Inhibitors of MEK kinase

Abstract

Provided herein are inhibitors of MEK kinase, pharmaceutical compositions comprising said inhibitory compounds, and methods for using said MEK kinase inhibitory compounds for the treatment of disease.

Description

INHIBITORS OF MEK KINASECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 581,106, filed on September 7, 2023, which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Activation of MEK initiates the mitogen-activated protein kinase (MAPK) pathway, which is a key cell signaling pathway in regulating proliferation, cellular growth, and survival. Given that dysregulation of MAPK signaling has been demonstrated to be a key driver of many cancers, therapies that target MEK kinase activity are desired for use in the treatment of cancer and other disorders characterized by aberrant MEK pathway signaling.BRIEF SUMMARY OF THE INVENTION

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

[0004] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):wherein,X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OH, orN(R5)2;R2is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F; and each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl.

[0005] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II):wherein,X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is an optionally substituted heteroaryl;R2is halo, -OH, -N(R5)2, optionally substituted alkyloxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F; and each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl.

[0006] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (III):wherein,W is N, C-F, or C-H;X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is -CN, -SO2R6, -SO(NH)R6;R2is hydrogen, halo, -OH, -N(R5)2, optionally substituted alkyloxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F; each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; andR6is selected from optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl.

[0007] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formulawherein,X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is -COR6;R2is hydrogen, halo, -OH, -N(R5)2, optionally substituted alkyloxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F; each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; andR6is selected from optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl.

[0008] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (V):wherein,X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is -COR6;R3is halo, -OH, -N(R5)2, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl;R4is selected from hydrogen or F; each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; andR6is selected from optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl.

[0009] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I)-(V), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0010] One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I)-(V), or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer.INCORPORATION BY REFERENCE

[0011] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.DETAILED DESCRIPTION OF THE INVENTION

[0012] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub combinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of' or "consist essentially of' the described features.Definitions

[0013] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0014] "Amino" refers to the -NH2 radical.

[0015] "Cyano" refers to the -CN radical.

[0016] "Nitro" refers to the -NO2 radical.

[0017] "Oxa" refers to the -O- radical.

[0018] " Oxo" refers to the =0 radical.

[0019] " Thioxo" refers to the =S radical.

[0020] " Imino" refers to the =N-H radical.

[0021] " Oximo" refers to the =N-OH radical.

[0022] "Hydrazino" refers to the =N-NH2 radical.

[0023] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e. ., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl ( / / -propyl), 1 -methylethyl ( / .w-propyl), 1 -butyl ( / / -butyl), 1 -methylpropyl (sec- butyl), 2-methylpropyl ( / .w-butyl), 1,1 -dimethylethyl (Ze / 7-butyl), 1 -pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3 group.

[0024] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above

[0025] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (z.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-1, 4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SIU, - OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, - N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0026] " Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa,-SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, - N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0027] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyan, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, - N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0028] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenyl ene comprises five to eight carbon atoms (e.g., Cs-Cs alkenyl ene). In other embodiments, an alkenyl ene comprises three to five carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluorom ethyl).

[0029] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SIU, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0030] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) n-electron system in accordance with the Huckel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include arylradicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, - Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb- C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkyl 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), 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), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0031] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0032] "Aralkenyl" refers to a radical of the formula -Rd-aryl where Rdis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0033] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0034] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0035] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (z.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbomyl (i.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -Rb-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb- N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais 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), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0036] "Carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0037] "Carbocyclylalkynyl" refers to a radical of the formula -Rc-carbocyelyl where Rcis an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0038] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0039] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0040] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0041] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, -Rb- ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, - Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb- S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkyl alkyl (optionallysubstituted 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), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0042] ".V-heterocyclyl" or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An A-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals.Examples of such A-hctcrocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0043] "C-heterocyclyl" or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0044] "Heterocyclylalkyl" refers to a radical of the formula -Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0045] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0046] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) n-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3 -benzodi oxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotri azolyl, benzo[4,6]imidazo[l,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[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furan onyl, furo[3,2-c]pyridinyl,5.6.7.8.9.10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5.6.7.8.9.10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl,5.8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyri dinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,1 -phenyl- l / / -pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl,optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)- ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb- S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais 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), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0047] "A'-hctcroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0048] " C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0049] "Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroaryl alkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0050] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted asdefined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0051] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans ) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (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-, meta-, and para- isomers around a benzene ring.

[0052] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0053] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can bemade by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0054] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0055] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0056] In certain embodiments, the compounds disclosed herein have some or all of theJH atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

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

[0058] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

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

[0060] Deuterium-transfer reagents, such as lithium aluminum deuteride (Li AID4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of Li AID4 is illustrated, by way of example only, in the reaction schemes below.

[0061] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.

[0062] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeableJH hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0063] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the MEK kinase inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferredpharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0064] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0065] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A,A-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0066] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.

[0067] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0068] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.MEK Kinase

[0069] Phosphorylation of mitogen-activated protein kinase (MAPK) occurs through the action of MEK. MAPK is localized to the cytoplasm of the cell through its specific association of the N- terminal 1-32 residues of MEK in unstimulated cells. To date, there are 7 MEK enzymes that have been identified, and these enzymes selective phosphorylate serin / threonine and tyrosine residues within the activation loop of their specific mitogen-activated protein kinase (MAPK) substrates. MEK family of genes consists of seven genes with MEK1 and MEK2 being the more significantgenes. MEK1 exists in human chromosome 15q22.31 and is encoded by the ene MAP2K1. MEK2 exists in human chromosome 9ql3.3 and is encoded by the gene MAP2K2.

[0070] MEK proteins have a molecular weight range between about 43 and 50 kDa. MEKs can have amino- and carboxy- terminal domains which are more diverse between the different MEK proteins but share extensive homology with the kinase domain. The MEK1 and MEK2 proteins are closely related and have three important domains: (1) a core protein kinase domain (that contains ATP binding site and catalytic apparatus); (2) an N-terminal domain (which contains the inhibitory / allosteric segment, nuclear export sequence, and docking site (D-domain) that aids in binding ERK substrates), and (3) a shorter C-terminal region (which contains the domain for versatile docking (DVD), serving as a determinant binding site for upstream components of the Ras / Raf / MEK / ERK signaling cascade).

[0071] MEK3 and MEK6 are similar functionally to MEK1 and MEK2, and encoded by MAP2K3 and. MAP 2 K6 genes, respectively, located on chromosome 17q. MEK3 has a 347 amino acid residues and MEK6 has 334 amino acid residues. While MEK6 differs from MEK3 in terms of the C- and N- terminal regions, the serine / threonine and tyrosine catalytic sites and ATP binding sites are conserved. MEK3 and MEK6 signaling pathways can be activated by growth factor stimulation through RTK, G-protein coupled receptors, intracellular receptors, and toll-like receptors. The cascade can be activated in response to various stimuli include, but not limited to tumor necrosis factor, interleukine-1, cytokines, UV irradiation, physical and chemical stress, and hormones. MEK3 and MEK6 can be activated by MPAK kinase kinases (MAPKKK), which in turn allows MEK3 and MEK to activate p38 MAPK. There are four isoforms of p38 MAP kinase (a, 0, y and 5). MEK6 can active all four isoforms, whereas MEK3 can only active the p38a and p380 isoforms. The MEK3 and MEK6 with p38 MAPK cascade can promote p53-dependent growth arrest to arrest the cell cycle.

[0072] MEK4 and MEK7 are part of the stress-activated protein kinase (SAPK) signaling cascade. MEK4 is encoded by MAP 2 K4 located on chromosome 17pl l.2, and MEK7 is encoded by MAP2K7 located on chromosome 19p 13.3. MEK4 and MEK7 are homologous to the other MEK inhibitors through the kinase domains, but differ in their N- and C-terminal subunits. After activation by upstream kinases, such as MAPKKK, Tpl-2, DLK, TAO1, TAO2, TAK1, ASK1, and ASK2, the threonine residues in the activation segment of MEK4 and MEK7, or MEK4 only is phosphorylated. MEK4 and MEK7 can work synergistically to activate JNK protein kinases such as JK1, JNK2, and TNK3. Further, the MEK4 and MEK7 with JNK signaling pathway can act as a key tumor suppression pathway. MEK4 and MEK7 along with substrate JNK can promote apoptosis by phosphorylating and inactivating anti-apoptoic proteins such as, but not including to Bcl2, Bcl-XL,and Mcl-1. MEK4 activity has been shown for normal hepatogensis, B and T-cell lymphopoiesis, and erythropoiesis. MEK4 has also been shown to be down-regulated in 75% of cases of ovarian cancer. There is also hypothesized that loss of MEK4-p38MAPK signaling cascade may be relevant to tumorigenesis.

[0073] MEK5 shares about a 40% identify with the other MEK protein kinases, and has a 448 amino acid sequence. MEK5 can be activated by hyperosmotic conditions, oxidative stress, and growth factors. The downstream target of MEK5 is ERK5, which is also known as big MAP kinase 1 (BMK1) since it is twice the size of other MAPKs. The PB 1 domain of MEK5 mediates the MEK5 interaction with MEKK2, MEKK3, or ERK5. MEK5-ERK5 signaling can enhance progression through the cell cycle. Overexpression of MEK5 has been associated with cancers of the colon, prostate, breast, lymphoma, and malignant mesothelioma.MEK Activation and Intracellular Signaling Pathways

[0074] Activation of MEK initiates the mitogen-activated protein kinase (MAPK) pathway, which is a key cell signaling pathway in regulating proliferation, cellular growth, and survival. MEK transmits mitogenic signals from outside of the cell to the nucleus through the signaling pathway. MEK1 and MEK2 participate in the in Ras / Raf / MEK / ERK signal transduction cascade, and are activated by ligands binding to receptor tyrosine kinases (RTK), which can lead to dimerization of the receptors and autophosphorylation of specific tyrosine residues in its C-terminal region. The activated receptors can then recruit and phosphorylate adaptor proteins Grb2 and SOS, which interact with GTPase Ras to activate it. H-Ras, K-Ras, and N-Ras function as molecular switches when inactive Ras-GDP is converted to active Ras-GTP. In the activated GTP -bound form, Ras activate Ras kinases (A-Raf, B-Raf, and C-Raf / RaF-1) which in turn activates MEK1 and MEK2 leading to the activation of ERK1 and ERK2.

[0075] Activated ERKs can translocate into the nucleus to initiate cellular responses such as apoptosis, angiogenesis, motility, cell proliferation, survival, differentiation, and stress response. The Raf / MEK / ERP MAP kinase pathway promotes cell survival by blocking NF-kB, which will lead to increased transcription of anti-apoptotic and pro-survival genes such as Bcl-2 and Mcl-1. The Ras / Raf / MEK / ERK signaling pathway is activated by several different mechanisms in human cancers. For example, increased ERK1 and ERK2 signaling is often due to direct mutational activity or amplification of genes encoding key components of the Ras / Raf / MEK / ERK pathway. In particular, studies have found that B-Raf is mutated in about 20% of all cancers and more than 60% of melanomas. ERK 1 and ERK2 can also be activated by MEKs in solid tumors including, but not limited to, melanoma, colon, and lung carcinomas.

[0076] In tumor cells, specific growth factors combine with transmembrane receptors on the cell surface, leading to increase in RAS activation, and once RAS is activated, the plasma membrane of the cell secretes and activates the downstream molecule RAF kinase. Activation of RAF kinase stimulates a series of protein kinases which form the RAS / RAF / MEK ERK signaling pathway. Further, BRAF and KRAS are two key oncogenes in the MEK signaling pathway, as well as the RAS / RAF / MAPK signaling pathways. Mutations in both KRAS and BRAF genes lead to proliferation, differentiation, and apoptosis of tumor cells by activating the MEK / RAS / RAF / ERK signaling pathway. Both KRAS and BRAF gene mutations have also been identified in non-small cell lung cancer (NSCLC). MEK inhibitors combined with chemotherapy treatment, BRAF inhibitors, immune checkpoint inhibitors, or epidermal growth factor receptor-tyrosine kinase inhibitors have shown improving clinical efficacy and causing delay in the occurrence of drug resistance (Han, J. et al. J Hematol Oncol 14; 1, 2021).

[0077] The BRAF gene is an important gene in the MAPK pathway, and associated with multiple tumor types, including, but not limited to melanoma, non-small cell lung cancer (NSCLC), and anaplastic thyroid cancer (ATC). BRAF inhibitors have shown efficacy in several cancers. Combination therapy targeting BRAF and MEK have been studied and demonstrated synergistic benefits. The combination blockade of BRAF and MEK are able to delay, or prevent resistance, in patients who develop resistance when BRAF inhibitors are administered as a single agent. BRAF and MEK inhibitor combinations have been approved by the FDA for use in cancer types including, but not limited to, BRAF mutations in melanoma, NSCLC, and ATC (Subbiah, V. et al. Trends in Cancer, Vol. 6, No. 92020). Further, patents treated with a combination of BRAF and MEK inhibitors have shown overall survival for metastatic melanoma.MEK Inhibitors

[0078] Several agents have been developed to target MEK, including small molecule inhibitors. Most small molecular inhibitors of MEK target the MEK1 and / or MEK2 enzyme. MEK inhibitors include, but are not limited to trametinib, GSK1120212, JTP 74057, pimasertib, selumetinib, PD- 0325901, Refametinib, RDEA119, BAY 869766, TAK733, MEK162 (ARRY 438162), RO5126766, WX-554, RO4987655, CH4987655, GDC-0973, AZD8330, ARRY-424704, ARRY- 704, and E6201. Small molecule inhibitors currently FDA-approved or undergoing clinical evaluations include TAK-733, binimetinib, cobimetrinib, trametinib, and selumetinib. Other MEK inhibitors include mirdametinib and pimasertib, along with the compounds disclosed in W02006 / 045514. Other compounds suitable as MEK inhibitors are also disclosed in US 5,525,625; WO 98 / 43960; WO 99 / 01421 ; WO 99 / 01426; WO 00 / 41505; WO 00 / 42002; WO 00 / 42003; WO00 / 41994; WO 00 / 42022; WO 00 / 42029; WO 00 / 68201 ; WO 01 / 68619; WO 02 / 06213; WO 03 / 077855; W003 / 077914; W02004 / 005284; and W02004 / 056789.

[0079] MEK inhibitors can be divided into two major classes, ATP non-competitive and ATP competitive inhibitors. Most MEK inhibitors are ATP non-competitive, and bind to an allosteric site adjacent to the ATP site. This allows for high specificity of non-competitive MEK inhibitors.

[0080] Trametinib is an allosteric ATP non-competitive inhibitor with potent activity against MEK1 and MEK2 kinases. Trametinib can include cell-cycle arrest by inhibition of p-ERKl and p- ERK2. Pimasertib is a selective allosteric ATP non-competitive inhibitor of MEK1 and MEK2. Pimasertib can inhibit tumor growth and regression. Selumetinib is also an ATP non-competitive inhibitor which is highly selective for MEK1 and MEK2. Studies have shown that its antitumor activity correlated with decreasing phosphorylation of ERK1 and ERK2. Refametinib is a cyclopropane- 1 -sulfonamide derivative which exhibits selective allosteric inhibition of MEK1 and MEK2. Rafametinib shows potent activity against xenographs of human melanoma, colon carcinoma, pancreatic cancer, and skin carcinoma in tumor models.

[0081] PD-0325901 is a specific and potent synthetic analog of CI-1040, another MEK inhibitor. PD-0325901 also inhibits phosphorylation of ERK1 and ERK2 in melanoma and papillary thyroid cancer cell lines with B-RAF mutation. MEK162 is an inhibitor which targets MEK1 and MEK2. Studies have examined MEK 162 in patients with N-Ras and B-Raf mutated advanced melanoma. RO5126766 is a very potent dual MEK / RAF inhibitor, and selectively binds to MEK1 and MEK2 to form a stable complex. The primary mechanism was shown to be through cell cycle arrest. RO4987655 is a highly selective small molecule MEK inhibitor. The compound is a 3-oxo- oxazinane ring structure which confers metabolic stability, and has antitumor efficacy. GDC-0973 is a derivative of methanone, and is a potent small molecule inhibitor of MEK1. GDC-0973 has antineoplastic activity in BRAE and KRAS mutant cancer cell lines. AZD8330 is a newer inhibitor of MEK1 and MEK2 which has been studied in patients with advanced solid tumors.

[0082] E6201 is an ATP competitive MEK inhibitor, and exhibits potent activity against melanoma cells. Since melanoma has a high probability to metastasize to the CNS, E6201 may be useful for permeating an intact blood-brain barrier (BBB) (Gampa, G. et al. Drug Metab Dispos. 46(5): 658- 666, 2018). E6201 may be beneficial for treating melanoma as a single agent or in combination with a BRAF inhibitor. Further, E6201 may be able to penetrate the BBB to achieve therapeutically active levels.

[0083] Despite the increased knowledge of cellular signaling pathways and limited success in translating this knowledge to medicines, there is a large unmet medical need for therapies operating via selective MEK inhibition.MEK Kinase Inhibitory Compounds

[0084] In one aspect, provided herein is a MEK kinase inhibitory compound.

[0085] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):wherein,X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OH, orN(R5)2;R2is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F; and each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl.

[0086] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II):wherein,X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is an optionally substituted heteroaryl;R2is halo, -OH, -N(R5)2, optionally substituted alkyloxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclyl alkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F; and each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl.

[0087] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (III):wherein,W is N, C-F, or C-H;X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is -CN, -SO2R6, -SO(NH)R6;R2is hydrogen, halo, -OH, -N(R5)2, optionally substituted alkyloxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F;each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; andR6is selected from optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl.

[0088] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formulawherein,X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is -COR6;R2is hydrogen, halo, -OH, -N(R5)2, optionally substituted alkyloxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F; each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; andR6is selected from optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl.

[0089] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (V):wherein,X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is -COR6;R3is halo, -OH, -N(R5)2, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclyl alkyl;R4is selected from hydrogen or F; each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; andR6is selected from optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl.

[0090] One embodiment provides an MEK kinase inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1.Numbered EmbodimentsEmbodiment 1. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):wherein,X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OH, orN(R5)2;R2is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F; andeach R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl.Embodiment 2. The compound of embodiment 1, or pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.Embodiment 3. The compound of embodiment 1, or pharmaceutically acceptable salt or solvate thereof, wherein R4is F.Embodiment 4. The compound of embodiment 1, or pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, or optionally substituted alkynyl.Embodiment 5. The compound of embodiment 1, or pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted alkyl.Embodiment 6. The compound of embodiment 1, or pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted carbocyclyl.Embodiment 7. The compound of embodiment 1, or pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted carbocyclylalkyl.Embodiment 8. The compound of embodiment 1, or pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted alkenyl.Embodiment 9. The compound of embodiment 1, or pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted alkynyl.Embodiment 10. The compound of embodiment 1, or pharmaceutically acceptable salt or solvate thereof, wherein R1N(R5)2.Embodiment 11. The compound of any one of embodiments 1-10, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted carbocyclylalkyl.Embodiment 12. The compound of any one of embodiments 1-10, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclylalkynyl.Embodiment 13. The compound of any one of embodiments 1-10, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aryl, or optionally substituted heteroaryl.Embodiment 14. The compound of any one of embodiments 1-10, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted heterocyclyl.Embodiment 15. The compound of any one of embodiments 1-10, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl.Embodiment 16. The compound of any one of embodiments 1-15, or pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen.Embodiment 17. The compound of any one of embodiments 1-15, or pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from halo.Embodiment 18. The compound of any one of embodiments 1-15, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted alkyl.Embodiment 19. The compound of any one of embodiments 1-18, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is I.Embodiment 20. The compound of any one of embodiments 1-18, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is Br.Embodiment 21. The compound of any one of embodiments 1-18, or pharmaceutically acceptable salt or solvate thereof, wherein X1is Cl, and X2is Br.Embodiment 22. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II):wherein,X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is an optionally substituted heteroaryl;R2is halo, -OH, -N(R5)2, optionally substituted alkyloxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclyl alkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F; andeach R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl.Embodiment 23. The compound of embodiment 22, or pharmaceutically acceptable salt or solvate thereof, wherein R1is an optionally substituted 5-membered nitrogen-containing heteroaryl.Embodiment 24. The compound of embodiment 22, or pharmaceutically acceptable salt or solvate thereof, wherein R1is an optionally substituted 6-membered nitrogen-containing heteroaryl.Embodiment 25. The compound of embodiment 23, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 5-membered nitrogen-containing heteroaryl is selected from an optionally substituted oxazole, optionally substituted isoxazole, optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted imidazole, optionally substituted thiazole, or optionally substituted isothiazole.Embodiment 26. The compound of embodiment 24, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 6-membered nitrogen-containing heteroaryl is selected from an optionally substituted pyridine, optionally substituted pyridazine, optionally substituted pyrimidine, or optionally substituted pyrazine.Embodiment 27. The compound of any one of embodiments 22-26, or pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen.Embodiment 28. The compound of any one of embodiments 22-26, or pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from halo.Embodiment 29. The compound of any one of embodiments 22-26, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted alkyl.Embodiment 30. The compound of any one of embodiments 22-29, or pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.Embodiment 31. The compound of any one of embodiments 22-29, or pharmaceutically acceptable salt or solvate thereof, wherein R4is F.Embodiment 32. The compound of any one of embodiments 22-31, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted carbocyclylalkyl.Embodiment 33. The compound of any one of embodiments 22-31, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclylalkynyl.Embodiment 34. The compound of any one of embodiments 22-31, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aryl, or optionally substituted heteroaryl.Embodiment 35. The compound of any one of embodiments 22-31, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted heterocyclyl.Embodiment 36. The compound of any one of embodiments 22-31, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl.Embodiment 37. The compound of any one of embodiments 22-36, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is I.Embodiment 38. The compound of any one of embodiments 22-36, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is Br.Embodiment 39. The compound of any one of embodiments 22-36, or pharmaceutically acceptable salt or solvate thereof, wherein X1is Cl, and X2is Br.Embodiment 40. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (III):wherein,W is N, C-F, or C-H;X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is -CN, -SO2R6, -SO(NH)R6;R2is hydrogen, halo, -OH, -N(R5)2, optionally substituted alkyloxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F;each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; andR6is selected from optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl.Embodiment 41. The compound of embodiment 40, or pharmaceutically acceptable salt or solvate thereof, wherein W is N.Embodiment 42. The compound of embodiment 40, or pharmaceutically acceptable salt or solvate thereof, wherein W is C-F.Embodiment 43. The compound of embodiment 40, or pharmaceutically acceptable salt or solvate thereof, wherein W is C-H.Embodiment 44. The compound of any one of embodiments 40-43, or pharmaceutically acceptable salt or solvate thereof, wherein R1is -CN.Embodiment 45. The compound of any one of embodiments 40-43, or pharmaceutically acceptable salt or solvate thereof, wherein R1is -SO2R6.Embodiment 46. The compound of any one of embodiments 40-43, or pharmaceutically acceptable salt or solvate thereof, wherein R1is -SO(NH)R6.Embodiment 47. The compound of any one of embodiments 40-46, or pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen.Embodiment 48. The compound of any one of embodiments 40-46, or pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from halo.Embodiment 49. The compound of any one of embodiments 40-46, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted alkyl.Embodiment 50. The compound of any one of embodiments 40-49, or pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.Embodiment 51. The compound of any one of embodiments 40-49, or pharmaceutically acceptable salt or solvate thereof, wherein R4is F.Embodiment 52. The compound of any one of embodiments 40-51, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted carbocyclylalkyl.Embodiment 53. The compound of any one of embodiments 40-51, or pharmaceutically acceptable salt or solvate thereof, wherein R2is hydrogen or halo.Embodiment 54. The compound of any one of embodiments 40-51, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkenyl, optionally substituted alkynyl,or optionally substituted carbocyclylalkynyl, optionally substituted aryl, or optionally substituted heteroaryl.Embodiment 55. The compound of any one of embodiments 40-51, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted heterocyclyl.Embodiment 56. The compound of any one of embodiments 40-51, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl.Embodiment 57. The compound of any one of embodiments 40-56, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is I.Embodiment 58. The compound of any one of embodiments 40-56, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is Br.Embodiment 59. The compound of any one of embodiments 40-56, or pharmaceutically acceptable salt or solvate thereof, wherein X1is Cl, and X2is Br.Embodiment 60. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IV):wherein,X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is -COR6;R2is hydrogen, halo, -OH, -N(R5)2, optionally substituted alkyloxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F;each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; andR6is selected from optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl.Embodiment 61. The compound of embodiment 60, or pharmaceutically acceptable salt or solvate thereof, wherein R6is optionally substituted alkyl.Embodiment 62. The compound of embodiment 60, or pharmaceutically acceptable salt or solvate thereof, wherein R6is optionally substituted carbocyclyl.Embodiment 63. The compound of embodiment 60, or pharmaceutically acceptable salt or solvate thereof, wherein R6is optionally substituted carbocyclylalkyl.Embodiment 64. The compound of any one of embodiments 60-63, or pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen.Embodiment 65. The compound of any one of embodiments 60-63, or pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from halo.Embodiment 66. The compound of any one of embodiments 60-65, or pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.Embodiment 67. The compound of any one of embodiments 60-65, or pharmaceutically acceptable salt or solvate thereof, wherein R4is F.Embodiment 68. The compound of any one of embodiments 60-67, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted carbocyclylalkyl.Embodiment 69. The compound of any one of embodiments 60-67, or pharmaceutically acceptable salt or solvate thereof, wherein R2is hydrogen or halo.Embodiment 70. The compound of any one of embodiments 60-67, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclylalkynyl, optionally substituted aryl, or optionally substituted heteroaryl.Embodiment 71. The compound of any one of embodiments 60-67, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted heterocyclyl.Embodiment 72. The compound of any one of embodiments 60-67, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl.Embodiment 73. The compound of any one of embodiments 60-72, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is I.Embodiment 74. The compound of any one of embodiments 60-72, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is Br.Embodiment 75. The compound of any one of embodiments 60-72, or pharmaceutically acceptable salt or solvate thereof, wherein X1is Cl, and X2is Br.Embodiment 76. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (V):wherein,X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is -COR6;R3is halo, -OH, -N(R5)2, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclyl alkyl;R4is selected from hydrogen or F; each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; andR6is selected from optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl.Embodiment 77. The compound of embodiment 76, or pharmaceutically acceptable salt or solvate thereof, wherein R6is optionally substituted alkyl.Embodiment 78. The compound of embodiment 76, or pharmaceutically acceptable salt or solvate thereof, wherein R6is optionally substituted carbocyclyl.Embodiment 79. The compound of embodiment 76, or pharmaceutically acceptable salt or solvate thereof, wherein R6is optionally substituted carbocyclylalkyl.Embodiment 80. The compound of any one of embodiments 76-79, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted carbocyclylalkyl.Embodiment 81. The compound of any one of embodiments 76-79, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted alkoxy.Embodiment 82. The compound of any one of embodiments 76-79, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclylalkynyl.Embodiment 83. The compound of any one of embodiments 76-79, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted aryl, or optionally substituted heteroaryl.Embodiment 84. The compound of any one of embodiments 76-79, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted heterocyclyl.Embodiment 85. The compound of any one of embodiments 76-79, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl.Embodiment 86. The compound of any one of embodiments 76-85, or pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.Embodiment 87. The compound of any one of embodiments 76-85, or pharmaceutically acceptable salt or solvate thereof, wherein R4is F.Embodiment 88. The compound of any one of embodiments 76-87, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is I.Embodiment 89. The compound of any one of embodiments 76-87, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is Br.Embodiment 90. The compound of any one of embodiments 76-87, or pharmaceutically acceptable salt or solvate thereof, wherein X1is Cl, and X2is Br.Embodiment 91. A compound, or pharmaceutically acceptable salt or solvate thereof, as provided in Table 1.Embodiment 92. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of embodiments 1-91 and a pharmaceutically acceptable excipient.Embodiment 93. A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of any one of embodiments 1-91, and a pharmaceutically acceptable carrier.Embodiment 94. A compound of any one of embodiments 1-91, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.Embodiment 95. A compound of any one of embodiments 1-91, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.Embodiment 96. Use of a compound of any one of embodiments 1-91, or pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.Embodiment 97. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound as described in any one of embodiments 1-91, or pharmaceutically acceptable salt or solvate thereof.Embodiment 98. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound as described in any one of embodiments 1-91, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.Embodiment 99. The use of embodiments 95 or 96, or the method of embodiments 97 or 98, wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.Embodiment 100. A method of inhibiting a MEK kinase enzyme comprising contacting the enzyme with a compound of any one of embodiments 1-91, wherein the MEK kinase is contacted in an in vitro setting.Embodiment IOL A method of inhibiting a MEK kinase enzyme comprising contacting the enzyme with a compound of any one of embodiments 1-91, wherein the MEK kinase is contacted in an in vivo setting.Preparation of Compounds

[0091] The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc.(Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.),Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0092] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modem Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the 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, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471- 60180-2; Otera, J. (editor) "Modem 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, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic 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, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0093] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesishouses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.Pharmaceutical Compositions

[0094] In certain embodiments, the MEK kinase inhibitory compound described herein is administered as a pure chemical. In other embodiments, the MEK kinase inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0095] Provided herein is a pharmaceutical composition comprising at least one MEK kinase inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0096] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I)-(V), or a pharmaceutically acceptable salt or solvate thereof.

[0097] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I)-(V), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0098] In certain embodiments, the MEK kinase inhibitory compound as described by Formula (I)- (V), or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis byproducts that are created, for example, in one or more of the steps of a synthesis method.

[0099] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0100] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0101] In certain embodiments, the MEK kinase inhibitory compound as described by Table 1, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method

[0102] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0103] In some embodiments, the MEK kinase inhibitory compound as described by Formula (I)-(V), or Table 1, or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0104] The dose of the composition comprising at least one MEK kinase inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0105] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0106] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.Methods of Treatment

[0107] One embodiment provides a compound of Formula (I)-(V), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. One embodiment provides a compound of Formula (I)-(V), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. One embodiment provides a pharmaceutical composition comprising a compound of Formula (I)-(V), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease. One embodiment provides a use of a compound of Formula (I)-(V), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease. Another embodiment provides the use wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.

[0108] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Formula (I)-(V), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I)-(V), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. Another embodiment provides the method wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.

[0109] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. One embodiment provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease. One embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease. Another embodiment provides the method wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.

[0110] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Table 1, or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. Another embodiment provides the method wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.

[0111] Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection.

[0112] One embodiment provides a method of inhibiting a MEK kinase enzyme comprising contacting the MEK kinase enzyme with a compound of Formula (I)-(V) or Table 1. Another embodiment provides the method of inhibiting a MEK kinase enzyme, wherein the MEK kinase enzyme is contacted in an in vivo setting. Another embodiment provides the method of inhibiting a MEK kinase enzyme, wherein the MEK kinase enzyme is contacted in an in vitro setting.

[0113] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.EXAMPLESI. Chemical Synthesis

[0114] In some embodiments, the MEK kinase inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:°C degrees Celsius5H chemical shift in parts per million downfield from tetramethylsilaneDCM di chloromethane (CH2CI2)DMF dimethylformamideDMSO dimethylsulfoxideEA ethyl acetateESI electrospray ionizationEt ethyl g gram(s) h hour(s)HPLC high performance liquid chromatographyHz hertzcoupling constant (in NMR spectrometry)LCMS liquid chromatography mass spectrometry / j. micro m multiplet (spectral); meter(s); milliM molarM+parent molecular ionMe methylMHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliterMS mass spectrometry nm nanometer(s)NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solutionPE petroleum etherRT room temperature s singlet (spectral) t triplet (spectral)T temperatureTFA trifluoroacetic acidTHF tetrahydrofuran

[0115] Example 1: 3,4,6-Trifluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0116] Step 1 : 3,4,6-trifluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid

[0117] To a stirred mixture of 2,3,4,6-tetrafluorobenzoic acid (4 g, 20.61 mmol) and 2- fluoro-4-iodoaniline (4.88 g, 20.61 mmol) in MeCN (40 mL) was added lithium amine (1.89 g, 82.44 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 h at 60 °C under nitrogen atmosphere. The resulting mixture was quenched with sat. NH4CI (aq.) (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed withbrine (2 x 60 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with the following conditions: Column: WelFlash TM C18-I, 20-40 pm, 330 g; Eluent A: Water (Plus 0.1% FA); Eluent B: MeCN; Gradient: 35% to 65% B in 25 min; Flow rate: 80 mL / min; Detector: 220 / 254 nm. The fractions contained desired product were combined and concentrated to afford 3,4,6-trifluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (3.5 g, 41%) as a yellow solid. MS ESI calculated for C13H6F4INO2 [M + H]+, 411.94, found 411.85; ‘HNMR (400 MHz, DMSO-<76) 5 13.82 (s, 1H), 8.54 (s, 1H), 7.59 (dd, J= 10.8, 2.0 Hz, 1H), 7.39 (dd, J= 8.4, 2.0 Hz, 1H), 7.34-7.27 (m, 1H), 6.79-6.74 (m, 1H).

[0118] Step 2: 3,4,6-Trifluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide

[0119] To a stirred mixture of 3,4,6-trifluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.24 mmol) and HATU (139 mg, 0.37 mmol) in DMF (2 mL) was added DIEA (126 mg, 0.98 mmol) dropwise at room temperature. The reaction mixture was stirred for 0.5 h at room temperature. To the above mixture was added ammonium acetate (94 mg, 1.25 mmol) in portions at room temperature. The reaction mixture was stirred for 16 h at room temperature. The residue was purified by reverse phase chromatography with the following conditions: Column: Wei Flash TM C18-I, 20 - 45 nm,120 g; Eluent A: Water (Plus 0.05% FA); Eluent B: MeCN; Gradient:5% to 40%B in 5min, 40% to 60%B in 25 min; Flow rate: 60 ml / min; Detector: 220 / 254 nm. The fractions contained desired product were combined and concentrated to afford 3,4,6-trifluoro-2-[(2- fluoro-4-iodophenyl)amino]benzamide (44.9 mg, 45%) as a white solid. MS ESI calculated for C13H7F4IN2O [M + H]+, 410.96, found 410.90; 'HNMR (400 MHz, Methanol-o ) 57.46 (dd, J = 10.4, 2.0 Hz, 1H), 7.39-7.36 (m, 1H), 6.96-6.93 (m, 1H), 6.70-6.68 (m, 1H).

[0120] Example 3: 6,7-Difluoro-5-((2-fluoro-4-iodophenyl)amino)-4H-chromen-4-one

[0121] Step 1 : 3,4,5-Trifluorophenyl acetate

[0122] To a stirred mixture of 3,4,5-trifluorophenol (2 g, 13.51 mmol) and TEA (2.05 g, 20.26 mmol) in DCM (40 mL) was added acetyl chloride (1.27 g, 16.21 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with CH2CI2 (3 x 40 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After fdtration, the filtrate was concentrated under reduced pressure to afford 3,4,5-trifluorophenyl acetate (2.4 g, crude). The crude product was used in the next step directly without further purification. 'H NMR (400 MHz, Chloroform-c / ) 5 6.88-6.78 (m, 2H), 2.31 (s, 3H).

[0123] Step 2: l-(2,3,4-Trifluoro-6-hydroxyphenyl)ethanone

[0124] A mixture of 3,4,5-trifluorophenyl acetate (10 g, 52.60 mmol) and AICI3 (10.52 g, 78.90 mmol) was stirred for 2 h at 80 °C. The resulting mixture was diluted water (5 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1). The fractions contained desired product were combined and concentrated to afford 1 -(2,3,4- trifluoro-6-hydroxyphenyl)ethanone (7.6 g, 76%) as a yellow oil. MS ESI calculated for C8H5F3O2 [M - H]+, 189.02, found 189.10; *HNMR (400 MHz, Chloroform-t / ) 5 12.74 (s, 1H), 6.62-6.57 (m, 1H), 2.82-2.59 (m, 3H).

[0125] Step 3: 5,6,7-Trifluoro-4H-chromen-4-one

[0126] A mixture of l-(2,3,4-trifluoro-6-hydroxyphenyl)ethanone (4 g, 21.04 mmol) in DMF-DMA (40 mL) was stirred for 1 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. To the above mixture were added DCM (40 mL) and conc.HCl (4 mL) at room temperature. The resulting mixture was stirred for additional 2 h at 45 °C. The resulting mixture was diluted with water (10 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1). The fractions contained desired product were combined and concentrated to afford 5,6,7-trifluoro-4 / 7-chromen-4-one (2.5 g, 60%) as a yellow solid. ‘HNMR (400 MHz, Chloroform- ) 5 7.78 (d, J= 6.0 Hz, 1H), 7.16-7.12 (m, 1H), 6.29 (d, .7 = 6.0 Hz, 1H).

[0127] Step 4: 6,7-Difluoro-5-((2-fluoro-4-iodophenyl)amino)-4H-chromen-4-one

[0128] To a stirred mixture of 2-fluoro-4-iodoaniline (284 mg, 1.199 mmol) in THF (8 mL) was added LiHMDS (2.00 mL, 2.00 mmol, 1 M in THF) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C under nitrogen atmosphere for 30 min. Tothe above mixture was added 5,6,7-trifluorochromen-4-one (200 mg, 1.00 mmol) in THF (2 mL) dropwise at -78 °C. The reaction mixture was stirred for additional 1 h at -60 °C. The reaction was quenched with sat. NH4CI (aq.) (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in MeCN (20 mL). The resulting mixture was filtered, the filter cake was washed with MeCN (2 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with the following conditions: Column: WelFlash TM C18-I, 20-40 pm, 120 g; Eluent A: Water (Plus 10 mmol / L NH4HCO3); Eluent B: MeCN; Gradient: 35% to 80% B in 25 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm. The fractions contained desired product were combined and concentrated to afford 6,7-difluoro-5-((2-fluoro-4-iodophcnyl)amino)-4 / / -chromcn- 4-one (39.1 mg, 9%) as a light yellow solid. MS ESI calculated for C15H7F3INO2 [M + H]+, 417.95, found 417.80; 'H NMR (400 MHz, Chloroform - ) 5 10.82 (s, 1H), 7.76 (d, J= 6.0 Hz, 1H), 7.52- 7.38 (m, 2H), 6.90-6.83 (m, 1H), 6.71 (dd, J= 10.0, 5.6 Hz, 1H), 6.27 (d, J= 6.0 Hz, 1H).

[0129] Example 4: 6-Ethynyl-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N- methy lb enzami de

[0130] Step 1 : Tert-butyl 6-bromo-2, 3, 4-trifluorobenzoate

[0131] To a stirred mixture of 6-bromo-2,3,4-trifluorobenzoic acid (5.8 g, 22.74 mmol) and DMAP (2.8 g, 22.92 mmol) in Z-BuOH (50 mL) was added BOC2O (10 g, 45.82 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 40 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted with PE / EA (10 / 1). The fractions contained desired product were combined and concentrated to afford Ze / 7-butyl 6-bromo-2,3,4- trifluorobenzoate (3.7 g, 52%) as a colorless oil. MS ESI calculated for CnHioBrFsCh [M + H]+, 310.98, 312.98, found 310.95, 312.95.

[0132] Step 2: Tert-butyl 2,3,4-trifluoro-6-[2-(trimethylsilyl)ethynyl]benzoate

[0133] To a stirred solution of tert-butyl 6-bromo-2,3,4-trifluorobenzoate (2.00 g, 6.43 mmol) and trimethylsilylacetylene (3.16 g, 32.15 mmol) in TEA (40.00 mL) were added Pd(PPha)2C12 (0.90 g, 1.28 mmol) and Cui (0.49 g, 2.57 mmol) in portions at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 80 °C. The resulting mixture was diluted with water (50 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1). The fractions contained desired product were combined and concentrated to afford tert-butyl 2,3,4-trifluoro-6-[2- (trimethylsilyl)ethynyl]benzoate (1.67 g, 79%) as a yellow oil. MS ESI calculated for CieHigFsCLSi [M + H]+, 329.11, found 329.15.

[0134] Step 3. Tert-butyl 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-[2- (trimethylsilyl)ethynyl]benzoate

[0135] To a stirred solution of tert-butyl 2,3,4-trifluoro-6-[2- (trimethylsilyl)ethynyl]benzoate (1.00 g, 3.04 mmol) and 2-fluoro-4-iodoaniline (0.72 g, 3.04 mmol) in ACN (10.00 mL) was added LiNFL (0.20 g, 9.13 mmol) dropwise at room temperature. The reaction mixture was stirred for 2 h at 60 °C. The resulting mixture was quenched with sat. NH4CI (aq.) (30 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1). The fractions contained desired product were combined and concentrated to afford tert-butyl 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-[2- (trimethylsilyl)ethynyl]benzoate (1.05 g, 63%) as a brown oil. MS ESI calculated for C22H23F3INO2Si [M - H]’, 544.05, found 544.05.

[0136] Step 4. 3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-[2- (trimethylsilyl)ethynyl]benzoic acid

[0137] To a stirred solution of tert-butyl 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6- [2-(trimethylsilyl)ethynyl]benzoate (0.40 g, 0.73 mmol) in DCM (19.00 mL) was added trifluoroacetic acid (1.00 mL) dropwise at room temperature. The reaction mixture was stirred for16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1). The fractions contained desired product were combined and concentrated to afford 3,4-difluoro-2-[(2- fluoro-4-iodophenyl)amino]-6-[2-(trimethylsilyl)ethynyl]benzoic acid (0.20 g, 55%) as a yellow solid. MS ESI calculated for CisHuFsINChSi [M - H]’, 487.99, found 487.95.

[0138] Step 5: 3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-methyl-6-[2-(trimethylsilyl)ethynyl]benzamide

[0139] To a stirred solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-[2-(trimethylsilyl)ethynyl]benzoic acid (0.10 g, 0 20 mmol) in DMF (2 mL) were added HATU (0.11 g, 0.30 mmol) and DIEA (0.13 g, 1.02 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for three times and stirred for 20 min at room temperature. To the above mixture was added methanamine hydrochloride (17.00 mg, 0.24 mmol) dropwise at room temperature. The reaction mixture was stirred for additional 2 h at room temperature. The resulting mixture was purified by reverse flash chromatography with the following conditions: The residue was purified by reverse phase chromatography with the following conditions: Column: WelFlash TM C18-I, 20-40 pm, 80 g; Eluent A: Water (Plus 10 mmol / L NH4HCO3); Eluent B: ACN; Flow rate: 60 mL / min; Gradient: 25% to 45% B in 25 min; Detector: 220 / 254 nm. The fractions contained desired product were combined and concentrated to afford 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]- / V-methyl-6-[2- (trimethylsilyl)ethynyl]benzamide (30 mg, 29%) as a yellow solid. MS ESI calculated for Ci9Hi8F3lN2OSi [M + H]+, 503.02, found 503.05.

[0140] Step 6: 6-Ethynyl-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N- methy lb enzami de

[0141] To a stirred solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-methyl-6-[2-(trimethylsilyl)ethynyl]benzamide (30.00 mg, 0.06 mmol) in DCM (5.00 mL) was added tri ethylamine trihydrofluoride (29.00 mg, 0.18 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for three times and stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with the following conditions: Column: WelFlash TM Cl 8-1, 20-40 pm, 120 g; Eluent A: Water (Plus 10 mmol / L NH4HCO3); Eluent B: ACN; Flow rate: 50 mL / min; Gradient: 45% to 55% B in 25 min; Detector: 220 / 254 nm; The fractions contained desired product were combined and concentrated to afford 6-ethynyl-3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]-A-methylbenzamide (10 mg, 39%) as an off-white solid. MS ESI calculated for C16H10F3IN2O [M + H]+, 430.98, found 431.00; ‘HNMR (400 MHz, DMSO-<76) 5 8.35-8.30 (m,1H), 7.66 (s, 1H), 7.52 (dd, J= 10.8, 2.0 Hz, 1H), 7.45 (dd, J= 10.4, 7.2 Hz, 1H), 7.32 (dd, J= 8.0, 1.6 Hz, 1H), 6.66-6.60 (m, 1H), 4.37 (s, 1H), 2.63 (d, J= 4.4 Hz, 3H).

[0142] Example 5: 3,4,6-Trifluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid

[0143] To a stirred solution of 2,3,4, 6-tetrafluorobenzoic acid (100 mg, 0.52 mmol) and 2- fluoro-4-iodoaniline (122 mg, 0.52 mmol) in ACN (1 mL) was added LiNH2 (36 mg, 1.55 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 h at 60 °C under nitrogen atmosphere. The resulting mixture was quenched with sat. NH4CI (aq.) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with the following conditions: Column: WelFlash TM C18-I, 20-40 pm, 120 g; Eluent A: Water (Plus 0.1% TFA); Eluent B: MeCN; Gradient: 45% to 60% B in 15 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm; The fractions contained desired product were combined and concentrated to afford 3,4,6-trifluoro-2-[(2- fluoro-4-iodophenyl)amino]benzoic acid (53.2 mg, 25%) as an off-white solid. MS ESI calculated for C13H6F4INO2 [M + H]+, 411.94, found 412.00; ’H NMR (400 MHz, Chloroform-^ ) 5 8.81 (s, 1H), 7.46 (dd, J= 10.0, 2.0 Hz, 1H), 7.40 (dt, J= 8.4, 1.6 Hz, 1H), 6.78-6.72 (m, 1H), 6.65-6.59 (m, 1H).

[0144] Example 9: l-(3,4,6-Trifluoro-2-((2-fluoro-4-iodophenyl) amino) phenyl) ethan-1- one

[0145] Step 1 : 3,4,6-Trifluoro-2-((2-fluoro-4-iodophenyl) amino)-N-methoxy-N- methy lb enzami de

[0146] To a stirred mixture of 3,4,6-trifluoro-2-[(2-fluoro-4-iodophenyl) amino] benzoic acid (500 mg, 1.22 mmol, Example 5) and HATU (925 mg, 2.43 mmol) in DMF (10 mL) was added DIEA (943 mg, 7.30 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 15 min. To the above mixture was added N, O-dimethylhydroxylamine hydrochloride (178 mg, 1.824 mmol). The reaction mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with the following conditions: Column: WelFlash TM C18-I, 20-40 pm, 120 g; Eluent A: Water (Plus 10 mmol / L NH4HCO3); Eluent B: MeCN; Gradient: 25% to 70% B in 25 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm. The fractions contained desired product were combined and concentrated to afford 3,4,6-trifluoro-2-[(2-fluoro-4-iodophenyl) amino]- / V-methoxy- / V-methylbenzamide (500 mg, 90%) as a brown oil. MS ESI calculated for C15H11F4IN2O2 [M + H]+, 454.98, found 455.00; 'H NMR (400 MHz, DMSO-fifc) <>' 7.57-7.51 (m, 1H), 7.42-7.30 (m, 2H), 6.73 (t, J = 8.4 Hz, 1H), 3.46 (s, 3H), 3.10-3.06 (m, 3H).

[0147] Step 2: l-(3,4,6-Trifluoro-2-((2-fluoro-4-iodophenyl) amino) phenyl) ethan-l-one

[0148] To a stirred solution of 3,4,6-trifluoro-2-[(2-fluoro-4-iodophenyl) amino]-.A- methoxy-A-methylbenzamide (320 mg, 0.705 mmol) in THF (3 mL) was added dropwise bromo(methyl)magnesium (2.82 mL, 2.820 mmol) (1 M in THF) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 3 h at 45 °C. The reaction was quenched with sat. NH4CI (3 mL) at -10 °C, and then the resulting mixture was extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with PE / EA (6:1) to afford l-{3,4,6-trifluoro-2-[(2-fluoro-4-iodophenyl) amino] phenyl} ethanone (140 mg, 48%) as a blue green solid. MS ESI calculated for C14H8F4INO [M - H]+, 407.96, found 407.85; 'H NMR (400 MHz, Chloroform - ) d 9.76 (s, 1H), 7.43-7.35 (m, 2H), 6.73-6.67 (m, 1H), 6.59-6.52 (m, 1H), 2.64 (d, J= 7.6 Hz, 3H).

[0149] Example 12: 2,3,5-Trifluoro-N-(2-fluoro-4-iodophenyl)-6-(isoxazol-5-yl) aniline

[0150] Step 1 : (E)-3-(dimethylamino)-l-(3,4,6-trifluoro-2-((2-fluoro-4-iodophenyl) amino) phenyl) prop-2-en- 1 -one

[0151] Into a 30 mL sealed tube were added DMF-DMA (3 mL) and l-{3,4,6-trifluoro-2- [(2-fluoro-4-iodophenyl) amino] phenyl} ethanone (120 mg, 0.293 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 2 h. The resulting mixture was purified by reverse phase chromatography with the following conditions: Column: WelFlash TM Cl 8-1, 20-40 pm, 120 g; Eluent A: Water (Plus 10 mmol / L NH4HCO3); Eluent B: MeCN; Gradient: 25% - 80% B in 25min; Flow rate: 60 mL / min; Detector: 220 / 254 nm. The fractions contained desired product were combined and concentrated to afford (£)-3-(dimethylamino)-l-(3,4,6-trifluoro-2-((2-fluoro-4- iodophenyl) amino) phenyl) prop-2-en-l-one (110 mg, 81%) as a green solid. MS ESI calculated for C17H13F4IN2O [M + H]+, 434.95, found 465.00; *HNMR (400 MHz, Chloroform-^ / ) d 7.77 (brs, 1H), 7.35 (dd, J= 10.4, 2.0 Hz, 1H), 7.30-7.26 (m, 1H), 6.63-6.54 (m, 2H), 5.49-5.44 (m, 1H), 3.15 (s, 3H), 2.89 (m, 3H).

[0152] Step 2: 2,3,5-Trifluoro-N-(2-fluoro-4-iodophenyl)-6-(isoxazol-5-yl) aniline

[0153] To a stirred solution of (E)-3-(dimethylamino)-l-(3,4,6-trifluoro-2-((2-fluoro-4- iodophenyl) amino) phenyl) prop-2-en-l-one (100 mg, 0.22 mmol) in EtOH (3 mL) was added hydroxylamine hydrochloride (45 mg, 0.65 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with the following conditions: Column: WelFlash TM C18-I, 20-40 pm, 120 g; Eluent A: Water (Plus 10 mmol / L NH4HCO3); Eluent B: MeCN; Gradient: 25% to 65% B in 25 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm. The fractions contained desired product to afford 2,3,5-trifluoro-A-(2-fluoro-4-iodophenyl)-6-(l,2-oxazol-5-yl) aniline (12.4 mg, 13%) as a yellow solid. MS ESI calculated for CI5H7F4IN2O [M + H]+, 434.95, found 434.95; ' H NMR (400 MHz, DMSO-r / g) d 8.61 (d, J= 2.0 Hz, 1H), 8.18 (brs, 1H), 7.58-7.51 (m, 1H), 7.49 (dd, J= 11.2, 2.0 Hz, 1H), 7.29-7.26 (m, 1H), 6.66 (t, J= 2.0 Hz, 1H), 6.62-6.57 (m, 1H).

[0154] Example 13: 6,7-difluoro-8-((2-fluoro-4-iodophenyl)amino)isoquinolin-l(2H)-one step 1

[0155] Step 1 : 3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid

[0156] To a stirred solution of 2,3,4-trifluorobenzoic acid (1 g, 5.68 mmol) and 2-fluoro-4- iodoaniline (1.34 g, 5.65 mmol) in ACN (20 mL) was added LiNH2 (0.43 g, 18.55 mmol) at roomtemperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 60 °C under nitrogen atmosphere. The resulting mixture was quenched with HC1 (con.) to pH 1 at 0 °C. The resulting mixture was diluted with water (30 mL). The precipitated solids were collected by filtration and washed with water (3 x 20 mL) to afford the crude product. The crude product was purified by trituration with DCM (10 mL) to afford 3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]benzoic acid (1.3 g, 58%) as a light brown solid. MS ESI calculated for C13H7F3INO2 [M + H]+, 393.95, found 393.90.

[0157] Step 2: 6,7-Difluoro-8-((2-fluoro-4-iodophenyl)amino)isoquinolin-l(2H)-one

[0158] To a stirred mixture of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (200 mg, 0.509 mmol) and dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (16 mg, 0.03 mmol) in benzonitrile (2.5 mL) were added silver acetate (85 mg, 0.51 mmol) and KHCO3 (10 mg, 0.10 mmol) at room temperature under nitrogen atmosphere. To the above mixture was added polyvinylformamide (217 mg, 3.05 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for additional 16 h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with the following conditions: Column: WelFlash TM C18-I, 20-40 pm, 120 g; Eluent A: Water (Plus 10 mmol / L NH4HCO3); Eluent B: ACN; Gradient: 55% to 75% B in 20 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm. The fractions contained desired product were combined and concentrated to afford 6,7-difluoro-8-((2-fluoro-4-iodophenyl)amino)isoquinolin-l(2 / f)-one (11.5 mg, 5%) as a white solid. MS ESI calculated for Ci5H8F3IN2O [M + H]+, 416.96, found 416.95; ’H NMR (400 MHz, DMSO-fl?6) 8 11.66 (s, 1H), 11.07 (s, 1H), 7.67 (dd, J= 10.4, 2.0 Hz, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.23-7.27 (m, 2H), 6.90-6.96 (m, 1H), 6.60 (d, J= 7.2 Hz, 1H).

[0159] Example 15: N-(2-Fluoro-4-iodophenyl)-4-methanesulfonylpyridin-3-amine step 25

[0160] Step 1 : 4-(Methylsulfanyl)-3-nitropyridine

[0161] To a stirred solution of Sodium methanethiolate (4.4 g, 63.08 mmol) in MeOH (100 mL) was added 4-chl oro-3 -nitropyridine (5 g, 31.54 mmol) in portions at room temperature. The resulting mixture was stirred for 30 min at 60 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1). The fractions contained desired product were combined and concentrated to afford 4- (methylsulfanyl)-3-nitropyridine (2 g, 37%) as a yellow solid. MS ESI calculated for CsEMSfcChS [M + H]+, 171.01, found 170.95;1HNMR (400 MHz, Chloroform-^ 89.38 (s, 1H), 8.63 (d, J = 5.6 Hz, 1H), 7.31 (d, . / - 5.6 Hz, 1H), 2.55 (s, 3H).

[0162] Step 2: 4-(Methylsulfanyl)pyridin-3-amine

[0163] To a stirred mixture of 4-(methylsulfanyl)-3-nitropyridine (1 g, 5.88 mmol) and Fe (1.6 g, 29.38 mmol) in THF (12 mL) and H2O (6 mL) was added NH4CI (0.6 g, 11.75 mmol) in portions at room temperature. The reaction mixture was stirred for 1 h at 70 °C under nitrogen atmosphere. The resulting mixture was fdtered, the filter cake was washed with MeCN (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversephase chromatography with the following conditions: Column: WelFlash TM Cl 8-1, 20-40 pm, 120 g; Eluent A: Water (Plus 10 mmol / L NH4HCO3); Eluent B: ACN; Gradient: 25% to 45% B in 25 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm. The fractions contained desired product were combined and concentrated to afford 4-(methylsulfanyl)pyridin-3-amine (650 mg, 78%) as a yellow oil. MS ESI calculated for C6H8N2S [M + H]+, 141.04, found 141.10; 'H NMR (400 MHz, Chloroform- / ) 5 8.04-7.96 (m, 2H), 7.05 (d, J= 5.2 Hz, 1H), 3.93 (s, 2H), 2.50 (s, 3H).

[0164] Step 3: 4-(Methylsulfonyl)pyridin-3-amine

[0165] To a stirred solution of 4-(methylsulfanyl)pyridin-3-amine (1 g, 7.13 mmolv) and Na2WO4 (0.19 g, 0.71 mmol) in EA (7.5 mL) and H2O (3.7 mL) was added H2O2 (30%) (2.77 mL, 35.67 mmol, 30%) dropwise at 0 °C. The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep- TLC (DCM I MeOH 20: 1) to afford 4-(Methylsulfonyl)pyridin-3-amine (0.46 g, 37%) as a yellow oil. MS ESI calculated for C6H8N2O2S [M + H]+, 173.03 found 173.10; 'H NMR (400 MHz, Chloroform-6 / ) 5 8.30 (s, 1H), 8.15 (d, J= 5.2 Hz, 1H), 7.55 (d, J= 5.2 Hz, 1H), 5.10 (s, 2H), 3.10 (s, 3H).

[0166] Step 4: N-(2-fhiorophenyl)-4-methanesulfonylpyridin-3-amine

[0167] To a stirred solution of 4-(Methylsulfonyl)pyridin-3-amine (150 mg, 0.87 mmol) and l-bromo-2-fluorobenzene (183 mg, 1.05 mmol) in dioxane (5 mL) were added / -BuONa (251 mg, 2.61 mmol) and BrettPhos (94 mg, 0.17 mmol) and BrettPhos Pd G3 (79 mg, 0.09 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 100 °C. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1). The fractions contained desired product were combined and concentrated to afford A-(2-fluorophenyl)-4- methanesulfonylpyri din-3 -amine (200 mg, 86%) as a yellow oil. MS ESI calculated for C12H11FN2O2S [M + H]+, 267.05, found 267.00; *HNMR (400 MHz, Chlorofon ) 8 8.51 (d, J = 1.6 Hz, 1H), 8.32 (d, J= 5.2 Hz, 1H), 7.72 (d, J= 5.2 Hz, 1H), 7.59 (s, 1H), 7.42-7.32 (m, 1H), 7.27-7.16 (m, 3H), 3.19 (s, 3H).

[0168] Step 5: N-(2-Fluoro-4-iodophenyl)-4-methanesulfonylpyridin-3-amine

[0169] To a stirred solution of A-(2-fluorophenyl)-4-methanesulfonylpyridin-3-amine (200 mg, 0.75 mmol) in THF (5 mL) and MeOH (0.5 mL) were added TsOH H2O (357 mg, 1.88 mmol) and NIS (203 mg, 0.90 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 3 h at 60 °C under nitrogen atmosphere. The resulting mixture was purifiedby reverse phase chromatography with the following conditions: Column: WelFlash TM Cl 8-1, 20- 40 pm, 120 g; Eluent A: Water (Plus 10 mmol / L NH4HCO3); Eluent B: ACN; Gradient: 25% to 45% B in 25 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm. The fractions contained desired product were combined and concentrated to afford ,V-(2-fluoro-4-iodophenyl)-4- methanesulfonylpyri din-3 -amine (139.5 mg, 47%) as an off-white solid. MS ESI calculated for C12H10FIN2O2S [M + H]+, 392.95, found 392.95; *HNMR (400 MHz, Ch loro for - ) S 8.53 (d, J = 1.6 Hz, 1H), 8.35 (d, J= 5.2 Hz, 1H), 7.70 (d, J= 5.2 Hz, 1H), 7.60-7.53 (m, 2H), 7.57-7.48 (m, 1H), 7.15-7.08 (m, 1H), 3.17 (s, 3H).

[0170] Example 18: 3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-(pyridin-4- yl)benzamide step 1 step 2

[0171] Step 1 : Tert-butyl 2,3,4-trifluoro-6-(pyridin-4-yl)benzoate

[0172] To a stirred mixture of tert-butyl 6-bromo-2,3,4-trifluorobenzoate (1 g, 3.21 mmol),K2CO3 (1.33 g, 9.62 mmol) and pyridin-4-ylboronic acid (0.40 g, 3.22 mmol) in 1,4-dioxane (10 mL) and H2O (2 mb) was added Pd(dppf)C12'DCM (0.23 g, 0.314 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 100 °C. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 / 1). The fractions contained desired product were combined and concentrated to afford tert-butyl 2,3,4-trifluoro-6-(pyridin-4-yl)benzoate (0.8 g, 80%) as a light brown solid. MS ESI calculated for C16H14F3NO2 [M + H]+, 310.10, found 310.05; 'H NMR (400MHz, DMSO-tL) 8 8.72-8.66 (m, 2H), 7.59 (ddd, J= 10.8, 6.9, 2.1 Hz, 1H), 7.43-7.37 (m, 2H), 1.31 (s, 9H).

[0173] Step 2: Tert-butyl 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-(pyridin-4- yl)benzoate

[0174] To a stirred solution of tert-butyl 2,3,4-trifluoro-6-(pyridin-4-yl)benzoate (200 mg, 0.65 mmol) and 2-fluoro-4-iodoaniline (153.4 mg, 0 65 mmol) in ACN (5 mb) was added lithium amine (44.66 mg, 1.95 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 h at 60 °C under nitrogen atmosphere. The resulting mixture was quenched with sat. NH4CI (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with the following conditions: Column: WelFlash TM C18-I, 20-40 pm, 120 g; Eluent A: Water (Plus 10 mmol / L NH4HCO3); Eluent B: ACN; Gradient: 30% to 65% B in 15 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm. The fractions contained desired product were combined and concentrated to afford tert-butyl 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6- (pyridin-4-yl)benzoate (120 mg, 35%) as a light yellow solid. MS ESI calculated for C22H18F3IN2O2 [M + H]+, 527.04, found 527.10; 'HNMR (400 MHz, DMSO ) 8 8.82-8.51 (m, 2H), 7.95 (s, 1H), 7.58-7.47 (m, 2H), 7.44-7.37 (m, 2H), 7.35-7.27 (m, 1H), 6.45-6.26 (m, 1H), 1.11 (s, 9H).

[0175] Step 3: 3,4-Difluoro-2-((2-fluoro-4-iodophenyl)amino)-6-(pyridin-4-yl)benzoic acid

[0176] To a stirred solution of tert-butyl 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6- (pyridin-4-yl)benzoate (500 mg, 0.950 mmol) in DCM (9 mL) was added TFA (3 mL). The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-(pyridin-4- yl)benzoic acid (246 mg, crude) as a yellow solid. The crude product was used in the next step directly without further purification. MS ESI calculated for C18H10F3IN2O2 [M + H]+, 470.95 found 470.97; 'HNMR (400 MHz, DMSO-cL) 8 8.82 (q, J= 5.5 Hz, 2H), 8.15 (s, 1H), 7.79-7.68 (m, 2H), 7.59.7.44 (m, 2H), 7.39-7.27 (m, 1H), 7.27-6.98 (m, 1H), 6.70-6.60 (m, 1H).

[0177] Step 4: 3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-(pyridin-4-yl)benzamide

[0178] To a stirred solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-(pyridin-4- yl)benzoic acid (100 mg, 0.21 mmol), HATU (121 mg, 0.32 mmol) and DIEA (99 mg, 0.76 mmol) in DMF (5 mL) was added NH4OAC (98 mg, 1.28 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was purified by reverse phase chromatography with thefollowing conditions: Column: WelFlash TM C18-I, 20-40 pm, 120 g; Eluent A: Water (Plus 10 mmol / L NH4HCO3); Eluent B: ACN; Gradient: 30% to 65% B in 20 min; Flow rate: 60 mL / min;Detector: 220 / 254 nm. The fractions contained desired product were combined and concentrated to afford 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-(pyridin-4-yl)benzamide (25.8 mg, 25%) as an off-white solid. MS ESI calculated for C18H11F3IN3O [M + H]+, 469.99, found 469.95;rH NMR (400 MHz, DMSO-t / 6) 5 8.64 (d, J= 5.2 Hz, 2H), 7.68 (s, 1H), 7.59-7.43 (m, 6H), 7.33 (d, J = 8.4 Hz, 1H), 6.63-6.53 (m, 1H).

[0179] Example 19: 3-Fluoro-5-[(2-fluoro-4-iodophenyl)amino]pyridine-4-carboxamide

[0180] Step 1 : 3-Fluoro-5-[(2-fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid

[0181] To a stirred solution of 3,5-difluoropyridine-4-carboxylic acid (100 mg, 0.63 mmol) and 2-fluoro-4-iodoaniline (148.98 mg, 0.63 mmol) in THF (1 mL) was added LiHMDS (1.89 mL, 1.89 mmol, 1 M in THF) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was quenched with water (10 mL) at room temperature and washed with EtOAc (2 x 5 mL). The water phase was acidified to pH 3 with cone. HC1. The precipitated solids were collected by filtration and washed with ACN (1 x 5 mL). The residue was purified by reverse phase chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (Plus 10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. The fractions contained desired product were combined and concentrated to afford 3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid (58.3 mg, 24%) as a yellow solid. MS ESI calculated for C12H7F2IN2O2 [M + H]+, 376.95, found 376.90; 'HNMR (400 MHz, DMSO-t / e) 8 8.86 (s, 1H), 8.13 (d, J= 28.1 Hz, 2H), 7.68 (dd, J= 10.5, 2.0 Hz, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.21-7.17 (m, 1H).

[0182] Step 2: 3-Fluoro-5-[(2-fluoro-4-iodophenyl)amino]pyridine-4-carboxamide

[0183] To a stirred solution of 3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]pyridine-4- carboxylic acid (2 g, 5.32 mmol) and HATU (3.03 g, 7.98 mmol) and DIEA (4.63 mL, 26.59 mmol) in DMF (0.5 mL) was added NH4CI (0.85 g, 15.95 mmol) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted withPE / EA (1 / 1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 19 x 250 mm, 5 pm; Mobile Phase A: water (Plus 0.1% FA), Mobile Phase B: MeOH-HPLC; Flow rate: 20 mL / min; Gradient: 55% B to 65% B in 15 min, 65% B; Wave Length: 254 nm. The fractions contained desired product were combined and concentrated to afford 3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]pyridine-4- carboxamide (874.9 mg, 43%) as a yellow solid. MS ESI calculated for C12H8F2IN3O [M + H]+, 375.97, found 375.95; 'H NMR (400 MHz, DMSO-fifc) 8 8.38 (s, 1H), 8.17-8.10 (m, 4H), 7.67 (dd, J= 10.8, 2.0 Hz, 1H), 7.49-7.47 (m, 1H), 7.17 (t, J= 8.4 Hz, 1H).

[0184] Example 29: 7,8-Difluoro-6-[(2-fluoro-4-iodophenyl)amino]-3,4-dihydro-2H-l,4- benzoxazepin-5-one step 2

[0185] Step 1 : Tert-butyl 6-bromo-2,3,4-trifluorobenzoate

[0186] To a stirred solution of 6-bromo-2,3,4-trifluorobenzoic acid (5 g, 19.61 mmol) and DMAP (2.4 g, 19.65 mmol) in Z-BuOH (50 mb) was added (Boc)2O (8.58 g, 39.31 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 40 °C undernitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 3). The fractions contained desired product were combined and concentrated to afford tert-butyl 6-bromo-2,3,4- trifluorobenzoate (3 g, 49%) as a light-yellow oil.rH NMR (400 MHz, Chloroform-^ / ) 5 7.31-7.22 (m, 1H), 1.63 (s, 9H).

[0187] Step 2: Tert-butyl 2,3,4-trifluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzoate

[0188] To a stirred mixture of tert-butyl 6-bromo-2,3,4-trifluorobenzoate (500 mg, 1.61 mmol) and bis(pinacolato)diboron (0.82 g, 3.23 mmol) in dioxane (8 m ) were added AcOK (0.95 g, 9.67 mmol) and Pd(dppf)C12-CH2C12 (130.93 mg, 0.16 mmol) in portions at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 16 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was diluted with DCM (50 mL). The resulting mixture was filtered, the filter cake was washed with DCM (3 x 20 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 2,3,4-trifluoro-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (500 mg, 86.86%) as a black solid. The crude product was used in the next step directly without further purification.1H NMR (400 MHz, Chloroform-6 / ) 57.19 (ddd, J= 9.2, 7.0, 2.0 Hz, 1H), 1.35 (s, 9H), 1.26 (d, J= 1.3 Hz, 23H).

[0189] Step 3: Tert-butyl 2,3, 4-trifluoro-6-hydroxybenzoate

[0190] To a stirred solution of tert-butyl 2,3,4-trifluoro-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (2 g, 5.584 mmol) in MeOH (30 mL) and H2O (10 mL) was added H2O2 (5.20 mL, 66.959 mmol, 30%) dropwise at 0 °C. The reaction mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with CH2Q2 (2 x 80 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with PE / EA (500 / 1). The fractions contained desired product were combined and concentrated to afford tert-butyl 2,3,4-trifluoro-6-hydroxybenzoate (500 mg, 36.08%) as a yellow oil. MS ESI calculated for C11H11F3O3 [M - H]+, 247.07, found 247.10; ’H NMR (400 MHz, DMSO- / 6) 8 10.89 (s, 1H), 6.77 (ddd, J= 12.1, 6.2, 2.3 Hz, 1H), 1.53 (s, 9H).

[0191] Step 4: Tert-butyl 6-(2-((tert-butoxycarbonyl)amino)ethoxy)-2,3,4-trifluorobenzoate

[0192] To a stirred solution of tert-butyl 2,3,4-trifluoro-6-hydroxybenzoate (0.35 g, 1.41 mmol), tert-butyl A-(2-hydroxyethyl)carbamate (0.34 g, 2.12 mmol) and triphenylphosphine (0.55 g, 2.12 mmol) in THF (7 mL) was added diisopropyl azodi carb oxy late (0.42 mL, 2.12 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 4 h at roomtemperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4 / 1). The fractions contained desired product were combined and concentrated to afford tert-butyl 6-(2-((tert- butoxycarbonyl)amino)ethoxy)-2,3,4-trifluorobenzoate (0.49 g, 89%) as a colorless oil. 'H NMR (400 MHz, Chloroform-c / ) 56.56-6.51 (m, 1H), 5.09 (s, 1H), 4.03 (t, J= 5. 1 Hz, 2H), 3.50 (q, J = 5.3 Hz, 2H), 1.59 (s, 9H), 1.44 (s, 9H).

[0193] Step 5: 6-(2-Aminoethoxy)-2,3,4-trifluorobenzoic acid

[0194] To a stirred solution of teH-butyl 6-{2-[(tert-butoxycarbonyl)amino]ethoxy}-2,3,4- trifluorobenzoate (0.49 g, 1 25 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) dropwise at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 0.1% formic acid), 5% to 20% B in 20 min; Detector: UV 254 / 220 nm. The fractions contained desired product were combined and concentrated to afford 6-(2-aminoethoxy)-2,3,4- trifluorobenzoic acid (0.24 g, crude) as a brown solid. MS ESI calculated for C9H8F3NO3 [M + H]+, 236.05, found 235.90.

[0195] Step 6: 6,7,8-Trifluoro-3,4-dihydro-2H-l,4-benzoxazepin-5-one

[0196] To a stirred solution of 6-(2-aminoethoxy)-2,3,4-trifluorobenzoic acid (230 mg, 0.98 mmol) and 4-methylmorpholine (0.30 g, 2.93 mmol) in / V,.V-dimethylformamide (3 mL) was added HATU (0.58 g, 1.47 mmol). The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, acetonitrile in water (Plus 10 mmol / L NH4HCO3), 5% to 35% B in 25 min; Detector: UV 254 / 220 nm. The fractions contained desired product were combined and concentrated to afford 6,7,8-trifluoro-3,4-dihydro-2 / 7-l,4-benzoxazepin-5-one (40 mg, 18%) as a white solid. MS ESI calculated for C9H6F3NO2 [M + H]+, 218.04, found 218.05.

[0197] Step 7: 7,8-Difluoro-6-[(2-fluoro-4-iodophenyl)amino]-3,4-dihydro-2H-l,4- benzoxazepin-5-one

[0198] To a stirred mixture of 6,7,8-trifluoro-3,4-dihydro-2 / f-l,4-benzoxazepin-5-one (35 mg, 0.16 mmol) and 2-fluoro-4-iodoaniline (42.02 mg, 0.18 mmol) in acetonitrile (0.5 mL) was added lithium amine (74 mg, 3.20 mmol) at room temperature. The reaction mixture was stirred for 24 h at 60 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford the crude product (48 mg), which was further purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 pm; Mobile Phase A: water (Plus 10 mmol / LNH4HCO3), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 50% to 65% B in 8 min; Detector: UV 254 / 220 nm. The fractions contained desired product were combined and concentrated to afford 7,8-difluoro-6-[(2-fluoro-4-iodophenyl)amino]-3,4-dihydro-2 / f-l,4- benzoxazepin-5-one (26.4 mg, 37%) as a white solid. MS ESI calculated for C15H10F3IN2O2 [M + H]+, 434.97, found 434.95; 'HNMR (400 MHz, DMSO-tZ,) 8 8.71 (t, J= 5.9 Hz, 1H), 8.48 (s, 1H), 7.58 (dd, J= 10.9, 2.0 Hz, 1H), 7.40 (d, J= 8.4 Hz, 1H), 6.96 (dd, J= 11.1, 6.5 Hz, 1H), 6.75-6.69 (m, 1H), 4.20 (t, J= 5.7 Hz, 2H), 3.27-3.23 (m, 2H).

[0199] Example 31: 6,7-Difluoro-8-[(2-fluoro-4-iodophenyl)amino]-3,4-dihydro-2H- isoquinolin- 1 -one

[0200] Step 1 : l,2,3-Trifluoro-5-[(E)-2-nitroethenyl]benzene

[0201] To a stirred solution of 3,4,5-trifluorobenzaldehyde (10.00 g, 62.46 mmol) and nitromethane (15.25 g, 249.85 mmol) in AcOH (40 mL) was added NE OAc (5.78 g, 74.96 mmol) at room temperature. The reaction mixture was stirred for 3 h at 100 °C. The resulting mixture was concentrated under reduced pressure and the residue was basified to pH 8 with sat. Na2CC>3 (aq.). The resulting mixture was extracted with EA (2 x 200 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (10 / 1). The fractions contained desired product were combined and concentrated to afford l,2,3-trifluoro-5-[(E)-2-nitroethenyl]benzene (5.00 g, 39%) as a brown solid. *H NMR (400 MHz, Chloroform-c / ) 87.86 (d, J= 13.7 Hz, 1H), 7.49 (d, J= 13.7, 1H), 7.23-7.19 (m, 2H).

[0202] Step 2: 2-(3,4,5-Trifluorophenyl)ethanamine

[0203] To a stirred mixture of LiAITU (4.20 g, 110.77 mmol) in THF (50 mL) was added l,2,3-trifluoro-5-[(E)-2-nitroethenyl]benzene (4.50 g, 22.15 mmol) in THF (50 mL) dropwise at 10 °C under nitrogen atmosphere. The reaction mixture was stirred for 2 h at 65 °C. The resulting mixture was allowed to cool down to 0 °C and quenched by slow addition of 4.2 mL of water, 4.2 mL of 15% sodium hydroxide solution and 12.6 mL of water. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (100 mL). The filtrate was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2-(3,4,5- trifluorophenyl)ethanamine (3.80 g, crude) as a brown oil which was directly used to next step without further purification. MS ESI calculated for CsHsFsN [M + H]+, 176.06, found 176.15.

[0204] Step 3: Propyl N-[2-(3,4,5-trifluorophenyl)ethyl]carbamate

[0205] To a stirred solution of 2-(3,4,5-trifluorophenyl)ethanamine (2.00 g, 11.42 mmol) and TEA (4.76 mL, 34.26 mmol) in DCM (20 mL) was added propyl carb onochlori date (1.93 mL, 17.13 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 10 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10 / 1). The fractions contained desired product were combined and concentrated to afford propyl JV-[2-(3,4,5- trifluorophenyl)ethyl]carbamate (0.88 g, 29%) as a brown oil. MS ESI calculated for C12H14F3NO2 [M + H]+, 262.10, found 261.90;1HNMR (400 MHz, Chloroform-^ 8 6.83-6.79 (m, 2H), 4.66 (s, 1H), 4.02 (t, J= 6.7 Hz, 2H), 3.40 (q, J= 6.6 Hz, 2H), 2.76 (t, J= 6.9 Hz, 2H), 1.65-1.62 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H).

[0206] Step 4: 6,7,8-Trifluoro-3,4-dihydro-2H-isoquinolin-l-one

[0207] A solution of propyl A-[2-(3,4,5-trifluorophenyl )ethyl]carbamate (0.50 g, 1.91 mmol) in trifluoromethanesulfonic acid (5 mL) was stirred for 16 h at 70 °C. The resulting mixture was diluted with water (20 mL) and extracted with EA (2 x 40 mL). The combined organic layers was washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1). The fractions contained desired product were combined and concentrated to afford 6,7,8-trifluoro-3,4-dihydro-2Z7-isoquinolin-l-one (0.11 g, 28%) as a yellow solid. MS ESI calculated for C9H6F3NO [M + H]+, 202.04, found 202.00;rHNMR (400 MHz, Chloroform - ) 6 6.89-6.84 (m, 1H), 6.45 (s, 1H), 3.54-3.50 (m, 2H), 2.94 (t, J= 6.6 Hz, 2H).

[0208] Step 5: 6,7-Difluoro-8-[(2-fluoro-4-iodophenyl)amino]-3,4-dihydro-2H-isoquinolin- 1-one

[0209] To a stirred mixture of 6,7,8-trifluoro-3,4-dihydro-2J / -isoquinolin-l-one (0.11 g, 0.55 mmol) and 2-fluoro-4-iodoaniline (0.14 g, 0.60 mmol) in ACN (1.2 mL) was added LiNHz (0.25 g, 10.94 mmol). The reaction mixture was stirred for 2 h at 60 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford the crude product (90 mg) which was further purified by Prep-HPLC with the following conditions: Column: Xselect CSH C18 OBD Column 30 x 150 mm 5 pm; Mobile Phase A: water (Plus 10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 55% to 65% B in 8 min; Detector: UV 254 / 220 nm. The fractions contained desired product were combined and concentrated to afford 6,7-difluoro-8-[(2- fluoro-4-iodophenyl)amino]-3,4-dihydro-2 / / -isoquinolin-l-one (30.6 mg, 13%) as a white solid. MS ESI calculated for C15H10F3IN2O [M + H]+, 418.98, found 419.00; 'HNMR (400 MHz, DMSO-<A) 5 10.54 (s, 1H), 8.40 (s, 1H), 7.62 (dd, J= 10.9, 2.3 Hz, 1H), 7.43 (d, J= 8.4 Hz, 1H), 7.02 (dd, J= 10.3, 6.9 Hz, 1H), 6.82-6.76 (m, 1H), 3.33-3.31 (m, 2H), 2.88 (t, J= 6.5 Hz, 2H).

[0210] Example 34: (R)-{3-[(2-Fluoro-4-iodophenyl)amino]pyridin-4-yl}(imino)methyl- X6-sulfanone

[0211] Example 35: (S)-{3-[(2-Fluoro-4-iodophenyl)amino]pyridin-4-yl}(imino)methyl-? 6- sulfanonestep 1Brettphos Pd G3, Brettphos, f-BuONa1 ,4-dioxane, 100 °C, 1 hstep 2

[0212] Step 1 : N-(2-Fluorophenyl)-4-(methylsulfanyl)pyridin-3-amine

[0213] To a stirred mixture of 4-(methylsulfanyl)pyridin-3-amine (0.80 g, 5.71 mmol), 1- bromo-2-fluorobenzene (1.50 g, 8.56 mmol), Z-BuONa (1.65 g, 17.12 mmol) and BrettPhos Pd G3 (1.03 g, 1.14 mmol) in 1,4-dioxane (8.0 mL) was added BrettPhos (1.23 g, 2.28 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 100 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1). The fractions contained desired product were combined and concentrated to afford A-(2-fluorophenyl)-4-(methylsulfanyl)pyridin-3-amine (0.80 g, 59%) as a light brown oil. MS ESI calculated for C12H11FN2S [M + H]+, 235.06, found 235.25, 'HNMR (400 MHz, Chloroform- ) 5 8.39 (s, 1H), 8.21 (d, J= 5.2 Hz, 1H), 7.16-7.06 (m, 3H), 7.05-7.01 (m, 1H), 6.96-6.86 (m, 1H), 5.66 (s, 1H), 2.51 (s, 3H).

[0214] Step 2: {3-[(2-Fluorophenyl)amino]pyridin-4-yl}(imino)methyl-L6-sulfanone

[0215] To a stirred mixture of A-(2-fluorophenyl)-4-(methylsulfanyl)pyridin-3-amine (0.80 g, 3.42 mmol) and ammonium carbamate (0.53 g, 6.83 mmol) in methanol (15 mL) was added phenyl-V-iodanediyl diacetate (2.75 g, 8.54 mmol). The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 3). The fractions contained desired product were combined and concentrated to afford {3-[(2-fluorophenyl)amino]pyridin-4- yl}(imino)methyl-X6-sulfanone (0.30 g, 33%) as a brown oil. MS ESI calculated for C12H12FN3OS[M + H]+, 266.07, found 266.00; ‘HNMR (400 MHz, Chloroform-^ / ) 5 8.53 (s, 1H), 8.47 (s, 1H), 8.26 (d, J= 5.1 Hz, 1H), 7.78 (d, J= 5.1 Hz, 1H), 7.42-7.30 (m, 1H), 7.26-7.14 (m, 3H), 3.21 (s, 3H).

[0216] Step 3: {3-[(2-Fluoro-4-iodophenyl)amino]pyridin-4-yl}(imino)methyl-X6-sulfanone

[0217] To a stirred solution of {3-[(2-fluorophenyl)amino]pyridin-4-yl}(imino)methyl-X6- sulfanone (0.30 g, 1.13 mmol) and / 2-toluenesulfonic acid monohydrate (0 60 g, 3.17 mmol) in THF (3 mL) and MeOH (3 mL) and 7V-iodosuccinimide (0.76 g, 3.39 mmol) was stirred for 1 h at 60 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1) to afford the crude product which was further purified by reverse chromatography with the following conditions: column, silica gel; mobile phase, acetonitrile in water (Plus 10 mmol / L NH4HCO3), 20% to 50% gradient in 30 min;Detector: UV 254 / 220 nm. The fractions contained desired product were combined and concentrated to afford {3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}(imino)methyl-X6-sulfanone (87.3 mg, 19%) as a light yellow solid. MS ESI calculated for C12H11FIN3OS [M + H]+, 391.97, found 391.90; 'HNMR (400 MHz, DMSO-t / 6) 8 8.88 (s, 1H), 8.52 (s, 1H), 8.30 (d, J= 5.0 Hz, 1H), 7.74 (dd, J= 10.5, 1.9 Hz, 1H), 7.70 (d, J= 5.0 Hz, 1H), 7.57-7.54 (m, 1H), 7.34 (t, J= 8.6 Hz, 1H), 5.13 (s, 1H), 3.18 (s, 3H).

[0218] Step 4: (R)-{3-[(2-Fluoro-4-iodophenyl)amino]pyridin-4-yl}(imino)methyl-2i6- sulfanone and (S)-{3-[(2-Fluoro-4-iodophenyl)amino]pyridin-4-yl}(imino)methyl-X6-sulfanone

[0219] The {3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}(imino)methyl-X6-sulfanone(160 mg, 0.38 mmol) was purified by Chiral-HPLC chromatography with the following conditions: Column: CHIRAL ART Cellulose-SC, 2 x 25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2 M NH3- MeOH)— HPLC, Mobile Phase B: MeOH: DCM= 1: 1— HPLC; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 13 min; Wave Length: 220 / 254 nm provided the separated isomers.

[0220] The faster eluting isomer (RT: 10.72 min.) afforded Example 34 (7?)-{3-[(2-fluoro- 4-iodophenyl)amino]pyridin-4-yl}(imino)methyl-X6-sulfanone (29.8 mg, 27%) as a white solid. MS ESI calculated for C12H11FIN3OS [M + H]+, 391.97, found 391.85;!H NMR (400 MHz, DMSO-cL) 8 8.88 (s, 1H), 8.51 (s, 1H), 8.29 (d, J= 5.0 Hz, 1H), 7.86-7.62 (m, 2H), 7.55 (d, J= 8.1 Hz, 1H), 7.33 (t, J= 8.6 Hz, 1H), 5.13 (s, 1H), 3.17 (s, 3H).

[0221] The slower eluting isomer RT: 12.18 min. afforded Example 35 (S)-{3-[(2-fluoro-4- iodophenyl)amino]pyridin-4-yl}(imino)methyl-X6-sulfanone (28.7 mg, 26%) as a white solid. MS ESI calculated for C12H11FIN3OS [M + H]+, 391.97, found 391.85;JH NMR (400 MHz, DMSO-c / ) 8 8.88 (s, 1H), 8.52 (s, 1H), 8.30 (d, J= 5.0 Hz, 1H), 7.85-7.74 (m, 1H), 7.69 (d, J= 5.0 Hz, 1H), 7.55 (d, J= 8.4 Hz, 1H), 7.34 (t, J= 8.6 Hz, 1H), 5.14 (s, 1H), 3.17 (s, 3H).

[0222] Example 39: 3-((2-Fluoro-4-iodophenyl)amino)isonicotinonitrile

[0223] To a stirred mixture of 3-fluoropyridine-4-carbonitrile (0.30 g, 2.46 mmol) and 2- fluoro-4-iodoaniline (0.64 g, 2.70 mmol) in ACN (5.00 mL) was added Cs2CC>3 (0.80 g, 2.46 mmol) at room temperature. The reaction mixture was stirred for 1 h at 60 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 pm; Mobile phase A: water (Plus 10 mmol / L NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 48% to 53% B in 8 min; Detector: UV 254 / 220 nm; The fractions contained desired product were combined and concentrated to afford 3-((2-fluoro-4- iodophenyl)amino)isonicotinonitrile (31.40 mg, 4%) as a white solid. MS ESI calculated for C12H7FIN3 [M + H]+, 339.97, found 339.95;XH NMR (400 MHz, DMSO-tA) 8 8.81 (s, 1H), 8.32 (s, 1H), 8.22 (d, J= 4.9 Hz, 1H), 7.77-7.62 (m, 2H), 7.52 (d, J= 8.5 Hz, 1H), 7.06 (t, J= 8.6 Hz, 1H).

[0224] Example 43: l-{3-[(2-Fluoro-4-iodophenyl)amino]pyridin-4-yl}ethanone

[0225] Step 1 : 3-[(2-Fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid

[0226] To a stirred mixture of 3-fluoropyridine-4-carboxylic acid (0.30 g, 2.12 mmol) and2-fluoro-4-iodoaniline (0.50 g, 2.12 mmol) in THF (3 mL) was added LiHMDS (6.38 mL, 6.38 mmol, 1 M in THF) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was quenched by the addition of water (3 mL) at room temperature and the solvent was removed under reduced pressure. The residue was acidified to pH 3 with 1 N HC1 (aq.). The precipitated solids were collected by filtration and washed with acetonitrile (30 mL). The residue was purified by reverse chromatography with the following conditions: column, C18 silica gel; mobile phase: ACN in water (Plus 10 mmol / L NH4HCO3), 5% to 30% gradient in 30 min; Detector: UV 254 / 220 nm. The fractions contained desired product were combined and concentrated to afford 3-[(2-fluoro-4- iodophenyl)amino]pyridine-4-carboxylic acid (93.6 mg, 12%) as a yellow solid. MS ESI calculated for CI2H8FIN2O2 [M + H]+, 358.96, found 358.95; 'H NMR (400 MHz, DMSO-6) 8 13.92 (brs,1H), 9.27 (s, 1H), 8.46 (s, 1H), 8.12 (d, J= 4.0 Hz, 1H), 7.74-7.72 (s, 2H), 7.55 (d, J= 8.0 Hz, 1H), 7.35 (t, J= 8.6 Hz, 1H).

[0227] Step 2: 3-[(2-Fhioro-4-iodophenyl)amino]-N-methoxy-N-methylpyridine-4- carb oxami de

[0228] To a stirred mixture of 3-[(2-fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid (0.3 g, 0.84 mmol), methoxy(methyl)amine hydrochloride (0.12 g, 1.26 mmol) and HATH (0.48 g, 1.26 mmol) in DMF (3 mL) was added DIEA (0.43 g, 3.35 mmol) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 2). The fractions contained desired product were combined and concentrated to afford 3- [(2-fluoro-4-iodophenyl)amino]-A-methoxy-A-methylpyridine-4-carboxamide (0.31 g, 90%) as a yellow oil. MS ESI calculated for C14H13FIN3O2 [M + H]+, 402.00, found 402.00; 'H NMR (400 MHz, Chloroform-t / ) 5 8.57 (s, 1H), 8.24 (d, J= 5.2 Hz, 1H), 7.48-7.44 (m, 2H), 7.41-7.38 (m, 1H), 7.34 (s, 1H), 7.06 (t, J= 8.6 Hz, 1H), 3.58 (s, 3H), 3.39 (s, 3H).

[0229] Step 3: l-{3-[(2-Fluoro-4-iodophenyl)amino]pyridin-4-yl}ethanone

[0230] To a stirred solution of 3-[(2-fluoro-4-iodophenyl)amino]-A-methoxy- / V- methylpyridine-4-carboxamide (0.31 g, 0.77 mmol) in THF (5 mL) was added MeMgBr (3.09 mL, 3.09 mmol, 1 M in THF) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was quenched with sat. NH4CI (aq.) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford the crude product which was purified by Prep- HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 pm; Mobile Phase A: water (Plus 10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 16% to 26% B in 8 min; Detector, UV 254 / 220 nm. The fractions contained desired product were combined and concentrated to afford l-{3-[(2-fluoro-4- iodophenyl)amino]pyridin-4-yl}ethanone (85.1 mg, 30%) as a yellow solid. MS ESI calculated for C13H10FIN2O [M + H]+, 356.98, found 356.95;XH NMR (400 MHz, DMSO-JA) 5 9.68 (s, 1H), 8.47 (d, .7 = 1.2 Hz, 1H), 8.48 (d, J= 5.2 Hz, 1H), 7.82 (d, J= 4.8 Hz, 1H), 7.76-7.73 (m, 1H), 7.55 (d, J = 4.4 Hz, 1H), 7.32 (t, J= 8.4 Hz, 1H), 2.67 (s, 3H).

[0231] Example 47: 3-[(2-Fluoro-4-iodophenyl) amino] pyridine-4-carbaldehyde

[0232] Step 1 : Methyl 3-[(2-fluoro-4-iodophenyl)amino]pyridine-4-carboxylate

[0233] To a stirred mixture of 3-[(2-fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid (0.35 g, 0.98 mmol) in methanol (10 mL) was added thionyl chloride (0.35 mL, 4.89 mmol) dropwise at 0 °C. The reaction mixture was stirred for 24 h at 70 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (Plus 0.5% TEA) (1 / 1). The fractions contained desired product were combined and concentrated to afford methyl 3-[(2-fluoro-4- iodophenyl)amino]pyridine-4-carboxylate (0.14 g, 38%) as a yellow solid. 'H NMR. (400 MHz, Chloroform-^ / ) 5 9.06 (s, 1H), 8.55 (s, 1H), 8.12 (d, J= 5.2 Hz, 1H), 7.77 (d, J= 52 Hz, 1H), 7.54- 7.51 (m, 1H), 7.48-7.46 (m, 1H), 7.19 (t, J= 8.4 Hz, 1H), 3.97 (s, 3H).

[0234] Step 2: {3-[(2-Fluoro-4-iodophenyl)amino]pyridin-4-yl}methanol

[0235] To a stirred mixture of methyl 3-[(2-fluoro-4-iodophenyl)amino]pyridine-4- carboxylate (0.14 g, 0.38 mmol) in methanol (3.5 mL) was added NaBH4 (0.11 g, 2.82 mmol) in portions at room temperature. The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was quenched with sat. NH4C1 (aq.) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by trituration with DCM (5 mL) to afford {3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}methanol (80 mg, 61%) as a white solid. MS ESI calculated for C12H10FIN2O [M + H]+, 344.98, found 344.95

[0236] Step 3: 3-[(2-Fluoro-4-iodophenyl) amino] pyridine-4-carbaldehyde

[0237] To a stirred solution of {3-[(2-fluoro-4-iodophenyl) amino] pyridin-4-yl} methanol (80 mg, 0.23 mmol) in CHCh (5 mL) was added MnCh (040 g, 4.64 mmol) at room temperature The reaction mixture was stirred for 48 h at room temperature. The resulting mixture was filtered and the filter cake was washed with CHCI3 (2 x 8 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: Xselect CSH C18 OBD Column 30 x 150 mm 5 pm; Mobile Phase A: ACN, Mobile Phase B: water (Plus 0.1% FA); Flow rate: 60 mL / min; Gradient: 45% to 50% B in 10 min; Detector: UV 254 / 220 nm. The fractions contained desired product were combined and concentrated to afford 3-[(2-fluoro-4- iodophenyl) amino] pyridine-4-carbaldehyde (7.2 mg, 8%) as a yellow solid. MS ESI calculated for Ci2H8FIN2O [M + H]+, 342.97, found 342.95;XH NMR (400 MHz, DMSO-cL) 5 10.08 (s, 1H), 9.26(s, 1H), 8.46 (s, 1H), 8.28 (d, J= 4.8 Hz, 1H), 7.77-7.71 (m, 2H), 7.58-7.55 (m, 1H), 7.33 (t, J= 8.8 Hz, 1H).

[0238] Example 57: 2-(3-((2-Fluoro-4-iodophenyl)amino)pyridin-4-yl)propan-2-ol

[0239] To a stirred solution of methyl 3-[(2-fluoro-4-iodophenyl)amino]pyridine-4- carboxylate (100 mg, 0.27 mmol) in THF (2 mL) was added MeMgBr (0.94 mL, 0.94 mmol, 1 M in THF) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was quenched with sat. NH4CI (aq.) at 0 °C. The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford the crude product which was further purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 pm; Mobile Phase A: water (Plus 10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 44% B to 58% B in 8 min, 58% B; Wave Length: 254 nm; RT1: 7.75 min. The fractions contained desired product were combined and concentrated to afford 2-(3-((2-fluoro- 4-iodophenyl)amino)pyridin-4-yl)propan-2-ol (22 mg, 22%) as an off-white solid. MS ESI calculated for C14H14FIN2O [M + H]+, 373.02, found 373.00; 'H NMR (400 MHz, DMSO-ofc) 5 8.51 (s, 1H), 8.45 (s, 1H), 8.15 (d, J= 5.1 Hz, 1H), 7.62 (dd, J= 10.8, 2.0 Hz, 1H), 7.41 (d, J= 8.5 Hz, 1H), 7.28 (d, J= 5.1 Hz, 1H), 7.09 (t, J= 8.8 Hz, 1H), 6.11 (s, 1H), 1.51 (s, 6H).

[0240] Example 68: N-(2-Fluoro-4-iodophenyl)-4-methanesulfmylpyri din-3 -amine

[0241] Step 1 : N-(2-Fluorophenyl)-4-methanesulfmylpyridin-3-amine

[0242] To a stirred solution of A-(2-fluorophenyl)-4-(methylsulfanyl)pyridin-3-amine (0.60 g, 2.56 mmol) in dichlormethane (6.00 mL) was added 3-chlorobenzene-l-carboperoxoic acid (85% purity) (0.75 g, 3.71 mmol) in portions at 0 °C. The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1). The fractions contained desired product were combined and concentrated to afford / V-(2-fluorophenyl)-4-methanesulfinylpyri din-3 -amine (0.55 g, 85%) as a reddish brown solid. MS ESI calculated for C12H11FN2OS [M + H]+, 251.06, found 251.10.

[0243] Step 2 : N-(2-Fluoro-4-iodophenyl)-4-methanesulfinylpyri din-3 -amine

[0244] To a stirred solution of A-(2-fluorophenyl)-4-methanesulfmylpyridin-3-amine (0.44 g, 1.75 mmol) in THF (2.20 mL) and MeOH (2.20 mL) were added -toluene sulfonicacid (0.93 g, 4.92 mmol) and NIS (0.39 g, 1.75 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 60 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 pm; Mobile Phase A: water (Plus 10 mmol / L ammonium bicarbonate), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 56% B to 64% B in 8 min; Wave Length: 254 nm; RT: 7 min. The fractions contained desired product were combined and concentrated to afford V-(2-fluoro-4-iodophenyl)-4- methanesulfinylpyri din-3 -amine (154.8 mg, 23%) as an off-white solid. MS ESI calculated for C12H10FIN2OS [M + H]+, 376.95, found 376.95; 'HNMR (400 MHz, DMSO-tC) 8 8.51 (d, J= 5.0 Hz, 1H), 8.32 (d, J= 1.2 Hz, 1H), 8.11 (s, 1H), 7.72 (d, J= 5.0 Hz, 1H), 7.63 (dd, J= 10.8, 1.9 Hz, 1H), 7.43-7.38 (m, 1H), 6.81 (t, J= 8.7 Hz, 1H), 2.78 (s, 3H).

[0245] The following compounds in Table 2 were prepared using procedures similar to those described in the preceding examples using appropriate starting materials.Table 2IL Biological Evaluation

[0246] To determine the effect of MEK inhibitor compounds disclosed herein on cellular MAPK signaling downstream of MEK, an assay monitoring phosphorylation of ERK was used. Melanoma derived cell line A-375, which harbors a BRAF V600 activating mutation was cultured and maintained as specified by the supplier (ATCC: Cat # CRL-1619; American Type Culture Collection; Manassas, VA 20110). Cells were seeded at 8000 cells / well in 24 pl growth media in a 384-well plate and allowed to adhere at 37 °C with 5% CO2 overnight. The following day, compounds were serially diluted into 10-point, 3-fold dilution curves in 384 well plates. Compound was transferred to cell plates using Echo550 such that the final concentration range was 0.508 nM to 10 mM in 0.1% DMSO with 0.1% DMSO being used as negative control. Cells were incubated with compounds for 1 hour at 37 °C with 5% CO2. Cells were lysed by addition of 8 pl 4X lysis buffer provided with HTRF kit (Advanced phospho-ERK (Thr202 / Tyr204) cellular kit; Cisbio; Cat # 64AERPEH) plus IX protease / phosphatase inhibitor cocktail. 20 pl lysate was transferred to HTRF plate followed by 2.5 pl each of anti-ERKl / 2-Europium / Terbium Cryptate and anti- phospho-ERKl / 2 antibody solutions per manufacturer’s instructions and incubated. Specific signal was measured at 665nm (donor) and 620nm (acceptor) on a Perkin Elmer Envision 2105 and the ratios used to calculate IC50 values within the Dotmatics Knowledge Solutions Studies curve fitting environment (Dotmatics, Bishops Stortford, UK, CM23). The IC50 values of representative compounds described herein are presented in Table 3.Table 3A: < 0.010 pM; B: > 0.01 pM to < 0.10 pM; C: > 0.10 pM to < 1 pM; D: < 1 pMIII. Preparation of Pharmaceutical Dosage Forms

[0247] Example 1 : Oral capsule

[0248] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. A capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.

[0249] Example 2: Solution for injection

[0250] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and is formulated as a solution in sesame oil at a concentration of 10-100 mg-eq / mL.

[0251] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMSWe claim:

1. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OH, orN(R5)2;R2is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F; and each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl. The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen. The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein R4is F. The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, or optionally substituted alkynyl. The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted alkyl.

6. The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted carbocyclyl.

7. The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted carbocyclylalkyl.

8. The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted alkenyl.9 The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted alkynyl.10 The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein R1N(R5)2.11 The compound of any one of claims 1-10, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted carbocyclylalkyl.12 The compound of any one of claims 1-10, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclylalkynyl.13 The compound of any one of claims 1-10, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aryl, or optionally substituted heteroaryl.14 The compound of any one of claims 1-10, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted heterocyclyl.15 The compound of any one of claims 1-10, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl.16 The compound of any one of claims 1-15, or pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen.17 The compound of any one of claims 1-15, or pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from halo.18 The compound of any one of claims 1-15, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted alkyl.19 The compound of any one of claims 1-18, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is I. 0 The compound of any one of claims 1-18, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is Br.

21. The compound of any one of claims 1-18, or pharmaceutically acceptable salt or solvate thereof, wherein X1is Cl, and X2is Br.

22. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II):wherein,X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is an optionally substituted heteroaryl;R2is halo, -OH, -N(R5)2, optionally substituted alkyloxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclyl alkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F; and each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl.

23. The compound of claim 22, or pharmaceutically acceptable salt or solvate thereof, wherein R1is an optionally substituted 5-membered nitrogen-containing heteroaryl.

24. The compound of claim 22, or pharmaceutically acceptable salt or solvate thereof, wherein R1is an optionally substituted 6-membered nitrogen-containing heteroaryl.

25. The compound of claim 23, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 5-membered nitrogen-containing heteroaryl is selected from an optionally substituted oxazole, optionally substituted isoxazole, optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted imidazole, optionally substituted thiazole, or optionally substituted isothiazole.

26. The compound of claim 24, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 6-membered nitrogen-containing heteroaryl is selected from an optionally substituted pyridine, optionally substituted pyridazine, optionally substituted pyrimidine, or optionally substituted pyrazine.

27. The compound of any one of claims 22-26, or pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen.

28. The compound of any one of claims 22-26, or pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from halo.

29. The compound of any one of claims 22-26, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted alkyl.

30. The compound of any one of claims 22-29, or pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.

31. The compound of any one of claims 22-29, or pharmaceutically acceptable salt or solvate thereof, wherein R4is F.

32. The compound of any one of claims 22-31, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted carbocyclylalkyl.

33. The compound of any one of claims 22-31, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclylalkynyl.

34. The compound of any one of claims 22-31, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aryl, or optionally substituted heteroaryl.

35. The compound of any one of claims 22-31, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted heterocyclyl.

36. The compound of any one of claims 22-31, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl.

37. The compound of any one of claims 22-36, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is I.

38. The compound of any one of claims 22-36, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is Br.

39. The compound of any one of claims 22-36, or pharmaceutically acceptable salt or solvate thereof, wherein X1is Cl, and X2is Br.

40. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (III):wherein,W is N, C-F, or C-H;X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is -CN, -SO2R6, -SO(NH)R6;R2is hydrogen, halo, -OH, -N(R5)2, optionally substituted alkyloxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F; each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; andR6is selected from optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl.

41. The compound of claim 40, or pharmaceutically acceptable salt or solvate thereof, wherein W is N.

42. The compound of claim 40, or pharmaceutically acceptable salt or solvate thereof, wherein W is C- F.

43. The compound of claim 40, or pharmaceutically acceptable salt or solvate thereof, wherein W is C- H.

44. The compound of any one of claims 40-43, or pharmaceutically acceptable salt or solvate thereof, wherein R1is -CN.

45. The compound of any one of claims 40-43, or pharmaceutically acceptable salt or solvate thereof, wherein R1is -SO2R6.

46. The compound of any one of claims 40-43, or pharmaceutically acceptable salt or solvate thereof, wherein R1is -SO(NH)R6.

47. The compound of any one of claims 40-46, or pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen.

48. The compound of any one of claims 40-46, or pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from halo.

49. The compound of any one of claims 40-46, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted alkyl.

50. The compound of any one of claims 40-49, or pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.

51. The compound of any one of claims 40-49, or pharmaceutically acceptable salt or solvate thereof, wherein R4is F.

52. The compound of any one of claims 40-51, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted carbocyclylalkyl.

53. The compound of any one of claims 40-51, or pharmaceutically acceptable salt or solvate thereof, wherein R2is hydrogen or halo.

54. The compound of any one of claims 40-51, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclylalkynyl, optionally substituted aryl, or optionally substituted heteroaryl.

55. The compound of any one of claims 40-51, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted heterocyclyl.

56. The compound of any one of claims 40-51, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl.

57. The compound of any one of claims 40-56, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is I.

58. The compound of any one of claims 40-56, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is Br.

59. The compound of any one of claims 40-56, or pharmaceutically acceptable salt or solvate thereof, wherein X1is Cl, and X2is Br.

60. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IV):wherein,X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is -COR6;R2is hydrogen, halo, -OH, -N(R5)2, optionally substituted alkyloxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl;R3is selected from hydrogen, halo, or optionally substituted alkyl;R4is selected from hydrogen or F; each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; andR6is selected from optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl.

61. The compound of claim 60, or pharmaceutically acceptable salt or solvate thereof, wherein R6is optionally substituted alkyl.

62. The compound of claim 60, or pharmaceutically acceptable salt or solvate thereof, wherein R6is optionally substituted carbocyclyl.

63. The compound of claim 60, or pharmaceutically acceptable salt or solvate thereof, wherein R6is optionally substituted carbocyclylalkyl.

64. The compound of any one of claims 60-63, or pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen.

65. The compound of any one of claims 60-63, or pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from halo.

66. The compound of any one of claims 60-65, or pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.

67. The compound of any one of claims 60-65, or pharmaceutically acceptable salt or solvate thereof, wherein R4is F.

68. The compound of any one of claims 60-67, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted carbocyclylalkyl.

69. The compound of any one of claims 60-67, or pharmaceutically acceptable salt or solvate thereof, wherein R2is hydrogen or halo.

70. The compound of any one of claims 60-67, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclylalkynyl, optionally substituted aryl, or optionally substituted heteroaryl.

71. The compound of any one of claims 60-67, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted heterocyclyl.

72. The compound of any one of claims 60-67, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl.

73. The compound of any one of claims 60-72, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is I.

74. The compound of any one of claims 60-72, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is Br.

75. The compound of any one of claims 60-72, or pharmaceutically acceptable salt or solvate thereof, wherein X1is Cl, and X2is Br.

76. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (V):wherein,X1and X2are independently selected from F, Cl, Br, or I; each Z is independently selected from hydrogen, or halo;R1is -COR6;R3is halo, -OH, -N(R5)2, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclylalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclyl alkyl;R4is selected from hydrogen or F; each R5is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; andR6is selected from optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl.

77. The compound of claim 76, or pharmaceutically acceptable salt or solvate thereof, wherein R6is optionally substituted alkyl.

78. The compound of claim 76, or pharmaceutically acceptable salt or solvate thereof, wherein R6is optionally substituted carbocyclyl.

79. The compound of claim 76, or pharmaceutically acceptable salt or solvate thereof, wherein R6is optionally substituted carbocyclylalkyl.

80. The compound of any one of claims 76-79, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted carbocyclylalkyl.

81. The compound of any one of claims 76-79, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted alkoxy.

82. The compound of any one of claims 76-79, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclylalkynyl.

83. The compound of any one of claims 76-79, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted aryl, or optionally substituted heteroaryl.

84. The compound of any one of claims 76-79, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted heterocyclyl.

85. The compound of any one of claims 76-79, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl.

86. The compound of any one of claims 76-85, or pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.

87. The compound of any one of claims 76-85, or pharmaceutically acceptable salt or solvate thereof, wherein R4is F.

88. The compound of any one of claims 76-87, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is I.

89. The compound of any one of claims 76-87, or pharmaceutically acceptable salt or solvate thereof, wherein X1is F, and X2is Br.

90. The compound of any one of claims 76-87, or pharmaceutically acceptable salt or solvate thereof, wherein X1is Cl, and X2is Br.

91. A compound, or pharmaceutically acceptable salt or solvate thereof, as provided in Table 1.

92. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 1-91 and a pharmaceutically acceptable excipient.

93. A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of any one of claims 1-91, and a pharmaceutically acceptable carrier.

94. A compound of any one of claims 1-91, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

95. A compound of any one of claims 1-91, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

96. Use of a compound of any one of claims 1-91, or pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

97. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound as described in any one of claims 1-91, or pharmaceutically acceptable salt or solvate thereof.

98. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound as described in any one of claims 1-91, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

99. The use of claims 95 or 96, or the method of claims 97 or 98, wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.

00. A method of inhibiting a MEK kinase enzyme comprising contacting the enzyme with a compound of any one of claims 1-91, wherein the MEK kinase is contacted in an in vitro setting.

01. A method of inhibiting a MEK kinase enzyme comprising contacting the enzyme with a compound of any one of claims 1-91, wherein the MEK kinase is contacted in an in vivo setting.

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