MET kinase inhibitors

Abstract

The present invention provides a MET receptor tyrosine kinase inhibitor, a pharmaceutical composition containing the inhibitory compound, and a method for using the MET kinase inhibitory compound for the treatment of a disease.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the interests of U.S. Patent Application No. 63 / 508,859, filed on 16 June 2023, which is incorporated herein by reference 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 of many organs, including the liver, pancreas, prostate, kidney, muscle, and bone marrow, during both embryonic and adult stages. Binding to hepatocyte growth factor induces receptor dimerization and activation. MET regulates many essential cellular processes during development and wound healing, including cell proliferation, survival, motility, and morphogenesis. Abnormal MET activity is found in many different human cancers. Therefore, therapies targeting MET kinase activity are desirable for use in the treatment of cancers and other diseases characterized by abnormal MET pathway signaling. [Overview of the project]

[0003] The present invention provides a MET kinase inhibitor, a pharmaceutical composition containing the inhibitory compound, and a method for using the inhibitory compound for the treatment of a disease.

[0004] One embodiment is given by formula (I):

[0005] [ka] We provide compounds having the structure, or pharmaceutically acceptable salts or solvates thereof. During the ceremony, V is independently N, CH, or CLR. X is independently N, CH, or CL 1 -R 1 And, Z is independently N, C-H, or C-L 2 -R 2 and W is C-H or N, Y 1 is independently N or C-R 3 and Y 2 is independently N or C-R 4 and Y 3 is independently N or C-R 3 and Y 4 is independently N or C-R 3 and L is a bond, halogen, -C-, -O-, -NH-, -N(optionally substituted C1-C6 alkyl)-, -N(optionally substituted C3-C6 cycloalkyl)-, -NHCO-, or -CONH-, L 1 is a bond, halogen, -C-, -O-, -NH-, -N(optionally substituted C1-C6 alkyl)-, -N(optionally substituted C3-C6 cycloalkyl)-, -NHCO-, or -CONH-, L 2 is a bond, halogen, -C-, -O-, -NH-, -N(optionally substituted C1-C6 alkyl)-, -N(optionally substituted C3-C6 cycloalkyl)-, -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 1This 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 This is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl, -NH (optionally substituted C3-C6 cycloalkyl), or an optionally substituted C3-C6 cycloalkyloxy. Each R 3 is selected from H, halogen, -CN, -NH2, -NH(optionally substituted C1-C6 alkyl), -N(optionally substituted C1-C6 alkyl)2, optionally substituted C1-C4 alkoxy, or optionally substituted C1-C4 alkyl, or R 3 and R 4 They bond to form a carbocykyl ring, R 4 This is 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 It is fluoro, R 6 , R 7 and R 8 Each is independently selected from H, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or -CN, provided that R 6 , R 7 or R 8 The condition is that at least one of them is not H, Q is fluoro, or -L2 -R 9 And, L 2 is a bond, -O-, or optionally substituted C1-C5 alkylene, and also, R 9 This is selected from the group consisting of hydrogen, halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 alkynyls, optionally substituted C1-C6 alkenyls, optionally substituted C3-C6 cycloalkyls, optionally substituted cycloalkylalkyls, optionally substituted heterocyclyls, and optionally substituted heterocyclylalkyls.

[0006] One embodiment is given by formula (II):

[0007] [ka] We provide compounds having the structure, or pharmaceutically acceptable salts or solvates thereof. During the ceremony, W is either CH or N. Y 1 These are independently N or CR 3 And, Y 2 These are independently N or CR 4 And, Y 3 These are independently N or CR 3 And, Y 4 These are independently N or CR 3 And, L is a bond, -O-, -NH-, -NHCO-, or -CONH-, L 1 These are bonds, -O-, -NH-, -NHCO-, or -CONH-, R 1 and R 2Each is independently selected from the group consisting of 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, and R 1 and R 2 They bond to form a carbon ring or heterocycle, Each R 3 is selected from H, halogen, -CN, -NH2, -NH (optionally substituted C1-C6 alkyl), -N (optionally substituted C1-C6 alkyl)2, optionally substituted C1-C4 alkoxy, or optionally substituted C1-C4 alkyl, or R 3 and R 4 They bond to form a carbocykyl ring, R 4 This is 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 It is fluoro, R 6 , R 7 and R 8 Each is independently selected from H, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or -CN, provided that R 6 , R 7 or R 8 The condition is that at least one of them is not H, Q is fluoro, or -L 2 -R 9 And, L 2is a bond, -O-, or optionally substituted C1-C5 alkylene, and R 9 is selected from the group consisting of hydrogen, 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.

[0008] One embodiment provides a compound having the structure of formula (III):

[0009]

Chemical formula

[0010] One embodiment provides the compounds listed in Table 1, or pharmaceutically acceptable salts or solvates thereof.

[0011] One embodiment provides a pharmaceutical composition comprising formula (I), formula (II), formula (III), or a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0012] One embodiment provides a method for treating a disease or disorder in a patient requiring treatment, the method comprising administering to the patient formula (I), formula (II), formula (III), or a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a method in which the disease or disorder is cancer.

[0013] Embedding by reference All publications, patents, and patent applications referenced herein are incorporated herein by reference for the specific purposes for which they are treated as identical herein. [Modes for carrying out the invention]

[0014] Detailed description of the invention Where used herein and in the appended claims, the singular nouns “a,” “and,” and “the” include plural nouns unless the context explicitly states otherwise. For example, a reference to “an agent” includes plural forms of such agents, and a reference to “the cell” includes one or more cells and their equivalents known to those skilled in the art. Where a range is used herein for physical properties such as molecular weight or chemical properties such as chemical formula, it is intended to include all combinations and partial combinations of the range, as well as specific embodiments therein. When referring to a number or range of numbers, the term “about” means that the number or range referred to is an approximation within the range of experimental variation (or statistical experimental error), and therefore, in some cases, the number or range will vary between 1% and 15% of the number or range referred to. The term “contains” (and related terms such as “contains,” “contains,” “has,” or “contains”) is not intended to exclude other particular embodiments, such as compositions, compositions, methods, or processes of any substance described herein, from “consisting of” or “essentially consisting of” the described features.

[0015] definition As used in this specification and the appended claims, the following terms have the meanings set forth below, unless otherwise specified.

[0016] "Amino" refers to the -NH2 group.

[0017] "Cyano" refers to the -CN group.

[0018] "Nitro" refers to the -NO2 group.

[0019] "Oxa" refers to the -O- group.

[0020] "Oxo" refers to the oxygen group.

[0021] "Thioxo" refers to the sulfur group.

[0022] "Imino" refers to the NH group.

[0023] "Oxymo" refers to the N-OH group.

[0024] "Hydrazino" refers to the N-NH2 group.

[0025] "Alkyl" refers to a linear or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturated bonds, and having 1 to 15 carbon atoms (for example, C1-C 15 Alkyl). In certain embodiments, the alkyl group contains 1 to 13 carbon atoms (for example, C1 to C13). 13 Alkyl). In certain embodiments, the alkyl group contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group contains 5 to 15 carbon atoms (e.g., C5-C 15(alkyl). In other embodiments, the alkyl contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is bonded to the rest of the molecule by a single bond. Unless otherwise specifically mentioned herein, the alkyl group may have the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and -S(O) t N(R a )2 (where t is 1 or 2) and is optionally substituted by one or more of, where each R ais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclic alkyl (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), heterocyclic (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic alkyl (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] "Alkoxy" refers to a group bonded through the oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0027] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms. In certain embodiments, alkenyl contains 2 to 8 carbon atoms. In other embodiments, alkenyl contains 2 to 4 carbon atoms. Alkenyl is bonded to the rest of the molecule by a single bond and includes, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. Unless otherwise specifically mentioned herein, alkenyl groups may have the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -OR a , -SR a , -OC(O)-Ra , -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 (where t is 1 or 2), -S(O) t Ure a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and -S(O) t N(R a ) is arbitrarily substituted by one or more of 2 (where t is 1 or 2), where each R a These are independently hydrogen, alkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyryl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyrylalkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0028] "Alkynyl" refers to a linear or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having 2 to 12 carbon atoms. In certain embodiments, the alkynyl contains 2 to 8 carbon atoms. In other embodiments, the alkynyl contains 2 to 6 carbon atoms. In other embodiments, the alkynyl contains 2 to 4 carbon atoms. The alkynyl is bonded to the rest of the molecule by single bonds, such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl. Unless otherwise specified herein, the alkynyl group is a substituent of the following: halo, cyano, nitro, oxo, thioxo, imino, oxymo, 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 (where t is 1 or 2), -S(O) t Ure a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and -S(O) t N(R a ) is arbitrarily substituted by one or more of 2 (where t is 1 or 2), where each R aThese are independently hydrogen, alkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyryl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyrylalkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0029] An "alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that links the rest of a molecule to a radical group, consisting only of carbon and hydrogen, without unsaturated bonds, and having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, and n-butylene. The alkylene chain is bonded to the rest of the molecule via single bonds and to the radical group via single bonds. The bonding points between the alkylene chain and the rest of the molecule and the radical group are through one carbon atom in the alkylene chain or through any two carbon atoms in the chain. In certain embodiments, the alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene contains 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene contains 1 carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specified herein, the alkylene chain may have the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, 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 Ra (where t is 1 or 2), -S(O) t Ure a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and -S(O) t N(R a ) is arbitrarily substituted by one or more of 2 (where t is 1 or 2), where each R a These are independently hydrogen, alkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyryl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyrylalkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0030] An "alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain that links the rest of a molecule to a radical group, consisting only of carbon and hydrogen, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms. The alkenylene chain is bonded to the rest of the molecule via single bonds and to the radical group via single bonds. In certain embodiments, an alkenylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, an alkenylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, an alkenylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, an alkenylene contains 2 carbon atoms (e.g., C2 alkenylene). In other embodiments, the alkenylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, the alkenylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkenylene). Unless otherwise specified herein, the alkenylene chain may have the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, 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 (where t is 1 or 2), -S(O) t Ure a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and -S(O) t N(R a) is arbitrarily substituted by one or more of 2 (where t is 1 or 2), where each R a These are independently hydrogen, alkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyryl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyrylalkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0031] An "alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that links the rest of a molecule to a radical group, consisting only of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having 2 to 12 carbon atoms. The alkylene chain is bonded to the rest of the molecule via single bonds and to the radical group via single bonds. In certain embodiments, the alkylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkylene). In other embodiments, the alkylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkylene). In other embodiments, the alkylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkylene). In other embodiments, the alkylene contains 2 carbon atoms (e.g., C2 alkylene). In other embodiments, the alkylylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkylylene). In other embodiments, the alkylylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkylylene). Unless otherwise specified herein, the alkylylene chain may have the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, 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 (where t is 1 or 2), -S(O) t Ure a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and -S(O) t N(R a) is arbitrarily substituted by one or more of 2 (where t is 1 or 2), where each R a These are independently hydrogen, alkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyryl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyrylalkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (which may optionally be substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0032] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only a hydrogen atom and 5 to 18 carbon atoms, and at least one ring in the ring system is completely unsaturated, i.e., it contains a cyclic delocalized (4n+2)π-electron system according to Hückel's theory. Examples of ring systems from which aryl groups are derived include, but are not limited to, benzene, fluorene, indan, indene, tetraline, and naphthalene. Unless otherwise specified herein, the term "aryl" or the prefix "ar" (as in "aralkyl") refers to 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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t Ure a (where t is 1 or 2), and -R b -S(O) t N(R a ) means that it contains an aryl group optionally substituted by one or more substituents independently selected from 2 (where t is 1 or 2), where each R aR is 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 (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), and each R b R is independently a directly bonded, or linear or branched alkylene or alkenylene chain, c The substituents are linear or branched alkylene or alkenylene chains, and each of the substituents is unsubstituted unless otherwise specified.

[0033] "Aralkill" is defined by formula -R c - Refers to the aryl group, in the formula, R c This refers to an alkylene chain as defined above, such as methylene or ethylene. The alkylene chain portion of the aralkyl group can be optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl group can be optionally substituted as described above for aryl groups.

[0034] "Aralkenyl" is derived from formula -R d - Refers to the aryl group, in the formula, R dThis is an alkenylene chain as defined above. The aryl portion of the aralkenyl group can be optionally substituted as described above for the aryl group. The alkenylene chain portion of the aralkenyl group can be optionally substituted as defined above for the alkenylene group.

[0035] "Aralkynyl" is derived from formula -R e - Refers to the aryl group, in the formula, R e This is an alkynylene chain as defined above. The aryl portion of the aralquinyl group can be optionally substituted as described above for the aryl group. The alkynylene chain portion of the aralquinyl group can be optionally substituted as defined above for the alkynylene chain.

[0036] "Aralcoxy" is the formula -OR c - Refers to a group bonded via an oxygen atom of an aryl group, R c This refers to an alkylene chain as defined above, such as methylene or ethylene. The alkylene chain portion of the aralkyl group can be optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl group can be optionally substituted as described above for aryl groups.

[0037] A "carbocyclyl" refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon group having 3 to 15 carbon atoms, consisting only of carbon and hydrogen atoms, and including fused or bridging ring systems. In certain embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains 5 to 7 carbon atoms. Carbocyclyls are bonded to the rest of the molecule by single bonds. Carbocyclyls can be saturated (i.e., containing only single C-C bonds) or unsaturated (i.e., containing one or more double or triple bonds). Fully saturated carbocyclyl groups are also called "cycloalkyls." Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also called "cycloalkenyls." Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Examples of polycyclic carbocyclyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norborneyl, dekalinyl, and 7,7-dimethylbicyclo[2.2.1]heptanyl. Unless otherwise specified herein, the term "carbocyclyl" includes optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, and -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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t Ure a (where t is 1 or 2), and -R b -S(O) t N(R a ) means that it contains a carbocyclyl group optionally substituted with one or more substituents independently selected from 2 (where t is 1 or 2), where each R a R is 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 (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), and each R bR is independently a directly bonded, or linear or branched alkylene or alkenylene chain, and c The substituents are linear or branched alkylene or alkenylene chains, and each of the substituents is unsubstituted unless otherwise specified.

[0038] "Carbocyclylalkyl" refers to the formula -R c - Refers to the carbocyclyl group, in the formula, R c This is an alkylene chain as defined above. The alkylene chain and the carbocyclyl group can be optionally substituted as defined above.

[0039] "Carbocyclylalkynyl" is defined by formula -R c - Refers to the carbocyclyl group, R c This is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl group can be optionally substituted as defined above.

[0040] "Carbocyclylalkoxy" is defined by the formula -OR c This refers to a group bonded via the oxygen atom of a carbocyclyl, R c This is an alkylene chain as defined above. The alkylene chain and the carbocyclyl group can be optionally substituted as defined above.

[0041] "Halo" or "halogen" refers to a substituent of bromo, chloro, fluoro, or iodine.

[0042] "Fluoroalkyl" refers to an alkyl group as defined above that has been substituted with one or more fluoro groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, and 1-fluoromethyl-2-fluoroethyl. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally substituted with the alkyl group as defined above.

[0043] A "heterocyclyl" refers to a stable 3- to 18-membered non-aromatic cyclic group containing 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified herein, heterocyclyl groups are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which optionally include fused or bridging ring systems. The heteroatoms in the heterocyclyl group are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl group is partially or completely saturated. The heterocyclyl is bonded to the rest of the molecule via any atom of the ring. Examples of such heterocyclyl groups include, but are not limited to, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolinil, imidazolidinil, isothiazolidinil, isoxazolidinil, morpholinil, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, oxazolidinil, piperidinil, piperazinil, 4-piperidonil, pyrrolidinil, pyrazolidinil, quinuclidinil, thiazolidinil, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomorpholinil, thiamorpholinil, 1-oxo-thiomorpholinil, and 1,1-dioxo-thiomorpholinil. Unless otherwise specified herein, the term "heterocyclyl" includes 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, -Rb -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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t Ure a (where t is 1 or 2), and -R b -S(O) t N(R a This means that it contains a heterocyclyl group as defined above, which is optionally substituted by one or more substituents selected from )2 (where t is 1 or 2), where each R aR is 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 (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), and each R b R is independently a directly bonded, or linear or branched alkylene or alkenylene chain, and c The substituents are linear or branched alkylene or alkenylene chains, and each of the substituents is unsubstituted unless otherwise specified.

[0044] An "N-heterocyclyl" or "N-bonded heterocyclyl" refers to a heterocyclyl group as defined above, which contains at least one nitrogen atom, and whose bond to the rest of the molecule is via the nitrogen atom in the heterocyclyl group. The N-heterocyclyl group can be optionally substituted as described above for the heterocyclyl group. Examples of such N-heterocyclyl groups include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0045] A "C-heterocyclyl" or "C-bonded heterocyclyl" refers to a heterocyclyl group as defined above, which contains at least one heteroatom, and whose bond to the rest of the molecule is via a carbon atom in the heterocyclyl group. The C-heterocyclyl group can be substituted as described above for the heterocyclyl group. Examples of such C-heterocyclyl groups include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl.

[0046] "Heterocyclylalkyl" refers to formula -R c It refers to the heterocyclyl group, and in the formula, R c This is an alkylene chain as defined above. When the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally bonded to the alkyl group at the nitrogen atom. The alkylene chain of the heterocyclylalkyl group is optionally substituted as defined above for the alkylene chain. The heterocyclyl portion of the heterocyclylalkyl group is optionally substituted as defined above for the heterocyclyl group.

[0047] "Heterocyclylalkoxy" is defined by the formula -OR c This refers to a group bonded via the oxygen atom of a heterocycline, where R is in the formula. c This is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally bonded to the alkyl group at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy group is optionally substituted as defined above for the alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy group is optionally substituted as defined above for the heterocyclyl group.

[0048] A "heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring group containing 2- to 17 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system in which at least one ring in the ring system is completely unsaturated, i.e., it contains a cyclic delocalized (4n+2)π-electron system according to Hückel's theory. Heteroaryls include fused ring systems or bridging ring systems. The heteroatoms in a heteroaryl group are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryls are bonded to the rest of the molecule via atoms in any of the rings. Examples of heteroaryls include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranil, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinil, benzotriazolyl, benzo[4,6]imidazo[ 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]pyridadinyl, 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]pyridadinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolyl, indolidinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthilidinyl, 1,6-naphthilidinolyl, oxadiazolyl, 2-oxo Azepinyl, oxazolyl, oxyranil, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenadinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, py Lido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridadinyl, 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] Examples of heteroaryl groups include, but are not limited to, 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-c]pyrimidinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, the term "heteroaryl" means a heteroaryl group as defined above, including 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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t Ure a (where t is 1 or 2), and -R b -S(O) t N(R a )2 (where t is 1 or 2) optionally substituted by one or more substituents selected from t, meaning that it contains a heteroaryl group as defined above, where each R aR is 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 (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), and each R b R is independently a directly bonded, or linear or branched alkylene or alkenylene chain, and c The substituents are linear or branched alkylene or alkenylene chains, and each of the substituents is unsubstituted unless otherwise specified.

[0049] An "N-heteroaryl" refers to a heteroaryl group as defined above, which contains at least one nitrogen atom, and whose bonding points with the rest of the molecule are mediated through the nitrogen atom in the heteroaryl group. The N-heteroaryl group can be optionally substituted for the heteroaryl group as described above.

[0050] A "C-heteroaryl" refers to a heteroaryl group as defined above, where the bond between the heteroaryl group and the rest of the molecule is via a carbon atom in the heteroaryl group. The C-heteroaryl group can be arbitrarily substituted for the heteroaryl group as described above.

[0051] "Heteroarylalkyl" refers to the compound of the formula -R c - Refers to the heteroaryl group, in the formula, R c This is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally bonded to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkyl group is optionally substituted as defined above for the heteroaryl group.

[0052] "Heteroarylalkoxy" refers to the formula -OR c This refers to a group bonded via the oxygen atom of a heteroaryl group, where R is in the formula. c This is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally bonded to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkoxy group is optionally substituted as defined above for the heteroaryl group.

[0053] The compounds disclosed herein, in some embodiments, contain one or more chiral centers, thus giving rise to enantiomers, diastereomers, and other stereoisomers defined as (R) or (S) from the viewpoint of absolute stereochemistry. Unless otherwise specified, all stereoisomers of the compounds disclosed herein are intended to be considered by this disclosure. Where the compounds described herein contain an alkene double bond, unless otherwise specified, this 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 also intended to be included. The term “geometric isomer” refers to the E or Z geometric isomer (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-isomers, meta-isomers, and para-isomers around a benzene ring.

[0054] A "tautomer" refers to a molecule in which proton transfer is possible from one atom within the molecule to another atom within the same molecule. The compounds presented herein exist as tautomers in certain embodiments. Under conditions where tautomerization is possible, a chemical equilibrium exists between the tautomers. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomer equilibrium include:

[0055] [ka]

[0056] The compounds disclosed herein, in some embodiments, for example, 2 H, 3 H, 11 C, 13 C and / or 14It is used in various isotopic enrichments in which the 1C content is concentrated. In a particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patents 5,846,514 and 6,334,997. As described in U.S. Patents 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or potency, thereby increasing the duration of action of the drug.

[0057] Unless otherwise specified, the structures described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having the structure of the present invention, except for carbon substitution by carbon-enriched carbon, are within the scope of this disclosure.

[0058] The compounds of this disclosure optionally contain unnatural proportions of atomic isotopes in one or more atoms constituting such compounds. For example, the compounds may contain isotopes, such as deuterium ( 2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 It may also be marked with C), etc. 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, 81Br, 125 All isotopic substitutions by I are assumed. 18 Isotope substitution with fluorine is anticipated. All isotope variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0059] In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 It is replaced with a hydrogen atom. Methods for synthesizing deuterium-containing compounds are known in the art, and the following are just a few non-limiting examples of synthesis methods.

[0060] Deuterium-substituted compounds are synthesized using various methods, as described in Dean, Dennis C., ed., 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.

[0061] Deuterated starting materials are readily available and, when subjected to the synthesis methods described herein, provide for the synthesis of deuterium-containing compounds. Numerous deuterium-containing reagents and building blocks are commercially available from chemical distributors such as Aldrich Chemical Co.

[0062] Deuterium transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and can be used to transfer deuterium-substituted carbon atoms to the reaction substrate under nucleophilic substitution conditions. The use of CD3I is illustrated in the following reaction scheme for illustrative purposes only.

[0063] [ka]

[0064] Deuterium transfer reagents, such as lithium aluminum deuteride (LiAlD4), are used to transfer deuterium to a reaction substrate under reducing conditions. The use of LiAlD4 is illustrated in the following reaction scheme for illustrative purposes only.

[0065] [ka]

[0066] Deuterium gas and palladium catalysts are used, for illustrative purposes only, to reduce unsaturated carbon-carbon bonds and carry out reductive substitution of aryl carbon-halogen bonds, as illustrated in the following reaction equations.

[0067] [ka]

[0068] In one embodiment, the compound disclosed herein contains one deuterium atom. In another embodiment, the compound disclosed herein contains two deuterium atoms. In another embodiment, the compound disclosed herein contains three deuterium atoms. In another embodiment, the compound disclosed herein contains four deuterium atoms. In another embodiment, the compound disclosed herein contains five deuterium atoms. In another embodiment, the compound disclosed herein contains six deuterium atoms. In another embodiment, the compound disclosed herein contains more than six deuterium atoms. In another embodiment, the compound disclosed herein is completely substituted with deuterium atoms and is irreplaceable. 1 It does not contain hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by a synthesis method that uses a deuterated synthetic building block as a starting material.

[0069] "Pharmacologically acceptable salts" include both acid-added and base-added salts. A pharmaceutically acceptable salt of any one of the MET kinase inhibitor compounds described herein is intended to encompass all pharmaceutically acceptable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid-added salts and pharmaceutically acceptable base-added salts.

[0070] "Pharmacologically acceptable acid addition salts" refer to salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid, which retain the biological efficacy and properties of the free base and are not biologically or otherwise undesirable. Salts formed with organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedioates, aromatic acids, and aliphatic and aromatic sulfonic acids are also included, such as 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, and salicylic acid. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monophosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacinates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, and methanesulfonates. Salts of amino acids such as alginates, glucons, and galacturons are also intended (see, for example, 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 desired acid in an amount sufficient to produce a salt, according to methods and techniques familiar to those skilled in the art.

[0071] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological efficacy and properties of a free acid and is not undesirable from a biological or other standpoint. These salts are prepared by adding an inorganic or organic base to a free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines such as alkali metals, alkaline earth metals, or organic amines. Examples of salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Examples of salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of 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, hydravamin, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. See Berge et al. (cited above).

[0072] "Pharmacologically acceptable solvates" refers to solvent-addition compositions. In some embodiments, solvates are formed during a process of preparation using either a stoichiometric or nonstoichiometric amount of solvent, such as water or ethanol. When the solvent is water, hydrates are formed; when the solvent is alcohol, alcoholates are formed. Solvates of the compounds described herein are readily prepared or formed during the processes described herein. The compounds provided herein may optionally exist in non-solvated and solvated forms. The terms "subject" or "patient" encompass mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia, namely non-human primates such as humans, chimpanzees and other apes and monkey species; farm animals such as cattle, 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 embodiment, the mammal is human.

[0073] As used herein, “treatment” or “to treat,” or “to alleviate” or “to improve,” are interchangeable. These terms refer to an approach to obtain a beneficial or desired outcome, including but not limited to therapeutic and / or preventive benefits. “Therapeutic benefit” means the elimination or improvement of the underlying disease being treated. The therapeutic benefit is also achieved by the elimination or improvement of one or more physiological symptoms associated with the underlying disease, such that improvement is observed in the patient, even though the patient still has the underlying disease. For a preventive benefit, the composition is administered in some embodiments to patients at risk of developing a particular disease, or to patients reporting one or more physiological symptoms of that disease, even if they have not been diagnosed with that disease.

[0074] 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 during both embryonic and adult stages, including epithelial cells of many organs such as the liver, pancreas, prostate, kidney, muscle, and bone marrow. MET regulates many essential cellular processes during development and wound healing, including cell proliferation, survival, motility, and morphogenesis. Abnormalities in MET activity are found 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.

[0075] The c-MET proto-oncogene is located on chromosomes 7q21-31, and its transcription is regulated by Ets (E-twenty-six), Pax3 (paired box3), AP2 (activator protein 2), and Tcf-4 (transcription factor 4). c-MET 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.

[0076] Structurally, MET is a single-pass transmembrane protein with an extracellular domain, a transmembrane hydrophobic sequence, and an intracellular domain containing a tyrosine kinase domain. The extracellular domain of MET consists 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, extending for approximately 50 residues and connecting the Sema domain to the IPT domain. The four IPT domains are associated with immunoglobulin-like domains and are found in integrins, plexins, and transcription factors. The C-terminal IPT domain is connected to a single transmembrane helix, which in turn connects the extracellular domain to the intracellular domain. The intracellular domain of the MET receptor includes a near-membrane domain containing the Y1003 residue involved in receptor downregulation, a tyrosine kinase catalytic domain containing the Y1234 and Y1235 residues involved in signal transduction, and an adapter protein docking site containing the Y1349 and Y1356 residues.

[0077] The extracellular portion of MET binds to its homologous ligand, hepatocyte growth factor (HGF), and its native isoform, NK1, resulting in the dimerization of the two MET proteins. This dimerization leads to the trans-autophosphorylation of two tyrosine residues (Y1234 and Y1235) located within the catalytic loop of the intracellular tyrosine kinase domain. Subsequently, tyrosine residues 1349 and 1356 of 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) responsible for downstream signal transduction.

[0078] HGF, the primary ligand for MET, is a secreted, single-chain 83kDa precursor protein. Full-length HGF contains an N-terminal (N) domain, four consecutive kringle (K1-K4) domains, and a serine protease homology (SPH) domain. Proteolysis between Arg494 and Val495 of HGF produces a 57kDa α-subunit and a 26kDa β-subunit, which are covalently linked by a disulfide bond between Cys487 of the α-subunit and Cys604 of the β-subunit. Both pro-HGF and cleaved HGF can bind to MET with high affinity, but only cleaved mature HGF can activate MET signaling. NK1, a native isoform of HGF, can also bind to and activate MET.

[0079] In malignant solid tumors, HGF is primarily expressed and released by surrounding stromal cells, enabling communication between tumor cells and stromal cells via HGF and forming a microenvironment that contributes to cancer progression. For example, HGF from the tumor stroma acts on tumor cells, promoting proliferation and metastasis, and also stimulates the production of HGF-inducing factors. These HGF-inducing factors, 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 the tumor. Thus, the interaction between tumor cells and stromal cells continuously drives tumor growth, invasion, and metastasis. Furthermore, HGF can also be produced by the tumor itself, a phenomenon that has been detected in renal cell carcinoma, colorectal cancer, breast cancer, glioma, multiple myeloma, as well as synovial sarcoma, osteosarcoma, and fibrosarcoma.

[0080] Dysregulation of the MET pathway in cancer occurs through a variety of mechanisms, including gene mutations, amplification, rearrangement, and protein overexpression. Several MET fusions have been identified, including fusions between c-MET and TPR (translocated promoter region nuclear basket protein gene) found in mutagenic osteosarcoma cell lines, and fusions between c-MET and KIF5B (kinesin family member 5B gene) detected in lung adenocarcinoma patients. Furthermore, mutations in the splice site of MET that result in 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 activation of MET, promoting tumorigenesis via downstream signaling pathways.

[0081] 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 crucial in regulating tissue homeostasis and wound healing, but in cancer, abnormal MET activation promotes tumor growth, metastasis, and drug resistance through these pathways.

[0082] The Ras / MAPK / ERK signaling pathway transmits signals from cell surface receptors, including MET, to DNA in the cell nucleus, where gene expression regulation occurs. While this signaling cascade involves many different proteins that propagate signals via protein phosphorylation, the pathway can generally be divided into three steps: (i) Ras activation, (ii) kinase signaling cascade, and (iii) translation and transcription regulation. Simply put, MET activation leads to Ras activation, which in turn phosphorylates RAF kinase, activating its protein kinase activity. RAF kinase then phosphorylates and activates MEK (MEK1 and MEK2), which in turn phosphorylates and activates the MAPK (also known as ERK) protein. MAPK activation modulates the activity of several transcription factors, thereby regulating protein expression. MAPK alters the levels and activity of transcription factors, leading to transcriptional changes in genes crucial for the cell cycle. Depending on the stimulus and cell type, this pathway can transmit signals that result in apoptosis or the prevention or induction of cell cycle progression. In cancer, abnormal Ras activation can lead to tumor growth, evasion of apoptosis, local tissue invasion, and metastasis.

[0083] 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 on the cell membrane, forming phosphatidylinositol (3,4,5)-triphosphate (PIP3). PIP3 binds to PKB / Akt on the cell membrane, allowing pyruvate dehydrogenase kinase 1 (PDK1) to access and phosphorylate T308 in the AKT "activation loop," resulting in partial activation of PKB / Akt. Subsequently, full activity of Akt is stimulated by phosphorylation of S473 of the carboxyl-terminal hydrophobic motif of Akt, either by mTOR or DNA-PK. Akt activation leads to additional substrate-specific phosphorylation events in both the cytoplasm and nucleus, including CREB activation, p27 inhibition, FOXO localization to the cytoplasm, PtdIns-3ps activation, and mTOR activation. Through these downstream effectors, the PI3K / Akt pathway mediates many cellular functions that drive cancer progression, including angiogenesis, metabolism, growth, proliferation, survival, protein synthesis, transcription, and apoptosis.

[0084] The JAK-STAT pathway is essential for a wide range of cytokines and growth factors, leading to critical cellular events such as cell differentiation, hematopoiesis, and immune system development. The JAK / STAT signaling pathway also plays a major role in the growth and survival of various cancer types. Activation of Janus kinase (JAK) by MET results in phosphorylation of signaling and transcriptional activator (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 and regulates the expression of many oncogenes, including BCL-XL, c-MYC, Mcl1, Survivin, BEGF, HIF-1α, HGF, IL-12, and MMP. Thus, the JAK / STAT pathway promotes tumor progression by enhancing cell proliferation, angiogenesis, metastasis, and immune evasion.

[0085] 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 an increase in cytoplasmic β-catenin concentration, which then translocates to the nucleus and interacts with T cell-specific factor (TCF) / lymphoid enhancer binding factor (LEF) and its co-activators, such as Pygopus and Bcl-9. This, in turn, enhances the expression of target genes, including c-Myc, cyclin D1, and CDKN1A, promoting cancer stem cell regeneration, proliferation, and differentiation, playing a crucial role in tumorigenesis and therapeutic response. Thus, by modulating various tumorigenetic signaling pathways, METs are major drivers of tumor growth, survival, invasion, and metastasis.

[0086] MET kinase inhibitors Several drugs, including small molecule inhibitors and monoclonal antibodies, have been developed to target MET or HGF. Monoclonal antibodies currently FDA-approved or under clinical evaluation include anti-MET antibodies (e.g., onartuzumab and emibetuzumab), anti-HGF antibodies (e.g., ficratuzumab and rilotumumab), and anti-MET / EGFR bispecific antibodies (e.g., amivantamab). These therapies prevent HGF from binding to MET, thereby halting MET activation. In addition, many small molecule MET inhibitors, including capmatinib, tepotinib, crizotinib, cabozantinib, MGCD265, AMG208, artiratinib, and golvatinib, have received FDA approval as cancer treatments. Of these, two selective MET inhibitors, capmatinib (Tabrecta®) and tepotinib (Tepmetko®), are FDA approved for the treatment of patients with advanced NSCLC who have MET exon 14 skipping mutations. Cabozantinib (Cabometyx®) is FDA approved for the treatment of locally advanced or metastatic differentiated thyroid cancer.

[0087] Small molecule MET-specific inhibitors are classified into two functionally distinct classes. Type I inhibitors (e.g., crizotinib, capmatinib, tepotinib, and savolitinib) preferentially bind to the active conformation of MET, while Type II inhibitors (e.g., cabozantinib and gresatinib) preferentially bind to the inactive conformation of MET. Furthermore, selective MET inhibitors include adenosine triphosphate competitive inhibitors and adenosine triphosphate non-competitive inhibitors (e.g., tivantinib). Type I MET inhibitors are further subdivided into Type Ia (e.g., crizotinib), which interacts with the solventfront G1163 residue, and Type Ib (e.g., capmatinib, tepotinib, and savolitinib), which bind to the kinase domain.

[0088] 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 kinase domain residues D1228 and Y1230 confer resistance to Type I MET inhibitors in vitro by weakening the interaction between the drug and the MET kinase domain. Clinically, resistance to all Type I MET inhibitors has been identified, and patients have secondary mutations at these sites. Furthermore, the Solventfront G1163R mutation confers resistance to the Type Ia MET inhibitor crizotinib, but not to Type Ib MET inhibitors such as tepotinib, savolitinib, or capmatinib in vitro. However, Type II MET inhibitors retain varying degrees of efficacy against many cancers with these mutations that render Type I inhibitors ineffective. Given the considerable resistance that mutations confer to MET inhibitors, there is a serious unmet clinical need for MET inhibitors that maintain efficacy against tumors with these and other mutations.

[0089] MET kinase inhibitor compounds In one embodiment, the compound provided herein is a MET kinase inhibitor.

[0090] One embodiment is given by formula (I):

[0091] [ka] We provide compounds having the structure, or pharmaceutically acceptable salts or solvates thereof. During the ceremony, V is independently N, CH, or CLR. X is independently N, CH, or CL 1 -R 1 And, Z is independent of N, CH, or CL 2 -R 2 And, W is either CH or N. Y 1These are independently N or CR 3 And, Y 2 These are independently N or CR 4 And, Y 3 These are independently N or CR 3 And, Y 4 These are independently N or CR 3 And, L is a bond, halogen, -C-, -O-, -NH-, -N(optionally substituted C1-C6 alkyl)-, -N(optionally substituted C3-C6 cycloalkyl)-, -NHCO-, or -CONH-. L 1 These are a bond, halogen, -C-, -O-, -NH-, -N(optionally substituted C1-C6 alkyl)-, -N(optionally substituted C3-C6 cycloalkyl)-, -NHCO-, or -CONH-. L 2 These are a bond, halogen, -C-, -O-, -NH-, -N(optionally substituted C1-C6 alkyl)-, -N(optionally substituted C3-C6 cycloalkyl)-, -NHCO-, or -CONH-. R is selected from the group consisting of H, halogens, -CN, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 alkenyls, optionally substituted C1-C6 alkynyls, optionally substituted C3-C6 cycloalkyls, optionally substituted cycloalkylalkyls, optionally substituted heterocyclyls, optionally substituted heterocyclylalkyls, optionally substituted heteroaryls, and optionally substituted heteroarylalkyls. R 1 This 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 2This is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl, -NH (optionally substituted C3-C6 cycloalkyl), or an optionally substituted C3-C6 cycloalkyloxy. Each R 3 is selected from H, halogen, -CN, -NH2, -NH(optionally substituted C1-C6 alkyl), -N(optionally substituted C1-C6 alkyl)2, optionally substituted C1-C4 alkoxy, or optionally substituted C1-C4 alkyl, or R 3 and R 4 They bond to form a carbocykyl ring, R 4 This is 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 It is fluoro, R 6 , R 7 and R 8 Each is independently selected from H, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or -CN, provided that R 6 , R 7 or R 8 The condition is that at least one of them is not H, Q is fluoro, or -L 2 -R 9 And, L 2 is a bond, -O-, or optionally substituted C1-C5 alkylene, and also, R 9This is selected from the group consisting of hydrogen, halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 alkynyls, optionally substituted C1-C6 alkenyls, optionally substituted C3-C6 cycloalkyls, optionally substituted cycloalkylalkyls, optionally substituted heterocyclyls, and optionally substituted heterocyclylalkyls.

[0092] One embodiment is given by formula (II):

[0093] [ka] We provide compounds having the structure, or pharmaceutically acceptable salts or solvates thereof. During the ceremony, W is either CH or N. Y 1 These are independently N or CR 3 And, Y 2 These are independently N or CR 4 And, Y 3 These are independently N or CR 3 And, Y 4 These are independently N or CR 3 And, L represents a bond, -O-, -NH-, -NHCO-, or -CONH-. L 1 These are bonds, -O-, -NH-, -NHCO-, or -CONH-, R 1 and R 2 Each is independently selected from the group consisting of 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, and R 1 and R 2They bond to form a carbon ring or heterocycle, Each R 3 is selected from H, halogen, -CN, -NH2, -NH(optionally substituted C1-C6 alkyl), -N(optionally substituted C1-C6 alkyl)2, optionally substituted C1-C4 alkoxy, or optionally substituted C1-C4 alkyl, or R 3 and R 4 They bond to form a carbocykyl ring, R 4 This is 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 It is fluoro, R 6 , R 7 and R 8 Each is independently selected from H, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or -CN, provided that R 6 , R 7 or R 8 The condition is that at least one of them is not H, Q is fluoro, or -L 2 -R 9 And, L 2 is a bond, -O-, or optionally substituted C1-C5 alkylene, and also, R 9 This is selected from the group consisting of hydrogen, halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 alkynyls, optionally substituted C1-C6 alkenyls, optionally substituted C3-C6 cycloalkyls, optionally substituted cycloalkylalkyls, optionally substituted heterocyclyls, and optionally substituted heterocyclylalkyls.

[0094] One embodiment is given by formula (III):

[0095] [ka] We provide compounds having the structure, or pharmaceutically acceptable salts or solvates thereof. During the ceremony, W is either CH or N. Y 1 These are independently N or CR 3 And, Y 2 These are independently N or CR 4 And, Y 3 These are independently N or CR 3 And, Y 4 These are independently N or CR 3 And, L is a bond, -O-, -NH-, or -N (optionally substituted C3-C6 cycloalkyl), L 1 is a bond, -O-, -NH-, or -N(optionally substituted C3-C6 cycloalkyl)-, R 1 and R 2 Each is independently selected from the group consisting of 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, and R 1 and R 2 They bond to form a carbon ring or heterocycle, Each R 3 This is selected from H, halogen, -CN, -NH2, -NH(optionally substituted C1-C6 alkyl), -N(optionally substituted C1-C6 alkyl)2, optionally substituted C1-C4 alkoxy, or optionally substituted C1-C4 alkyl. R4 This is 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 It is fluoro, R 6 , R 7 and R 8 Each is independently selected from H, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or -CN, provided that R 6 , R 7 or R 8 The condition is that at least one of them is not H, Q is fluoro, or -L 2 -R 9 And, L 2 is a bond, -O-, or optionally substituted C1-C5 alkylene, and also, R 9 This is selected from the group consisting of hydrogen, halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 alkynyls, optionally substituted C1-C6 alkenyls, optionally substituted C3-C6 cycloalkyls, optionally substituted cycloalkylalkyls, optionally substituted heterocyclyls, and optionally substituted heterocyclylalkyls.

[0096] In some embodiments, the MET kinase inhibitor compounds described herein, or pharmaceutically acceptable salts or solvates thereof, have the structures provided in Table 1.

[0097] [Table 1-1]

[0098] [Table 1-2]

[0099] [Table 1-3]

[0100] [Table 1-4]

[0101] [Table 1-5]

[0102] [Table 1-6]

[0103] [Table 1-7]

[0104] [Table 1-8]

[0105] [Table 1-9] Numbered Embodiments Embodiment 1. Formula (I):

[0106] [ka] A compound having the structure, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, V is independently N, CH, or CLR. X is independently N, CH, or CL 1 -R1 And, Z is independent of N, CH, or CL 2 -R 2 And, W is either CH or N. Y 1 These are independently N or CR 3 And, Y 2 These are independently N or CR 4 And, Y 3 These are independently N or CR 3 And, Y 4 These are independently N or CR 3 And, L is a bond, halogen, -C-, -O-, -NH-, -N(optionally substituted C1-C6 alkyl)-, -N(optionally substituted C3-C6 cycloalkyl)-, -NHCO-, or -CONH-. L 1 These are a bond, halogen, -C-, -O-, -NH-, -N(optionally substituted C1-C6 alkyl)-, -N(optionally substituted C3-C6 cycloalkyl)-, -NHCO-, or -CONH-. L 2 These are a bond, halogen, -C-, -O-, -NH-, -N(optionally substituted C1-C6 alkyl)-, -N(optionally substituted C3-C6 cycloalkyl)-, -NHCO-, or -CONH-. R is selected from the group consisting of H, halogens, -CN, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 alkenyls, optionally substituted C1-C6 alkynyls, optionally substituted C3-C6 cycloalkyls, optionally substituted cycloalkylalkyls, optionally substituted heterocyclyls, optionally substituted heterocyclylalkyls, optionally substituted heteroaryls, and optionally substituted heteroarylalkyls. R 1This 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 This is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl, -NH (optionally substituted C3-C6 cycloalkyl), or an optionally substituted C3-C6 cycloalkyloxy. Each R 3 is selected from H, halogen, -CN, -NH2, -NH(optionally substituted C1-C6 alkyl), -N(optionally substituted C1-C6 alkyl)2, optionally substituted C1-C4 alkoxy, or optionally substituted C1-C4 alkyl, or R 3 and R 4 They bond to form a carbocykyl ring, R 4 This is 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 It is fluoro, R 6 , R 7 and R 8 Each is independently selected from H, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or -CN, provided that R 6 , R 7 or R 8 The condition is that at least one of them is not H, Q is fluoro, or -L 2-R 9 And, L 2 is a bond, -O-, or optionally substituted C1-C5 alkylene, and also, R 9 This refers to a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of hydrogen, halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 alkynyls, optionally substituted C1-C6 alkenyls, optionally substituted C3-C6 cycloalkyls, optionally substituted cycloalkylalkyls, optionally substituted heterocyclyls, and optionally substituted heterocyclylalkyls. Embodiment 2. Formula (II):

[0107] [ka] A compound having the structure, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, W is either CH or N. Y 1 These are independently N or CR 3 And, Y 2 These are independently N or CR 4 And, Y 3 These are independently N or CR 3 And, Y 4 These are independently N or CR 3 And, L represents a bond, -O-, -NH-, -NHCO-, or -CONH-. L 1 These are bonds, -O-, -NH-, -NHCO-, or -CONH-, R 1 and R 2Each is independently selected from the group consisting of 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, and R 1 and R 2 They bond to form a carbon ring or heterocycle, Each R 3 is selected from H, halogen, -CN, -NH2, -NH(optionally substituted C1-C6 alkyl), -N(optionally substituted C1-C6 alkyl)2, optionally substituted C1-C4 alkoxy, or optionally substituted C1-C4 alkyl, or R 3 and R 4 They bond to form a carbocyclyl ring, R 4 This is 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 It is fluoro, R 6 , R 7 and R 8 Each is independently selected from H, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or -CN, provided that R 6 , R 7 or R 8 The condition is that at least one of them is not H, Q is fluorine, or -L 2 -R 9 And, L 2is a bond, -O-, or optionally substituted C1-C5 alkylene, and also, R 9 This refers to a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of hydrogen, halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 alkynyls, optionally substituted C1-C6 alkenyls, optionally substituted C3-C6 cycloalkyls, optionally substituted cycloalkylalkyls, optionally substituted heterocyclyls, and optionally substituted heterocyclylalkyls. Embodiment 3. Formula (III):

[0108] [ka] A compound having the structure, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, W is either CH or N. Y 1 These are independently N or CR 3 And, Y 2 These are independently N or CR 4 And, Y 3 These are independently N or CR 3 And, Y 4 These are independently N or CR 3 And, L is a bond, -O-, -NH-, or -N (optionally substituted C3-C6 cycloalkyl), L 1 is a bond, -O-, -NH-, or -N(optionally substituted C3-C6 cycloalkyl)-, R 1 and R 2Each is independently selected from the group consisting of 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, and R 1 and R 2 They bond to form a carbon ring or heterocycle, Each R 3 This is selected from H, halogen, -CN, -NH2, -NH(optionally substituted C1-C6 alkyl), -N(optionally substituted C1-C6 alkyl)2, optionally substituted C1-C4 alkoxy, or optionally substituted C1-C4 alkyl. R 4 This is 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 It is fluoro, R 6 , R 7 and R 8 Each is independently selected from H, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or -CN, provided that R 6 , R 7 or R 8 The condition is that at least one of them is not H, Q is fluoro, or -L 2 -R 9 And, L 2 is a bond, -O-, or optionally substituted C1-C5 alkylene, and R 9This refers to a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of hydrogen, halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 alkynyls, optionally substituted C1-C6 alkenyls, optionally substituted C3-C6 cycloalkyls, optionally substituted cycloalkylalkyls, optionally substituted heterocyclyls, and optionally substituted heterocyclylalkyls. Embodiment 4. The compound described in Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein V is N. Embodiment 5. The compound described in Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein V is CLR. Embodiment 6. A compound according to any one of Embodiments 1 or 4-5, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N. Embodiment 7.X is CL 1 -R 1 The compound described in Embodiment 1 or any one of Embodiments 4-5, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 8. A compound according to any one of Embodiments 1 or 4-5, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is N. Embodiment 9.R 2 The compound described in any one of Embodiments 1 or 4-7, or a pharmaceutically acceptable salt or solvate thereof, is optionally substituted C3-C4 cycloalkyl or optionally substituted C3-C4 cycloalkyloxy. Embodiment 10. A compound according to any one of Embodiments 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH. Embodiment 11. A compound according to any one of Embodiments 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein W is N. Embodiment 12.Y 1 A compound according to any one of Embodiments 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein N is present. Embodiment 13.Y 1 CR 3The compound described in any one of Embodiments 1 to 11, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 14.Y 2 A compound according to any one of Embodiments 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, wherein N is present. Embodiment 15.Y 2 CR 3 The compound described in any one of Embodiments 1 to 13, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 16.Y 3 A compound according to any one of Embodiments 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein N is present. Embodiment 17.Y 3 CR 4 The compound described in any one of Embodiments 1 to 15, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 18.Y 4 A compound according to any one of Embodiments 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, wherein is N. Embodiment 19.Y 4 CR 3 The compound described in any one of Embodiments 1 to 17, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 20.R 6 A compound according to any one of Embodiments 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is fluoro. Embodiment 21.L 2 A compound according to any one of Embodiments 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is -O-. Embodiment 22.R 9 The compound according to any one of Embodiments 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted with a C1-C6 alkyl group or optionally substituted with a C3-C6 cycloalkyl group. Embodiment 23.L 1A compound according to Embodiment 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is -O-. Embodiment 24.L 1 The compound according to Embodiment 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is bonded to the compound. Embodiment 25.L 1 A compound according to Embodiment 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is bonded or -O-. Embodiment 26.R 1 The compound described in any one of Embodiments 23 to 25, or a pharmaceutically acceptable salt or solvate thereof, wherein the C1-C6 alkyl is optionally substituted. Embodiment 27.R 1 However, the compound described in any one of Embodiments 23 to 25, or a pharmaceutically acceptable salt or solvate thereof, is an optionally substituted C1-C2 alkyl. Embodiment 28.R 2 The compound described in any one of Embodiments 23 to 27, or a pharmaceutically acceptable salt or solvate thereof, wherein the C1-C6 alkyl is optionally substituted. Embodiment 29.R 2 The compound described in any one of Embodiments 23 to 27, or a pharmaceutically acceptable salt or solvate thereof, wherein the C1-C2 alkyl is optionally substituted. Embodiment 30.R 9 The compound described in any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein the C1-C6 alkyl is optionally substituted. Embodiment 31.R 9 The compound described in any one of Embodiments 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein the C1-C4 alkyl is optionally substituted. Embodiment 32.R 9 The compound described in any one of Embodiments 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein the C1-C2 alkyl is optionally substituted. Embodiment 33.R 9The compound described in any one of Embodiments 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein the C1 alkyl is optionally substituted. Embodiment 34.R 9 A compound according to any one of Embodiments 1 to 30, wherein the compound is CH3, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 35.R 9 The compound described in any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted with a C3-C6 cycloalkyl group. Embodiment 36.R 9 The compound described in any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted with a C3-C4 cycloalkyl group. Embodiment 37.R 9 The compound described in any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted with a C5-C6 cycloalkyl group. Embodiment 38.R 9 The compound described in any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted with cyclopropyl. Embodiment 39.R 9 A compound according to any one of Embodiments 1 to 29, wherein is cyclopropyl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 40.R 8 A compound according to any one of Embodiments 1 to 39, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is fluoro. Embodiment 41.R 8 A compound according to any one of Embodiments 1 to 39, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is hydrogen. Embodiment 42.R 7 A compound according to any one of Embodiments 1 to 41, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is fluoro. Embodiment 43.R 7A compound according to any one of Embodiments 1 to 41, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is hydrogen. Embodiment 44.R 6 A compound according to any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is hydrogen. Embodiment 45.R 6 A compound according to any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is fluoro. Embodiment 46.Q is -L 2 -R 9 The compound described in any one of the above embodiments, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 47. Compounds as provided in Table 1, or pharmaceutically acceptable salts or solvates thereof. Embodiment 48. A pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. Embodiment 49. A method for preparing a pharmaceutical composition, comprising mixing a compound described in any one of Embodiments 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable carrier. Embodiment 50. A compound according to any one of Embodiments 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating the body of a human or animal. Embodiment 51. A compound according to any one of Embodiments 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer or neoplastic disease. Embodiment 52. Use of a compound described in any one of Embodiments 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical product for the treatment of cancer or neoplastic disease. Embodiment 53. A method for treating cancer in a patient requiring treatment for cancer, comprising administering a compound described in any one of Embodiments 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, to the patient requiring treatment for cancer. Embodiment 54. A method for treating cancer in a patient requiring treatment for cancer, comprising administering to the patient a pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. Embodiment 55. A method for inhibiting a MET kinase enzyme, the method comprising contacting a compound described in any one of Embodiments 1 to 47 with a MET kinase enzyme, wherein the MET kinase is contacted in an in vitro setting.

[0109] Preparation of compounds The compounds used in the synthetic chemical reactions described herein are prepared starting from commercially available chemicals and / or compounds described in the chemical literature, according to organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" include Acros Organics (Pittsburgh, Pennsylvania), Aldrich Chemical (Milwaukee, Wisconsin, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (Westchester, Pennsylvania), Crescent Chemical Co. (Hoboge, New York), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, New York), Fisher Scientific Co. (Pittsburgh, Pennsylvania), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah), ICN Biomedicals, Inc. (Costa Mesa, California), Key Organics (Cornwall, UK), Lancaster Synthesis (Wyndham, New Hampshire), Maybridge Chemical Co. Ltd. (Cornwall, UK), and Parish Chemical It is available from standard commercial sources, including Pfaltz & Bauer, Inc. (Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, Connecticut), Polyorganix (Houston, Texas), Pierce Chemical Co. (Rockford, Illinois), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, New Jersey), TCI America (Portland, Oregon), Trans World Chemicals, Inc. (Rockville, Maryland), and Wako Chemicals USA, Inc. (Richmond, Virginia).

[0110] Suitable reference books and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide references to articles describing their preparation, include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York, SRSandler et al., "Organic Functional Group Preparations," 2nd edition, Academic Press, New York, 1983; HOHouse, "Modern Synthetic Reactions," 2nd edition, WABenjamin, Inc., Menlo Park, Calif., 1972; TLGilchrist, "Heterocyclic Chemistry," 2nd edition, John Wiley & Sons, New York, 1992; and J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th edition, Wiley-Interscience, New York, 1992. Additional suitable references and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide references to articles describing their preparation, 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; and March, J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2, Otera, J. (ed.) "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 Examples include "Chemistry," 2nd edition (1993), Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999), John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942-2000), John Wiley & Sons, over 55 volumes; and "Chemistry of Functional Groups," John Wiley & Sons, 73 volumes.

[0111] Specific reactants and similar reactants can be arbitrarily identified through indexes of known chemicals compiled by the American Chemical Society's Chemical Abstracts Service, which are available in most public and university libraries, as well as in online databases (for more information, contact the American Chemical Society (Washington, D.C.)). Chemicals that are known but not commercially available in catalogs can be arbitrarily prepared by custom chemical synthesis companies, many of which are standard chemical suppliers (e.g., those listed above) offer custom synthesis services. A helpful reference for the preparation and selection of pharmaceutical salts of the compounds described herein is PHStahl & CGWermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0112] Specific examples provided herein were prepared using General Synthesis Method 1 (described below). A haloheterocyclic compound (a) was reacted with nitrophenol (b) in the presence of a base such as DIEA (N,N-diisopropylethylamine) to obtain a nitro compound (c). Compound (c) was reduced with a reducing agent such as hydrogen gas in the presence of Pd / C to obtain an amine compound (d). Subsequently, amine (d) was coupled with an acid (e) using a coupling agent such as HATU to provide the compound of formula (A). Alternatively, amine (d) was reacted with an acid chloride (f) in the presence of a base such as DIEA to provide the compound of formula (A).

[0113] [ka] The haloheterocyclic compound (g) was reacted with 2-fluoro-4-nitrophenol (h) to obtain ether (i), which was then reduced to amine (j) using the same method as described in General Synthesis Method 1.

[0114] [ka]

[0115] Further examples provided herein were prepared using General Synthesis Method 2 (described below). Amine (j) was coupled with acid (k) using a coupling agent such as HATU to obtain compound (l). Compound (l) was then reacted with alcohol (m) using a base such as DBU to obtain the compound of formula (B).

[0116] [ka]

[0117] Some of the examples provided herein were prepared using general synthesis method 3 (described below). An ester (n) was reacted with an alcohol (m) using a base such as DBU to obtain an intermediate (o), which was then saponified to an acid (p) in water using a base such as lithium hydroxide. Subsequently, the acid (p) was coupled with an amine (j) using a coupling agent such as HATU to obtain the compound of formula (C).

[0118] [ka]

[0119] Using appropriate starting materials, the MET kinase inhibitor compounds described herein by Table 1 were synthesized using the general synthesis methods 1, 2, or 3 described above for the compounds of formula (A), (B), or (C).

[0120] 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 administered, for example, as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21 stIt is combined with a pharmaceutically appropriate or acceptable carrier (hereinafter also referred to herein as a pharmaceutically appropriate (or acceptable) excipient, a physiologically appropriate (or acceptable) excipient, or a physiologically appropriate (or acceptable) carrier) selected based on a chosen route of administration and standard pharmaceutical practice, as described in Ed. Mack Pub. Co., Easton, PA (2005)).

[0121] Provided herein are pharmaceutical compositions comprising at least one MET kinase inhibitor compound, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier (or excipient) is acceptable or appropriate if it is compatible with the other components of the composition and is not harmful to the recipient of the composition (i.e., the subject or patient).

[0122] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I) to (III) or Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0123] One embodiment provides a method for preparing a pharmaceutical composition, comprising mixing a compound of formulas (I) to (III) or Table 1, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable carrier.

[0124] In certain embodiments, the MET kinase inhibitor compounds of formulas (I) to (III) or those listed in Table 1, or their pharmaceutically acceptable salts or solvates, are substantially pure in that they contain less than about 5%, less than about 2%, less than about 1%, less than about 0.5%, or less than 0.1% of other small organic molecules, such as unreacted intermediates or synthetic byproducts generated in one or more steps of the synthesis method.

[0125] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules made from hard or soft gelatin, methylcellulose, or other suitable materials that readily dissolve in the gastrointestinal tract. In some embodiments, suitable non-toxic solid carriers are used, for example, those containing pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. (e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21) st See Ed. Mack Pub. Co., Easton, PA (2005).

[0126] In some embodiments, the MET kinase inhibitor compounds listed in Table 1, or their pharmaceutically acceptable salts or solvates, are formulated for administration by injection. In some cases, the injectable formulation is aqueous. In some cases, the injectable formulation is non-aqueous. In some cases, the injectable formulation is an oily formulation, such as sesame oil.

[0127] The dose of a composition comprising at least one MET kinase inhibitor compound described herein varies depending on the condition of the subject or patient (e.g., human). In some embodiments, such factors include general health status, age, and other factors.

[0128] Pharmaceutical compositions are administered in a manner appropriate to the disease being treated (or prevented). The appropriate dosage, as well as the appropriate duration and frequency of administration, are determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, the appropriate dosage and treatment regimen provide a sufficient amount of the composition to deliver therapeutic and / or preventive benefits (e.g., more frequent complete or partial remission, longer disease-free survival and / or overall survival, or improved clinical outcomes such as reduced symptom severity). The optimal dosage is usually determined using experimental models and / or clinical trials. The optimal dosage depends on the patient's body mass, weight, or blood volume.

[0129] Oral doses typically range from approximately 1.0 mg to approximately 1000 mg, administered 1 to 4 times a day, or more.

[0130] Treatment methods One embodiment provides compounds of formulas (I) to (III) or Table 1, or pharmaceutically acceptable salts or solvates thereof, for use in methods of treating the human or animal body.

[0131] One embodiment provides compounds of formulas (I) to (III) or Table 1, or pharmaceutically acceptable salts or solvates thereof, for use in methods for treating cancer or neoplastic diseases.

[0132] One embodiment provides a pharmaceutical composition for use in a method of treating cancer or neoplastic diseases, comprising a compound of formula (I) to (III) or Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0133] One embodiment provides the use of compounds of formulas (I) to (III) or Table 1, or pharmaceutically acceptable salts or solvates thereof, in the manufacture of a pharmaceutical for the treatment of cancer or neoplastic diseases.

[0134] In some embodiments, a method is provided for treating cancer in a patient requiring treatment for cancer, comprising administering a compound of formula (I) to (III) or Table 1, or a pharmaceutically acceptable salt or solvate thereof, to the patient requiring treatment for cancer. In some embodiments, a method is provided for treating cancer in a patient requiring treatment for cancer, comprising administering a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient, to the patient requiring treatment for cancer.

[0135] This specification provides a method for administering a pharmaceutical composition orally. This specification also provides a method for administering a pharmaceutical composition by injection.

[0136] One embodiment provides a method for inhibiting MET kinase, comprising contacting the MET kinase with a compound of formulas (I) to (III) or Table 1. Another embodiment provides a method for inhibiting MET kinase, in which the MET kinase is contacted in an in vivo setting. Another embodiment provides a method for inhibiting MET kinase, in which the MET kinase is contacted in an in vitro setting.

[0137] Other embodiments and uses will be apparent to those skilled in the art in view of this disclosure. The following examples are provided solely to illustrate various embodiments and should not be construed as limiting the invention in any way.

[0138] Examples I. Chemical synthesis In some embodiments, the MET kinase inhibitor compounds disclosed herein are synthesized according to the following examples. As used below and throughout the description of the invention, the following abbreviations should be understood to have the following meanings unless otherwise specified. °C (Celsius) δ H Chemical shift (downfield from tetramethylsilane, parts per million) DCM Dichloromethane (CH2Cl2) DMF Dimethylformamide DMSO (Dimethyl Sulfoxide) EA ethyl acetate ESI Electrospray Ionization Et ethyl g grams h time HPLC (High-Performance Liquid Chromatography) Hz Hertz J coupling constant (NMR spectroscopy) LCMS (Liquid Chromatography Mass Spectrometry) μ (micron) m: multiline (spectrum), meter, millimeter M molar concentration M + Parental molecular ions Me methyl MHz (megahertz) min mol: mole, molecule (molar weight) mL (milliliter) MS Mass Spectrometry nm (nanometer) NMR nuclear magnetic resonance pH is an indicator of the potential of hydrogen, or the acidity or basicity of an aqueous solution. PE (Petroleum Ether) RT room temperature s Singlet (spectrum) t Triplet (spectrum) T temperature TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran)

[0139] Example 1: N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)-3,5-difluorophenyl)-2-fluorobenzamide

[0140] [ka]

[0141] White solid.MS ESI calculated value C 24 H 17 F3N2O4[M+H] + 455.11 (actual measurement: 455.05).1 H NMR(400MHz,DMSO-d6)δ 10.95(s,1H),8.51(d,J=5.2Hz,1H),7.79-7.70(m,3H),7.69-7.61(m,1H),7.56(s ,1H),7.44(s,1H),7.43-7.36(m,2H),6.63(d,J=5.2Hz,1H),3.97(d,J=2.8Hz,6H). 19 F NMR(377MHz,DMSO-d6)δ -114.58(1F),-126.68(2F).

[0142] Example 2: N-(3,5-difluoro-4-((6-(2-hydroxyethoxy)-7-methoxyquinoline-4-yl)oxy)phenyl)-2-fluorobenzamide]

[0143]

change

[0144] White solid. MS ESI calculated value (C) 25 H 19 F3N2O5[M+H] + ,485.12 measured value 485.05. 1 H NMR(400MHz,DMSO-d6)δ 10.93(s,1H),8.51(d,J=5.2Hz,1H),7.80-7.69(m,3H),7.69-7.65(m,1H),7.58(s,1H),7.44(s,1H),7.44-7.36 (m,2H),6.62(d,J=5.2Hz,1H),4.93(t,J=5.2Hz,1H),4.20(t,J=4.8Hz,2H),3.98(s,3H),3.82(t,J=5.2Hz,2H). 19 F NMR(376MHz,DMSO-d6)δ -114.57(1F),-126.49(2F).

[0145] Example 3: (S)-N-(3,5-difluoro-4-((6-((1-hydroxypropane-2-yl)oxy)-7-methoxyquinoline-4-yl)oxy)phenyl)-2-fluorobenzamide

[0146]

change

[0147] White solid. MS ESI calculated value C26 H 21 F3N2O5[M+H] + ,499.14 measured value 499.10. 1 H NMR(400MHz,DMSO-d6)δ 10.93(s,1H),8.50(d,J=5.2Hz,1H),7.80-7.69(m,3H),7.68-7.59(m,2H),7.44(s,1H),7.43-7.34(m,2H),6.61(d,J=5.2Hz ,1H),4.93(t,J=5.6Hz,1H),4.68(t,J=5.6Hz,1H),3.96(s,3H),3.68-3.64(m,1H),3.57-3.53(m,1H),1.31(d,J=6.0Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ -114.56(1F),-126.55(2F).

[0148] Example 4: N-(3,5-difluoro-4-((6-(2-hydroxyethoxy)-7-methoxy-1,5-naphthyridine-4-yl)oxy)phenyl)-2-fluorobenzamide

[0149]

change

[0150] White solid. MS ESI calculated value C 24 H 18 F3N3O5[M+H] + ,486.12 measured value 486.15. 1 H NMR(400MHz,DMSO-d6)δ 10.86(s,1H),8.56(d,J=5.2Hz,1H),7.76-7.59(m,5H),7.45-7.34(m,2H),6.94(d,J =5.2Hz,1H),4.86(s,1H),4.38(t,J=5.2Hz,2H),3.99(s,3H),3.77(t,J=5.2Hz,2H). 19 F NMR(377MHz,DMSO-d6)δ -114.55(1F),-126.77(2F).

[0151] Example 5: N-(3,5-difluoro-4-((7-(2-hydroxyethoxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-2,6-difluorobenzamide

[0152]

change

[0153] オフホワイトのsolid.MS ESI calculated value C 25 H 18 F4N2O5[M+H] + ,503.12 measured value 503.15. 1 H NMR(400MHz,DMSO-d6)δ 11.32(s,1H),8.50(d,J=5.2,1H),7.73-7.65(m,2H),7.65-7.63(m,1H),7.56(s,1H),7.45(s,1H),7.37-7.27( m,2H),6.67(d,J=5.2Hz,1H),4.95(t,J=5.6Hz,1H),4.19(t,J=4.8Hz,2H),4.01(s,3H),3.84(t,J=4.8Hz,2H). 19 F NMR(376MHz,DMSO-d6)δ -113.80(2F),-126.01(2F).

[0154] Example 6: N-(3,5-difluoro-4-((6-methoxy-7-(2-morpholinoethoxy)quinoline-4-yl)oxy)phenyl)-2-fluorobenzamide

[0155]

change

[0156] オフホワイトのsolid.MS ESI calculated value C 29 H 26 F3N3O5[M+H] + ,554.18 measured value 554.20. 1 H NMR(400MHz,DMSO-d6)δ 10.92(s,1H),8.51(d,J=5.2Hz,1H),7.80-7.69(m,3H),7.65-7.60(m,1H),7.56(s,1H),7.47(s,1H),7.45-7.35(m,2H) ,6.62(d,J=5.2Hz,1H),4.30(t,J=5.6Hz,2H),3.97(s,3H),3.64-3.57(m,4H),2.81(t,J=5.6Hz,2H),2.62-2.54(m,4H). 19F NMR(377MHz,DMSO-d6)δ -114.57(1F),-126.48(2F).

[0157] Example 7: N-(3,5-difluoro-4-((7-(3-fluoropropoxy)-1,5-naphthyridine-4-yl)oxy)phenyl)-2-fluorobenzamide

[0158] [ka]

[0159] Step 1: 3-Bromo-5-(3-fluoropropoxy)pyridine

[0160] To a stirred solution of 5-bromopyridine-3-ol (3 g, 17.24 mmol) in DMF (30 mL), Cs2CO3 (11.2 g, 34.48 mmol) and 1-bromo-3-fluoropropane (2.93 g, 20.6 mmol) were added at room temperature. The resulting reaction mixture was stirred at 90°C for 1 hour. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was quenched with H2O (100 mL) and extracted with RINKAN (100 mL x 2). The combined organic extract was washed with brine solution (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by silica gel column chromatography and eluted with 20% RINKAN / petroleum ether to obtain 3-bromo-5-(3-fluoropropoxy)pyridine (4 g, 99%) as a colorless liquid. LC-MS: m / z 236.18 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ:8.29-8.24(m,2H),7.37(t,J=2.4Hz,1H),4.70(t,J=6.0Hz,1H),4.58(t,J=5.6Hz,1H),4.14(t,J=5.6Hz,2H),2.25-2.13(m,2H).

[0161] Step 2: N-(5-(3-fluoropropoxy)pyridine-3-yl)-1,1-diphenylmethanymine

[0162] In a sealed tube, a stirred solution of 3-bromo-5-(3-fluoropropoxy)pyridine (3.5 g, 14.95 mmol) in toluene (35 mL) was mixed with BINAP (1.86 g, 2.99 mmol), Cs2CO3 (14.6 g, 44.85 mmol), and diphenylmethanymine (4 g, 22.4 mmol), and the mixture was purged with nitrogen gas. Then, Pd(OAc)2 (0.33 g, 1.49 mmol) was added at room temperature, and the resulting reaction mixture was heated at 90 °C for 16 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was filtered through a small Celite pad, washed with ELISA (100 mL), and concentrated under reduced pressure. The crude compound was purified by silica gel (100-200 mesh) column chromatography and eluted with 20% ethyl acetate / petroleum ether to obtain N-(5-(3-fluoropropoxy)pyridine-3-yl)-1,1-diphenylmethaneimine (4 g, 80%) as a yellow liquid. LC-MS: m / z 335.45 [M+H] + .

[0163] Step 3: 5-(3-fluoropropoxy)pyridine-3-amine

[0164] A stirring solution of N-(5-(3-fluoropropoxy)pyridine-3-yl)-1,1-diphenylmethaneimine (4.0 g, 11.96 mmol) in 1,4-dioxaneHCl (4N, 20 mL) was stirred at 0°C for 4 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was concentrated under reduced pressure and washed with diethyl ether (100 mL) to obtain the crude compound. The crude mass was dissolved in DCM (100 mL), washed with aqueous NaOH solution (50 mL), the organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 5-(3-fluoropropoxy)pyridine-3-amine (2 g, 98%) as a brown liquid. LC-MS: m / z 170.1 [M+H] + .

[0165] Step 4: 5-(((5-(3-fluoropropoxy)pyridine-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0166] To a stirred solution of 5-(3-fluoropropoxy)pyridine-3-amine (2.3 g, 13.52 mmol) in ethanol (25 mL), the compound (5.4 g, 27.059 mmol) was added at room temperature under a nitrogen atmosphere. After the starting material was removed, the reaction mixture was filtered, washed with EtOH (20 mL), and dried under vacuum to obtain 5-(((5-(3-fluoropropoxy)pyridine-3-yl)amino)-methylene)-2,2-dimethyl-1,3-dioxan-4,6-dione (3.2 g, 73%) as an off-white solid. The crude compound was used for the next step without further purification. LC-MS: m / z [M+H] + =324.34.

[0167] Step 5: 7-(3-fluoropropoxy)-1,5-naphthyridine-4-ol

[0168] A stirred solution of 5-(((4-(2,2-difluorocyclopropoxy)-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione 7 (3.2 g, 9.86 mmol) in diphenyl ether (35 mL) under an inert atmosphere was heated at 220 °C for 15 minutes. The reaction was monitored by LC-MS. After completion of the starting materials, the reaction mixture was poured into petroleum ether (100 mL) and the solid was precipitated. The resulting solid precipitate was filtered and dried under vacuum to obtain 7-(3-fluoropropoxy)-1,5-naphthiridine-4-ol (1.3 g, 59.2%) as a yellow solid. The crude compound was used for the next step without further purification. LC-MS: m / z [MH] - =221.30.

[0169] Step 6: 8-(2,6-difluoro-4-nitrophenoxy)-3-(3-fluoropropoxy)-1,5-naphthyridine

[0170] To a stirred solution of 6-(2,2-difluorocyclopropoxy)-7-methoxyquinoline-4-ol (1.3 g, 5.85 mmol) in DMF (13 mL), Cs2CO3 (3.81 g, 11.7 mmol) and 1,2,3-trifluoro-5-nitrobenzene (1.24 g, 7.02 mmol) were added at room temperature under an inert atmosphere. The reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was quenched with H2O (100 mL) and extracted with ELISA (50 mL x 2). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude substance. This was purified by column chromatography using 50%-80% petroleum ether and ethyl acetate to obtain 8-(2,6-difluoro-4-nitrophenoxy)-3-(3-fluoropropoxy)-1,5-naphthiridine (0.8 g, 36.5%) as an off-white solid. Positional isomers are 1 Confirmed by 1H NMR analysis. LC-MS: m / z 380.04 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ:8.76-8.72(m,2H), 8.01(dd,J=4.0Hz,10.8Hz,2H), 7.69(d,J=2.8Hz,1H), 6.76( d,J=5.2Hz,1H), 4.77(t,J=5.6Hz,1H), 4.66(t,J=5.6Hz,1H), 4.31(t,J=6.0Hz,2H), 2.35-2.26(m, 2H).

[0171] Step 7: 3,5-difluoro-4-((7-(3-fluoropropoxy)-1,5-naphthyridine-4-yl)oxy)aniline

[0172] To a stirred solution of 2-chloro-8-(2,6-difluoro-4-nitrophenoxy)-3-methoxy-1,5-naphthyridine (0.6 g, 1.58 mmol) in ethanol (6 mL) and water (3 mL), iron powder (0.44 g, 7.90 mmol) and ammonium chloride (0.42 g, 7.90 mmol) were added. The resulting reaction mixture was heated at 80°C for 1 hour. The progress of the reaction was monitored by LC-MS. After the starting materials were complete, the reaction mixture was filtered through a small Celite pad and washed with ELISA (100 mL). The crude compound was dissolved in ethyl acetate (100 mL), the organic layer was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain 3,5-difluoro-4-((7-(3-fluoropropoxy)-1,5-naphthyridine-4-yl)oxy)aniline (0.170 g, 30.7%) as an off-white solid. The crude compound was used for the next step without further purification. LC-MS: m / z[M+H] + =350.15; 1 H NMR(400MHz,DMSO-d6)δ:8.75(d,J=2.8Hz,1H),8.70(d,J=5.2Hz,1H),7.81(d,J=2.8Hz,1H),6.74(d,J=5.2Hz,1H),6.4 2(d,J=10.8Hz,2H),5.83(s,2H),4.74(t,J=6.0Hz,1H),4.62(t,J=6.0Hz,1H),4.34(t,J=6.4Hz,2H),2.29-2.07(m,2H).

[0173] Step 8: N-(3,5-difluoro-4-((7-(3-fluoropropoxy)-1,5-naphthyridine-4-yl)oxy)phenyl)-2-fluorobenzamide

[0174] To a stirred solution of 3,5-difluoro-4-((7-(3-fluoropropoxy)-1,5-naphthyridine-4-yl)oxyaniline (0.1 g, 0.29 mmol) in DCM (2 mL), DIPEA (0.23 mL, 1.43 mmol) and 2-fluorobenzoyl chloride (0.05 g, 0.315 mmol) were added at 0°C. The resulting reaction mixture was stirred at room temperature for 30 minutes. The progress of the reaction was monitored by LC-MS. After completion of the starting materials, the reaction mixture was diluted with DCM (20 mL), the organic layer was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, and concentrated to obtain the crude compound. The crude compound was purified by reverse-phase preparative HPLC to obtain N-(3,5-difluoro-4-((7-(3-fluoropropoxy)-1,5-naphthyridine-4-yl)oxy)phenyl)-2-fluorobenzamide (0.018 g, 13.34%) as an off-white solid. LC-MS: m / z [M+H] + =472.18; 1 H NMR(400MHz,DMSO-d6)δ:10.92(s,1H),8.78(d,J=2.8Hz,1H),8.73(d,J=5.2Hz,1H),7.85(d,J=2.8Hz,1H),7.75-7.69(m,3H),7.67-7.61 (m,1H),7.43-7.36(m,2H),6.90(d,J=4.8Hz,1H),4.74(t,J=6.0Hz,1H),4.63(t,J=6.0Hz,1H),4.35(t,J=6.4Hz,2H),2.28-2.19(m,2H).

[0175] Example 14: N-(4-((5,7-dimethoxy-1,6-naphthyridine-4-yl)oxy)-3,5-difluorophenyl)-2-fluorobenzamide

[0176] [ka]

[0177] White solid. MS ESI calculated value C 23 H 16 F3N3O4[M+H] + 456.11 (actual measurement value: 456.00). 1H NMR(400MHz,DMSO-d6)δ 10.93(s,1H),8.65(d,J=5.2Hz,1H),7.79-7.60(m,4H),7.50-7.32(m,2H),6.75(s,1H),6.61(d,J=5.2Hz,1H),4.09(s,3H),3.98(s,3H). 19 F NMR(400MHz,DMSO-d6)δ -114.53(1F),-126.51(2F).

[0178] Example 21: N-(3,5-difluoro-4-((7-(3-fluoropropoxy)-1,5-naphthyridine-4-yl)oxy)phenyl)-4-fluoronicotinamide

[0179]

change

[0180] オフホワイトのsolid. 1 H NMR(400MHz,DMSO-d6)δ:11.19(br s,1H),8.82(d,J=0.8Hz,1H),8.78(d,J=2.8Hz,1H),8.73(d,J=5.2Hz,1H),8.65(dd,J=4.8Hz,0.80Hz,1H),7.85(d,J=2.8Hz,1H),7.78-7. 70(m,3H),6.91(d,J=5.2Hz,1H),4.74(t,J=6.0Hz,1H),4.62(t,J=6.0Hz,1H),4.35(t,J=6.0Hz,2H),2.28-2.18(m,2H);LCMS:98.66%,m / z 473.21[M+H] + .

[0181] Example 33: N-(4-((2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0182]

change

[0183] Step 1: 7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-amine

[0184] To a stirred solution of 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (10 g, 66.15 mmol) in THF (100 mL), N-bromosuccinimide (12 g, 67.48 mmol) and one drop of H2SO4 were added at -78°C. The resulting reaction mixture was allowed to return to room temperature and stirred for 3 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was poured into ice water, and the compound was extracted using RINKAN (2 × 300 mL). The combined organic layers were washed with water (100 mL) and brine solution (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 7-bromo-2,3-dihydrobenzo-[b][1,4]dioxin-6-amine (14 g, 91%) as a brown solid. This compound was used for the next step without further purification. LC-MS: m / z 232.08 [M+2] +.

[0185] Step 2: 5-(((7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0186] To a stirred solution of 5-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-amine (6 g, 26.08 mmol) in EtOH (60 mL), 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxan-4,6-dione (5.34 g, 28.69 mmol) was added at room temperature. The resulting reaction mixture was heated under reflux for 1 hour. The progress of the reaction was monitored by TLC. After completion of the starting materials, the reaction mixture was filtered and dried under reduced pressure to obtain 5-(((7-bromo-2,3-dihydrobenzo-[b][1,4]dioxin-6-yl)amino)methylene)-2,2-dimethyl-1,3-dioxan-4,6-dione (9 g, 89%) as an off-white solid. LC-MS: m / z 384.17[M+H] + ; 1H NMR(400MHz,CDCl3)δ:11.49(d,J=13.6Hz,1H),8.47(d,J=14.0Hz,1H),7.14(s,1H),6.92(s,1H),4.28(s,4H),1.75(s,6H).

[0187] Step 3: 6-Bromo-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-ol

[0188] A stirred solution of 5-(((7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)methylene)-2,2-dimethyl-1,3-dioxan-4,6-dione (5 g, 13.01 mmol) in diphenyl ether (50 mL) was heated at 220 °C for 1 hour. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was diluted with petroleum ether (150 mL), filtered, and dried under reduced pressure to obtain 6-bromo-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-ol (3 g, 81%) as an off-white solid. LC-MS: m / z 280.09 [M+H] + .

[0189] Step 4: 2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-ol

[0190] 6-bromo-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-ol (5 g, 17.72 mmol) in MeOH (25 mL) and THF (25 mL) was stirred, and Pd / C (0.9 g) was added at room temperature. The resulting reaction mixture was then stirred under an H2 bladder (1 atm) for 16 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was filtered through a Celite pad. The filtrate was concentrated to obtain 2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-ol (3 g, 83%) as a brown solid. LC-MS: m / z 204.00 [M+H] + .

[0191] Step 5: 10-Chloro-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline

[0192] To a stirred solution of 2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-ol (4 g, 19.69 mmol) in DCM (10 mL), phosphoryl chloride (18.40 mL, 190.0 mmol) was added at room temperature. The resulting reaction mixture was then heated at 80 °C for 6 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was diluted with DCM (200 mL) and washed with NaHCO3 (5 × 100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain 10-chloro-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolone (3 g, 73%) as a brown solid, which was used for the next step without further purification. LC-MS: m / z 222.17 [M+H] + .

[0193] Step 6: 10-(2,6-difluoro-4-nitrophenoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline

[0194] To a stirred solution of 10-chloro-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolone 7 (900 mg, 4.6 mmol) in diglyme (15 mL), 2,6-difluoro-4-nitrophenol (1.07 g, 6.09 mmol), potassium carbonate (280.60 mg, 2.03 mmol), and N-ethyl-N-isopropylpropan-2-amine (1.57 g, 12.18 mmol) were added at room temperature. The resulting reaction mixture was then heated at 130 °C for 16 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was diluted with siRNA (30 mL) and washed with ice-cold water (30 mL). The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by ISCO, and the product was eluted with 45-60% EA:PE. The pure fraction was concentrated to obtain 10-(2,6-difluoro-4-nitrophenoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline (700 mg, 47%) as a brown solid. LC-MS: m / z 361.18 [M+H] +.1H NMR(400MHz,CDCl3)δ:8.55(d,J=4.8Hz,1H),8.01(d,J=7.2Hz,2H),7.67(d,J =9.2Hz,1H),7.39(d,J=9.2Hz,1H),6.53(d,J=5.2Hz,1H),4.39-4.37(m,4H).

[0195] Step 7: 4-((2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-yl)oxy)-3,5-difluoroaniline

[0196] To a stirred solution of 10-(2,6-difluoro-4-nitrophenoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline (100 mg, 0.6 mmol) in THF (2 mL) and MeOH (2 mL), palladium carbon (20 mg) was added at room temperature. The resulting reaction mixture was then stirred under H2 bladder pressure (1 atm) for 16 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to obtain 4-((2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-yl)oxy)-3,5-difluoroaniline (60 mg, 87%) as a brown solid. This amine was used for the next step without further purification. LC-MS: m / z 331.18 [M+H] + .

[0197] Step 8: N-(4-((2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0198] To a stirred solution of 4-((2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-yl)oxy)-3,5-difluoroaniline (100 mg, 0.32 mmol) in DME (5 mL), HATU (345.3 mg, 0.9 mmol), 4-methoxynicotinic acid (55 mg, 0.36 mmol), and DIPEA (117 mg, 0.9 mmol) were added at room temperature. The resulting reaction mixture was then heated at 90 °C for 16 hours. The progress of the reaction was monitored by LC-MS. After complete consumption of the starting materials, the reaction mixture was diluted with ELISA (20 mL) and washed with ice-cold water (2 × 20 mL). The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by MS preparative HPLC to obtain N-(4-((2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide (55 mg, 39%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ:10.68(s,1H),8.63(s,1H),8.61(d,J=6.0Hz,1H),8.48(d,J=5.2Hz,1H),7.74(d,J=10.0Hz,2H),7.55( d,J=8.8Hz,1H),7.42(d,J=8.8Hz,1H),7.27(d,J=6.0Hz,1H),6.66(d,J=5.2Hz,1H),4.44-4.39(m,4H),3.97(s,3H).LC-MS:m / z 464.20[MH] - .

[0199] Example 35: N-(4-((2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-yl)oxy)-2,3,5-trifluorophenyl)-4-methoxynicotinamide

[0200] [ka]

[0201] Step 1: 6-Bromo-10-(2,3,6-trifluoro-4-nitrophenoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline

[0202] To a stirred solution of 6-bromo-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-ol (1.2 g, 4.25 mmol) in ACN (25 mL), Cs2CO3 (2.76 g, 8.5 mmol) and 1,2,3,4-tetrafluoro-5-nitrobenzene (0.82 g, 4.25 mmol) were added at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After consumption of the starting materials, the reaction mixture was quenched with H2O (50 mL) and extracted with RINKAN (50 mL x 2). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography and eluted with 70% ethyl acetate / petroleum ether to obtain 6-bromo-10-(2,3,6-trifluoro-4-nitrophenoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolone (1g, 51.5%) as a pale yellow solid. The structure was confirmed by 2D NMR analysis. LC-MS: m / z 459[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:8.70(d,J=4.8Hz,1H),8.44-8.41(m,1H),7.91(s,1H),7.17(d,J=5.2Hz 1H),4.39(s,4H).

[0203] Step 2: 4-((2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-yl)oxy)-2,3,5-trifluoroaniline

[0204] To a stirred solution of 6-bromo-10-(2,3,6-trifluoro-4-nitrophenoxy)-2,3-dihydro-[1,4]dioxyno-[2,3-f]quinoline (1 g, 2.18 mmol) in ethyl acetate (15 mL), Pd / C 10% wet (100 mg, cat.) was added, and the reaction mixture was stirred under hydrogen balloon pressure for 16 hours. The progress of the reaction was monitored by LC-MS. After the starter material was complete, the reaction mixture was filtered through a Celite bed, washed with MeOH (15 mL), and the filtrate was concentrated to obtain the crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography and eluted with 70% siRNA / petroleum ether to obtain 4-((2,3-dihydro-[1,4]dioxyno-[2,3-f]quinoline-10-yl)oxy)-2,3,5-trifluoroaniline (0.5 g, 65.7%) as an off-white solid. LC-MS: m / z 349.43[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:8.47(d,J=5.2Hz,1H),7.53(d,J=8.8Hz,1H),7.40(d,J=9.2Hz,1H),6.66-6.60(m,2H),5.90(s,2H),4.42-4.37(m,4H).

[0205] Step 3: N-(4-((2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-yl)oxy)-2,3,5-trifluorophenyl)-4-methoxynicotinamide

[0206] To a stirred solution of 4-methoxynicotinic acid (0.3 g, 0.86 mmol) in DCM, oxalyl chloride (0.11 mL, 1.29 mmol) was added at 0°C. Then, a catalytic amount of DMF was added, and stirring was continued at room temperature for 1 hour. After complete consumption of the starting materials, the reaction mixture was concentrated under vacuum. The crude acid chloride was dissolved in DCM and added at 0°C to a solution of 4-((2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-yl)oxy)-2,3,5-trifluoroaniline and DIPEA (0.594 mL, 3.594 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by LC-MS. After the completion of the starting materials, the reaction mixture was diluted with DCM (20 mL), the organic layer was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, and concentrated to obtain the crude compound. The crude compound was purified by reverse-phase preparative HPLC to obtain N-(4-((2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10-yl)oxy)-2,3,5-trifluorophenyl)-4-methoxy-nicotinamide (0.012 g, 4.8%) as an off-white solid. LC-MS: m / z = 484.27 [M + H] + ; 1 H NMR(400MHz,DMSO-d6)δ:10.43(s,1H),8.73(s,1H),8.59(d,J=6.0Hz,1H),8.51(d,J=5.2Hz,1H),8.17-8.13(m,1H),7. 57(d,J=9.2Hz,1H),7.43(d,J=9.2Hz,1H),7.26(d,J=6.0Hz,1H),6.79(d,J=5.2Hz,1H),4.43-4.39(m,4H),3.99(s,3H).

[0207] Example 36: N-(4-((2,2-dimethyl-[1,3]dioxolo[4,5-f]quinoline-9-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0208] [ka]

[0209] Step 1: 6-Bromo-2,2-dimethylbenzo[d][1,3]dioxol-5-amine

[0210] To a stirred solution of 2,2-dimethylbenzo[d][1,3]dioxol-5-amine (3 g, 18.161 mmol) in ACN (75 mL), NBS (3.2 g, 18.161 mmol) was added in small increments over 10 minutes at 0°C. The resulting reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was evaporated under reduced pressure, and the resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel (100-200 mesh) flash column chromatography and eluted with 5% RINKAN / petroleum ether to obtain 6-bromo-2,2-dimethylbenzo[d][1,3]dioxol-5-amine (1.5 g, 33%) as a brown liquid. LC-MS: m / z 246.06 [M+2] + .

[0211] Step 2: (E)-5-(((6-bromo-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)imino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0212] To a stirred solution of 6-bromo-2,2-dimethylbenzo[d][1,3]dioxol-5-amine (1.5 g, 6.145 mmol) in EtOH (26 mL), 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxan-4,6-dione (1.26 g, 6.33 mmol) was added at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the resulting precipitate was collected by filtration, washed with n-pentane, and then dried under vacuum to obtain (E)-5-(((6-bromo-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)imino)methyl)-2,2-dimethyl-1,3-dioxan-4,6-dione (1.6 g, 65%) as an off-white solid. LC-MS: m / z 400.20 [M+2] + .

[0213] Step 3: 5-Bromo-2,2-dimethyl-[1,3]dioxolo[4,5-f]quinoline-9-ol

[0214] (E)-5-(((6-bromo-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)imino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.6 g, 4.018 mmol) was stirred in diphenyl ether at 210°C for 1 hour. After 1 hour, the progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was cooled to 40°C, then petroleum ether (50 mL) was added, and the resulting precipitate was collected by filtration to obtain 5-bromo-2,2-dimethyl-[1,3]dioxol[4,5-f]quinoline-9-ol (0.65 g, 54%) as a brown solid. The crude compound was used directly in the next step without further purification. LC-MS: m / z 298.12 [M+2] + .

[0215] Step 4: 5-Bromo-9-(2,6-difluoro-4-nitrophenoxy)-2,2-dimethyl-[1,3]dioxolo[4,5-f]quinoline

[0216] To a stirred solution of 5-bromo-2,2-dimethyl-[1,3]dioxolo[4,5-f]quinoline-9-ol (0.6 g, 2.026 mmol) in DMF (15 mL), Cs2CO3 (1.65 g, 5.066 mmol) and 1,2,3-trifluoro-5-nitrobenzene (0.43 g, 2.431 mmol) were added at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound (2.0 g) was purified by silica gel (100-200 mesh) flash column chromatography and eluted with 25% ethyl acetate / petroleum ether to obtain 5-bromo-9-(2,6-difluoro-4-nitrophenoxy)-2,2-dimethyl-[1,3]dioxolo[4,5-f]quinoline (0.55 g, 59%) as a pale yellow solid. LC-MS: m / z 455.19 [M+2] + .

[0217] Step 5: 4-((2,2-dimethyl-[1,3]dioxolo[4,5-f]quinoline-9-yl)oxy)-3,5-difluoroaniline

[0218] To a stirred solution of 5-bromo-9-(2,6-difluoro-4-nitrophenoxy)-2,2-dimethyl-[1,3]dioxolo[4,5-f]quinolone (0.2 g, 0.441 mmol) in ethyl acetate (10 mL), 10% Pd / C (50 mg, dry) was added at room temperature. The resulting reaction mixture was stirred under H2 gas bladder pressure at room temperature for 16 hours. The progress of the reaction was monitored by LC-MS. After completion of the starting materials, the reaction mixture was filtered through a small Celite pad, washed with ethyl acetate (50 mL), and concentrated under reduced pressure to obtain 4-((2,2-dimethyl-[1,3]dioxolo-[4,5-f]quinoline-9-yl)oxy)-3,5-difluoroaniline (0.12 g, 79%) as an off-white solid. LC-MS: m / z [M+H] + =345.27; 1 H NMR(400MHz,DMSO-d6)δ:8.46(d,J=5.2Hz,1H),7.56(d,J=8.8Hz,1H),7.49(d,J =8.8Hz,1H),6.52(d,J=5.2Hz,1H),6.42-6.39(m,2H),5.83(s,2H),1.76(s,6H).

[0219] Step 6: N-(4-((2,2-dimethyl-[1,3]dioxolo[4,5-f]quinoline-9-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0220] To a stirred solution of 4-methoxynicotinic acid (0.025 g, 0.16 mmol) in DCM (2 mL), oxalyl chloride (0.1 mL) was added at room temperature. The resulting reaction mixture was stirred at room temperature for 30 minutes. The progress of the reaction was monitored by TLC. After the starting material was completely consumed, the reaction mixture was concentrated under reduced pressure in an N2 gas atmosphere. Then, a solution of 4-((2,2-dimethyl-[1,3]dioxolo[4,5-f]quinoline-9-yl)oxy)-3,5-difluoroaniline (0.1 g, 0.29 mmol) and DIPEA (0.06 mL, 0.349 mmol) in DCM (3 mL) were added to a freshly prepared acid chloride at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. After the complete consumption of the starting material, the reaction mixture was diluted with water (25 mL) and extracted with DCM (2 × 25 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound (150 mg) was purified by preparative HPLC to obtain N-(4-((2,2-dimethyl-[1,3]dioxolo[4,5-f]quinoline-9-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide (15 mg, 10.7%) as an off-white solid. LC-MS: m / z[M+H] + =480.30; 1 H NMR(400MHz,DMSO-d6)δ:10.69(s,1H),8.63(s,1H),8.61(d,J=5.6Hz,1H),8.48(d,J=5.2Hz,1H),7.75(d,J=10.4Hz,2H ),7.60(d,J=8.8Hz,1H),7.53(d,J=8.8Hz,1H),7.27(d,J=6.0Hz,1H),6.63(d,J=5.2Hz,1H),3.97(s,3H),1.78(s,6H).

[0221] Example 38: 4-Cyclopropoxy-N-(4-((5,7-dimethoxy-1,6-naphthyridine-4-yl)oxy)-3,5-difluorophenyl)nicotinamide

[0222] [ka]

[0223] White solid. MS ESI calculated value C 25 H 20 F2N4O5[M+H] + ,495.14 measured value 495.10. 1 H NMR(400MHz,DMSO-d6)δ 10.63(s,1H),8.66-8.62(m,3H),7.72(s,1H),7.69(s,1H),7.51(d,J=5.6Hz,1H),6.76(s, 1H),6.61(d,J=5.2Hz,1H),4.11(s,3H),4.10-4.08(m,1H),3.98(s,3H),1.04-0.72(m,4H). 19 F NMR(376MHz,DMSO-d6)δ -126.53(2F).

[0224] Example 39: N-(4-((5,7-dimethoxy-1,6-naphthyridine-4-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0225]

change

[0226] White solid. MS ESI calculated value C 23 H 18 F2N4O5[M+H] + ,469.12 measured value 469.10. 1 H NMR(400MHz,DMSO-d6)δ 10.70(s,1H),8.65(d,J=5.2Hz,1H),8.64(s,1H),8.62(d,J=6.0Hz,1H),7.76-7.70(m,2H),7. 28(d,J=6.0Hz,1H),6.76(s,1H),6.60(d,J=5.2Hz,1H),4.09(s,3H),3.98(s,3H),3.96(s,3H). 19 F NMR(400MHz,DMSO-d6)δ -126.61(2F).

[0227] Example 42: 4-Cyclopropoxy-N-(3,5-difluoro-4-((5-methoxy-1,6-naphthyridine-4-yl)oxy)phenyl)nicotinamide

[0228]

change

[0229] White solid. MS ESI calculated value C 24 H 18 F2N4O4[M+H] + 465.13 measured value 465.10. 1 H NMR(400MHz,DMSO-d6)δ 10.64(s,1H),8.81(d,J=5.2Hz,1H),8.64(d,J=6.0Hz,1H),8.62(s,1H),8.29(d,J=6.0Hz,1H),7.73(s,1H),7.71(s,1H) ,7.51(d,J=6.0Hz,1H),7.48(d,J=6.0Hz,1H),6.90(d,J=5.2Hz,1H),4.11(s,3H),4.10-4.09(m,1H),0.98-0.74(m,4H). 19 F NMR(376MHz,DMSO-d6)δ -126.48(2F).

[0230] Example 45: N-(3,5-difluoro-4-((5-methoxy-1,6-naphthyridine-4-yl)oxy)phenyl)-4-methoxynicotinamide

[0231]

change

[0232] White solid. MS ESI calculated value C 22 H 16 F2N4O4[M+H] + ,439.11 measured value 439.05. 1 H NMR(400MHz,DMSO-d6)δ 10.70(s,1H),8.81(d,J=5.2Hz,1H),8.64(s,1H),8.62(d,J=6.0Hz,1H),8.29(d,J=6.0Hz,1H),7.78(s,1H) ,7.76(s,1H),7.48(d,J=6.0Hz,1H),7.28(d,J=6.0Hz,1H),6.89(d,J=5.2Hz,1H),4.09(s,3H),3.98(s,3H). 19 F NMR(376MHz,DMSO-d6)δ -126.56(2F).

[0233] Example 53: N-(4-((6-(1-carbamoylcyclopropoxy)-7-methoxyquinoline-4-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0234]

change

[0235] オフホワイトのsolid. 1 H NMR(400MHz,DMSO-d6)δ:10.69(s,1H),8.71-8.53(m,3H),7.74(d,J=10.0Hz,2H),7.56(s,1H),7.55(d,J=10.0Hz,1H),7.46-7.44(m,2H),7.29(br s,1H),6.61(d,J=5.2Hz,1H),3.96(s,3H),3.95(s,3H),1.51-1.48(m,2H),1.2-1.17(m,2H);LC-MS:m / z[M+H] + =537.22.

[0236] Example 55: N-(3,5-difluoro-4-((7-methoxy-6-(1-methylcyclopropoxy)quinoline-4-yl)oxy)phenyl)-4-methoxynicotinamide

[0237]

change

[0238] Step 1: 2-Methoxy-1-(1-methylcyclopropoxy)-4-nitrobenzene

[0239] To a stirred solution of 1-methylcyclopropan-1-ol (0.758 g, 10.52 mmol) in DMF (15 mL), sodium hydride (0.31 g, 13.14 mmol) was added at 0°C. The reaction mixture was stirred for 15 minutes, and then 1-fluoro-2-methoxy-4-nitrobenzene (1.5 g, 8.765 mmol) was added to the reaction mixture. The resulting reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with RINKAN (3 × 50 mL). The combined organic phases were washed with water (50 mL) and brine solution (2 × 50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain 2-methoxy-1-(1-methylcyclopropoxy)-4-nitrobenzene (1.2 g, 61%) as a white solid. This compound was used for the next step without further purification. LC-MS: m / z [M + H] + =224.19.

[0240] Step 2: 3-Methoxy-4-(1-methylcyclopropoxy)aniline

[0241] To a stirred solution of 2-methoxy-1-(1-methylcyclopropoxy)-4-nitrobenzene (1.2 g, 5.37 mmol) in ethyl acetate (15 mL), palladium activated carbon (0.25 g) was added. The resulting reaction mixture was stirred under hydrogen balder pressure at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the completion of the starting materials, the reaction mixture was filtered through a small Celite pad, washed with siRNA (100 mL), and concentrated under reduced pressure to obtain 3-methoxy-4-(1-methylcyclopropoxy)aniline (1 g, 96%). The crude compound was used for the next step without further purification. LC-MS: m / z [M+H] + =194.18.

[0242] Step 3: 7-Methoxy-6-(1-methylcyclopropoxy)quinoline-4-ol

[0243] To a stirred solution of 3-methoxy-4-(1-methylcyclopropoxy)aniline 4 (1 g, 5.17 mmol) in EtOH (10 mL), 2-(ethoxymethylene)-5,5-dimethyl-1,3-dioxane-4,6-dione (1.55 g, 7.76 mmol) was added at room temperature. The resulting reaction mixture was heated at 90 °C for 1 hour. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was diluted with EtOH (30 mL), filtered to obtain a solid mass, and dried to obtain an off-white solid. The obtained solid was heated in diphenyl ether (10 mL) at 225 °C for 30 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and diluted with petroleum ether (100 mL). Petroleum ether was decanted, stirred again in ethyl acetate (50 mL), filtered, and dried to obtain 7-methoxy-6-(1-methylcyclopropoxy)quinoline-4-ol (1 g, 80%) as a brown solid. LC-MS: m / z 246.22 [M+H] + .

[0244] Step 4: 4-(2,6-difluoro-4-nitrophenoxy)-7-methoxy-6-(1-methylcyclopropoxy)quinoline

[0245] To a stirred solution of 7-methoxy-6-(1-methylcyclopropoxy)quinoline-4-ol (1.0 g, 4.07 mmol) in ACN (25 mL), 1,2,3-trifluoro-5-nitrobenzene 7 (0.88 g, 4.89 mmol) and Cs2CO3 (3.98 g, 12.23 mmol) were added at room temperature. The resulting reaction mixture was then stirred for 16 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was filtered through a small pad of Celite, washed with siRNA (100 mL), and concentrated under reduced pressure. The crude compound was dissolved in ethyl acetate (100 mL), the organic layer was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude compound. This was purified by column chromatography using 40% ethyl acetate in petroleum ether as the eluent to obtain 4-(2,6-difluoro-4-nitrophenoxy)-7-methoxy-6-(1-methylcyclopropoxy)quinoline (0.5 g, 30%) as a yellow solid.1 H NMR(400MHz,CDCl3)δ:8.53(d,J=5.2Hz,1H),8.07-8.03(m,2H),7.85(s,1H),7.45(s,1H),6. 41(d,J=5.2Hz,1H),4.02(s,3H),1.7(s,3H),1.22-1.16(m,2H),0.86-0.83(m,2H);LC-MS:m / z 403.17[M+H] + .

[0246] Step 5: 3,5-difluoro-4-((7-methoxy-6-(1-methylcyclopropoxy)quinoline-4-yl)oxy)aniline

[0247] To a stirred solution of 4-(2,6-difluoro-4-nitrophenoxy)-7-methoxy-6-(1-methylcyclopropoxy)-quinoline (0.5 g, 1.24 mmol) in ethanol (10 mL) and water (4 mL), iron powder (0.35 g, 6.21 mmol) and ammonium chloride (0.33 g, 6.21 mmol) were added. The resulting reaction mixture was stirred at 80°C for 1 hour. The progress of the reaction was monitored by LC-MS. After completion of the starting materials, the reaction mixture was filtered through a small Celite pad, washed with ethyl acetate (100 mL), and concentrated under reduced pressure. The crude compound was dissolved in ethyl acetate (50 mL), the organic layer was washed with water (50 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain the crude compound, which was purified by column chromatography using 60% ethyl acetate in petroleum ether as the eluent to obtain 3,5-difluoro-4-((7-methoxy-6-(1-methylcyclopropoxy)quinoline-4-yl)oxyaniline (0.35 g, 75%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ:8.49(d,J=5.2Hz,1H),7.76(s,1H),7.39(s,1H),6.52(d,J=5.2Hz,1H),6.41(d,J= 10.4Hz,2H),5.82(s,2H),3.91(s,3H),1.59(s,3H),1.00-0.98(m,2H),0.88-0.85(m,2H);LC-MS:m / z[M+H] + =373.25.

[0248] Step 6: N-(3,5-difluoro-4-((7-methoxy-6-(1-methylcyclopropoxy)quinoline-4-yl)oxy)phenyl)-4-methoxynicotinamide

[0249] To a stirred solution of methyl 3,5-difluoro-4-((7-methoxy-6-(1-methylcyclopropoxy)quinoline-4-yl)oxy)aniline (0.1 g, 0.27 mmol) in DCM (5 mL), DIPEA (0.13 mL, 0.8 mmol) and 4-methoxynicotinoyl chloride (0.055 g, 0.32 mmol) were added at 0°C. The resulting reaction mixture was stirred at room temperature for 30 minutes. The progress of the reaction was monitored by LC-MS. After completion of the starting materials, the reaction mixture was diluted with DCM (50 mL), the organic layer was washed with water (50 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain the crude compound, which was purified by preparative HPLC to obtain N-(3,5-difluoro-4-((7-methoxy-6-(1-methyl-cyclo-propoxy)quinoline-4-yl)oxy)phenyl)-4-methoxynicotinamide (0.012 g, 8%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ:10.69(s,1H),8.63-8.60(m,2H),8.51(d,J=5.2Hz,1H),7.79-7.74(m,3H),7.43(s,1H),7.28(d,J=6. 0Hz,1H),6.63(d,J=5.2Hz,1H),3.97(s,3H),3.93(s,3H),1.60(s,3H),1.03-1.00(m,2H),0.89-0.87(m,2H);LC-MS:m / z[M+H] + =508.11.

[0250] Example 57: N-(4-((6-cyclopropoxy-7-methoxyquinoline-4-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0251] [ka]

[0252] An off-white solid. 1H NMR(400MHz,DMSO-d6)δ:10.70(s,1H),8.63(s,1H),8.61(d,J=6.0Hz,1H),8.51(d,J=5.2Hz,1H),7.88(s,1H),7.75(d,J=10.4Hz,2H),7.43(s, 1H),7.28(d,J=6.0Hz,1H),6.62(d,J=5.2Hz,1H),4.10-4.06(m,1H),3. 97(s,3H),3.94(s,3H),0.92-0.87(m,2H),0.79-0.75(m,2H).LC-MS:m / z 494.32[M+H] + .

[0253] Example 64: N-(3,5-difluoro-4-((6-isopropoxy-7-methoxyquinoline-4-yl)oxy)phenyl)-4-methoxynicotinamide

[0254]

change

[0255] Light brown solid. 1 H NMR(400MHz,DMSO-d6)δ:10.69(s,1H),8.63-8.60(m,2H),8.49(d,J=5.2Hz,1H),7.74(d,J=10.4Hz,2H),7.56(s,1H),7.43(s, 1H),7.27(d,J=5.6Hz,1H),6.59(d,J=5.2Hz,1H),4.88-4.82(m,1H),3.96(s,3H),3.94(s,3H)1.36(d,J=6.0Hz,6H).LC-MS:m / z 496.14[M+H] + .

[0256] Example 66: N-(4-((6-(cyclopropylamino)-7-methoxy-1,5-naphthyridine-4-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0257]

change

[0258] オフホワイトのsolid. 11H NMR (400 MHz, DMSO-d6) δ: 10.59 (s, 1H), 8.60 (m, 2H), 8.38 (d, J = 5.2 Hz, 1H), 7.63 (d, J = 10.0 Hz, 2H), 7.34 (s, 1H), 7.28 (d, J = 6.0 Hz, 1H), 7.14 (br s, 1H), 6.95 (d, J = 4.8 Hz, 1H), 3.96 (s, 6H), 2.85 - 2.78 (m, 1H), 0.67 - 0.56 (m, 4H); LCMS: m / z 494.23 [M+H] + .

[0259] Example 67: N-(4-((1-Cyclopropyl-2,3-dihydro-1H-[1,4]oxazino[3,2-g]quinoline-9-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0260]

Chem.

[0261] Step 1: 4-Cyclopropyl-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0262] To a stirred solution of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1 g, 5.55 mmol) and cyclopropylboronic acid (1.43 g, 16.65 mmol) in toluene (10 mL), 4-dimethylaminopyridine (2.034 g, 16.65 mmol) and potassium bis(trimethylsilyl)amide (1 M in THF, 5.5 mL, 5.5 mmol) were added at room temperature. The reaction mixture was then degassed with O2 gas for 5 minutes, followed by the addition of anhydrous copper(II) acetate (2.016 g, 11.10 mmol) at room temperature. The resulting reaction mixture was stirred at 100 °C for 16 hours under O2 gas. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was filtered through a Celite pad, washed with siRNA (25 mL), and the collected filtrate was washed with water (50 mL) and brine (50 mL). The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography and eluted with 13% siRNA / petroleum ether to obtain 4-cyclopropyl-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.6 g, 57%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ:7.81(dd,J=2.4Hz,J=8.8Hz,1H),7.66(d,J=2.8Hz,1H),7.11(d,J=9.2Hz,1 H),4.25-4.23(m,2H),3.45-3.43(m,2H),2.52-2.45(m,1H),0.97-0.92(m,2H),0.71-0.67(m,2H).

[0263] Step 2: 4-Cyclopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-amine

[0264] To a stirred solution of 4-cyclopropyl-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.8 g, 3.63 mmol) in ethanol (8 mL) and water (8 mL), iron powder (1.014 g, 18.16 mmol) and ammonium chloride (0.972 g, 18.163 mmol) were added at room temperature. The resulting reaction mixture was stirred at 90°C for 3 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was diluted with siRNA (50 mL), then filtered through a Celite pad, the pad was washed with an excess of siRNA, the collected filtrate was washed with H2O (50 mL) and brine (50 mL), filtered, and evaporated to obtain 4-cyclopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-amine (0.65 g, 97%) as a brownish viscous liquid, which was used in the next step without further purification of the crude compound. LC-MS: m / z 191.06 [M+H] + .

[0265] Step 3: (E)-5-(((4-Cyclopropyl-3,4-Dihydro-2H-Benzo[b][1,4]oxazin-7-yl)imino)methyl)-2,2-Dimethyl-1,3-Dioxane-4,6-Dione

[0266] To a stirred solution of 4-cyclopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-amine (0.65 g, 3.417 mmol) in ethanol (6.5 mL), 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (0.821 g, 4.1 mmol) was added at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. After stirring at room temperature for 1 hour, the resulting precipitate was collected by filtration, washed with petroleum ether, and then dried under vacuum to obtain (E)-5-(((4-cyclopropyl-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-yl)imino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.0 g, 84%) as a pale yellow solid, which was used in the next step without further purification. LC-MS: m / z 287.04[M+H] + .

[0267] Step 4: 1-Cyclopropyl-2,3-dihydro-1H-[1,4]oxazino[3,2-g]quinoline-9-ol

[0268] (E)-5-(((4-cyclopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)imino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (0.2 g, 0.58 mmol) was stirred in diphenyl ether (2 mL) at 220 °C for 30 minutes. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was diluted with water and extracted with DCM (2 × 50 mL). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound (120 mg). The crude compound was purified by silica gel (230-400 mesh) flash column chromatography and eluted with 5% MeOH / DCM to obtain 1-cyclopropyl-2,3-dihydro-1H-[1,4]oxazino[3,2-g]-quinoline-9-ol (57 mg, 40%) as a light brown solid. 1 H NMR(400MHz,DMSO-d6)δ:11.37(s,1H),7.70-7.68(m,2H),6.81(s,1H),5.88(d,J=7.2Hz,1H),4.29(t ,J=4.4Hz,J=8.8Hz,2H),3.31-3.30(m,2H),2.35-2.32(m,1H),0.86-0.84(m,2H),0.60-0.59(m,2H).

[0269] Step 5: 1-Cyclopropyl-9-(2,6-difluoro-4-nitrophenoxy)-2,3-dihydro-1H-[1,4]oxadino[3,2-g]quinoline

[0270] To a stirred solution of 1-cyclopropyl-2,3-dihydro-1H-[1,4]oxazino[3,2-g]quinoline-9-ol 7 (0.130 g, 0.53 mmol) in DMF (6.5 mL), cesium carbonate (0.437 g, 1.34 mmol) and 1,2,3-trifluoro-5-nitrobenzene (0.124 g, 0.698 mmol) were added at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2 × 25 mL). The combined organic extract was washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound (0.2 g). The crude compound was purified by silica gel (100-200 mesh) flash column chromatography and eluted with 40% ethyl acetate / petroleum ether to obtain 1-cyclopropyl-9-(2,6-difluoro-4-nitrophenoxy)-2,3-dihydro-1H-[1,4]oxazino[3,2-g]quinoline (0.1 g, 46%) as a yellow solid. LC-MS: m / z 400.03 [M+H] + .

[0271] Step 6: 4-((1-Cyclopropyl-2,3-dihydro-1H-[1,4]oxazino[3,2-g]quinoline-9-yl)oxy)-3,5-difluoroaniline

[0272] To a stirred solution of 1-cyclopropyl-9-(2,6-difluoro-4-nitrophenoxy)-2,3-dihydro-1H-[1,4]oxazino[3,2-g]quinoline (0.1 g, 0.25 mmol) in EtOH (2 mL) and water (2 mL), iron powder (0.042 g, 0.75 mmol) and ammonium chloride (0.040 g, 0.75 mmol) were added at room temperature. The resulting reaction mixture was stirred at 80°C for 2 hours. The progress of the reaction was monitored by TLC. After the starting materials were complete, the reaction mixture was filtered through a small Celite pad, washed with ELISA (25 mL), and concentrated under reduced pressure. The crude compound was dissolved in ethyl acetate (25 mL), the organic layer was washed with water (25 mL) and brine (25 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain 4-((1-cyclopropyl-2,3-dihydro-1H-[1,4]oxazino[3,2-g]quinoline-9-yl)oxy)-3,5-difluoroaniline (0.08 g, 86%) as an off-white solid. LC-MS: m / z[M+H] + =370.18; 1 H NMR(400MHz,DMSO-d6)δ:8.33(d,J=5.2Hz,1H),7.67(s,1H),7.20(s,1H),6.43-6.38(m,3H),5.80(s,2H) ),4.33(t,J=4.4Hz,2H),3.42(t,J=4.8Hz,2H),2.50-2.49(m,1H),0.93-0.89(m,2H),0.69-0.65(m,2H).

[0273] Step 7: N-(4-((1-Cyclopropyl-2,3-dihydro-1H-[1,4]oxazino[3,2-g]quinoline-9-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0274] To a stirred solution of 4-((1-cyclopropyl-2,3-dihydro-1H-[1,4]oxazino[3,2-g]quinoline-9-yl)oxy)-3,5-difluoroaniline (0.06 g, 0.16 mmol) and methyl 4-methoxynicotinate (0.032 g, 0.195 mmol) in toluene (1.0 M solution in toluene, 0.325 mL, 0.325 mmol) at room temperature, trimethylaluminum (1.0 M solution in toluene, 0.325 mL, 0.325 mmol) was added. The resulting reaction mixture was stirred at 90°C for 1 hour. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was diluted with water (25 mL) and extracted with DCM (2 × 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound (0.08 g). The crude compound was purified by reverse-phase preparative HPLC to obtain N-(4-((1-cyclopropyl-2,3-dihydro-1H-[1,4]oxazino[3,2-g]quinoline-9-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide (0.018 g, 22%) as an off-white solid. LC-MS: m / z[M+H] + =505.20 1 H NMR(400MHz,DMSO-d6)δ:10.68(s,1H),8.63(s,1H),8.61(d,J=5.6Hz,1H),8 .35(d,J=5.2Hz,1H),7.74(d,J=10.4Hz,2H),7.69(s,1H),7.27(d,J=6.0Hz,1 H),7.24(s,1H),6.49(d,J=5.2Hz,1H),4.34(t,J=4.4Hz,2H),3.97(s,3H),3. 44(t,J=4.4Hz,2H),2.55-2.51(m,1H),0.93-0.91(m,2H),0.70-0.68(m,2H).

[0275] Example 68: N-(4-((6-(cyclopropylamino)-7-fluoroquinoline-4-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0276] [ka]

[0277] Step 1: N-Cyclopropyl-2-Fluoro-4-Nitroaniline

[0278] Potassium carbonate (3.9 g, 28.29 mmol) was added at room temperature to a mixture of 1,2-difluoro-4-nitrobenzene (2.5 g, 15.714 mmol) and cyclopropanamine (1.077 g, 18.857 mmol) in DMSO (37.5 mL). The resulting reaction mixture was then stirred for 3 hours. The progress of the reaction was monitored by LC-MS. After the completion of the reaction, the reaction mixture was quenched with ice-cold water (150 mL), and the resulting suspension was filtered and dried to obtain N-cyclopropyl-2-fluoro-4-nitroaniline (3 g, 97%) as a yellow solid, which was used for the next step without further purification. LC-MS: m / z 197.00 [M+H] + . 1 H NMR(400MHz,CDCl3)δ:8.04-8.01(m,1H),7.87(dd,J=2.4Hz,11.6Hz,1H),7.04(t,J=8.8Hz,1H),5.02(br s,1H),2.57-2.54(m,1H),0.92-0.87(m,2H),0.65-0.62(m,2H).

[0279] Step 2: tert-butylcyclopropyl(2-fluoro-4-nitrophenyl)carbamate

[0280] A mixture of N-cyclopropyl-2-fluoro-4-nitroaniline (0.2 g, 1.019 mmol) and Boc-anhydrous (0.556 g, 2.55 mmol) in THF (3.0 mL) was mixed with LiHMDS (1.00 mL, 1.2 molar concentration in THF, 1.2 mmol) at room temperature. The resulting mixture was then heated at 40 °C for 6 hours. The progress of the reaction was monitored by LC-MS. After the completion of the reaction, the reaction mixture was diluted with siRNA (30 mL) and washed with water (30 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated to obtain tert-butylcyclopropyl (2-fluoro-4-nitrophenyl)carbamate (0.10 g, 89%) as an off-white solid, which was used for the next step without further purification. LC-MS: m / z 197 [M + H - 100] + .

[0281] Step 3: tert-butyl(4-amino-2-fluorophenyl)(cyclopropyl)carbamate

[0282] To a stirred solution of tert-butylcyclopropyl(2-fluoro-4-nitrophenyl)carbamate (2.1 g, 7.087 mmol) in EtOH and water (21.0 mL, 2:1), iron powder (2.77 g, 49.61 mmol) and ammonium chloride (2.65 g, 49.61 mmol) were added at room temperature. The resulting mixture was then heated at 80°C for 3 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was filtered and concentrated under reduced pressure. The crude compound was diluted with SiO2 (150 mL) and washed with water (150 mL). The organic phase was dried over Na2SO4 and concentrated to obtain tert-butyl(4-amino-2-fluorophenyl)(cyclopropyl)carbamate (1.8 g, 66%) as a yellow syrup, which was used for the next step without further purification. LC-MS: m / z 267.40 [M+H] + .

[0283] Step 4: tert-butyl cyclopropyl (4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)methyl)amino)-2-fluorophenyl)carbamate

[0284] A mixture of tert-butyl(4-amino-2-fluorophenyl)(cyclopropyl)carbamate (0.5 g, 1.88 mmol) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (0.350 g, 1.88 mmol) in EtOH (7.5 mL) was heated at 80°C for 1 hour. The reaction was monitored by LC-MS. After complete consumption of the starting materials, the reaction mass was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 10-15% ethyl acetate in petroleum ether to obtain tert-butylcyclopropyl(4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)methyl)amino)-2-fluorophenyl)carbamate (3 g, 83%) as a yellow syrup. LC-MS: m / z 419.49 [MH] - .

[0285] Step 5: tert-butyl cyclopropyl (7-fluoro-4-hydroxyquinoline-6-yl) carbamate

[0286] A stirred solution of tert-butylcyclopropyl (4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-fluorophenyl)carbamate (0.6 g, 1.43 mmol) in Dowtherm® (2.4 mL) was heated at 220 °C for 1 hour. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was diluted with petroleum ether (100 mL), filtered, and dried to obtain tert-butylcyclopropyl (7-fluoro-4-hydroxyquinoline-6-yl)carbamate (0.25 g, 55%) as a brown solid, which was used for the next step without further purification. LC-MS: m / z 319.41 [M+H] + .

[0287] Step 6: tert-butyl(4-chloro-7-fluoroquinoline-6-yl)(cyclopropyl)carbamate

[0288] To a stirred solution of tert-butylcyclopropyl(7-fluoro-4-hydroxyquinoline-6-yl)carbamate (2 g, crude) in DCE (30.0 mL), phosphorus oxychloride (4.81 g, 31.41 mmol) was added at room temperature. The resulting reaction mixture was then heated at 60 °C for 1 hour. The progress of the reaction was monitored by LC-MS. After complete consumption of the starting materials, the reaction mixture was diluted with DCM (30 mL) and washed with NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude compound was dissolved in THF (20 mL), KHMDS (7.85 mL, 15.70 mmol) was added, and Boc-anhydrous (3.43 g, 15.70 mmol) was added at room temperature, and the mixture was stirred for 3 hours. The progress of the reaction was monitored by LC-MS. The reaction mixture was diluted with Depositphotos (100 mL) and washed with saturated NaHCO3 solution (100 mL). The organic phase was dried over Na2SO4 and then concentrated. The crude compound was purified by ISCO, and the product was eluted with 25-35% EA:PE. The resulting fraction was concentrated to obtain tert-butyl(4-chloro-7-fluoroquinoline-6-yl)(cyclopropyl)carbamate (1.2 g, 56%) as a yellow syrup. LC-MS: m / z 337.39 [M+H] + .

[0289] Step 7: tert-butyl cyclopropyl (4-(2,6-difluoro-4-nitrophenoxy)-7-fluoroquinoline-6-yl)carbamate

[0290] Potassium carbonate (0.123 g, 0.891 mmol) was added at room temperature to a mixture of tert-butyl(4-chloro-7-fluoroquinoline-6-yl)(cyclopropyl)carbamate (0.2 g, 0.594 mmol) and 2,6-difluoro-4-nitrophenol (0.104 g, 0.594 mmol) in diphenyl ether (3.0 mL). The resulting reaction mixture was then heated at 140 °C for 4 hours. The progress of the reaction was monitored by LC-MS. After the completion of the reaction, the reaction mixture was diluted with ELISA (30 mL) and washed with water (30 mL). The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by ISCO, and the product was eluted with 20-35% EA:PE. The obtained fraction was concentrated to yield tert-butylcyclopropyl(4-(2,6-difluoro-4-nitrophenoxy)-7-fluoroquinoline-6-yl)carbamate (0.1 g, 35%) as a yellow solid, which was used for the next step without further purification. LC-MS: m / z 476.50 [M+H] +

[0291] Step 8: tert-butyl(4-(4-amino-2,6-difluorophenoxy)-7-fluoroquinoline-6-yl)(cyclopropyl)carbamate

[0292] To a stirred solution of tert-butylcyclopropyl (4-(2,6-difluoro-4-nitrophenoxy)-7-fluoroquinoline-6-yl)carbamate (0.35 g, 0.736 mmol) in EtOH (5.25 mL) and water (1.75 mL), iron powder (0.206 g, 3.68 mmol) and ammonium chloride (0.195 g, 3.681 mmol) were added at room temperature, and the resulting reaction mixture was then heated at 80 °C for 3 hours. The progress of the reaction was monitored by LC-MS. After the completion of the reaction, the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude compound was diluted with ELISA (50 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4 and then concentrated to obtain tert-butyl(4-(4-amino-2,6-difluorophenoxy)-7-fluoroquinoline-6-yl)(cyclopropyl)carbamate (250 mg, 76%) as a white solid. LC-MS: m / z 446.21[M+H] + .

[0293] Step 9: N-(4-((6-(cyclopropylamino)-7-fluoroquinoline-4-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0294] To a stirred solution of tert-butyl(4-(4-amino-2,6-difluorophenoxy)-7-fluoroquinoline-6-yl)(cyclopropyl)carbamate (0.25 g, 0.561 mmol) and methyl 4-methoxynicotinate (0.141 g, 0.842 mmol) in toluene (5.0 mL), 2.0 M trimethylaluminum (0.70 mL, 1.403 mmol) in toluene was added at room temperature. The resulting reaction mixture was then heated at 90 °C for 3 hours. The reaction was monitored by LC-MS. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to obtain the crude compound. The crude compound was dissolved in 1,4-dioxane (5.0 mL), and HCl (2.105 mL, 8.419 mmol) in dioxane was added at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, the crude product was diluted with ethyl acetate (100 mL), and washed with water (100 mL). The organic layer was dried over Na₂SO₄ and concentrated to obtain the crude product, which was purified by reverse-phase preparative HPLC to obtain N-(4-((6-(cyclopropylamino)-7-fluoroquinoline-4-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide (36 mg, 13%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ:10.70(s,1H),8.63(s,1H),8.61(d,J=6.0Hz,1H),8.41(d,J=4.8Hz,1H),7 .75(d,J=10.0Hz,2H),7.65(d,J=12.4Hz,1H),7.50(d,J=9.2Hz,1H),7.27(d,J=5.6Hz,1H),6.73(br s,1H),6.62(d,J=5.2Hz,1H),3.97(s,3H),2.59-2.50(m,1H),0.82-0.79(m,2H),0.57-0.56(m,2H);LC-MS:m / z 481.24[M+H] + .

[0295] Example 70: N-(4-((6-(cyclopropylamino)-7-methoxyquinoline-4-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0296] [ka]

[0297] Step 1: 6-Bromo-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinoline

[0298] To a stirred solution of 6-bromo-4-chloro-7-methoxyquinoline (1 g, 3.669 mmol) in diphenyl ether (10 mL), potassium carbonate (1.26 g, 9.173 mmol) and 2,6-difluoro-4-nitrophenol (0.964 mg, 5.504 mmol) were added at room temperature and heated at 150 °C for 2 hours. The reaction was monitored by TLC (TLC: mobile phase: 70% siRNA, RF: 0.4, UV-visible). After complete consumption of the starting materials, the RM was poured into ice-cold water to obtain a solid. This solid was filtered and dried under high vacuum to obtain 6-bromo-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinoline (1.1 g, 73.33%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ:8.67(d,J=5.2Hz,1H),8.58(s,1H),8.08(dd,J=4.0,8.8Hz,2H),7.49(s,1H),6.40(d,J=5.2Hz,1H),4.07(s,3H)LC-MS:m / z 413.27[M+H] + .

[0299] Step 2: 4-((6-bromo-7-methoxyquinoline-4-yl)oxy)-3,5-difluoroaniline

[0300] To a stirred solution of 6-bromo-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinoline (0.5 g, 1.216 mmol) in ethanol (10 mL) and water (5 mL), iron (0.399 g, 7.296 mmol) and ammonium chloride (0.406 g, 7.296 mmol) were added. The resulting reaction mixture was stirred at 70°C for 3 hours. After complete conversion of the starting materials, the reaction mixture was filtered through Celite and washed with ethyl acetate. The two layers were separated, the organic layer was washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 4-((6-bromo-7-methoxyquinoline-4-yl)oxy)-3,5-difluoroaniline (0.35 g, 76.4%) as a mint-green solid. LC-MS: m / z 381.34 [M + H] + .

[0301] Step 3: N-(4-((6-bromo-7-methoxyquinoline-4-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0302] To a stirred solution of 4-((6-bromo-7-methoxyquinoline-4-yl)oxy)-3,5-difluoroaniline (0.2 g, 0.525 mmol) in toluene (4 mL), methyl 4-methoxynicotinate (0.132 g, 0.787 mmol) and trimethylaluminum (0.227 g, 1.574 mmol) were added. The resulting reaction mixture was stirred at 70°C for 2 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (50 mL), the organic layer was washed with brine (2 × 30 mL), and the mixture was dried over anhydrous sodium sulfate to obtain the crude compound. The crude compound was purified using Combiflash (24 g YMC silica column), and the compound was eluted with 5-10% MeOH in DCM. The required fraction was concentrated under reduced pressure to obtain N-(4-((6-bromo-7-methoxyquinoline-4-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide (0.18 g, 98.61%) as an off-white solid. 1H NMR(400MHz,DMSO)δ:10.70(s,1H),8.70(d,J=5.2Hz,1H),8.62-8.60(m,2H),8.54(s,1H),7.76(d,J=5 .2Hz,1H),7.58(s,1H),7.28(s,J=6.0,1H),6.72(s,J=5.2Hz,1H),4.04(s,3H),3.96(s,1H);LC-MS:m / z 516.29[M+H] + .

[0303] Step 4: Synthesis of N-(4-((6-(cyclopropylamino)-7-methoxyquinoline-4-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0304] To a stirred solution of N-(4-((6-bromo-7-methoxyquinoline-4-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide (0.3 g, 0.581 mmol) in dioxane (3 mL), cyclopropanamine (0.083 g, 1.453 mmol) was added, followed by cesium carbonate (0.473 g, 1.453 mmol) at room temperature, and the mixture was purged with N2 for 10 minutes. Next, Pd2(dba)3 (0.027 g, 0.029 mmol) and xanthophos (0.003 mg, 0.006 mmol) were added under an N2 atmosphere. The reaction mixture was heated at 90 °C for 4 hours. The reaction mixture was filtered through Celite, washed with ethyl acetate (50 mL), the organic layer was washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude compound. The crude compound was purified by reverse-phase chromatography to obtain the title compound, N-(4-((6-(cyclopropylamino)-7-methoxyquinoline-4-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide, as an off-white solid. 1 H NMR(400MHz,DMSO)δ:10.68(s,1H),8.61(t,J=5.6Hz,2H),8.31(d,J=5.2Hz,1H),7.75 (d,J=10Hz,2H),7.34(s,1H),7.28-7.26(m,2H),6.48(d,J=5.2Hz,1H),6.07-6.06(br s,1H),3.96(s,6H),2.49(m,1H),0.8-0.76(m,2H),0.57-0.53(m,2H).LC-MS:m / z 492.483[M+H]+ .

[0305] Example 76: N-(4-((6-cyclopropyl-7-methoxyquinoline-4-yl)oxy)-3,5-difluorophenyl)-4-methoxynicotinamide

[0306]

change

[0307] White solid. MS ESI calculated value C 26 H 21 F2N3O4[M+H] + ,478.15 measured value 478.10. 1 H NMR(400MHz,DMSO-d6)δ 10.69(s,1H),8.63(s,1H),8.61(d,J=5.6Hz,1H),8.57(d,J=5.2Hz,1H),7.76(s,1H),7.74(s,2H),7.42(s,1H),7.28(d, J=5.6Hz,1H),6.58(d,J=5.2Hz,1H),4.02(s,3H),3.97(s,3H),2.28-2.24(m,1H),1.08-0.97(m,2H),0.86-0.77(m,2H). 19 F NMR(376MHz,DMSO-d6)δ -126.66(2F).

[0308] Example 88: N-(3,5-difluoro-4-((7-(2-hydroxyethoxy)-6-methoxyquinoline-4-yl)oxy)phenyl)nicotinamide

[0309]

change

[0310] White solid. MS ESI calculated value C 24 H 19 F2N3O5[M+H] + ,468.13, measured value 468.15. 1H NMR(400MHz,DMSO-d6)δ 10.89(s,1H),9.14(d,J=0.8Hz,1H),8.82(dd,J=4.8,2.8Hz,1H),8.51(d,J=5.2Hz,1H),8.35-8.31(m,1H),7.88-7.80(m,2H),7.65-7.6 0(m,1H),7.57(s,1H),7.45(s,1H),6.60(d,J=5.2Hz,1H),4.96(t,J=5.2Hz,1H),4.20(t,J=4.8Hz,2H),3.98(s,3H),3.89-3.84(m,2H). 19 F NMR(376MHz,DMSO-d6)δ -126.62(2F).

[0311] II. Biological Evaluation Example 1a: MET mobility shift assay

[0312] Small molecule inhibition of MET kinase activity was evaluated using a fluorescence-based microfluidic mobility shift assay. MET catalyzes the production of ADP from ATP during phosphoryl transfer to the substrate peptide, FLPeptide 30 (5-FAM-KKKKEEIYFFF-CONH2) (Perkin Elmer, 760430). 0.625 nM MET enzyme (Carna Biosciences, 08-151) was prepared with 10 mM MgCl2 and 1.5 μM substrate peptide in a buffer containing 50 mM HEPES, 1 mM EGTA, 0.01% Brij-35, 0.05% BSA, and 2 mM DTT, and pre-incubated at room temperature for 30 minutes before reaction initiation. 100 μM ATP was added to initiate the reaction. The mobility shift assay separated the fluorescently labeled peptide (substrate and phosphorylated product) electrophoretically after 60 minutes of kinase reaction. The reaction was terminated by the addition of 0.5 M EDTA. Both the substrate and the product were measured, and the ratio of these values ​​was used to generate the substrate-to-product conversion rate (%) using a LabChip EZ reader (Perkin Elmer). 50The values ​​were calculated using the conversion inhibition rate with the Dotmatics Knowledge Solutions Studies curve fitting environment (Dotmatics, Bishops Stortford, UK, CM23), and are presented in Table 2.

[0313] Example 1b: MET D1228N mobility shift assay

[0314] Small molecule inhibition of MET D1228N kinase activity was evaluated using a fluorescence-based microfluidic mobility shift assay. MET D1228N catalyzes the production of ADP from ATP during phosphoryl transfer to the substrate peptide, FLPeptide 30 (5-FAM-KKKKEEIYFFF-CONH2) (Perkin Elmer, 760430). 0.313 nM MET D1228N enzyme (Signalchem, M52-12IG) was prepared in a buffer containing 50 mM HEPES, 1 mM EGTA, 0.01% Brij-35, 0.05% BSA, and 2 mM DTT, using 10 mM MgCl2 and 1.5 μM substrate peptide, and pre-incubated at room temperature for 30 minutes before reaction initiation. 100 μM ATP was added to initiate the reaction. After a 60-minute kinase reaction, a mobility shift assay was performed to electrophoretically separate the fluorescently labeled peptides (substrate and phosphorylated product). The reaction was terminated by the addition of 0.5 M EDTA. Both the substrate and product were measured, and the ratio of these values ​​was used to generate the substrate-to-product conversion rate % using a LabChip EZ reader (Perkin Elmer). IC 50 The values ​​were calculated using the conversion inhibition rate with the Dotmatics Knowledge Solutions Studies curve fitting environment (Dotmatics, Bishops Stortford, UK, CM23), and are presented in Table 2.

[0315] Example 1c: CellTiter-Glo cell viability assay

[0316] Ba / F3-TPR-MET cells and Ba / F3-TPR-MET-D1228N cells were seeded at 3000 cells per well in 96-well plates using 90 μL of growth medium and incubated overnight at 37°C and 5% CO2. The following day, the compound was serially diluted in DMSO from a maximum dose of 10 mM for nine 3-fold dilution curves. After 100-fold dilution in growth medium, it was further diluted 10-fold in cell plates to a final volume of 100 μL in 0.1% DMSO. The compound and cells were incubated together at 37°C and 5% CO2 for 72 hours. The CellTiter-Glo® 2.0 assay determines the number of viable cells in culture by quantifying ATP, which indicates the presence of metabolically active cells. The luminescence reading is directly proportional to the number of viable cells in culture. CellTiter-Glo reagent (Promega, G9243) and cell plates were equilibrated to room temperature for at least 15 minutes, and then 100 μL of CellTiter-Glo was added to each well to achieve a reagent-to-culture ratio of 1:1. The samples were placed on a shaker for 2 minutes, then incubated at room temperature in the dark for 30 minutes. Luminescence was read with a Perkin Elmer Envision plate reader 2105 and IC was measured in the Dotmatics Knowledge Solutions Studies curve fitting environment (Dotmatics, Bishops Stortford, UK, CM23). 50 This is used to calculate the value, which is shown in Table 2.

[0317] Table 2 shows representative data for exemplary compounds.

[0318] [Table 2-1]

[0319] [Table 2-2]

[0320] [Table 2-3]

[0321] [Table 2-4] Note: IC for biochemical assays 50 Data and cell assay EC 50 The data is shown within the following range. A: ≤0.10 μM B: >0.10μM ~ ≤1.0μM C: >1.0μM ~ ≤10μM D:>10μM NT: Untested

[0322] III. Preparation of Pharmaceutical Dosage Forms Example 1: Oral capsule

[0323] The active ingredient is one of the compounds listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof. Oral capsules are prepared by mixing 1 to 1000 mg of the active ingredient with starch or other suitable powder mixtures. The mixture is then incorporated into oral administration units, such as hard gelatin capsules, suitable for oral administration.

[0324] Example 2: Solution for injection

[0325] The active ingredient is one of the compounds listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg equivalent / mL.

[0326] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are included within the spirit and scope of this application and the appended claims.

Claims

1. Equation (I): 【Chemistry 1】 A compound having the structure, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, V is independently N, C-H, or C-L-R. X is independently N, C-H, or C-L １ -R １ And, Z is independently N, C-H, or C-L ２ -R ２ And, W is C-H or N, Y １ These are independently N or CR ３ And, Y ２ These are independently N or CR ４ And, Y ３ is independently N or C-R ３ and Y ４ These are independently N or CR ３ And, L is a bond, halogen, -C-, -O-, -NH-, -N(optionally substituted C1-C6 alkyl)-, -N(optionally substituted C3-C6 cycloalkyl)-, -NHCO-, or -CONH-. L １ These are a bond, halogen, -C-, -O-, -NH-, -N(optionally substituted C1-C6 alkyl)-, -N(optionally substituted C3-C6 cycloalkyl)-, -NHCO-, or -CONH-. L ２ These are a bond, halogen, -C-, -O-, -NH-, -N(optionally substituted C1-C6 alkyl)-, -N(optionally substituted C3-C6 cycloalkyl)-, -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 This 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 This is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl, -NH (optionally substituted C3-C6 cycloalkyl), or an optionally substituted C3-C6 cycloalkyloxy. Each R ３ H, halogen, -CN, -NH ２ -NH (arbitrarily substituted C1-C6 alkyl), -N (arbitrarily substituted C1-C6 alkyl) ２ , selected from optionally substituted C1-C4 alkoxy or optionally substituted C1-C4 alkyl, or R ３ and R ４ They bond to form a carbocykyl ring, R ４ 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, -NH ２ -NH (optionally substituted C1-C6 alkyl), or -N (optionally substituted C1-C6 alkyl) ２ Selected independently from, R ５ It is fluoro, R ６ , R ７ and R ８ Each is independently selected from H, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or -CN, provided that R ６ , R ７ or R ８ The condition is that at least one of them is not H, Q is fluoro, or -L ２ -R ９ And, L ２ is a bond, -O-, or optionally substituted C1-C5 alkylene, and, R ９ This is selected from the group consisting of hydrogen, halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 alkynyls, optionally substituted C1-C6 alkenyls, optionally substituted C3-C6 cycloalkyls, optionally substituted cycloalkylalkyls, optionally substituted heterocyclyls, and optionally substituted heterocyclylalkyls. A compound, or a pharmaceutically acceptable salt or solvate thereof.

2. Formula (II): 【Chemistry 2】 A compound having the structure, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, W is C-H or N, Y １ These are independently N or CR ３ And, Y ２ These are independently N or CR ４ And, Y ３ These are independently N or CR ３ And, Y ４ These are independently N or CR ３ And, L is a bond, -O-, -NH-, -NHCO-, or -CONH-, L １ These are bonds, -O-, -NH-, -NHCO-, or -CONH-, R １ and R ２ Each is independently selected from the group consisting of 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, and R １ and R ２ They bond to form a carbon ring or heterocycle, Each R ３ H, halogen, -CN, -NH ２ -NH (arbitrarily substituted C1-C6 alkyl), -N (arbitrarily substituted C1-C6 alkyl) ２ , selected from optionally substituted C1-C4 alkoxy or optionally substituted C1-C4 alkyl, or R ３ and R ４ They bond to form a carbocykyl ring, R ４ 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, -NH ２ -NH (optionally substituted C1-C6 alkyl), or -N (optionally substituted C1-C6 alkyl) ２ Selected independently from, R ５ It is fluoro, R ６ , R ７ and R ８ Each is independently selected from H, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or -CN, provided that R ６ , R ７ or R ８ The condition is that at least one of them is not H, Q is fluoro, or -L ２ -R ９ And, L ２ is a bond, -O-, or optionally substituted C1-C5 alkylene, and, R ９ This is selected from the group consisting of hydrogen, halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 alkynyls, optionally substituted C1-C6 alkenyls, optionally substituted C3-C6 cycloalkyls, optionally substituted cycloalkylalkyls, optionally substituted heterocyclyls, and optionally substituted heterocyclylalkyls. A compound, or a pharmaceutically acceptable salt or solvate thereof.

3. Formula (III): 【Transformation 3】 A compound having the structure, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, W is C-H or N, Y １ These are independently N or CR ３ And, Y ２ These are independently N or CR ４ And, Y ３ These are independently N or CR ３ And, Y ４ These are independently N or CR ３ And, L is a bond, -O-, -NH-, or -N (optionally substituted C3-C6 cycloalkyl), L １ is a bond, -O-, -NH-, or -N (optionally substituted C3-C6 cycloalkyl), R １ and R ２ Each is independently selected from the group consisting of 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, and R １ and R ２ They bond to form a carbon ring or heterocycle, Each R ３ H, halogen, -CN, -NH ２ -NH (arbitrarily substituted C1-C6 alkyl), -N (arbitrarily substituted C1-C6 alkyl) ２ Selected from optionally substituted C1-C4 alkoxy or optionally substituted C1-C4 alkyl, R ４ 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, -NH ２ -NH (optionally substituted C1-C6 alkyl), or -N (optionally substituted C1-C6 alkyl) ２ Selected independently from, R ５ It is fluoro, R ６ 、 R ７ and R ８ are each independently selected from H, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or -CN, provided that at least one of R ６ 、 R ７ or R ８ is not H, Q is fluoro, or -L ２ -R ９ And, L ２ is a bond, -O-, or optionally substituted C1-C5 alkylene, and, R ９ is selected from the group consisting of hydrogen, 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, A compound, or a pharmaceutically acceptable salt or solvate thereof.

4. The compound according to claim 1, wherein V is N, or a pharmaceutically acceptable salt or solvate thereof.

5. The compound according to claim 1, wherein V is C-L-R, or a pharmaceutically acceptable salt or solvate thereof.

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

7. X is C-L １ -R １ The compound according to claim 1, or any one of claims 4 to 5, or a pharmaceutically acceptable salt or solvate thereof.

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

9. R ２ The compound according to claim 1, or any one of claims 4 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted C3-C4 cycloalkyl or optionally substituted C3-C4 cycloalkyloxy.

10. A compound according to any one of claims 1 to 9, wherein W is C-H, or a pharmaceutically acceptable salt or solvate thereof.

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

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

13. Y １ CR ３ The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof.

14. Y ２ A compound according to any one of claims 1 to 13, wherein is N, or a pharmaceutically acceptable salt or solvate thereof.

15. Y ２ CR ３ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof.

16. Y ３ A compound according to any one of claims 1 to 15, wherein is N, or a pharmaceutically acceptable salt or solvate thereof.

17. Y ３ CR ４ The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof.

18. Y ４ A compound according to any one of claims 1 to 17, wherein is N, or a pharmaceutically acceptable salt or solvate thereof.

19. Y ４ CR ３ The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof.

20. R ６ A compound according to any one of claims 1 to 19, wherein is fluoro, or a pharmaceutically acceptable salt or solvate thereof.

21. L ２ A compound according to any one of claims 1 to 20, wherein is -O-, or a pharmaceutically acceptable salt or solvate thereof.

22. R ９ The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted with a C1-C6 alkyl group or optionally substituted with a C3-C6 cycloalkyl group.

23. L １ The compound according to claim 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein is -O-.

24. L １ The compound according to claim 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein the bond is a linkage.

25. L １ The compound according to claim 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein the bond is -O-.

26. R １ The compound according to any one of claims 23 to 25, wherein the C1-C6 alkyl group is optionally substituted, or a pharmaceutically acceptable salt or solvate thereof.

27. R １ The compound according to any one of claims 23 to 25, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted with a C1-C2 alkyl group.

28. R ２ The compound according to any one of claims 23 to 27, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted with a C1-C6 alkyl group.

29. R ２ The compound according to any one of claims 23 to 27, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is an optionally substituted C1-C2 alkyl group.

30. R ９ The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted with a C1-C6 alkyl group.

31. R ９ The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted with a C1-C4 alkyl group.

32. R ９ The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted with a C1-C2 alkyl group.

33. R ９ The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein the C1 alkyl is optionally substituted.

34. R ９ CH ３ The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof.

35. R ９ The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted with a C3-C6 cycloalkyl group.

36. R ９ The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted with a C3-C4 cycloalkyl group.

37. R ９ The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted with a C5-C6 cycloalkyl group.

38. R ９ The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is optionally substituted with cyclopropyl.

39. R ９ A compound according to any one of claims 1 to 29, wherein is cyclopropyl, or a pharmaceutically acceptable salt or solvate thereof.

40. R ８ A compound according to any one of claims 1 to 39, wherein is fluoro, or a pharmaceutically acceptable salt or solvate thereof.

41. R ８ A compound according to any one of claims 1 to 39, wherein the compound is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

42. R ７ A compound according to any one of claims 1 to 41, wherein is fluoro, or a pharmaceutically acceptable salt or solvate thereof.

43. R ７ A compound according to any one of claims 1 to 41, wherein the compound is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

44. R ６ A compound according to any one of claims 1 to 43, wherein the compound is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

45. R ６ A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt or solvate thereof, wherein is fluoro.

46. Q is -L ２ -R ９ The compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt or solvate thereof.

47. The compounds provided in Table 1, or their pharmaceutically acceptable salts or solvates.

48. A pharmaceutical composition comprising a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

49. A method for preparing a pharmaceutical composition, comprising mixing a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable carrier.

50. A compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating the body of a human or animal.

51. A compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer or neoplastic disease.

52. Use of a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical for the treatment of cancer or neoplastic disease.

53. A method for treating cancer in a patient requiring treatment for cancer, comprising administering a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, to the patient requiring treatment for cancer.

54. A method for treating cancer in a patient requiring treatment for cancer, comprising administering to the patient a pharmaceutical composition comprising a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

55. A method for inhibiting a MET kinase enzyme, the method comprising contacting a compound according to any one of claims 1 to 47 with a MET kinase enzyme, wherein the MET kinase is contacted in an in vitro setting.

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