(s,1H),3.89(s,3H),3.89-3.85(m,1H),2.63(s,3H),0.95-0.89(m,4H).

[0710] Step 3: 4-Cyclopropoxy-6-methylpyridine-3-carboxylic acid

[0711] A mixture of methyl 4-cyclopropoxy-6-methylpyridine-3-carboxylate (110 mg, 0.531 mmol) and lithium hydroxide (63 mg, 2.655 mmol) in tetrahydrofuran (1 mL) and water (1 mL) was stirred for 2 hours at room temperature. The mixture was acidified to pH 6 with hydrochloric acid (4N in water). The mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (Column: WelFlash™ C18-I, 20-40 μm, 40 g, Eluent A: water (plus 10 mmol / L hydrochloric acid), Eluent B: acetonitrile, Gradient: 2% to 5% B in 10 min, Flow rate: 40 mL / min, Detector: UV 220 / 254 nm). The desired fractions were concentrated under reduced pressure to give 4-cyclopropoxy-6-methylpyridine-3-carboxylic acid (270 mg, crude) as a white solid. MS ESI calculated for C 10 H 11 NO3[M+H] + ,194.10 found 194.05. 1 H NMR(400MHz,DMSO-d6)δ8.73(s,1H),7.80(s,1H),7.38(s,1H),4.23-4.18(m,1H),2.71(s,3H),0.96-0.92(m,2H),0.82-0.78(m,2H).

[0712] Step 4: tert-butyl N-[2-({4-[4-(4-cyclopropoxy-6-methylpyridin-3-amido)-2,6-difluorophenoxy]quinolin-7-yl}oxy)ethyl]-N-methylcarbamate

[0713] A mixture of 4-cyclopropoxy-6-methylpyridine-3-carboxylic acid (160 mg, 0.828 mmol) and N,N-diisopropylethylamine (58 mg, 0.448 mmol) in propylphosphonic anhydride (2 mL, 1N in ethyl acetate) was stirred at room temperature for 5 minutes. To the above mixture, tert-butyl N-(2-{[4-(4-amino-2,6-difluorophenoxy)quinolin-7-yl]oxy}ethyl)-N-methylcarbamate (100 mg, 0.224 mmol) was added at room temperature. The resulting mixture was stirred at 70° C. for 2 hours. The mixture was cooled to room temperature. The mixture was basified to pH 8 with saturated sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3×50 mL) and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate / ethanol (4 / 3 / 1) and concentrated under reduced pressure to give tert-butyl N-[2-({4-[4-(4-cyclopropoxy-6-methylpyridin-3-amido)-2,6-difluorophenoxy]quinolin-7-yl}oxy)ethyl]-N-methylcarbamate (85 mg, 61%) as a white oil. MS ESI calculated for C 33 H 34 F2N4O6[M+H] + ,621.20 found 621.20.

[0714] Step 5: 4-Cyclopropoxy-N-[3,5-difluoro-4-({7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-6-methylpyridine-3-carboxamide

[0715] To a stirred mixture of tert-butyl N-2-({4-[4-(4-cyclopropoxy-6-methylpyridin-3-amido)-2,6-difluorophenoxy]quinolin-7-yl}oxy)ethyl]-N-methylcarbamate (85 mg, 0.137 mmol) in dichloromethane (4 mL), hydrochloric acid (4 mL, 4N in dioxane) was added at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The mixture was basified to pH 8 with ammonia (gas, 7N in methanol). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (plus 10 mmol / L ammonium bicarbonate); Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 29% to 39% B; Detector: UV 220 / 254 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to give 4-cyclopropoxy-N-[3,5-difluoro-4-({7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-6-methylpyridine-3-carboxamide (32.4 mg, 45%) as a white solid. MS ESI calculated for C 28 H 26 F2N4O4[M+H] + ,521.20 found 521.20. 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.64(d,J=5.2Hz,1H),8.51(s,1H),8.2 6(d,J=9.2Hz,1H),7.76-7.66(m,2H),7.45(d,J=2.4Hz,1H),7.37(s,1H),7.35 (dd,J=9.2,2.4Hz,1H),6.63(d,J=5.2Hz,1H),4.22(t,J=5.6Hz,2H),4.06-4. 02(m,1H),2.92(t,J=5.6Hz,2H),2.55(s,3H),2.38(s,3H),0.93-0.80(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-126.79(2F).

[0716] Example 116: 4-Cyclopropoxy-N-(3,5-difluoro-4-{[7-(2-hydroxyethoxy)-6-methoxyquinolin-4-yl]oxy}phenyl)-6-methylpyridine-3-carboxamide

[0717] [ka]

[0718] Synthesized using a method similar to that of Examples 97 and 115. White solid. MS ESI calculated for C 28 H 25 F2N3O6[M+H] + ,538.20 found 538.10. 1 H NMR(400MHz,DMSO-d6)δ10.46(s,1H),8.52(s,1H),8.50(d,J=5.2Hz,1H),7.75-7.67(m,2H),7.56(s,1H),7.44(s,1H),7.37(s,1H),6.61(d,J =5.2Hz,1H),4.95(t,J=5.2Hz,1H),4.19(t,J=5.2Hz,2H),4.10-4.03(m,1H),3.98(s,3H),3.84-3.80(m,2H),2.55(s,3H),0.95-0.78(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-126.59(2F).

[0719] Example 117: 4-Cyclopropoxy-N-[3,5-difluoro-4-({6-methoxy-7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)phenyl]-6-methylpyridine-3-carboxamide

[0720] [ka]

[0721] Synthesized using a method similar to that of Examples 52 and 115. White solid. MS ESI calculated for C 29 H28 F2N4O5[M+H] + ,551.20, found 551.30. 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.54-8.48(m,2H),7.75-7.67(m,2H),7.56(s,1H),7.45(s,1H),7.38(s,1H),6.61(d,J=5.2 Hz,1H),4.22(t,J=5.6Hz,2H),4.10-4.04(m,1H),3.98(s,3H),2.94(d,J=5.6Hz,2H),2.55(s,3H),2.39(s,3H),0.94-0.77(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-126.60(2F).

[0722] Example 118: 4-Cyclopropoxy-N-(3,5-difluoro-4-((7-(2-hydroxyethoxy)-6-methoxyquinolin-4-yl)oxy)phenyl)-2-fluoropyridine-3-carboxamide

[0723] [ka]

[0724] Step 1: Ethyl 2-chloro-4-cyclopropoxypyridine-3-carboxylate

[0725] To a stirred solution of ethyl 2,4-dichloropyridine-3-carboxylate (2 g, 9.09 mmol) and cyclopropanol (2.1 g, 36.35 mmol) in dimethyl sulfoxide (20 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.7 g, 18.17 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 16 hours. The mixture was cooled to room temperature. The reaction was quenched by the addition of room temperature water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1 / 1) and concentrated under reduced pressure to give ethyl 2-chloro-4-cyclopropoxypyridine-3-carboxylate (800 mg, 36%) as a yellow oil. MS ESI calculated for C 11 H 12 ClNO3[M+H] + ,242.05,244.05 found 242.00,244.00. 1 H NMR (400MHz, CDCl3) δ8.29(d,J=6.0Hz,1H),7.18(d,J=6.0Hz,1H),4.40(q,J=7.2Hz,2H),3.88-3.86(m,1H),1.37(t,J=7.2Hz,3H),0.92-0.78(m,4H).

[0726] Step 2: Ethyl 4-cyclopropoxy-2-fluoropyridine-3-carboxylate

[0727] To a stirred solution of ethyl 2-chloro-4-cyclopropoxypyridine-3-carboxylate (800 mg, 3.310 mmol) in dimethyl sulfoxide (10 mL) was added cesium fluoride (2.51 g, 16.55 mmol) at room temperature. The resulting mixture was stirred at 90° C. for 96 hours. The mixture was cooled to room temperature. The reaction was quenched by the addition of room temperature water (50 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (150 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Column: XBridge Prep Phenyl OBD Column, 19 x 250 mm, 5 μm; Mobile Phase A: Water (plus 10 mmol / L ammonium bicarbonate); Mobile Phase B: Acetonitrile; Flow Rate: 25 mL / min; Gradient: 40% to 42% B in 12 min; Detector: UV 220 / 254 nm) and concentrated under reduced pressure to give ethyl 4-cyclopropoxy-2-fluoropyridine-3-carboxylate (150 mg, 20%) as a white solid. MS ESI calculated for C 11 H 12 FNO3[M+H] + ,226.08 found 226.05, 1 H NMR(400MHz,CDCl3)δ8.17(d,J=6.0Hz,1H),7.17(d,J=6.0Hz,1H),4.40(q,J=7.2Hz,2H),3.95-3.86(m,1H),1.38(t,J=7.2Hz,3H),0.90-0.89(m,4H).

[0728] Step 3: 4-Cyclopropoxy-2-fluoropyridine-3-carboxylic acid

[0729] To a stirred solution of ethyl 4-cyclopropoxy-2-fluoropyridine-3-carboxylate (150 mg, 0.666 mmol) in tetrahydrofuran (2 mL) was added lithium hydroxide (80 mg, 3.340 mmol) and water (1 mL) at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The mixture was acidified to pH 5 with hydrochloric acid (aqueous). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (Column: WelFlash™ C18-I, 20-40 μm, 120 g, Eluent A: water (plus 10 mmol / L ammonium bicarbonate), Eluent B: acetonitrile, Gradient: 30% to 60% B in 25 min, Flow rate: 60 mL / min, Detector: UV 220 / 254 nm). Fractions containing the desired product were collected and concentrated under reduced pressure to give 4-cyclopropoxy-2-fluoropyridine-3-carboxylic acid (69 mg, 52%) as a white solid. MS ESI calculated for C9H8FNO3 [M+H] + ,198.05 found 198.00, 1 H NMR(400MHz,CDCl3)δ8.24(d,J=6.0Hz,1H),7.23(d,J=6.0Hz,1H),3.97-3.91(m,1H),0.95-0.91(m,4H).

[0730] Step 4: N-{4-[(7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-6-methoxyquinolin-4-yl)oxy]-3,5-difluorophenyl}-4-cyclopropoxy-2-fluoropyridine-3-carboxamide

[0731] A solution of 4-cyclopropoxy-2-fluoropyridine-3-carboxylic acid (69 mg, 0.350 mmol) in oxalyl chloride (1 mL) was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure. Dichloromethane (2 mL) was added to the above mixture, followed by the addition of 4-[(7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-6-methoxyquinolin-4-yl)oxy]-3,5-difluoroaniline (100 mg, 0.210 mmol) in small portions. N,N-Diisopropylethylamine (90 mg, 0.700 mmol) was then added to the above mixture with stirring. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1 / 1), and concentrated under reduced pressure to give N-{4-[(7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-6-methoxyquinolin-4-yl)oxy]-3,5-difluorophenyl}-4-cyclopropoxy-2-fluoropyridine-3-carboxamide (25 mg, 10%) as a white solid. MS ESI calculated for C 33 H 36 F3N3O6Si[M+H] + ,656.23 found 656.20.

[0732] Step 5: 4-Cyclopropoxy-N-(3,5-difluoro-4-{[7-(2-hydroxyethoxy)-6-methoxyquinolin-4-yl]oxy}phenyl)-2-fluoropyridine-3-carboxamide

[0733] To a stirred solution of N-{4-[(7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-6-methoxyquinolin-4-yl)oxy]-3,5-difluorophenyl}-4-cyclopropoxy-2-fluoropyridine-3-carboxamide (20 mg, 0.030 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The mixture was basified to pH 8 with ammonia (7N in methanol). The resulting mixture was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; Mobile phase A: water (plus 10 mmol / L ammonium bicarbonate); Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 30% to 40% B in 8 min; Detector: UV 220 / 254 nm. Fractions containing the desired product were pooled, concentrated, and lyophilized to give 4-cyclopropoxy-N-(3,5-difluoro-4-{[7-(2-hydroxyethoxy)-6-methoxyquinolin-4-yl]oxy}phenyl)-2-fluoropyridine-3-carboxamide (1.9 mg, 11%) as a white solid. MS ESI calculated for C 27 H 22 F3N3O6[M+H] + ,542.15 found 542.10. 1 H NMR(400MHz,CD3OD)δ8.49(d,J=5.2Hz,1H),8.25(d,J=6.0Hz,1H),7.70(s,1H),7.66-7.57(m,2H),7.48(d,J=6.0Hz,1H),7.43(s,1H),6 .62(d,J=5.2Hz,1H),4.28(t,J=4.4Hz,2H),4.14-4.10(m,1H),4.07(s,3H),4.03(t,J=4.4Hz,2H),1.05-0.95(m,2H),0.88-0.86(m,2H). 19 F NMR(377MHz,CD3OD)δ-73.95(1F),-127.76(2F).

[0734] Example 119: N-(3,5-difluoro-4-((6-methoxy-7-(3-(methylamino)propoxy)quinolin-4-yl)oxy)phenyl)-4-methoxypyridine-3-carboxamide

[0735] [ka]

[0736] Synthesized using a similar method to Example 118. Light brown solid. 1 H NMR(400 MHzDMSO-d6)δ11.18(s,1H),8.77(brs,1H),8.76(brs,2H),8.26(d,J=5.2 Hz,1H),7.73(s,2H),7.71(s,1H),7.61(s,1H),7.26(d,J=6.0Hz,1H),7.12 (brs,1H),4.35-4.25(m,4H),4.04(s,3H),3.20-3.10(m,2H),2.62(t,J=5. 6Hz,3H),2.23-2.18(m,2H),1.34(t,J=6.8Hz,3H),1.24(brs,1H)ppm.LCMS m / z: 557[M+H] + .

[0737] Example 120: 4-Cyclopropoxy-N-(3,5-difluoro-4-((7-(2-methoxyethoxy)quinolin-4-yl)oxy)phenyl)pyridazine-3-carboxamide

[0738] [ka]

[0739] Step 1: Ethyl 6-chloro-4-cyclopropoxypyridazine-3-carboxylate

[0740] To a stirred mixture of ethyl 4,6-dichloropyridine-3-carboxylate (1 g, 4.52 mmol) and cyclopropanol (0.39 g, 6.78 mmol) in dimethyl sulfoxide (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.38 g, 9.05 mmol) at room temperature. The resulting mixture was stirred at 50° C. for 16 hours. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 330 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 30% to 60% B in 25 min; Flow rate: 80 mL / min; Detector: UV 220 / 254 nm). The desired fractions were concentrated under reduced pressure to give ethyl 6-chloro-4-cyclopropoxypyridazine-3-carboxylate (500 mg, 46%) as a yellow oil. MS ESI calculated for C 10 H 11 ClN2O3[M+H] + ,243.05 found 243.20. 1 H NMR(400MHz,DMSO-d6)δ7.33(s,1H),4.41-4.36(m,1H),3.47(q,J=7.2Hz,2H),1.60(t,J=7.2Hz,3H),0.84-0.79(m,2H),0.75-0.69(m,2H).

[0741] Step 2: Ethyl 4-cyclopropoxypyridazine-3-carboxylate

[0742] A solution of ethyl 6-chloro-4-cyclopropoxypyridazine-3-carboxylate (500 mg, 2.060 mmol) and Pd / C (387 mg, 1.030 mmol) in methanol (10 mL) was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered, and the filter cake was washed with methanol (3 × 10 mL). The filtrate was concentrated under reduced pressure to give ethyl 4-cyclopropoxypyridazine-3-carboxylate (374 mg, 87%) as a yellow solid. MS ESI calculated for C 10 H12 N2O3[M+H] + ,209.08 found 209.05. 1 H NMR(400MHz,DMSO-d6)δ9.19(d,J=6.4Hz,1H),7.72(d,J=6.4Hz,1H),4.38(q,J=7.2Hz ,2H),4.21-4.15(m,1H),1.31(t,J=7.2Hz,3H),0.99-0.86(m,2H),0.82-0.75(m,2H).

[0743] Step 3: 4-Cyclopropoxypyridazine-3-carboxylic acid

[0744] A mixture of ethyl 4-cyclopropoxypyridazine-3-carboxylate (374 mg, 1.796 mmol) and lithium hydroxide (215 mg, 8.980 mmol) in tetrahydrofuran (4 mL) and water (2 mL) was stirred at room temperature for 5 hours. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 6 with hydrochloric acid (aq). The precipitated solid was collected by filtration and washed with water (2 x 10 mL) to give 4-cyclopropoxypyridazine-3-carboxylic acid (258 mg, 79%) as a white solid. MS ESI calculated for C8H8N2O3 [M+H] + ,181.05 found 181.20.

[0745] Step 4: 4-Cyclopropoxy-N-(3,5-difluoro-4-{[7-(2-methoxyethoxy)quinolin-4-yl]oxy}phenyl)pyridazine-3-carboxamide

[0746] A mixture of 4-cyclopropoxypyridazine-3-carboxylic acid (31 mg, 0.173 mmol) in oxalyl chloride (2 mL) was stirred at 75° C. for 16 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. To the above reaction mixture, 3,5-difluoro-4-{[7-(2-methoxyethoxy)quinolin-4-yl]oxy}aniline (60 mg, 0.173 mmol) and tetrahydrofuran (2 mL) were added and stirred at room temperature for 5 minutes. To the final reaction mixture, N,N-diisopropylethylamine (45 mg, 0.346 mmol) was added and stirred at room temperature for 5 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; Mobile phase A: water (plus 10 mmol / L ammonium bicarbonate); Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 36% to 46% B in 8 min; Detector: UV 220 / 254 nm. Fractions containing the desired product were pooled, concentrated, and lyophilized to give 4-cyclopropoxy-N-(3,5-difluoro-4-{[7-(2-methoxyethoxy)quinolin-4-yl]oxy}phenyl)pyridazine-3-carboxamide (0.9 mg, 1%) as a yellow solid. MS ESI calculated for C 26 H 22 F2N4O5[M+H] + ,509.16 found 509.15. 1 H NMR(400MHz,DMSO-d6)δ11.24(s,1H),9.25(d,J=6.4Hz,1H),8.65(d,J=5.2Hz,1H), 8.27(d,J=9.2Hz,1H),7.82-7.78(m,2H),7.77(d,J=6.4Hz,1H),7.46(d,J=2.4Hz,1H ),7.36(dd,J=9.2,2.4Hz,1H),6.66(d,J=5.2Hz,1H),4.34(t,J=5.6Hz,2H),4.19-4. 16(m,1H),3.76(t,J=5.6Hz,2H),3.39(s,3H),0.95-0.88(m,2H),0.81-0.79(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-126.51(2F).

[0747] Example 121: N-(3,5-difluoro-4-((7-(2-hydroxyethoxy)-6-methoxyquinolin-4-yl)oxy)phenyl)-4-methoxypyridine-3-carboxamide

[0748] [ka]

[0749] Step 1: N-{4-[(7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-6-methoxyquinolin-4-yl)oxy]-3,5-difluorophenyl}-4-methoxypyridine-3-carboxamide

[0750] To a stirred mixture of 4-methoxypyridine-3-carboxylic acid (128 mg, 0.840 mmol) and propylphosphonic anhydride (1.5 mL, 50% in ethyl acetate) in pyridine (3 mL) was added 4-[(7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-6-methoxyquinolin-4-yl)oxy]-3,5-difluoroaniline (200 mg, 0.420 mmol, synthesized in Step 3 of Example 97) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 55% to 75% B in 25 min; Flow rate: 60 mL / min; Detector: UV 220 / 254 nm). The desired fractions were collected and concentrated under reduced pressure to give N-{4-[(7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-6-methoxyquinolin-4-yl)oxy]-3,5-difluorophenyl}-4-methoxypyridine-3-carboxamide (143 mg, 56%) as a white solid. MS ESI calculated for C 31 H 35 F2N3O6Si[M+H] +,612.23 found 612.15. 1 H NMR(400MHz,CDCl3)δ9.54(s,1H),9.37(s,1H),8.73(d,J=6.0Hz,1H),8.54(d,J=5.2Hz,1H),7.64(s,1H),7.60-7.53(m,2H),7.28(s,1H),7. 03(d,J=6.0Hz,1H),6.56(d,J=5.2Hz,1H),4.33(t,J=5.2Hz,2H),4.20(s,3H),4.14(t,J=5.2Hz,2H),4.08(s,3H),0.94(s,9H),0.15(s,6H).

[0751] Step 2: N-(3,5-difluoro-4-{[7-(2-hydroxyethoxy)-6-methoxyquinolin-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide

[0752] To a stirred solution of N-{4-[(7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-6-methoxyquinolin-4-yl)oxy]-3,5-difluorophenyl}-4-methoxypyridine-3-carboxamide (143 mg, 0.234 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (1.5 mL) at room temperature. The resulting mixture was stirred for 1 hour at room temperature. The mixture was basified to pH 8 with saturated sodium bicarbonate (aqueous). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (WelFlash™ C18-I, 20-40 μm, 120 g column; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 30% to 50% B in 25 min; Flow rate: 60 mL / min; Detector: UV 220 / 254 nm). The desired fractions were concentrated under reduced pressure to give N-(3,5-difluoro-4-{[7-(2-hydroxyethoxy)-6-methoxyquinolin-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide (48 mg, 41%) as a white solid. MS ESI calculated for C 25 H 21 F2N3O6[M+H]+ ,498.14 found 498.30. 1 H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.64(s,1H),8.62(d,J=6.0Hz,1H),8.50(d,J=5.2Hz,1H),7.81-7.71(m,2H),7.56(s,1H),7.45(s,1 H),7.28(d,J=6.0Hz,1H),6.61(d,J=5.2Hz,1H),4.96(t,J=5.2Hz,1H),4.20(t,J=4.8Hz,2H),3.98(s,3H),3.97(s,3H),3.88-3.84(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-126.56(2F).

[0753] Example 122: N-(3,5-difluoro-4-{[6-(2-hydroxyethoxy)-7-methoxyquinolin-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide

[0754] [ka]

[0755] Step 1: 1-(benzyloxy)-2-methoxy-4-nitrobenzene

[0756] To a stirred mixture of 2-methoxy-4-nitrophenol (100.00 g, 591.24 mmol) and potassium carbonate (245.14 g, 1773.72 mmol) in N,N-dimethylformamide (1 L) was added benzyl bromide (121.35 g, 709.49 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 1.5 hours. The mixture was cooled to room temperature and quenched with water (1 × 3 L). The resulting mixture was extracted with ethyl acetate (3 × 3 L). The combined organic layers were washed with water (5 × 2 L) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 1-(benzyloxy)-2-methoxy-4-nitrobenzene (143.40 g, 94%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ7.86(dd,J=8.8,2.4Hz,1H),7.78(d,J=2.4Hz,1H),7.49-7.26(m,5H),6.95(d,J=8.8Hz,1H),5.27(s,2H),3.98(s,3H).

[0757] Step 2: 4-(benzyloxy)-3-methoxyaniline

[0758] To a stirred mixture of 1-(benzyloxy)-2-methoxy-4-nitrobenzene (73.40 g, 283.11 mmol) and iron powder (79.05 g, 1415.56 mmol) in tetrahydrofuran (700 mL) was added ammonium chloride (30.29 g, 566.22 mmol) and water (700 mL) at room temperature. The resulting mixture was stirred at 70 °C for 4 hours. The mixture was cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with methanol (5 × 200 mL). The filtrate was concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with water (10 × 200 mL). The solid was collected and dried under reduced pressure to give 4-(benzyloxy)-3-methoxyaniline (64 g, crude) as a yellow solid. MS ESI calculated for C 14 H 15 NO2[M+H] + ,230.11 found 229.85.

[0759] Step 3: 5-({[4-(benzyloxy)-3-methoxyphenyl]amino}methylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0760] A mixture of 4-(benzyloxy)-3-methoxyaniline (64.00 g, 279.13 mmol) and 5-(methoxymethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (62.36 g, 334.96 mmol) in isopropyl alcohol (600 mL) was stirred at 110 °C for 4 hours. After the reaction, the mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with isopropyl alcohol (5 × 200 mL). The solid was collected and dried under reduced pressure to give 5-({[4-(benzyloxy)-3-methoxyphenyl]amino}methylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (92 g, crude) as a yellow solid. MS ESI calculated for C 21 H 21 NO6[M+H] + ,384.14 found 383.95.

[0761] Step 4: 6-(benzyloxy)-7-methoxyquinolin-4-ol

[0762] 5-({[4-(benzyloxy)-3-methoxyphenyl]amino}methylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (92.00 g, 239.96 mmol) in diphenyl ether (1 L) was stirred at 220° C. for 1 h. The mixture was cooled to room temperature. The residue was dissolved in petroleum ether (5 L). The precipitated solid was collected by filtration and washed with petroleum ether (5×500 mL). The solid was collected and dried under reduced pressure to give 6-(benzyloxy)-7-methoxyquinolin-4-ol (66.30 g, crude) as a yellow solid. MS ESI calculated for C 17 H 15 NO3[M+H] + ,282.11 found 281.95.

[0763] Step 5: 6-(benzyloxy)-4-chloro-7-methoxyquinoline

[0764] To a stirred mixture of 6-(benzyloxy)-7-methoxyquinolin-4-ol (66.30 g, 235.68 mmol) and phosphorus oxychloride (54.20 g, 353.52 mmol) in 1,2-dichloroethane (600 mL) was added N,N-diisopropylethylamine (60.92 g, 471.36 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature. The resulting mixture was quenched with water (1 L) and extracted with dichloromethane (5 × 2 L). The combined organic layers were washed with water (3 × 1 L) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 6-(benzyloxy)-4-chloro-7-methoxyquinoline (76 g, crude) as a yellow solid. MS ESI calculated for C 17 H 14 ClNO2[M+H] + ,300.07,302.07 found 299.85,301.85.

[0765] Step 6: 6-(benzyloxy)-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinoline

[0766] To a stirred mixture of 6-(benzyloxy)-4-chloro-7-methoxyquinoline (17.00 g, 56.71 mmol) and 2,6-difluoro-4-nitrophenol (11.92 g, 68.06 mmol) in 1-methyl-2-pyrrolidinone (170 mL) was added N,N-diisoprop...

Claims

1. Formula (I) 【Chemistry 1】 or a pharma- ceutically acceptable salt or solvate thereof, wherein V is independently N or C-L-R; X is independently N or C-L １ -R １ and Z is N or C-R ２ where V, X, and Z are not all necessarily N; W is C—H or N; Y １ are independently N or C-R ３ and Y ２ are independently N or C-R ４ and Y ３ are independently N or C-R ３ and Y ４ are independently N or C-R ３ and L is a bond, —O—, —NH—, —NHCO—, or —CONH—; L １ is a bond, —O—, —NH—, —NHCO—, or —CONH—, R is H, halogen, —CN, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkenyl, optionally substituted C １ -C ６ Alkynyl, optionally substituted C ３ -C ６ selected from the group consisting of cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; R １ is H, halogen, —CN, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkenyl, optionally substituted C １ -C ６ Alkynyl, optionally substituted C ３ -C ６ selected from the group consisting of cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; R ２ is H, halogen, —CN, optionally substituted C １ -C ６ Alkyl, -NH (optionally substituted C １ -C ６ alkyl), or optionally substituted C １ -C ４ is an alkoxy; R ３ are H, halogen, -CN, and -NH, respectively. ２ , -NH (optionally substituted C １ -C ６ alkyl), -N(optionally substituted C １ -C ６ Alkyl) ２ , optionally substituted C １ -C ４ Alkoxy, or optionally substituted C １ -C ４ alkyl, R ４ is H, halogen, —CN, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkoxy, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -NH ２ , -NH (optionally substituted C １ -C ６ alkyl), or -N(optionally substituted C １ -C ６ Alkyl) ２ are independently selected from R ５ is fluoro, R ６ , R ７ , and R ８ each independently represents H, halogen, optionally substituted C １ -C ４ Alkyl, optionally substituted C １ -C ４ alkoxy, or -CN, where R ６ , R ７ , or R ８ At least one of is not H, Q is fluoro or -L ２ -R ９ and L ２ is -O- or optionally substituted C １ -C ５ is alkylene, and R ９ is halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkynyl, optionally substituted C １ -C ６ Alkenyl, optionally substituted C ３ -C ６ A compound, or a pharma- ceutically acceptable salt or solvate thereof, selected from the group consisting of cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl.

2. 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein V is N.

3. 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein V is C-L-R.

4. 4. The compound of any one of claims 1 to 3, or a pharma- ceutically acceptable salt or solvate thereof, wherein X is N.

5. X is C-L １ -R １ 4. The compound according to any one of claims 1 to 3, which is: or a pharma- ceutically acceptable salt or solvate thereof.

6. 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt or solvate thereof, wherein Z is N.

7. Z is C-R ２ 6. The compound according to any one of claims 1 to 5, which is: or a pharma- ceutically acceptable salt or solvate thereof.

8. 8. The compound of any one of claims 1 to 7, or a pharma- ceutically acceptable salt or solvate thereof, wherein W is C--H.

9. 8. The compound of any one of claims 1 to 7, or a pharma- ceutically acceptable salt or solvate thereof, wherein W is N.

10. Y １ The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt or solvate thereof, wherein

11. Y １ is C-R ３ 10. The compound of any one of claims 1 to 9, which is: or a pharma- ceutically acceptable salt or solvate thereof.

12. Y ２ The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt or solvate thereof, wherein

13. Y ２ is C-R ３ 12. The compound of any one of claims 1 to 11, which is: or a pharma- ceutically acceptable salt or solvate thereof.

14. Y ３ The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt or solvate thereof, wherein

15. Y ３ is C-R ４ 14. The compound of any one of claims 1 to 13, wherein:

16. Y ４ The compound according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt or solvate thereof, wherein

17. Y ４ is C-R ３ 16. The compound of any one of claims 1 to 15, wherein:

18. R ６ 18. The compound of any one of claims 1 to 17, or a pharma- ceutically acceptable salt or solvate thereof, wherein is fluoro.

19. L ２ The compound of any one of claims 1 to 18, or a pharma- ceutically acceptable salt or solvate thereof, wherein: is -O-.

20. R ９ is optionally substituted C １ -C ６ Alkyl, or optionally substituted C ３ -C ６ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt or solvate thereof, which is cycloalkyl.

21. Formula (II) 【Chemistry 2】 wherein: R ６ , R ７ , and R ８ are each independently selected from H or halogen, with the proviso that R ６ , R ７ , or R ８ At least one of is not H, R ９ is an optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ cycloalkyl, and optionally substituted cycloalkylalkyl; R １０ is H, R １１ is H, halogen, -NH ２ , -CN, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkoxy, -NH (optionally substituted C １ -C ６ alkyl), or -N(optionally substituted C １ -C ６ Alkyl) ２ and R １２ is H, halogen, -NH ２ , -CN, optionally substituted C １ -C ６ Alkyl, or optionally substituted C １ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, which is alkoxy.

22. X is C-L １ -R １ 22. The compound of claim 21, wherein:

23. L １ The compound of claim 22, or a pharma- ceutically acceptable salt or solvate thereof, wherein: is -O-.

24. L １ 23. The compound of claim 22, or a pharma- ceutically acceptable salt or solvate thereof, wherein is a single bond.

25. R １ is H, or a pharma- ceutically acceptable salt or solvate thereof.

26. R １ is optionally substituted C １ -C ６ 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

27. R １ is optionally substituted C １ -C ２ 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

28. R １ is optionally substituted C １ 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

29. L １ is a single bond, R １ 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt or solvate thereof, wherein is hydrogen.

30. 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt or solvate thereof, wherein L is -O-.

31. R is optionally substituted C １ -C ６ 31. The compound of any one of claims 1 to 30, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

32. R is optionally substituted C １ -C ４ 31. The compound of any one of claims 1 to 30, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

33. R is optionally substituted C １ -C ２ 31. The compound of any one of claims 1 to 30, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

34. Formula (III) 【Chemistry 3】 wherein: R ６ , R ７ , and R ８ are each independently selected from H or halogen, with the proviso that R ６ , R ７ , or R ８ At least one of is not H, R ９ is an optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ cycloalkyl, and optionally substituted cycloalkylalkyl; R １０ is H, R １１ is H, halogen, -NH ２ , -CN, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkoxy, -NH (optionally substituted C １ -C ６ alkyl), or -N(optionally substituted C １ -C ６ Alkyl) ２ and R １２ is H, halogen, optionally substituted C １ -C ６ Alkyl, or optionally substituted C １ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, which is alkoxy.

35. Formula (IV) 【Chemistry 4】 wherein: R ６ , R ７ , and R ８ are each independently selected from H or halogen, with the proviso that R ６ , R ７ , or R ８ At least one of is not H, R ９ is an optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ cycloalkyl, and optionally substituted cycloalkylalkyl; R １０ is H, R １１ is H, halogen, -NH ２ , -CN, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkoxy, -NH (optionally substituted C １ -C ６ alkyl), or -N(optionally substituted C １ -C ６ Alkyl) ２ and R １２ is H, halogen, optionally substituted C １ -C ６ Alkyl, or optionally substituted C １ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, which is alkoxy.

36. 36. The compound of claim 34 or 35, or a pharma- ceutically acceptable salt or solvate thereof, wherein V is C-L-R.

37. 37. The compound of claim 36, or a pharma- ceutically acceptable salt or solvate thereof, wherein L is -O-.

38. 37. The compound of claim 36, or a pharma- ceutically acceptable salt or solvate thereof, wherein L is a single bond.

39. 40. The compound of claim 38, or a pharma- ceutically acceptable salt or solvate thereof, wherein R is H.

40. R is optionally substituted C １ -C ６ 40. The compound of any one of claims 1 to 20 or 34 to 38, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

41. R is optionally substituted C １ -C ２ 40. The compound of any one of claims 1 to 20 or 34 to 38, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

42. R is optionally substituted C １ 40. The compound of any one of claims 1 to 20 or 34 to 38, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

43. 40. The compound of any one of claims 1 to 20 or 34 to 39, or a pharma- ceutically acceptable salt or solvate thereof, wherein L is a single bond and R is hydrogen.

44. L １ 44. The compound of any one of claims 1 to 20 or 34 to 43, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

45. R １ is optionally substituted C １ -C ６ 45. The compound of any one of claims 1 to 20 or 34 to 44, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

46. R １ is optionally substituted C １ -C ４ 45. The compound of any one of claims 1 to 20 or 34 to 44, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

47. R １ is optionally substituted C １ -C ２ 45. The compound of any one of claims 1 to 20 or 34 to 44, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

48. R ９ is optionally substituted C １ -C ６ 48. The compound of any one of claims 1 to 47, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

49. R ９ is optionally substituted C １ -C ４ 48. The compound of any one of claims 1 to 47, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

50. R ９ is optionally substituted C １ -C ２ 48. The compound of any one of claims 1 to 47, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

51. R ９ is optionally substituted C １ 48. The compound of any one of claims 1 to 47, or a pharma- ceutically acceptable salt or solvate thereof, wherein:

52. R ９ is CH ３ 48. The compound of any one of claims 1 to 47, which is: or a pharma- ceutically acceptable salt or solvate thereof.

53. R ９ is optionally substituted C ３ -C ６ 48. The compound of any one of claims 1 to 47, or a pharma- ceutically acceptable salt or solvate thereof, which is cycloalkyl.

54. R ９ is optionally substituted C ３ -C ４ 48. The compound of any one of claims 1 to 47, or a pharma- ceutically acceptable salt or solvate thereof, which is cycloalkyl.

55. R ９ is optionally substituted C ５ -C ６ 48. The compound of any one of claims 1 to 47, or a pharma- ceutically acceptable salt or solvate thereof, which is cycloalkyl.

56. R ９ 48. The compound of any one of claims 1 to 47, or a pharma- ceutically acceptable salt or solvate thereof, wherein is optionally substituted cyclopropyl.

57. R ９ 48. The compound of any one of claims 1 to 47, or a pharma- ceutically acceptable salt or solvate thereof, wherein: is cyclopropyl.

58. R １１ 58. The compound of any one of claims 21 to 57, or a pharma- ceutically acceptable salt or solvate thereof, wherein is hydrogen.

59. R ８ 59. The compound of any one of claims 1 to 58, or a pharma- ceutically acceptable salt or solvate thereof, wherein is fluoro.

60. R ８ 59. The compound of any one of claims 1 to 58, or a pharma- ceutically acceptable salt or solvate thereof, wherein is hydrogen.

61. R ７ 61. The compound of any one of claims 1 to 60, or a pharma- ceutically acceptable salt or solvate thereof, wherein is fluoro.

62. R ７ 61. The compound of any one of claims 1 to 60, or a pharma- ceutically acceptable salt or solvate thereof, wherein is hydrogen.

63. R ６ 63. The compound of any one of claims 1-17 or 19-62, or a pharma- ceutically acceptable salt or solvate thereof, wherein: is hydrogen.

64. R ６ 63. The compound of any one of claims 1-17 or 19-62, or a pharma- ceutically acceptable salt or solvate thereof, wherein: is fluoro.

65. Q is -L ２ -R ９ 65. The compound of any one of claims 1 to 64, which is: or a pharma- ceutically acceptable salt or solvate thereof.

66. A compound provided in Table 1, or a pharma- ceutically acceptable salt or solvate thereof.

67. 66. A pharmaceutical composition comprising a compound according to any one of claims 1 to 65, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient.

68. 66. A method for preparing a pharmaceutical composition, comprising the step of mixing a compound according to any one of claims 1 to 65, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier.

69. 66. A compound according to any one of claims 1 to 65, or a pharma- ceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

70. 66. A compound according to any one of claims 1 to 65, or a pharma- ceutically acceptable salt or solvate thereof, for use in a method for the treatment of cancer or a neoplastic disease.

71. 66. Use of a compound according to any one of claims 1 to 65, or a pharma- ceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

72. 66. A method of treating cancer in a patient in need of such treatment, comprising administering to said patient a compound according to any one of claims 1 to 65, or a pharma- ceutically acceptable salt or solvate thereof.

73. 66. A method of treating cancer in a patient in need of such treatment, comprising administering to said patient a pharmaceutical composition comprising a compound according to any one of claims 1 to 65, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient.

74. 66. A method of inhibiting MET kinase enzyme, said method comprising contacting said MET kinase enzyme with a compound according to any one of claims 1 to 65, wherein MET kinase is contacted in an in vitro environment.

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